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Single Technology Appraisal

Bulevirtide for treating chronic hepatitis D [ID3732]

Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL (STA)

Bulevirtide for treating chronic hepatitis D [ID3732]

Contents:

The following documents are made available to consultees and commentators. The final scope and final stakeholder list are available on the NICE website.

Pre-technical engagement documents

1. Company submission from Gilead Sciences

2. Clarification questions and company responses

• a. Clarification question response

• b. Clarification question response appendix

3. Patient group, professional group and NHS organisation submissions from:

• a. British Association for Sexual Health and HIV

• b. Royal College of Pathologists

• c. UK Clinical Pharmacy Association

4. External Assessment Group report prepared by BMJ Group

5. External Assessment Group report – factual accuracy check

Post-technical engagement documents

6. Technical engagement response from company

• a. Company’s technical engagement response form

• b. Supplementary Appendix

7. Technical engagement responses from consultees and commentators:

• a. NHS England

• b. British Association for Sexual Health and HIV

• c. Royal College of Pathologists

8. External Assessment Group critique of company response to technical engagement prepared by BMJ Group

• a. EAG technical engagement response form

• b. EAG technical engagement response report

• c. EAG technical engagement response report addendum

9. Data on the epidemiology of HDV infection in the UK prepared by UKHSA

Any information supplied to NICE which has been marked as confidential, has been redacted. All personal information has also been redacted.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

Bulevirtide for treating chronic hepatitis D [ID3732]

Document B

Company evidence submission

April 2022

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

Contents

Contents ..................................................................................................................... 2 Tables and figures ...................................................................................................... 3 Abbreviations .............................................................................................................. 7 B.1 Decision problem, description of the technology and clinical care pathway ....... 10 B.2 Clinical effectiveness .......................................................................................... 33 B.3 Cost effectiveness ............................................................................................ 111 B.4 References ....................................................................................................... 163 B.5 Appendices ...................................................................................................... 184 Appendix C: Summary of product characteristics (SmPC) and UK public assessment report ...................................................................................................................... 185 Appendix D: Identification, selection and synthesis of clinical evidence ................. 202 Appendix E: Subgroup analysis .............................................................................. 232 Appendix F: Adverse reactions ............................................................................... 240 Appendix G: Published cost-effectiveness studies ................................................. 241 Appendix H: Health-related quality-of-life studies ................................................... 247 Appendix I: Cost and healthcare resource identification, measurement and valuation ............................................................................................................................... 259 Appendix J: Clinical outcomes and disaggregated results from the model ............. 260 Appendix K: Price details of treatments included in the submission ....................... 263 Appendix L: Checklist of confidential information .................................................... 264 Appendix M: Summary of base-case analysis inputs .............................................. 265 Appendix N: Post-hoc analysis of ALT response .................................................... 282 Appendix O: MYR 301 efficacy extrapolation .......................................................... 285

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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Tables and figures

Tables

Table 1: The decision problem ................................................................................. 11 Table 2: Technology being evaluated ....................................................................... 16 Table 3: Studies investigating the efficacy and safety of bulevirtide ......................... 33 Table 4: Clinical effectiveness evidence: MYR 301 .................................................. 35 Table 5: Clinical effectiveness evidence: MYR 202 .................................................. 36 Table 6: Summary of trial methodology for MYR 301 ............................................... 37 Table 7: Key eligibility criteria for MYR 301 .............................................................. 40 Table 8: Summary of MYR 301 datasets .................................................................. 46 Table 9: Patient demographics and baseline characteristics in MYR 301 (FAS) ....... 47 Table 10: Summary of trial methodology for MYR 202 ............................................. 49 Table 11: Key eligibility criteria for MYR 202 ............................................................ 52 Table 12: Patient demographics and characteristics at baseline in MYR 202 ........... 54 Table 13: Summary of statistical analyses: MYR 301 ............................................... 57 Table 14: Summary of statistical analyses: MYR 202 ............................................... 60 Table 15: ALT normalisation at Weeks 24 and 48 (FAS; MYR 301) ......................... 67 Table 16: HDV RNA decrease by ≥2-log10 IU/mL at Weeks 24 and 48 (FAS; MYR 301) .......................................................................................................................... 67 Table 17: Undetectable HDV RNA at Weeks 24 and 48 (FAS; MYR 301) ................ 69 Table 18: Liver stiffness (FibroScan[®] ) at Week 48 (FAS; MYR 301)......................... 70 Table 19: Change in METAVIR fibrosis stage to Week 48 (FAS; MYR 301)............. 71 Table 20: EQ-5D-3L evaluation summary by level and visit in the bulevirtide 2 mg group (FAS; MYR 301) ............................................................................................. 73 Table 21: EQ-5D-3L evaluation summary by level and visit in the delayed treatment group (FAS; MYR 301) ............................................................................................. 74 Table 22: Summary statistics on log-10 transformed HDV RNA levels (mITT) ......... 79 Table 23: Mean change in liver stiffness (FibroScan[®] ) from baseline (mITT; MYR 202) .......................................................................................................................... 83 Table 24: List of studies included in the DMA base-case .......................................... 88 Table 25: Patient characteristics of studies considered for DMA base-case ............. 89 Table 26: Summary of outcomes reported across included studies at Week 48 ....... 89 Table 27: Missed doses of bulevirtide at Week 48 (SAS; MYR 301) ........................ 94 Table 28: Overview of AEs (SAS; MYR 301) ............................................................ 95 Table 29: AEs in ≥5% of patients in any treatment group (SAS; MYR 301) ................ 96 Table 30: SAEs reported across any treatment group (SAS; MYR 301) ................... 97 Table 31: Overview of AEs (SAS; MYR 202) .......................................................... 101 Table 32: Most common AEs reported by subjects treated with bulevirtide (SAS; MYR 202) ............................................................................................................... 102 Table 33: Summary list of published cost-effectiveness studies ............................. 112 Table 34: Summary of clinical assumptions in model ............................................. 118 Table 35: Features of the economic analysis .......................................................... 119 Table 36: Distribution of patients amongst fibrosis stages, model base-case ......... 123 Table 37: Distribution of patients amongst fibrosis stages, scenario analysis ......... 123

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Table 38: Combined response rates observed in MYR 301, applied in model basecase ........................................................................................................................ 124 Table 39: Bulevirtide and BSC response rates, model base-case .......................... 124 Table 40: Virologic response rates observed in MYR 301, applied in scenario analysis .................................................................................................................. 125 Table 41: Bulevirtide and BSC response rates, model scenario ............................. 125 Table 42: Bulevirtide and BSC combined response, extrapolated timepoints ......... 127 Table 43: Bulevirtide and BSC virologic response, extrapolated timepoints ........... 128 Table 44: Fibrosis and liver disease transition rates ............................................... 129 Table 45: Disease progression treatment hazard ratios, suboptimal responders .... 130 Table 46: Fibrosis and liver disease transition rates amongst sub-optimal responders ............................................................................................................................... 131 Table 47: Disease progression treatment hazard ratios, complete responders ...... 131 Table 48: Fibrosis and liver disease transition rates amongst complete responders ............................................................................................................................... 132 Table 49: Fibrosis regression on treatment in responder patients .......................... 133 Table 50: Adverse event rates included in the model ............................................. 134 Table 51: Liver-related mortality risk applied in the model ...................................... 135 Table 52: Regression analysis of 48-week MYR 301 utility values ......................... 136 Table 53. Mean baseline utility values from the MYR 301 trial, by compensated cirrhosis status ....................................................................................................... 137 Table 54: Health state utility values applied for F0-F4 health states, model scenario ............................................................................................................................... 138 Table 55: Health state utility values by response status, model base case ............ 139 Table 56: Health state utility values by response status, model scenario ............... 139 Table 57: Utility decrements associated with adverse events included in the model ............................................................................................................................... 140 Table 58: Summary of utility values for cost-effectiveness analysis ....................... 140 Table 59: Drug acquisition costs applied in the model ............................................ 142 Table 60: Monitoring resource use for bulevirtide patients ...................................... 143 Table 61: Monitoring resource use for BSC patients ............................................... 143 Table 62: Monitoring resource use unit costs ......................................................... 144 Table 63: Health-state costs applied in the model .................................................. 146 Table 64: HBV antiviral medication costs applied in the model ............................... 146 Table 65: Adverse event unit costs ......................................................................... 147 Table 66: Summary features of QALY shortfall analysis ......................................... 148 Table 67: Summary of health state benefits and utility values for QALY shortfall analysis .................................................................................................................. 148 Table 68: Summary of QALY shortfall analysis ....................................................... 149 Table 69: Assumptions applied in the model .......................................................... 150 Table 70: Base-case results ................................................................................... 152 Table 71: Net health benefit .................................................................................... 152 Table 72: Probabilistic cost-effectiveness results ................................................... 153 Table 73: OWSA results, bulevirtide vs BSC .......................................................... 157 Table 74: Scenario analyses results ....................................................................... 159 Table 75: Database searches in the clinical SLR .................................................... 203 Table 76: Clinical inclusion and exclusion criteria ................................................... 207 Table 77: Studies included in the DMA ................................................................... 210

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Table 78: List of included studies at data extraction not deemed relevant for the DMA

............................................................................................................................... 211 Table 79: List of excluded studies at data extraction .............................................. 213 Table 80: Quality assessment full results for MYR 301 ........................................... 227 Table 81: Quality assessment full results for MYR 202 ........................................... 230 Table 82: Combined response at Week 48 by cirrhosis status subgroup (FAS; MYR 301) ........................................................................................................................ 232 Table 83: Combined response at Week 48 by IFN treatment subgroup (FAS; MYR 301) ........................................................................................................................ 234 Table 84: Virologic response at Week 48 by IFN treatment subgroup (FAS; MYR 301) ........................................................................................................................ 236 Table 85: ALT normalisation at Week 48 by IFN treatment subgroup (FAS; MYR 301) ........................................................................................................................ 238 Table 86: PICO eligibility criteria for cost-effectiveness studies .............................. 241 Table 87: PICO eligibility criteria for HRQoL SLR ................................................... 247 Table 88: Overview of HRQoL and utility studies .................................................... 252 Table 89: Outcomes of studies reporting HRQoL and utilities ................................. 254 Table 90: Summary of cost and resource use studies ............................................ 259 Table 91: Clinical outcomes from the model, bulevirtide vs BSC ............................ 260 Table 92: Summary of QALY gain by health state .................................................. 261 Table 93: Summary of costs by health state ........................................................... 261 Table 94: Summary of predicted resource use by category of cost ........................ 262 Table 95: Details of intervention costs, including concomitant medicines, for each formulation used in the model ................................................................................ 263 Table 96: Details of comparators and subsequent treatment costs, including concomitant medicines, for each formulation used in the model ............................. 263 Table 97: Summary of variables applied in the economic model ............................ 265 Table 98: Parameter estimates from EMAX model with continuity correction, combined response, IFN experienced sub-group ................................................... 285 Table 99: Parameter estimates from EMAX model with continuity correction, virologic response, IFN experienced sub-group .................................................................... 285 Table 100: Predicted combined response rates from EMAX model with continuity correction ................................................................................................................ 285

Figures

Figure 1: Bulevirtide mechanism of action ................................................................ 15 Figure 2: Epidemiological cascade for CHD in the UK .............................................. 20 Figure 3: Time to event-free survival in participants with and without cirrhosis ......... 22 Figure 4: PROs in people with CHD versus CHB ..................................................... 26 Figure 5: Treatment algorithm for adult CHD ............................................................ 28 Figure 6: Proposed positioning of bulevirtide in the adult CHD treatment pathway ... 30 Figure 7: MYR 301 study design and dosing ............................................................ 39 Figure 8: MYR 202 study design .............................................................................. 51 Figure 9: Combined response at Weeks 24 and 48 (FAS; MYR 301) ....................... 65 Figure 10: Mean VAS score (FAS; MYR 301) ........................................................... 76

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Figure 11: HDV RNA response at Week 24 (mITT) .................................................. 78 Figure 12: Mean log10 transformed HDV RNA levels over time ................................. 80 Figure 13: Combined response at Weeks 24 and 48 (mITT) .................................... 81 Figure 14: Summary plot of meta-analysis for combined response at Week 48 ....... 90 Figure 15: Summary plot of meta-analysis for undetectable HDV RNA or reduction (≥2-log10) at Week 48 ............................................................................................... 91 Figure 16: Summary plot of meta-analysis for ALT normalisation at Week 48 .......... 92 Figure 17: Model structure ...................................................................................... 117 Figure 18: PSA scatterplot ...................................................................................... 154 Figure 19: Cost-effectiveness acceptability curve, bulevirtide vs BSC .................... 154 Figure 20: OWSA results, bulevirtide vs BSC ......................................................... 156 Figure 21: PRISMA flow for the clinical SLR and DMA ........................................... 209 Figure 22: Patient flow for MYR 301 ....................................................................... 225 Figure 23: Patient flow for MYR 202 ....................................................................... 226 Figure 24: Forest plot of combined response at Week 48 by IFN treatment subgroup (FAS; MYR 301) ..................................................................................................... 235 Figure 25: Forest plot of virologic response at Week 48 by IFN treatment subgroup (FAS; MYR 301) ..................................................................................................... 237 Figure 26: Forest plot of ALT normalisation at Week 48 by IFN treatment subgroup (FAS; MYR 301) ..................................................................................................... 239 Figure 27: PRISMA flow for the economic SLR (Database inception to December 2021) ...................................................................................................................... 246 Figure 28: PRISMA flow for the utility and HRQoL SLR (Database inception to December 2021) .................................................................................................... 251 Figure 29: Evolution of ALT response over 48 weeks in patients showing a virologic response in the bulevirtide 2 mg treatment group (MYR 301) ................................ 282 Figure 30: Evolution of ALT response over 48 weeks in patients showing a nonvirologic response in the bulevirtide 2 mg treatment group (MYR 301) .................. 283 Figure 31: Evolution of ALT response over 48 weeks in the delayed treatment arm (MYR 301) .............................................................................................................. 284

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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Abbreviations

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

B.1 Decision problem, description of the technology and clinical care pathway

B.1.1 Decision problem

The submission focuses on part of the technology’s marketing authorisation, specifically adults with chronic hepatitis delta (CHD) who have compensated liver disease, and evidence of significant fibrosis (METAVIR stage greater than or equal to F2), whose disease has responded inadequately to interferon-based therapy (hereafter referred to as IFN-based therapy), or who are ineligible to receive IFNbased therapy due to intolerance or contraindication. Bulevirtide has received conditional marketing authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adults with compensated liver disease. It should be noted that based on the anticipated positioning of bulevirtide within the UK treatment pathway, this submission appraises the clinical and costeffectiveness of bulevirtide in a narrower population than that defined in the final scope issued by NICE.

The proposed position in the treatment pathway is narrower than the marketing authorisation because:

• This is relevant to NHS clinical practice and the anticipated positioning of bulevirtide within the UK treatment pathway.

• This position reflects where bulevirtide treats the population with the highest unmet need i.e., where IFN-based therapy is not a treatment option.

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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Table 1: The decision problem

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732] © Gilead (2022) All rights reserved Page 13 of 183

Key : BSC: best supportive care; CG: clinical guidelines; CHD: chronic hepatitis delta; HBsAg; hepatitis b surface antigen; HDV: hepatitis delta virus; IFN: interferon; PEG-IFN: peginterferon alfa-2a; RNA: ribonucleic acid.

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B.1.2 Description of the technology being evaluated

Bulevirtide, formerly known as Myrcludex B, is a novel, first-in-disease and first-inclass entry inhibitor that binds specifically to the sodium taurocholate co-transporting peptide (NTCP) and acts as a potent, highly selective entry inhibitor of HDV into hepatocytes (1,2). Bulevirtide does not directly interfere with viral production or elimination of the virus, and instead acts as a post-attachment step, likely misdirecting the entry route of HDV to an unproductive cellular pathway (Figure 1). By blocking the essential entry receptor, the de novo infection of hepatocytes is decreased, viral spread is inhibited, and the life cycle of HDV is disrupted. A reduction in the number of infected cells ultimately protects uninfected and newly formed hepatocytes from new and re-infection (3–5).

Figure 1: Bulevirtide mechanism of action

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Key : BLV: bulevirtide; HDV: hepatitis delta virus; HSPG: heparan sulphate proteoglycan; NTCP: sodium taurocholate cotransporting polypeptide.

Source : MYR Pharmaceuticals. Mechanism of Action (6)

In June 2015, bulevirtide was granted orphan designation (EU/3/15/1500) by the European Commission (EC) because of the seriousness of HDV infection, the lack of licensed treatment options, and the rarity of HDV infection (7). Bulevirtide (2 mg given subcutaneously [SC] once daily) was subsequently granted conditional marketing authorization for the treatment of CHD in adults with compensated liver

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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disease under the brand name HEPCLUDEX[®] in Europe (7), representing an important step towards addressing the current unmet needs in CHD as the first approved treatment for this indication.

Table 2 provides an overview of the technology being evaluated. The Summary of Product Characteristics (SmPC) is included in Appendix C1.1 SmPC (8).

Table 2: Technology being evaluated

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Key : CHD: chronic hepatitis delta; EMA: European Medicines Agency; HBV: hepatitis B virus; HDV: hepatitis delta virus; MHRA: Medicines and Healthcare products Regulatory Agency; NTCP: sodium-taurocholate co-transporting polypeptide; PAS: patient access scheme; RNA: ribonucleic acid; NA: nucleos(t)ide analogue; SC: subcutaneous.

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B.1.3 Health condition and position of the technology in the treatment pathway

B.1.3.1 Disease overview

Hepatitis delta represents the most severe form of viral hepatitis (4,9). Hepatitis delta is caused by HDV, a defective RNA virus that requires the presence of the hepatitis B surface antigen (HBsAg) for its complete replication and transmission. As such, this form of hepatitis only occurs in individuals who are also infected with the hepatitis B virus (HBV) (10).

Hepatitis delta can cause acute or fulminant hepatitis (11), and occurs either as a coinfection with HBV, which can be self-limiting, or as a superinfection in a patient with chronic hepatitis B (CHB) infection (12). The majority (52.0%) of people suffering from acute hepatitis delta will develop CHD, of which 76% will develop chronic hepatitis. In some people with hepatitis delta, the progression to chronic hepatitis occurs quickly, with 39.2% of people with acute infection developing chronic hepatitis within 1.5 years on average (10). People with chronic hepatitis display an array of clinical manifestations, ranging from non-specific symptoms to rapidly progressing hepatitis. People with hepatitis delta may not display any obvious symptoms until liver function is compromised, and this can mean that diagnosis is often fortuitous or may follow the appearance of late complications (13), especially if the NICE hepatitis B (chronic) clinical guideline CG165, which stipulates that adults who are HBsAg positive should be tested for anti-HDV.

CHD is defined as an infection lasting ≥6 months (14,15). Rates of disease progression, including liver-related events, cirrhosis, hepatocellular carcinoma (HCC) and death, are greater with CHD than for patients with CHB monoinfection (16). Several cohort studies have found that this risk may be as much as nine times higher than in CHB monoinfected patients (17). Approximately 70% of patients with CHD develop cirrhosis within 5-10 years (18), with cirrhotic patients at a three-fold greater risk of developing HCC, and a two-fold greater risk of mortality, than HDV-negative cirrhotic patients (19). Overall mortality rates as a result of CHD have been observed at 11% within the first six months of the disease (10), and as high as 50% within five

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years for cirrhotic patients (10,20). Therefore, development of cirrhosis and HCC is linked to increased morbidity and mortality, and early treatment of CHD is advantageous, as it could slow disease progression and prevent the onset of these difficult-to-treat and potentially life-threatening complications (21–24).

The aim of CHD treatment is to prevent the development of complications of liver disease, such as HCC, cirrhosis, decompensation, requirement for liver transplantation (LT), and death (25). However, at present, the therapeutic options for patients with CHD are limited, and there is no approved treatment for CHD available to patients in the UK (26). NAs, while effective in patients with CHB wherein they are widely used, have not been shown to have a meaningful effect on HDV RNA levels in patients with CHD as they do not inhibit production of HBsAg (the HBV protein required by HDV) (27). Furthermore, IFN-based therapy may be used off-label, but its usage and effectiveness are limited by low treatment eligibility, low response rates, and tolerability concerns, leading to discontinuations, further disease progression, and a significant impact on health-related quality of life (HRQoL) (4,16,28,29). For example, only 25% of patients who receive IFN-based therapy maintain a sustained virologic response after 1 year of treatment (13,30). Overall, IFN-based therapy is estimated to provide a lasting benefit for approximately 10% of patients (16). Given the progressive course of the disease, there is a considerable unmet need for an approved antiviral therapy for the treatment of CHD for patients whose disease has responded inadequately to IFN-based therapy, or who are ineligible to receive IFN-based therapy due to intolerance or contraindication.

Hepatitis delta is recognised as an orphan disease by the European Medicines Agency (EMA), indicating that prevalence is below the threshold of 5 in 10,000 people (7). An estimated 241 HDV-RNA positive patients are treated annually in the UK, of which 152 have evidence of significant fibrosis (METAVIR stage greater than or equal to F2) and have failed, are contraindicated to, or are intolerant of, IFNbased therapy (Figure 2). Clinical experts consulted by Gilead in preparation for this submission confirmed that this figure was broadly accurate and may even be an overestimate of patient numbers (31).

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Figure 2: Epidemiological cascade for CHD in the UK

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Key : BLV: bulevirtide; HBV: hepatitis B virus; HDV: hepatitis delta virus; IFN: interferon; MA: marketing authorisation; UK: United Kingdom.

aBased on British Liver Trust estimates (32).

bBased on the estimated proportion of HBV patients co-infected with HDV in the UK population (33).

cBased on GSI assumption (34).

dBased on exclusions, assuming 9% of diagnosed patients have decompensated cirrhosis, 9% of diagnosed patients have hepatocellular carcinoma, and 2% of patients have required liver transplantation (35).

eBased on GSI assumption (34).

fBased on assumption that 50% of patients are eligible for IFN-based therapy, of which 25% achieve a sustained response (13,30).

gBased on fibrosis stage split in Romeo et al . (2009) (35).

Notes : *Non-response defined as failure of, intolerance of, or contraindicated to, IFN-based therapy.

B.1.3.2 Burden of disease

B.1.3.2.1 Clinical burden

Once a person is infected with HDV, recovery is unlikely, and the chance of this decreases as the disease progresses. Only 10% of patients with CHD experience spontaneous recovery (10). In the early phases of infection, people may experience hepatitis flares, followed by a decrease in HDV replication and subsequent reactivation of HBV (35). For those who do not recover at early stages of the disease, hepatitis delta is associated with an accelerated fibrosis progression, early

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liver decompensation with cirrhosis, and increased risk of HCC, leading to greater liver-related mortality compared to HBV or HCV monoinfection (21,22,36).

Persistent viral replication and hepatic inflammation leads to the rapid development of liver cirrhosis in people with hepatitis delta (37). It is expected that 70% of people with hepatitis delta will progress to cirrhosis within 5 - 10 years (18), and 29.7% of those that progress will develop cirrhosis within 3 - 4 years (10). A 2020 retrospective study conducted by Kamal et al . (2020), which included 337 people with anti-HDV positivity followed for up to 6.5 years, found that individuals with hepatitis delta and cirrhosis have a greater risk for liver-related events than those without cirrhosis (Figure 3) (38). The likelihood of progressing to cirrhosis is substantially increased in people with CHD, with the majority of these people (53.8%) progressing to cirrhosis within 3 - 4 years (10). The likelihood of progression to cirrhosis is also far greater in people with HDV than in other types of viral hepatitis, such as HCV or HBV monoinfection. For example, 10-20% of people with HCV will develop cirrhosis within 20 years, while for HBV, progression to cirrhosis occurs in 20% of patients within 5 years (39,40).

Following the development of liver cirrhosis, people with CHD may develop symptoms of decompensation, such as ascites, encephalopathy, or variceal bleeding. Compared to those with compensated cirrhosis (CC), patients with decompensated cirrhosis (DCC) have a lower overall rate of survival after 1 year (75% vs 78%) and 5 years (45% vs 67%) (41). LT is often indicated as the only effective therapy option to treat DCC (42). The estimated annual incidence of liver decompensation in people with hepatitis delta and cirrhosis ranges from 2.6% to 3.6% (4). Of note, if HDV is not treated post-transplant, infection of the transplanted liver is likely to occur and can reduce the lifespan of the new liver (43).

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Figure 3: Time to event-free survival in participants with and without cirrhosis

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Notes: Risk-free survival for composite liver-related outcomes and liver-related death/liver transplantation. Source : Adapted from Kamal et al. (2020) (38).

In addition to an increased risk of cirrhosis and liver decompensation, hepatitis delta is also associated with an increase in the overall risk of HCC compared to people with HBV alone (37,44). Results from a meta-analysis of 93 studies showed that, overall, CHD is associated with a significantly increased risk of HCC compared to HBV monoinfection (44). In addition, HCC commonly occurs against a backdrop of cirrhosis, which is the primary cause of 70-80% of cases (45). In patients with CHD who progress to HCC, progression typically occurs within 10 years (10). Results from Bockmann et al . (2020) suggest a high rate (16%) of HCC in 1,127 people with hepatitis delta over three years in Germany (22), while estimates from a study of 200 western European patients suggest a threefold increase in HCC incidence among people with CHD and cirrhosis compared to people with cirrhosis alone (19).

Primary liver cancer represents the eighth most common cause of cancer-related deaths in the UK (46). The main primary liver cancer subtype, HCC, is associated with a high mortality rate, with a median survival following diagnosis of 6 to 20 months (24,47). In the UK, only one third of patients (33.8%) survive to 2 years, with that number reducing to 18.3% at 5 years (47). Currently, the only treatment option for people with HCC due to coinfection or superinfection with HDV and HBV is LT (43,48,49). Compared to people with HBV, people with hepatitis delta require LT more frequently, with 3.44 cases/1,000 person-months versus 0.78 cases/1,000 person-months (50).

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The LT procedure, and the associated drugs used to prevent rejection of the donor liver, can cause bleeding, blood clots, infection, mental confusion, seizures and rejection of the donor liver. Furthermore, side effects associated with anti-rejection medications, which are required for the lifetime of the individual following LT, include bone thinning, diabetes, headaches, and high blood pressure and cholesterol (51). As such, despite LT offering a treatment option for people with hepatitis delta and end-stage liver disease, it has limitations in terms of accessibility and post-transplant management, highlighting the need for effective treatments at an earlier stage of the disease.

In summary, the rapid progression of disease and development of severe liver complications places a substantial clinical burden on people with CHD (35). As a result, there remains a significant unmet need for an effective treatment at an earlier stage of disease, to prevent downstream consequences. Due to variation in awareness, characteristics of the patient population (see Section B.1.4), limited testing, and issues related to diagnosing techniques, hepatitis delta may have an under-recognised role in the causation of liver-related deaths (33).

B.1.3.2.2 Outcomes for adults with CHD

As highlighted in Section B.1.3.3, the aim of CHD treatment is to prevent the development of complications of liver disease, such as HCC, cirrhosis, decompensation, requirement for LT, and death (25). However, the demonstration of these morbidity- and mortality-related outcomes is not appropriate nor practical for clinical research in hepatitis, as it would require large sample sizes and a prolonged follow-up period. As a result, clinical trials have relied on endpoints such as virological and histological outcomes as surrogate markers, which are likely to predict clinical benefit in people with hepatitis (52).

According to the US Food and Drug Administration (FDA) guidance on developing treatments for CHD, and discussions from the 2019 (European Association for the Study of the Liver) EASL– American Association for the Study of Liver Disease (AASLD) Conference, surrogate endpoints in clinical trials should provide evidence for both a decline in virologic replication, and an improvement in associated liver

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inflammation as evidenced by a biochemical response (25,53). The main surrogate endpoint used to predict clinical benefit, as recommended by the FDA, is a combined response, or ‘the proportion of trial patients with undetectable serum HDV RNA (defined as undetectable HDV RNA [HDV RNA <LoD, where LoD=6 IU/mL] or decrease in HDV RNA by ≥2-log10 IU/mL from baseline) and alanine aminotransferase (ALT) normalisation’ (53).

Increases in HDV RNA levels are associated with increased infectivity, progression of disease, and development of long-term complications (20). High HDV RNA levels are correlated with disease activity and have been shown to be associated with disease progression to cirrhosis and an increased risk of HCC (35). In a study by Braga et al . (2014), HDV RNA levels were shown to positively correlated with neuroinflammatory activity and fibrosis stage, with advanced fibrosis being associated with an HDV viral load ≥2-log10 (54). In a 2009 Italian study by Romeo et al ., which analysed data from participants who had been HDV positive for at least six months, HDV viraemia was found to be the strongest predictor of cirrhosis, liver decompensation, HCC and death (35). Roulot et al . (2020) found that detectable HDV RNA is associated with decompensation (36). Results from the same study indicate a trend for increased levels of HDV viraemia in individuals with cirrhosis but without complications compared to those with clinical decompensation and HCC (36). Similarly, results from a study by Yamashiro et al . (2004) suggest that levels of HDV RNA were significantly higher in people with CHD and cirrhosis compared to asymptomatic carriers (55). These results suggest that HDV RNA may be related to progression to CHD, and therefore a reduction in HDV RNA levels is a highly relevant endpoint to predict a clinical benefit in people with CHD (56).

Similar to a reduction in HDV RNA replication, a biochemical response (defined as normalisation of ALT based on the upper limit of normal [ULN]) is also suggested to predict long-term clinical benefit in people with CHD. ALT is a liver enzyme that indicates ongoing inflammation or injury to liver cells as it is released into the blood as hepatocytes die. It is a general (not specific to HDV infection) marker of current liver damage. Elevated ALT has been associated with long-term complication such as cirrhosis and HCC (57). Sustained reduction in ALT, as observed in patients

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receiving effective therapy for HBV monoinfection (58,59), correlates with improved long-term liver-related outcomes, including reduction in cirrhosis and HCC (60).

The use of ALT normalisation has been included in multiple Phase 3 clinical trials in viral hepatitis as an indicator of efficacy. In a community-based prospective cohort study by Chen et al . (2011), which included 23,820 participants with CHB, it was indicated that the cumulative lifetime risk of developing cirrhosis increased in correlation with higher ALT levels. Likewise, the study presented evidence that the cumulative lifetime risk of developing HCC increased with higher levels of ALT (61). Furthermore, in a study by Zachou et al . (2010), which included 80 subjects with CHD, elevated ALT serum levels were associated with the development of fibrosis (62).

Given the association of ALT and disease progression in viral hepatitis, the normalisation of ALT is also shown to correlate with an improvement in morbidity (63). A study by Choi et al . (2020), which included 4,639 participants with CHB who initiated treatment with entecavir or tenofovir (TDF), found that ALT normalisation was independently associated with a proportionally lower risk of HCC, regardless of fatty liver or cirrhosis at baseline and while on treatment (64). Furthermore, the association of ALT and risk of hepatic events is further evidenced by Wong et al ., (2018), who found that participants with normalised ALT at 3, 6, 9, and 12 months of treatment had a reduced risk of hepatic events compared to participants without normalised ALT (65). However, clinical expert feedback highlighted that a decline in HDV RNA and ALT normalisation may not always occur in parallel, and therefore ALT normalisation can be viewed as a lagging indicator of treatment response (31).

B.1.3.2.3 Humanistic burden

In addition to the substantial clinical burden, people infected with hepatitis delta may suffer from negative effects on quality of life (QoL) (66–68). A 2017 German retrospective study by Stahmeyer et al . investigated QoL, using the EuroQoL-5 Dimension (EQ-5D) time trade-off method and Visual Analogue Scale (VAS) method (where score of 1 refers to perfect health and a score of 0 refers to death), in 117 participants with HBV, of which 16 participants were coinfected with HDV. Of the

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participants with hepatitis delta, QoL scores were approximately 0.81 and 0.64 for EQ-5D and VAS, respectively (67). The same study also found that people with hepatitis delta experience a restriction in QoL due to the disease, with 52% of people reporting moderate, severe, or very severe restriction in QoL (67). Treatment of hepatitis delta has also been found to impact QoL, with depression a common sideeffect of PEG-IFN treatment. A study conducted in Turkey by Dagli et al . (2018) reported high scores of depression in all participants with hepatitis delta (n=28), during and at the end of PEG-IFN treatment (66).

In a single-centre study by Buti et al . (2021) examining patient reported outcome (PRO) scores in people with CHD receiving NA therapy, people coinfected with hepatitis delta experienced more impairment in PRO scores compared to population norms, reporting more severe abdominal symptoms and more impairment in their daily activities (Figure 4) (66). PRO scores range from 0-100, where higher scores indicate a better QoL.

Figure 4: PROs in people with CHD versus CHB

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Key : CHB: chronic hepatis B; CHD: chronic hepatitis delta; CLDQ: Chronic Liver Disease Questionnaire; FACIT -F: Functional Assessment of Chronic Illness Therapy-Fatigue; PRO: patient-reported outcome; WPAI: Work Productivity and Activity Impairment. Notes : all parameters were normalised to a scale of 0–100. T-student test and Mann-Whitney U-test were used for parametric and non-parametric categories, respectively. P-values of 0.05 or less were considered statistically significant. *p<0.10; **p<0.05. Source : Adapted from Buti et al . (2021) (66).

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B.1.3.2.4 Economic and societal burden

The cost of living with hepatitis delta is currently based on evidence from the US. People with hepatitis delta experience a significantly higher health care resource utilisation (HCRU) and cost burden (69). In addition, people with hepatitis delta incurred significantly higher total annual health care service costs of $23,605 per individual, compared to $18,228 for people with HBV alone (69). The economic burden associated with hepatitis delta is also driven by disease severity, with an increase in healthcare costs associated with hepatitis delta increase as the disease progresses (70).

Furthermore, hepatitis delta is associated with indirect costs related to lost productivity of people due to work absenteeism. Loss of work productivity related to hepatitis delta and treatment is estimated at $14, $180, and $506 in 2010 over one year for people CC, DCC, and HCC, per person, respectively (70).

B.1.3.3 Clinical care pathway

Treatment guidelines for HDV are used to inform the most appropriate management of people with CHD. Current guidance for HDV patient management in Europe, issued by EASL, is limited to a sub-section within the clinical guidelines for the management of HBV infection (27). In the US, AASLD has published a standalone guideline for the diagnosis and management of people with CHD (71). Whilst NICE do not provide full guidelines on the treatment of chronic HDV - potentially due to the orphan nature of the disease and lack of approved treatment options - they do provide recommendations for drug treatment in adults with HBV-HDV co-infection (72).

B.1.3.3.1 EASL guidelines

The EASL guidelines strongly recommend treatment with PEG-IFN for at least 48 weeks in HDV-HBV coinfected patients with compensated liver disease, irrespective of on-treatment response pattern if well-tolerated, illustrating the paucity of treatment options available for these patients. NA therapy, which has no activity against HDV but is highly effective in inhibiting HBV, is recommended in HDV-HBV co-infected patients with ongoing HBV DNA replication (27).

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B.1.3.3.2 NICE guidelines

The NICE treatment pathway for adults with CHB provides recommendations for the diagnosis and antiviral treatment of CHD (Figure 5).

NICE clinical guideline CG165 for the diagnosis and management of CHB stipulates that adults who are HBsAg positive should be tested for anti-HDV (72). Those confirmed as having been exposed to HDV must then be tested for current infection using a HDV RNA PCR test. Adult patients co-infected with CHB and hepatitis delta infection, who have evidence of significant fibrosis (METAVIR fibrosis stage greater than or equal to F2 or Ishak stage greater than or equal to 3), should be offered a 48-week course of PEG-IFN (72). The use of PEG-IFN is off-label as treatment of patients infected with HDV is not within the marketing authorisation (73), In addition, the technology appraisal guidance [TA96] does not apply to adults with CHB known to be co-infected with hepatitis delta (74). Treatment with PEG-IFN should be stopped if there is no decrease in HDV RNA after 6 months to 1 year of treatment. Otherwise, treatment should be continued with response evaluated annually (72).

Figure 5: Treatment algorithm for adult CHD

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Key: CHD: chronic hepatitis delta; HBV: hepatitis B virus; HDV: hepatitis delta virus; RNA: ribonucleic acid; PEG-IFN: peginterferon-alpha-2a. Source : Adapted from NICE clinical guidance CG165 for hepatitis B (72).

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B.1.3.3.3 Unmet needs with current treatment

National and international guidelines for hepatitis delta are limited to recommending off-label PEG-IFN (27,72). EASL guidelines recommend 48 weeks of treatment with PEG-IFN, irrespective of response pattern if well tolerated, illustrating the paucity of available treatment options to patients with CHD (27). A study by Romeo et al . (2009) found that 58.7% of patients at enrolment had received no treatment for CHD, while only 39.1% received treatment with IFN-based therapy over a period of 233 months (35), further highlighting the absence of effective therapeutic options.

There is some evidence to suggest that off-label treatment with IFN-based therapy may result in some impact on liver histology, such as improvement in fibrosis and clearance of HDV, decreased risk of liver decompensation or need for LT, as well as overall survival, however the evidence is limited (20).A substantial portion (~50%) of patients are ineligible for IFN-based therapy, due to contraindications, intolerabilities, or advanced liver disease (36). In addition, of those who do receive treatment, only 25% achieve a sustained response, and approximately 50% of these individuals relapse (13,30). Taking these factors into consideration, IFN-based therapy is estimated to provide a lasting benefit for only 10% of CHD patients (16).

In the absence of off-label IFN-based therapy, the only treatment option for patients with CHD is BSC, generally defined as symptomatic treatment as well as treatment for the underlying CHB where indicated. Treatments for HBV, such as NAs, demonstrate no efficacy against CHD because the replication of HDV is completely autonomous from that of HBV (4). HDV only requires the envelope glycoprotein HBsAg from HBV. Thus, whilst HBV-specific treatments such as NAs strongly suppress HBV replication, they have no effect on HDV replication and little effect on HBsAg production (4).

As a reflection of the above, experts consulted during the development of the European Public Assessment Report (EPAR) agreed that there is an unmet medical need for bulevirtide, and that chronic HDV infected, or HDV-RNA positive adult patients with compensated liver cirrhosis, would constitute a patient population in

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urgent need of treatment with bulevirtide , thus supporting a conditional approval to provide timely access (3).

B.1.3.3.4 Proposed positioning of bulevirtide in the adult CHD pathway

Bulevirtide is a novel, first-in-disease and first-in-class entry inhibitor, and the only approved treatment for CHD. Bulevirtide is positioned as a treatment option for adults with CHD who have compensated liver disease, and evidence of significant fibrosis (METAVIR stage greater than or equal to F2), whose disease has responded inadequately to IFN-based therapy, or who are ineligible to receive IFN-based therapy due to intolerance or contraindication.

The proposed positioning of bulevirtide is displayed schematically in Figure 6.

Figure 6: Proposed positioning of bulevirtide in the adult CHD treatment pathway

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==> picture [430 x 125] intentionally omitted <==

Key: CHD: chronic hepatitis delta; HBV: hepatitis B virus; HDV: hepatitis delta virus; RNA: ribonucleic acid; PEG-IFN: peginterferon-alpha-2a.

There are currently no approved treatments available in the UK for the treatment of CHD, and off-label treatment with IFN-based therapy is associated with limited efficacy and an unfavourable safety profile, with only 10% of patients experiencing a

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lasting benefit as a result of treatment (16). The limitations of current off-label treatment with IFN-based therapy, as described in Section B.1.3.3.3, present a significant unmet need for an effective treatment for hepatitis delta to reduce morbidity and side-effects among patients whose disease has responded inadequately to IFN-based therapy, or who are ineligible to receive IFN-based therapy due to intolerance or contraindication.

Therefore, the availability of a treatment for these patients would provide a valuable addition to the treatment armamentarium. The following text provides more detail on the unmet need that exists in the proposed positioning of bulevirtide.

- Adults with CHD: inadequate response to IFN based therapy

In clinical trials, only 25% of patients demonstrate a sustained response to IFNbased therapy, and approximately 50% of these individuals will eventually relapse once treatment with IFN-based therapy is completed, giving an overall response rate of 10% (13,30). In the post-hoc analysis of the HIDIT-II study, which included people with HBV and HDV, Bremer et al . (2021) found that HDV relapses occurred in 67% of individuals with detectable low HDV RNA after PEG-IFN treatment at Week 48, and in 77% of people who had undetectable HDV RNA after PEG-IFN treatment at Week 96 (75).

Adults with CHD: intolerant of IFN-based therapy

Treatment of hepatitis delta with IFN-based therapy is associated with significant toxicity (29). Adverse events (AEs) as a result of treatment are frequent and severe, which resulted in 20% of patients withdrawing prematurely from therapy in the HIDITII trial (76). Unwanted side-effects caused by treatment with IFN-based therapy include flu-like symptoms, myalgias, arthralgias, exacerbation of psychiatric illnesses, haematologic toxicity, and elevation of transaminases (20). These have the potential to lead to treatment discontinuation and low treatment compliance. Many side-effects can only be managed through dose adjustment or the cessation of treatment (29).

- Adults with CHD: ineligible for treatment with IFN based therapy

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Additionally, clinical experience indicates that only 50% of patients are eligible for therapy with IFN-based therapy, due to contraindications, intolerabilities or advanced liver disease (36). As a result, many patients do not initiate treatment. In an Italian study analysing 299 patients with HDV followed-up over a mean period of 233 months, only 39.1% of patients received treatment with IFN-based therapy (35).

B.1.4 Equality considerations

Clinical experts consulted by Gilead raised several issues with regards to equality, including language barriers and patient voice (31). A retrospective study of HDV coinfection in South London found the prevalence of anti-HDV in ~1,000 carriers of HBsAg with chronic liver disease was 8.5%, with 28.1% the HDV-infected subjects born in southern or eastern Europe, 26.8% born in Africa, and 7.3% born in central Asia (77). Due to the implementation of HBV vaccination programmes, the incidence of HDV has significantly decreased in Europe. However, due to increased migration of people from highly endemic areas, this decline has recently been reversed (78). A pattern of increasing migrant HDV infections and a decline in native HDV infections in Europe has resulted in a dual epidemiology of hepatitis delta: an aging domestic cohort with advanced liver fibrosis, representing the end stage of the natural history, and a younger generation of foreign born patients who account for the majority of new infections (28).

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B.2 Clinical effectiveness

B.2.1 Identification and selection of relevant studies

A systematic literature review (SLR) was conducted to identify the clinical evidence relevant to the technology being appraised.

See Appendix D1.3 for full details of the process and methods used to identify and select the clinical evidence relevant to bulevirtide for the treatment of adults with CHD who have compensated liver disease.

B.2.2 List of relevant clinical effectiveness evidence

Five trials were identified in the clinical SLR that provide direct clinical evidence for the efficacy and safety of bulevirtide for the treatment of adults with CHD. Table 3 provides justification for the bulevirtide studies considered relevant to this submission, and those that will not be described in this section. A description of the studies providing relevant clinical effectiveness evidence can be found in Table 77 (Appendix D1.3).

Table 3: Studies investigating the efficacy and safety of bulevirtide

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Key: BSC: best supportive care; IFN: interferon; NA: nucleos(t)ide analogue; PEG-IFN: peginterferon-alpha-2a.

One Phase 3 trial (MYR 301) and one supportive Phase 2 trial (MYR 202) were identified in the clinical SLR that provide direct clinical evidence for the efficacy and safety of bulevirtide for the treatment of adult subjects with CHD against BSC. The pivotal MYR 301 multicentre, open-label, Phase 3 clinical trial evaluating the efficacy and safety of bulevirtide compared to BSC in adults with CHD is ongoing. Therefore, the primary source of data underpinning this submission is available from the MYR 301 interim week 48 clinical study report (CSR), dated January 2022 (59). To date, two conference abstracts relating to interim data are available in the public domain (79,81), with additional interim data expected to be published at the EASL International Liver Congress, 22-26 June 2022 (94).

Supporting clinical evidence of the efficacy and safety of bulevirtide for the treatment of CHD is available from the MYR 202 Phase 2 trial. The SLR identified three publications relating to MYR 202 in the public domain (82,83,85). Results from MYR 202 have also been presented in the EMA EPAR (95).

Interim data at 24 weeks for MYR 301 was published in the Journal of Hepatology (79), while an exploratory analysis focusing on PROs was published in Hepatology (81). Results from MYR 202 were presented in the Journal of Hepatology (82–85). Where possible, information will be sourced from the public domain.

Patients enrolled in MYR 301 will be treated for 144 weeks with bulevirtide, before a follow-up period of 96 weeks to assess off-treatment response (i.e., a total of 240 weeks). Table 4 and Table 5 present a summary of the relevant clinical effectiveness evidence for bulevirtide.

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Table 4: Clinical effectiveness evidence: MYR 301

Key: CHD: chronic hepatitis delta; HDV: hepatitis delta virus. Notes : outcomes in bold are those directly used in the economic modelling.

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Table 5: Clinical effectiveness evidence: MYR 202

Key: ALT: alanine aminotransferase; CHD: chronic hepatitis delta; TDF: tenofovir.

MYR 202 studied patients with CHD and quantifiable HDV virus replication, including a proportion for whom previous treatment with IFN-based therapy failed or who were considered IFN-based therapy intolerant, as well as patients with compensated cirrhosis. Bulevirtide was compared against TDF alone, a treatment for the underlying hepatitis B. This comparator is aligned to the comparator in this submission, of BSC. In addition, the sub-population of patients who had failed or were intolerant to IFN-based therapy aligns to the population proposed in the decision problem. Therefore, despite data from MYR 202 not being used to populate the economic model, the study provides an additional source of supporting evidence and is included in Sections B.2.2 to B.2.6.

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B.2.3 Summary of methodology of the relevant clinical effectiveness evidence

B.2.3.1 MYR 301

B.2.3.1.1 Trial methodology

Table 6: Summary of trial methodology for MYR 301

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Key : AASLD: American Association for the Study of Liver Diseases; ALT: alanine aminotransferase; BLV: bulevirtide; CHB: chronic hepatitis B; CHD: chronic hepatitis delta; CSR: clinical study report; EASL: European Association for the Study of the Liver; EQ-5D: EuroQol (5 dimensions [EQ-5D-3L]); HDV: hepatitis delta virus; HIV: human immunodeficiency virus; LoD: law of detection; NA: nucleos(t)ide analogue; PCR: polymerase chain reaction; RNA: ribonucleic acid; ULN: upper limit of normal. Source : MYR 301 CSR (59).

B.2.3.1.2 Trial design

MYR 301 is an ongoing Phase 3 multicentre, open label, randomised clinical study evaluating the efficacy and safety of bulevirtide treatment (2 mg and 10 mg) in people with CHD, in comparison to delayed treatment. The dose regimen approved by the MHRA and under review in this submission, is bulevirtide 2 mg (8). The study design for MYR 301 is depicted in Figure 7.

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Figure 7: MYR 301 study design and dosing

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Key : BLV: bulevirtide; EOS: end of study; EOT: end of treatment; mg/d: milligrams per day. Notes : *Combined response is defined as undetectable HDV RNA or a ≥2-log10 IU/mL decline from baseline and ALT normalisation. Source : MYR 301 CSR (59).

Approximately 150 adult subjects with CHD were to be assessed to evaluate the efficacy and safety of bulevirtide, with the proportion of responders achieving a combined response after 48 weeks as the primary endpoint. A combined response was defined as the fulfilment of both of the following:

• Undetectable (< LoD) HDV RNA or decrease by ≥2-log10 IU/mL from baseline at Week 48

• ALT normalisation (ALT ≤ ULN regardless of baseline ALT level) at Week 48

Of note, ALT normalisation at Week 48 was defined as an ALT value within normal range as defined by each central lab based on their standard procedures. Normal ALT was defined as ≤ 31 U/L for females and ≤ 41 U/L for males for study sites in Russia. For all other sites, the normal ALT range was ≤ 34 U/L for females and ≤ 49 U/L for males (59).

Participants were randomly assigned to a treatment group in a 1:1:1 ratio, by means of an electronic randomization system, with stratification for the presence of liver cirrhosis. The three groups are described below:

• Group A : bulevirtide 10 mg/day for 96 weeks after an observational period of 48 weeks

• Group B : bulevirtide 2 mg/day for 144 weeks

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 Group C : bulevirtide 10 mg/day for 144 weeks

Last observation carried forward (LOCF) was used to impute missing values for the combined response if the missing value was related to COVID-19; otherwise, a missing equals failure approach was employed i.e., participants with a missing value were considered as non-responders. Subjects in the delayed bulevirtide arm received no treatment for hepatitis delta for the initial 48 weeks of the study in the observational period. Participants who had ongoing treatment with NAs for CHB were allowed to continue their treatment as prescribed in screening and during study participation. For participants with no ongoing treatment with NAs for CHB, treatment was to be initiated at the baseline visit or later if indicated, in accordance with the current EASL/AASLD guidelines (72,96). At Week 48, participants in the delayed bulevirtide arm were to be switched to bulevirtide 10 mg for 96 weeks (144 weeks of treatment in total). After Week 144, a follow-up period of 96 weeks (off-treatment) was also included for all treatment groups i.e., a total of 240 weeks (59).

The selection of doses in MYR 301 was based on results obtained at Week 24 in the MYR 202 study (59).

B.2.3.1.3 Eligibility criteria

The key inclusion and exclusion criteria for MYR 301 are described in Table 7.

Table 7: Key eligibility criteria for MYR 301

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Key : ALT: alanine aminotransferase; HCV: hepatitis C virus; HDV: hepatitis delta virus; HIV: human immunodeficiency virus; IFN: interferon; PCR: polymerase chain reaction; ULN: upper limit of normal. Source : Section 7.2, MYR 301 CSR (59).

For a full list of eligibility criteria please refer to the CSR (59).

Prospective participants were screened within 28 days before the baseline visit (day 1) to determine eligibility for participation in the study. Eligibility was determined by the following assessments:

• Inclusion/exclusion criteria

• Medical history

• Prior and concomitant therapy

• Weight, height, body mass index (BMI)

• Physical examination

• Vital signs include body temperature, heart rate, and blood pressure.

• 12-lead electrocardiogram (ECG)

• Abdominal ultrasound

• Transient elastometry (FibroScan[®] )

• Breath alcohol test

• Liver biopsy

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Liver biopsy had to be performed within ± 7 days from the date of the visit for participants who did not have medical contraindications for the procedure. If baseline liver biopsy samples were not available (were not provided to central laboratory or were considered as non-evaluable by central laboratory), subsequent liver biopsy was not to be performed.

B.2.3.1.4 Settings and locations where the data were collected

Subjects were randomised and treated with bulevirtide at 16 study sites: seven in Russia, five in Germany, three in Italy, and one in Sweden. Treatment and all study procedures were performed on an outpatient basis (except for hospitalisation for biopsy procedure, if required). Central laboratories were blinded to actual treatment allocation.

B.2.3.1.5 Trial drugs and concomitant medications

Bulevirtide

In MYR 301, the study drug was bulevirtide. This was provided as a lyophilised powder for single use in sterile vials of 5.0 or 2.0 mg/vial. The product was reconstituted in 1 ml water for injection prior to administration. The dosages of bulevirtide used in the study were 2 mg or 10 mg according to the treatment group randomly assigned. Participants randomised to the bulevirtide 10 mg treatment group were required to receive two injections of bulevirtide 5 mg daily for this dose level, compared with one injection daily for the bulevirtide 2 mg treatment group. Dose adjustments were not allowed in the study. Bulevirtide was administered by subjects at home, or by the healthcare professional at the site when the subject was attending a study centre visit.

Concomitant medication

Patients who received treatment with TDF or entecavir for chronic HBV infection were allowed to continue treatment as prescribed on screening and during study participation. Treatment with TDF or entecavir was provided to previously untreated patients with chronic HBV infection, if indicated in accordance with the current

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EASL/AASLD treatment guidelines (27,96), at a baseline visit or later in the study. Treatment with an NA was initiated if one of the following conditions was met:

• HBV DNA >2,000 IU/mL and ALT >ULN, or HBV DNA >2,000 IU/mL and at least moderate necroinflammation or fibrosis, or HBV DNA >2,000 IU/mL and ALT >ULN and at least moderate necroinflammation or fibrosis

• Liver cirrhosis with any detectable HBV DNA level

• Patients with HBV DNA >20,000 IU/ml and ALT >2x ULN should start treatment regardless of the degree of fibrosis

• Family history of cirrhosis or HCC

• Presence of extrahepatic manifestations

In patients in whom TDF was contraindicated, entecavir (tablets) was provided.

Restricted medication

Restricted medications included systemic glucocorticosteroids, immunomodulatory agents, and antiviral drugs for HBV and/or HDV treatment (apart from allowed NAs). For the full list of restricted medications, please see the CSR (58).

B.2.3.1.6 Outcomes used in the economic model or specified in the scope, including primary outcome

The primary efficacy endpoint to evaluate the efficacy of bulevirtide was the proportion of subjects achieving a combined response at Week 48. Combined response was defined as fulfilment of the following:

• Undetectable (< LoD) HDV RNA or decrease by ≥2-log10 IU/mL from baseline at Week 48

• ALT normalisation (ALT ≤ ULN regardless of baseline ALT level) at Week 48

As highlighted in Section B.1.3.2.2, a combined response was recommended by the FDA as the key surrogate endpoint able to provide evidence for both a decline in

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virologic replication, and an improvement in associated liver inflammation evident by a biochemical response (53).

Other secondary efficacy endpoints used to evaluate the optimal treatment duration of bulevirtide include:

• HDV RNA decrease by ≥2-log10 IU/mL from baseline to Week 48

• HDV RNA decrease by ≥2-log10 IU/mL or undetectable HDV RNA at Week 48

• Undetectable HDV RNA at Week 48

• ALT normalisation at Week 48

• Change from baseline in liver stiffness and histological activity at Week 48

The proportion of subjects with a sustained virologic response (defined as undetectable HDV RNA recorded at 24 weeks and 48 weeks after the scheduled end of treatment) will be assessed at study weeks 168 and 192 and therefore is not described in this submission.

Quality of life captured by the European Quality of Life 5 Dimensions 3 Level (EQ5D-3L) quality of life scale was an additional exploratory endpoint. However, as elaborated in Section B.2.6.1.2, the baseline EQ-5D-3L scores observed in MYR 301 were not affected by cirrhotic status. As such, the face validity of EQ-5D-3L data collected during MYR 301 may be questioned; further discussion around the EQ-5D3L data is provided in Section B.2.12.1.

Safety evaluations used to assess the safety of bulevirtide monitored the frequency and nature of AEs, based on the assessment of clinical events, physical examination, vital signs, ECG, and laboratory tests. Changes in vital signs, heart rate, and laboratory tests (haematology, coagulogram, biochemistry, blood bile salts, vitamin D) were all assessed.

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B.2.3.1.7 Patient datasets and baseline characteristics

Efficacy analyses were performed using the full analysis set (FAS), unless otherwise specified. The FAS comprised all participants either randomised to the delayed treatment group, or randomised to bulevirtide and who received bulevirtide at least once after randomisation. The safety population was the same as the FAS and is defined as all randomised patients who received at least one dose of bulevirtide (59). Safety data were analysed by treatment group according to the actual treatment received (not the randomised treatment).

It is worth noting that in MYR 301, a total of were excluded from the Week 48 per protocol analysis set (PPAS). were excluded from analysis in the delayed treatment arm, as had their visit for the primary endpoint (Week 48) performed outside the protocol-specified window (>14 days) and withdrew from the study due to pregnancy. Of the in the bulevirtide 2 mg treatment group excluded from the PPAS, had major protocol deviation where the study drug was administered incorrectly (categorised as a missed dose), and was withdrawn before Week 48 due to withdrawal of consent. Finally, in the

were excluded from were excluded from had their visit for the

bulevirtide 10 mg treatment group were excluded from the PPAS due to withdrawal of consent ( ), physician decision ( ), and the observation of a major protocol deviation where the assessment procedure was not performed (59).

A summary of the analysis sets is provided in Table 8.

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Table 8: Summary of MYR 301 datasets

Key : BLV: bulevirtide.

Notes : Percentages were based on the number of subjects within each treatment group. Source : Table 11, MYR 301 CSR (59).

Table 9 presents key demographic and baseline characteristics for the MYR 301 full analysis set. Demographic and baseline characteristics were generally similar among the three study groups.

The median age of all treated patients was years (range: years). In a retrospective study by Spaan et al. (2020), which analysed 107 patients with HBV/HDV coinfection attending an outpatient clinic in London, England, the median age of patients was observed to be 36.0 years (range: 16 to 61 years) (78). In the UK, the implementation of NICE clinical guideline CG165 likely results in an improved HDV diagnosis rate versus that seen in the locations used for data collection in MYR 301, namely Russia, Germany, Italy, and Sweden. As a result, the age of patients enrolled in the MYR 301 study may be slightly higher than what is observed in UK clinical practice.

The majority of patients were white (82.7%), and over half of participants were male (57.3%). Almost half of the subjects ( ) had cirrhosis at the time of enrolment, and of subjects had prior treatment with IFN-based therapy (59). UK clinical experts highlighted that most patients with CHD in the UK are offered a treatment course of IFN as per the NICE clinical guideline CG165 (72). These clinical experts were of the belief that the population enrolled in MYR 301 is broadly representative of the patients that they treat in UK clinical practice (31). Notably, in a UK-specific retrospective study conducted by Spaan et al . (2020), the median age was 36.0 years (78).

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Table 9: Patient demographics and baseline characteristics in MYR 301 (FAS)

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==> picture [452 x 422] intentionally omitted <==

----- Start of picture text -----
HDV Genotype 5 0 0 1 (2.0) 1 (0.7)
HBV Genotype, n (%)
Genotype A
Genotype D
Genotype E
No data
HBV DNA (log10 IU/mL)
n/nmiss
Mean (SD) 0.885 (0.989) 1.311 (1.300) 1.110 (1.263) 1.098 (1.194)
HDV DNA (log10 IU/mL)
n/nmiss
Mean (SD)
HBeAg Status, n (%)
Negative 47 (92.2) 45 (91.8) 43 (86.0) 135 (90.0)
HBsAg (log10 IU/mL)
n/nmiss
Mean (SD) 3.676 (0.465) 3.667 (0.511) 3.615 (0.575) 3.653 (0.516)
ALT (U/L)
Mean (SD)
Previous IFN- based therapy, n (%)
No
Yes
----- End of picture text -----

Key : ALT: alanine aminotransferase; BLV: bulevirtide; BMI: body mass index; HBeAg: hepatitis B e surface antigen: HBsAg: hepatitis b surface antigen; HBV: hepatitis B virus; HDV: hepatitis delta virus; IFN: interferon; IQR: interquartile range; n/nmiss: number of participants with evaluable/missing data; Q1: first quartile; Q3: third quartile.

Notes : Child-Pugh score and class are presented for cirrhotic patients only, with percentages based on the number of cirrhotic subjects. Assessments of liver fibrosis were performed only for those subjects who consented to undergo a liver biopsy at baseline and Week 48. Percentages were based on the number of subjects within each treatment group. Source : Tables 9 and 10, MYR 301 CSR (59).

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B.2.3.2 MYR 202

B.2.3.2.1 Trial methodology

Table 10: Summary of trial methodology for MYR 202

Key : ALT: alanine aminotransferase; BLV: bulevirtide; CHD: chronic hepatitis delta; CSR: clinical study report; HDV: hepatitis delta virus; RNA: ribonucleic acid; TDF: tenofovir; ULN: upper limit of normal. Source : MYR 202 CSR (58)

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B.2.3.2.2 Trial design

MYR 202 was a randomised, open-label, multicentre Phase 2 clinical study aiming to investigate the efficacy and safety of bulevirtide when administered in combination with TDF compared with TDF alone.

TDF is a highly effective inhibitor of HBV polymerase used to manage the patients underlying HBV infection. HDV usually supresses HBV replication (13), however there is a risk that as HDV is supressed, the suppression of HBV wanes and patients experience a rapid rise in HBV viral load leading to increasing liver damage (12). Therefore, it is important that, where treating patients with CHD, the patient is regularly assessed for concurrent HBV therapy. As a result, TDF was used as a concomitant treatment for subjects randomised into one of the bulevirtide treatment groups and is also used as a monotherapy in the comparator arm of the study.

MYR 202 studied patients with CHD and quantifiable HDV virus replication, including a proportion for whom previous treatment with IFN-based therapy failed or who were considered IFN-based therapy intolerant, as well as patients with compensated cirrhosis.

TDF was administered in all study groups A-D in doses according to the label for HBV infection (97). As described in the decision problem, in the absence of off-label IFN-based therapy, this ongoing treatment of the underlying hepatitis B infection where indicated is considered as BSC.

Eligible patients were randomly assigned to four treatment groups (randomisation ratio 1:1:1:1) stratified by the presence of liver cirrhosis (yes/no):

• Group A : bulevirtide 2 mg/day SC for 24 weeks + TDF, with an additional 24week follow-up period on Tenofovir treatment.

• Group B : bulevirtide 5 mg/day SC for 24 weeks +TDF, with an additional 24week follow-up period on tenofovir treatment.

• Group C : bulevirtide 10 mg/day SC for 24 weeks, with an additional 24-week follow-up period on TDF treatment.

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 Group D : TDF for 48 weeks.

Groups A, B and C received different doses of bulevirtide and TDF for 24 weeks, after which there was a follow-up period of 24 weeks with continued TDF treatment only. Patients from group D received TDF during both the treatment period of 24 weeks and during the follow-up period of 24 weeks. Upon the completion of the treatment period, patients entered a 24-week follow up period, resulting in a trial duration of 72 weeks (Figure 8).

During the study, patients in groups A, B and C injected bulevirtide SC once daily (dose dependent on group allocation) and administered TDF orally once daily. Patients allocated to group D received TDF orally once daily (Figure 8).

Figure 8: MYR 202 study design

==> picture [286 x 109] intentionally omitted <==

==> picture [286 x 108] intentionally omitted <==

Key : BLV: bulevirtide; d: day; HDV: hepatitis delta virus; EOS: end of study; RNA: ribonucleic acid; TDF: tenofovir. Notes : *HDV RNA response defined as a negative PCR result for HDV RNA or a ≥2-log10 IU/mL decline from baseline Source : MYR 202 CSR (58).

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B.2.3.2.3 Eligibility criteria

The key inclusion and exclusion criteria for MYR 202 are described in Table 11.

Table 11: Key eligibility criteria for MYR 202

Key Inclusion Criteria

Key Exclusion Criteria

• Age from 18 to 65 years at the time of ICF signature.

• Positive serum HBsAg for at least 6 months before screening.

• Positive serum anti-HDV antibody for at least 6 months before screening.

• Positive PCR results for serum HDV RNA at screening.

• Patients with liver cirrhosis, irrespective of previous IFN treatment*.

• Patients without liver cirrhosis, who failed prior IFN treatment or for whom, in the opinion of the investigator, is currently contraindicated (including history of IFN intolerance)**.

• ALT level >1 x ULN, but less than 10 x ULN.

• Child-Pugh score of B-C or over 6 points.

• Creatine clearance is <60ml/min

• HCV or HIV coinfection. Patients with anti-HCV antibodies can be enrolled, if screening HCV RNA test is negative.

• Use of IFNs within 30 days before screening.

• Malignant tumours in any organ system, including HCC, in the past or current history.

• Systemic connective-tissue diseases.

• Decompensated liver disease in the current or previous history.

Key : ALT: alanine aminotransferase; HBsAg: hepatitis B surface antigen; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HDV: hepatitis delta virus; HIV: human immunodeficiency virus; ICF: informed consent form; IFN: interferon; PCR: polymerase chain reaction; RNA: ribonucleic acid; ULN: upper limit of normal.

Notes : *Patients with liver cirrhosis could be included in case the interim analysis provided a positive safety assessment. The sponsor notified the centres on the results of the analysis and the permission to enrol cirrhotic patients. **Patients with previous interferon treatment could be enrolled only at least 20 days after the last interferon dose. Source : Section 9.3, MYR 202 CSR (58).

For a full list of eligibility criteria please refer to the CSR (58).

B.2.3.2.4 Settings and locations where the data were collected

In MYR 202, a total of 16 centres enrolled at least one subject. These centres were divided across Germany, which contributed four study centres, and Russia, who were responsible for the remaining 12 centres. Treatment and all study procedures were performed on an outpatient basis.

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B.2.3.2.5 Trial drugs and concomitant medications

Bulevirtide

In MYR 202, the study drug was bulevirtide. This was provided as a lyophilised powder for single use in sterile vials. The dosages of bulevirtide used in the study were 2, 5 or 10 mg according to the treatment group randomly assigned. Dose adjustment could be performed in groups B and C if a patient developed a study drug-related AE.

TDF

The reference product, TDF (VIREAD[®] ) was provided in the form of a film-coated tablet for oral administration The dosage of TDF used in the study was 254mg (tenofovir disoproxil 245mg, equivalent to tenofovir disoproxil fumarate 300mg).

Concomitant medications

Concomitant medications were allowed in the event of treatment-related AEs in either of the treatment arms.

The following concomitant treatments were prohibited:

• Systemic glucocorticosteroids

• Psychotropic agents, drugs, and psychoactive substances

The use of immunomodulatory agents and antiviral drugs, apart from TDF, had to be discussed with the medical monitor before treatment initiation.

B.2.3.2.6 Outcomes used in the economic model or specified in the scope, including primary outcome

The MYR 202 study assessed the efficacy and safety of bulevirtide (bulevirtide 2 mg, 5 mg, and 10 mg) in suppressing HDV replication in adults with CHD, in combination with TDF over 24 weeks when compared to TDF alone.

The study’s primary endpoint was:

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• HDV RNA response, defined as HDV RNA negativity or a reduction by ≥2log10 IU/mL from baseline to Week 24.

Key secondary endpoints included:

• Change from baseline in HDV RNA levels

• Changes in ALT values (defined as ALT values ≤ 31 U/L for female patients and ≤ 41 U/L for male patients) at treatment Week 24 and Week 48

• Combined response, defined as the achievement of an HDV RNA response (HDV RNA negativity or ≥2-log10 IU/mL decline) and normal ALT simultaneously at Week 24 and Week 48

• Lack of fibrosis progression based on transient elastometry (FibroScan[®] ) at Week 24

Safety was assessed throughout the study by the monitoring of adverse events (AEs), physical examinations, vital signs, 12-lead ECGs, development of antibulevirtide antibodies, and clinical laboratory tests (58).

B.2.3.2.7 Patient datasets and baseline characteristics

The baseline characteristics of patients in MYR 202 are shown in Table 12.

Table 12: Patient demographics and characteristics at baseline in MYR 202

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Key : ALT: alanine aminotransferase; BLV: bulevirtide; HDV: BMI: body mass index; hepatitis delta virus, IFN: interferon; RNA: ribonucleic acid.

Notes : Percentages are based on the number of participants within each treatment group. Source : Tables 13, MYR 202 CSR (58).

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B.2.4 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence

B.2.4.1 MYR 301

B.2.4.1.1 Analysis population

All analyses of the efficacy endpoints were performed using the FAS and the PPAS. If the randomised analysis set differed from the size of the FAS by more than 10%, the analysis of the primary efficacy variable was also to be performed on the randomised analysis set (59).

The analysis of safety was performed on the safety analysis set (SAS), defined as all participants randomised to delayed bulevirtide treatment or randomised to bulevirtide and who received bulevirtide at least once after randomisation (59).

B.2.4.1.2 Sample size

To account for the repeated analysis of response, the nominal 2-sided significance level of 0.05 was split among the 2 time points, with 0.01 for Week 24 leaving 0.04 for Week 48. At each time point, the bulevirtide doses were compared with delayed treatment in terms of a hierarchical testing procedure, starting with the higher dose at the respective adjusted 2-sided significance levels (59).

The expected response rates at Week 48 for the bulevirtide 2 mg and 10 mg doses were at least 45%. The conservative expectation for the delayed treatment response rates was 8% or less. These assumptions were based on results from the preceding Phase 2 MYR 202 study (59).

With a sample size of 47 participants per treatment group, a Fisher’s exact test with a 0.04 2-sided significance level had 97.8% power to detect this between the individual bulevirtide treatment groups and the delayed treatment group proportions. The power to reject both null hypotheses simultaneously was 95.6% (59).

The sample size was increased slightly to 50 subjects per treatment group to account for few potential early withdrawals before exposure. Hence, 150 participants were planned to be randomised (59).

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B.2.4.1.3 Statistical analysis

A summary of statistical analyses for MYR 301 is available in Table 13.

Table 13: Summary of statistical analyses: MYR 301

Key : ALT: alanine aminotransferase; BLV: bulevirtide; CI: confidence interval; HDV: hepatitis delta virus; LOCF: last observation carried forward; MEF: missing equals failure; RNA: ribonucleic acid. Source : MYR 301 CSR (59).

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Primary efficacy analysis

For the primary analysis, two-sided Fisher’s exact tests at an overall significance level of 0.05 were performed to compare the response rates for each treatment group. In terms of a hierarchical testing procedure, the second null hypothesis was not rejected if the first null hypothesis could not be rejected (59).

The primary efficacy endpoint was summarised using counts and percentages, together with a 95% exact (Clopper-Pearson) confidence interval (CI) for the true percentage (59).

Due to the expected low number of responders under delayed treatment, the analysis was not stratified by cirrhosis (yes/no) or other covariables (59).

Secondary efficacy analysis

For the key secondary endpoint, defined as undetectable HDV RNA at Week 48, the same 2-step approach as described for the primary endpoint was used. Two-sided Fisher’s exact tests were performed for each of the bulevirtide treatment groups compared with the control group of the delayed treatment. A hierarchical testing procedure was also used for this endpoint, where a two-sided Fisher test was only performed if both primary null hypotheses were rejected. To maintain control of the family-wise error rate, the same nominal levels of significance used for the primary analyses were also used (59).

The proportions of participants with ALT normalisation at Week 48 for each of the bulevirtide treatment groups were compared with the control group of delayed treatment using Fisher’s exact test. Exact unconditional CIs based on scores for the proportion differences were calculated, with corresponding CIs of 95% (59).

As the first and only baseline measurement for liver stiffness (as measured by elastography) occurred at Week 48, the main analysis of this endpoint was analysed using analysis of covariance without repeated measures (59).

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Subgroup analyses

All descriptive summaries of efficacy data were presented for the subgroups based on the presence of cirrhosis for both the FAS and PPAS (59).

Safety analyses

All evaluations of safety data were performed on the SAS (59).

B.2.4.1.4 Participant flow

Details of participant flow in MYR 301 are provided in Appendix D1.2.

B.2.4.2 MYR 202

B.2.4.2.1 Analysis population

The primary endpoint was analysed in the modified intention-to-Treat (mITT) set, defined as all randomised patients who received at least one dose of the study treatment. The data was also analysed in the Per Protocol (PP) population, which defined as a subset of mITT population completed the 24-week treatment period who had no major protocol violations (58).

Safety evaluation parameters were analysed in the safety analysis set, which was defined as all subjects who received at least one dose of the study medication in the bulevirtide groups or tenofovir in group of observation after randomisation (58).

B.2.4.2.2 Sample size

Using a two-sided test with a power of 80%, a significance level of �� = 0.05⁄3 ≈ 0.0167 (using Bonferroni correction to adjust for multiple testing; the three active treatment groups were tested separately against the control group), and a superiority limit (test margin) of 5%, a sample size of 28 patients per group was deemed sufficient to detect a 34% increase in response compared to the control group, assuming a response rate of 3% for the control group.

Assuming a drop-out rate of 5%, a total number of 30 patients per treatment group where needed (58).

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B.2.4.2.3 Statistical analysis

A summary of the statistical analyses for MYR 202 is available in Table 14.

Table 14: Summary of statistical analyses: MYR 202

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number of 30 patients per treatment group where needed.

Key : BLV: bulevirtide; CI: confidence interval; MEF: missing equals failure; mITT: modified intention-to-treat; TDF: tenofovir. Source : MYR 202 CSR (58).

Primary efficacy endpoint

Per protocol, the primary efficacy analysis was carried out when all bulevirtide - treated patients had completed the 24-week treatment period. One-sided continuitycorrected Wald tests for superiority, with the superiority limit set to 5%, were used to test null hypotheses of no clinically significant difference in the proportion of responders compared to the TDF only group at Week 24. Separate comparisons were made for each of the three bulevirtide treatment groups, and adjusted p-values were computed using the Bonferroni-Holm method (58).

As supportive analysis, Fisher’s exact test was used to test a null hypothesis of no difference in proportions of responders in a two-sided alternative hypothesis. Separate tests were performed for each of the three bulevirtide treatment groups against the TDF only group at Week 24 (58).

The primary efficacy endpoint was summarised using counts and percentages, together with a 95% exact (Clopper-Pearson) CI for the true percentage (58).

Secondary efficacy endpoints

For the analysis of secondary efficacy endpoints, van Elteren tests and Fisher’s exact tests were used to compare differences between bulevirtide in combination of TDF and TDF alone (58).

Safety analyses.

All evaluations of safety data were performed on the SAS (58).

B.2.4.2.4 Participant Flow

Details of participant flow in MYR 202 are provided in Appendix D1.2.

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B.2.5 Critical appraisal of the relevant clinical effectiveness evidence

The critical appraisal of MYR 301 and MYR 202 was conducted using the quality assessment tool developed by the University of York’s Centre for Reviews and Dissemination (CRD), as recommended by NICE (98). Full results are presented in appendix D1.3.

B.2.6 Clinical effectiveness results of the relevant studies

Summary of clinical effectiveness results

• The efficacy and safety of bulevirtide in the treatment of adults with CHD has been demonstrated in a pivotal multicentre, open-label, randomised MYR 301 trial.

• The MYR 301 population presented a group with particularly poor prognosis, with of patients cirrhotic at baseline, and having failed prior therapy with IFN.

• of the bulevirtide 2 mg treated participants achieved the primary

• efficacy endpoint of combined response at Week 48, compared with of participants in the delayed treatment group ( ).

• A subgroup analysis demonstrates that subjects naïve to treatment with IFN demonstrate a combined response consistent with those with prior IFN exposure, supporting consistency of response.

• The proportions of participants achieving HDV RNA response at Week 48 in the bulevirtide 2 mg treatment group was , compared with in the delayed treatment group ( ).

• The bulevirtide 2 mg treatment group achieved ALT normalisation in of participants, compared with of delayed treatment group participants ( ).

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• The efficacy and safety of bulevirtide in the treatment of adults with CHD was also investigated in a smaller multicentre, open-label, randomized MYR 202 trial, where HDV RNA response at Week 24 was observed in 53.6% of participants treated with bulevirtide 2 mg + TDF, compared to 3.6% of participants receiving TDF alone (p<0.0001).

B.2.6.1 MYR 301

Bulevirtide is indicated for adults with CHD who have compensated liver disease, and evidence of significant fibrosis (METAVIR stage greater than or equal to F2), whose disease has responded inadequately to IFN-based therapy, or who are ineligible to receive IFN-based therapy due to intolerance or contraindication.

As discussed in Section B.2.7, subgroup analyses based on prior IFN-based therapy suggests that the achievement of a combined response is consistent amongst IFNbased therapy naïve patients and those with prior IFN-based therapy exposure (99). IFN-based therapy has a different mechanism of action, and thus there is no clinically plausible reason why a patient treated with IFN-based therapy could not demonstrate a meaningful response after treatment with bulevirtide.

In addition, as outlined in Section B.2.12, due to the orphan nature of the disease (26), only 150 patients were recruited for the MYR 301 study, who were randomised in a 1:1:1 ratio to one of three treatment groups (~50 patient per arm). In view of the relatively small sample size, and consistency shown between subgroups, we present results of the full MYR 301 population in this submission. For further detail on how response differs by subgroup, please see Section B.2.7.

B.2.6.1.1 Results of primary outcome

The primary outcome of MYR 301 was a combined response at Week 48, as defined in Section B.2.3.1.6. As the bulevirtide marketing authorisation is for 2 mg bulevirtide dose, the data for the 10 mg arm are not summarised herein.

At Week 48, there was a statistically significant treatment effect for subjects receiving bulevirtide 2 mg compared with subjects in the delayed treatment group

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( ). The proportion of patients who achieved a combined response was ( subjects, 95% CI: ) in the bulevirtide 2 mg group, compared to ( subjects, 95% CI: ) in the delayed treatment arm (59).

At Week 24, the proportion of patients who achieved a combined response in the bulevirtide 2 mg treatment arm was 36.7% (18 of 49 subjects, 95% CI:

) (59). The observed increase in the proportion of responders from Week 24 to Week 48 is consistent with the mechanism of action of bulevirtide, which prevents the infection of new hepatocytes but does not inhibit virus production by cells infected prior to treatment initiation (see Section B.1.2). Thus, it is possible that, as infected hepatocytes continue to be cleared by the immune system alongside bulevirtide preventing the infection of new cells, the proportion of responders may increase further with continued treatment beyond Week 48. It is anticipated that longer-term data at Week 96 will become available in which will provide further evidence of the benefit of continued treatment with bulevirtide.

In addition, post-hoc analyses visualising the evolution of ALT improvement for patients showing a virologic response show

(see Figure 29, Appendix N).

30, Appendix N),

(see Figure (see

Figure 31, Appendix N) (100).

Furthermore, as the inclusion criteria for ALT level ranged between >1x ULN to 10x ULN, many patients may have experienced a significant benefit with bulevirtide but will not be classified as a responder to treatment. As demonstrated in Figure 29 and Figure 30 in Appendix N,

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(100).

In this regard, the continued improvement in ALT levels over time demonstrates an evolving level of response. Data collection is still ongoing with MYR 301, with 96week data expected to become available in .

Figure 9: Combined response at Weeks 24 and 48 (FAS; MYR 301)

==> picture [434 x 232] intentionally omitted <==

Key : BLV: bulevirtide; CI: confidence interval; FAS: full analysis set.

Notes : Mean data with error bars representing 95% CI are shown. Combined response was defined as undetectable HDV RNA (HDV RNA <LLoD, where LLoD=6 IU/mL) or decrease in HDV RNA by ≥2-log10 IU/mL from baseline, and ALT normalisation (defined as an ALT value within the normal range). Source : Table 14.2.1-1, MYR 301 CSR (59).

Similar results were obtained in the analysis of the combined response in the PPAS at Weeks 24 and 48, as a supportive analysis to the main FAS analysis. At Weeks 24 and 48, in the bulevirtide 2 mg group, ( subjects, 95% CI: ) and ( subjects, 95% CI: ) of participants, respectively, were responders, compared to no responders and ( subjects, 95% CI: ) of participants in the delayed treatment group. A statistically significant difference ( ) in the proportion of responders was observed between the bulevirtide 2 mg group and the delayed treatment group at both timepoints (59).

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B.2.6.1.2 Results of secondary and exploratory outcomes - HDV RNA decrease by ≥2 log10 IU/mL or undetectable HDV RNA at Week 48

A statistically significant difference was observed between the 2 mg bulevirtide treatment group and the delayed treatment arm ( ). Overall, of subjects ( subjects, 95% CI: ) in the bulevirtide 2 mg group achieved a virologic response at Week 48. Only of participants ( subjects, 95% CI: ) in the delayed treatment arm demonstrated a virologic response (59).

The consensus from the 2019 EASL-AASLD Conference was that a 2-log10 decrease in HDV RNA might suffice as a primary endpoint for clinical trials for a maintenance treatment for CHD (25). In MYR 301, viral response was defined as either of the following virologic parameters:

• HDV RNA decrease by ≥2-log10 IU/mL from baseline

• Undetectable HDV RNA

ALT normalisation at Week 48

Statistically significant differences in ALT normalisation were observed in the 2 mg bulevirtide treatment group at both Week 48 and Week 24 ( ) compared to the delayed treatment arm (59). ALT normalisation was achieved at Week 48 by

of participants ( subjects, 95% CI: ) in the bulevirtide 2 mg treatment group. Only of participants ( subjects, 95% CI: ) in the delayed treatment arm achieved ALT normalisation (Table 15) (59).

The proportion of participants demonstrating a response remained relatively constant across both treatment groups from Week 24 to Week 48. At Week 24, the proportion of participants demonstrating ALT normalisation was 53.1% (26 of 49 subjects, 95% CI: ) in the bulevirtide 2 mg treatment group, while only 5.9% (3 of 51 subjects, 95% CI: ) of participants in the delayed treatment arm achieved ALT normalisation (59).

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Table 15: ALT normalisation at Weeks 24 and 48 (FAS; MYR 301)

Key : ALT: alanine aminotransferase; BLV: bulevirtide; CI: confidence interval; FAS: full analysis set. Notes : A confidence level of 95% is used for within group CIs and for CIs in different proportions. Fisher’s exact tests were used for each comparison of BLV 2 mg and 10 mg versus delayed treatment using a significance level of 0.05. Source : Table 14.2.2.2-1, MYR 301 CSR (59).

- HDV RNA decrease by ≥2 log10 IU/mL at Week 48

At Week 48, the proportion of responders observed to have an HDV RNA decrease by ≥2-log10 IU/mL (>99%) from baseline increased to ( subjects, 95% CI: ) in the bulevirtide 2 mg group. No additional responders were observed in the delayed treatment arm (59).

An HDV RNA decrease by ≥2-log10 IU/mL from baseline at Week 24 was observed in 55.1% (27 of 49 subjects, 95% CI: ) of participants in the bulevirtide 2 mg treatment group. Only 3.9% (2 of 51 subjects, 95% CI: ) of participants in the delayed treatment arm achieved a ≥2-log10 IU/mL from baseline (Table 16) (59).

Table 16: HDV RNA decrease by ≥2-log10 IU/mL at Weeks 24 and 48 (FAS; MYR 301)

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Key : BLV: bulevirtide; CI: confidence interval; FAS: full analysis set; HDV: hepatitis delta virus; RNA: ribonucleic acid. Notes : A confidence level of 95% is used for within group CIs. For difference in proportions, the confidence level used is 99% for 24 weeks and 96% for week 48. Fisher’s exact tests were used for each comparison of BLV 10 mg versus BLV 2 mg and using a significance level of 0.05. Source : Table 14.2.3.3-1, MYR 301 CSR (59).

Undetectable HDV RNA at Week 48

There was a positive trend for the proportion of subjects experiencing undetectable HDV RNA from baseline to Week 48. The proportion of responders in the bulevirtide 2 mg group from Week 24 to Week 48. The proportion of responders with undetectable HDV RNA at Week 48 was ( subjects, 95% CI:

). There was no statistical difference between the proportion of responders with undetectable HDV RNA levels between the bulevirtide 2 mg group and the delayed treatment group (59).

At Week 24, the proportion of responders with undetectable HDV RNA was 6.1% (3 of 49 subjects, 95% CI: ) in the bulevirtide 2 mg treatment group. There was no statistically significant difference observed in HDV RNA undetectability between the active treatment group and the delayed treatment arm.

There were with undetectable HDV RNA in the delayed treatment group at any time point, including Week 48 (Table 17) (59). As highlighted in Section

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B.1.3.3, BSC, defined as ongoing treatment for underlying hepatitis B infection, does not have a meaningful effect on HDV RNA levels in patients with CHD (27).

Table 17: Undetectable HDV RNA at Weeks 24 and 48 (FAS; MYR 301)

Key : BLV: bulevirtide; CI: confidence interval; FAS: full analysis set. Notes : A confidence level of 95% is used for within group CIs. For difference in proportions, the confidence level used is 99% for 24 weeks and 96% for week 48. Fisher’s exact tests were used for each comparison of BLV 10 mg versus BLV 2 mg and using a significance level of 0.01 at Week 24. Source : Table 14.2.2.1-1, MYR 301 CSR (59).

Change from baseline in liver stiffness and histological activity at Week 48

FibroScan[®] assessment of liver stiffness acts as an early marker for evaluating the severity and prognosis of CHD, as the amount of liver fibrosis is correlated with the future risk of developing cirrhosis and liver-related complications (101).

At Week 48, the FibroScan[®] measurement of liver stiffness indicated that the bulevirtide 2 mg ( kPa) group had a decrease in liver stiffness from baseline. Conversely, subjects in the delayed treatment group ( kPa) experienced a significant increase in liver stiffness over 48 weeks ( ) (Table 18). A decrease in liver stiffness (measured by FibroScan[®] ) confirms an improvement in the clinical status of the participants treated with the licensed 2 mg dosage of bulevirtide. It can represent a decline in liver inflammation, as well as an improvement in liver fibrosis (59).

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Table 18: Liver stiffness (FibroScan[®] ) at Week 48 (FAS; MYR 301)

Key : BLV: bulevirtide; FAS: full analysis set; IQR: interquartile range; kPa: kilopascal; n/miss: number of subjects with evaluable/missing data; SD: standard deviation; Q1: first quartile; Q3: third quartile. Notes : Baseline is defined as the last valid evaluation prior to the first dose of study medication for bulevirtide 2 mg and last value before or at randomisation for the delayed treatment. Source : Table 14.2.2.3-3, MYR 301 CSR (59).

Aside from the liver stiffness measurements summarised above, assessments of liver fibrosis were performed only for those subjects who consented to undergo a liver biopsy at baseline and Week 48. For of 51 subjects ( ) in the delayed treatment group and of 49 participants ( ) in the bulevirtide 2 mg group, biopsy data were unavailable for these assessments and considered ‘missing’ (101).

In the subset of participants with available data, the percentage of subjects who experienced an improvement in METAVIR fibrosis stage was numerically higher in the bulevirtide 2 mg treatment group compared to the delayed treatment arm (Table 19) (101).

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Table 19: Change in METAVIR fibrosis stage to Week 48 (FAS; MYR 301)

Key : BLV: bulevirtide; FAS: full analysis set.

Notes : Percentages are based on the number of subjects within each treatment group with observed data. Percentage for ‘missing. Category is based on the number of subjects within each treatment group. Improvement is defined as a decrease of at least one point; worsening is defined as an increase of at least one point. Source : Table 14.2.3.1-1, MYR 301 CSR (59).

In addition, an exploratory sub-study of MYR 301 by Allweiss et al . (2021) took core liver biopsies from a subgroup of patients treated with bulevirtide at baseline and Week 48. The frequency of HDV antigen (HDAg) positive hepatocytes declined by median in the bulevirtide 2 mg treatment group, with subjects ( ) achieving an undetectable HDAg. A median increase in HDAg-positive hepatocytes of was observed in the delayed treatment group, with only subjects ( ) experiencing undetectable HDAg (80).

The amount of HDAg-positive hepatocytes strongly correlated with intrahepatic HDV RNA levels. At Week 48, a median decline in intrahepatic HDV RNA levels was observed in the bulevirtide 2 mg group, with subjects ( ) achieving undetectable HDV RNA. Such a strong reduction in intrahepatic HDV RNA levels further supports the novel mechanism of action of bulevirtide. In the delayed treatment group, a median intrahepatic HDV RNA increase of was observed, with participants ( ) achieving undetectable HDV RNA (80). Changes in host gene expression also correlated with HDV viral load. This indicates that the therapeutic reduction of HDV viral load also diminishes liver inflammation (80).

There is the possibility that responding to treatment may induce a regression in liver fibrosis and cirrhosis for those achieving a combined response, as has been observed upon NA treatment of HBV monoinfected patients (102). In a previous study in patients with hepatitis delta responding to PEG-IFN therapy, Farci et al . (2004) reported regression in four of six patients with sustained biochemical

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response. These patients had active cirrhosis in their first three liver biopsies and an absence of fibrosis in their last liver biopsy. The publication concluded that there was an association between fibrosis regression and a significant decrease in HDV viral load (103).

EQ-5D-3L at Week 48

A summary of the EQ-5D-3L data for the bulevirtide 2 mg group and the delayed treatment arm can be found in Table 20 and Table 21.

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Table 20: EQ-5D-3L evaluation summary by level and visit in the bulevirtide 2 mg group (FAS; MYR 301)

Key : BLV: bulevirtide; FAS: full analysis set.

Notes : Baseline is defined as the last valid evaluation prior to the first dose of study medication for bulevirtide 2 mg and 10 mg, and last value before or at randomisation for the delayed treatment. Percentages are based on the number of subjects within each treatment group. For the FAS, subjects are analysed as randomised (i.e., planned treatment).

Source : Tables 14.2.3.9-11, 14.2.3.9-17, 14.2.3.9-23, 14.2.3.9-29, and 14.2.3.9-35, MYR 301 CSR (59).

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Table 21: EQ-5D-3L evaluation summary by level and visit in the delayed treatment group (FAS; MYR 301)

Key : BLV: bulevirtide; FAS: full analysis set.

Notes : Baseline is defined as the last valid evaluation prior to the first dose of study medication for bulevirtide 2 mg and 10 mg, and last value before or at randomisation for the delayed treatment. Percentages are based on the number of subjects within each treatment group. For the FAS, subjects are analysed as randomised (i.e., planned treatment).

Source : Tables 14.2.3.9-11, 14.2.3.9-17, 14.2.3.9-23, 14.2.3.9-29, and 14.2.3.9-35, MYR 301 CSR (59).

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At Week 48, scores for the individual EQ-5D-3L domains, EuroQol Visual Analogue, fatigue severity scale, and Hepatitis Quality of Life Questionnaire™ (HQLQ) components were

==> picture [450 x 33] intentionally omitted <==

between the bulevirtide 2 mg treatment group compared with the delayed treatment group (59).

For the QoL analysis, although inferential statistics (p values) were presented, the results should be interpreted with caution as multiple endpoints were tested, and the study was not powered to test these exploratory endpoints (59).

Overall, a large proportion of evaluable subjects in the bulevirtide 2 mg group experienced no problems with mobility ( ), self-care ( ), or with the performance of usual activities ( ) at baseline. With regards to pain/discomfort, subjects ( ) in the bulevirtide 2 mg group reported some problems at baseline, which after treatment declined to subjects ( ) at Week 48. In contrast, within the delayed treatment group, the proportion of patients reporting some problems with pain/discomfort did not show a large decline from baseline to Week 48, changing from ( subjects) to ( subjects) of participants (59).

Similarly, subjects ( ) reported experiencing anxiety/depression at baseline in the bulevirtide 2 mg treatment arm, with reporting an extreme problem. By Week 48, only subjects ( ) in the bulevirtide 2 mg treatment arm experienced problems with anxiety/depression, with patients reporting extreme problems (59). However, the same magnitude of effect was not observed in the delayed treatment arm. A total of subjects ( ) in the delayed treatment arm reported some problems at baseline, which after treatment declined to subjects ( ) at Week 48. The proportion of patients experiencing extreme problems with anxiety/depression remained unchanged from baseline to Week 48 ( ) (59).

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Statistical analysis using the observed odds ratios (OR) for each of the five dimensions of EQ-5D-3L between the

delayed treatment group and the bulevirtide 2 mg treatment group at Week 48 (59).

The total mean VAS score was (range: ) at screening and increased over time, with higher mean score of (range: ) at Week 24, and (range: ) at Week 48. At Week 48, the largest increase in mean VAS score was found in the bulevirtide 2 mg group (mean score of , range: ), while the delayed treatment group had a mean increase from baseline of (range: ) (Figure 10) (59).

Figure 10: Mean VAS score (FAS; MYR 301)

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Key : BLV: bulevirtide; FAS: full analysis set; VAS: visual analogue scale.

Notes : Scale represents point score value (0-100), where 0=worst health state and 100=best health state) on the visual analogue scale.

Source : Table 14.2.3.9-43, MYR 301 CSR (59).

Given the general scarcity of quantitative data on health utilities for patients with HDV, it is important to assess the utility values reported in the MYR 301 clinical trial to evaluate their validity. The EQ-5D-3L data collected at baseline in this study indicated that disease EQ-5D-3L scores did not differ by cirrhosis status; patients with no cirrhosis at baseline had an EQ-5D-3L score of , compared to for patients with cirrhosis at baseline (59). Clinical experts confirmed that a difference of just was an unexpected result (31). As highlighted in Section B.1.3.2, people with HDV and cirrhosis have a greater risk for liver-related events than those without cirrhosis (see Figure 3) (38).

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Furthermore, these findings are inconsistent with previous research that indicates cirrhosis negatively affects patients’ HRQoL. A study in HBV infected patients in Canada reported EQ-5D-3L utility values of 0.920 and 0.880 in patients without and with compensated liver cirrhosis respectively (104), while a study in China also reported a higher EQ-5D-3L utility value for patients without liver cirrhosis (0.800) versus patients with compensated liver cirrhosis (0.700) (105). Similarly, a metaanalysis of patients with HCV infection reported EQ-5D-3L values of 0.829 and 0.717 for patients with and without compensated liver cirrhosis, respectively (106).

B.2.6.2 MYR 202

MYR 202 was a dose ranging Phase 2 study which assessed the efficacy and safety of bulevirtide (2, 5, or 10 mg) in supressing HDV replication in adults with CHD, in combination with TDF over 24 weeks compared to TDF alone. Efficacy data for the bulevirtide 2 mg treatment and TDF monotherapy treatment arms are summarised herein. Note however, that solely the 2 mg dose has marketing authorisation.

B.2.6.2.1 Results of primary outcome

A significant HDV RNA response was observed in 53.6% (15 of 28 subjects, 95% CI: 33.9%, 72.5%) of participants treated in the bulevirtide 2 mg + TDF treatment group (p<0.0001). No substantial HDV RNA response was observed in the TDF treatment arm, with only 3.6% (1 of 28 subjects, 95% CI: 0.1%, 18.3%) of participants achieving the primary endpoint (Figure 11) (58).

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Figure 11: HDV RNA response at Week 24 (mITT)

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Key : BLV: bulevirtide; CI: confidence interval; HDV: hepatitis delta virus; mITT: modified intention-to-treat; RNA: ribonucleic acid; TDF: tenofovir.

Notes : Error bars representing 95% CI are shown. HDV RNA response was defined as a negative PCR result of HDV RNA (undetectable HDV RNA or a ≥2-log10 IU/mL decline from baseline to Week 24. Source : Table 16, MYR 202 CSR (58).

B.2.6.2.2 Results of relevant secondary outcomes

Change from Baseline in HDV RNA Levels at Week 24 and Week 48

A significant mean decline in HDV RNA levels from baseline of -1.918 log10 IU/mL was observed in the bulevirtide 2 mg + TDF treatment group (p<0.0001), while no significant decline in HDV RNA level was seen in the TDF monotherapy group (58).

After treatment cessation with bulevirtide, mean HDV RNA rebounded to baseline values by Week 48 (Figure 12; Table 22). As demonstrated in Section B.2.6.1, the continuation of bulevirtide treatment beyond 24 weeks is associated with an increasing number of virologic responders. Given the increase in responder rate, the optimal treatment duration of bulevirtide monotherapy may exceed 48 weeks (58), with the current bulevirtide licence stating that ‘treatment should be continued as long as associated with clinical benefit.’

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Table 22: Summary statistics on log-10 transformed HDV RNA levels (mITT)

Key : BLV: bulevirtide; CfB: change from baseline; HDV: hepatitis delta virus; RNA: ribonucleic acid. Notes : Baseline is defined as the last valid evaluation prior to the first dose of study medication. Source : Table 19, MYR 202 CSR (58).

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Figure 12: Mean log10 transformed HDV RNA levels over time

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Key : HDV: hepatitis delta virus; mITT: modified intention-to-treat; MXB, myrcludex B (now known as bulevirtide); PPAS: per protocol analysis set; RNA: ribonucleic acid. Notes: (A) Changes in mean log10 transformed HDV RNA levels from baseline to Week 48 in the mITT analysis set. (B) Changes in mean log10 transformed HDV RNA levels from baseline to Week 48 in the PPAS. Source : Figures 14.2.2.1 and 14.2.2.2 (58).

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Combined response at Week 24 and Week 48

At Week 24, the proportion of patients with a combined response was significantly higher in the bulevirtide 2 mg + TDF treatment group versus the TDF monotherapy arm. At the end of treatment, 21.4% (6 of 28 subjects, 95% CI: 8.3%, 41.0%) of participants in the bulevirtide 2 mg + TDF treatment group achieved a combined response. No case of combined response was observed in the TDF monotherapy group at Week 24 (Figure 13) (58).

Furthermore, 28.1% (9 of 32 subjects, 95% CI: 13.7%, 46.7%) of participants achieved a combined response in the bulevirtide 5 mg + TDF treatment arm, while 36.7% (11 of 30 subjects, 95% CI: 19.9%, 56.1%) of participants demonstrated a combined response in the bulevirtide 10 mg + TDF treatment cohort (Figure 13) (58).

Figure 13: Combined response at Weeks 24 and 48 (mITT)

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Key : BLV: bulevirtide; CI: confidence interval; HDV: hepatitis delta virus; mITT: modified intention-to-treat; RNA: ribonucleic acid; TDF: tenofovir.

Notes : Percentages are based on the number of participants within each treatment group. Error bars representing 95% CI are shown. Combined response was defined as an HDV RNA response (undetectable HDV RNA or a ≥2-log10 IU/mL decline from baseline) and ALT normalisation. Source : Table 25, MYR 202 CSR (58).

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Change in ALT values at Week 24 and Week 48

After 24 weeks of treatment, a significantly higher proportion of patients treated with bulevirtide 2 mg + TDF had normal ALT levels compared to patients receiving TDF monotherapy (p<0.005). Normal ALT levels were achieved by 42.9% (12 of 28 subjects, 95% CI: 24.5%, 62.8%) of participants, while only 7.1% (2 of 28 subjects, 95% CI: 0.9%, 23.5%) of subjects in the TDF monotherapy group demonstrated achieved normal ALT levels (58).

By Week 48, at 24 weeks post-treatment discontinuation, there was no significant difference in the proportion of patients with normal ALT levels between the

bulevirtide 2 mg + TDF treatment group and the TDF monotherapy arm (p>0.05). In the bulevirtide 2 mg + TDF treatment group, the proportion of subjects with normal ALT levels had reduced to 14.3% (4 of 28 subjects, 95% CI: 4.0%, 32.7%). On the other hand, the TDF monotherapy group demonstrated a small increase in ALT response, with 14.3% (4 of 28 subjects, 95% CI: 4.0%, 32.7%) of participants achieving ALT normalisation (58).

An equally high level of response at Week 24 was observed across the bulevirtide 5 mg + TDF and bulevirtide 10 mg + TDF treatment groups, with normalised ALT achieved in 50.0% (16 of 32 subjects, 95% CI: 31.9%, 68.1%) and 40.0% (95% CI: 22.7%, 59.4%) of subjects respectively. At Week 48, 24 weeks post-treatment discontinuation, no significant difference in the proportion of patients with normal ALT values between the treatment groups was demonstrated (p<0.005). The level of response in the bulevirtide 5 mg + TDF and bulevirtide 10 mg + TDF also reduced to 3.1% (1 of 32 subjects, 95% CI: 0.1%, 16.2%) and 10.0% (3 of 30 subjects, 95% CI: 2.1%, 26.5%) respectively (58).

Lack of fibrosis progression based on transient elastometry (FibroScan®) at Week 24

At Week 24, larger mean decreases in liver stiffness were observed in all bulevirtide groups compared to the TDF only group. The mean change from baseline at Week

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24 for BLV 2 mg + TDF was -2.85 ± 2.65 kPa compared to -0.78 ± 3.17 kPa for TDF only (58).

Table 23: Mean change in liver stiffness (FibroScan[®] ) from baseline (mITT; MYR 202)

Key : BLV: bulevirtide; CI: confidence interval; kPa: kilopascals; mITT: modified intention-to-treat; SD: standard deviation; TDF: tenofovir.

Source : Table 14.2.9.1, MYR 202 CSR (58).

B.2.6.3 Summary of results

The efficacy and safety of bulevirtide for the treatment of adults with CHD was investigated in the multicentre, open-label, randomised pivotal Phase 3 MYR 301 trial, as well as the supporting MYR 202 clinical study.

The MYR 301 population represented a group with particularly poor prognosis, with of patients cirrhotic at baseline, and having failed prior therapy with IFN-based therapy (59). Clinical experts suggested that the baseline characteristics observed were generalisable to patients currently seen in UK clinical practice (31). However, in a 2020 retrospective study, Spaan et al . found a lower median age of 36.0 years in a UK population (78).

Overall, of patients in the bulevirtide 2 mg treatment group achieved a combined response at Week 48, compared to just in the delayed treatment arm ( ) (59). Data from previous studies suggests that patients achieving undetectable HDV RNA or a ≥2-log10 decline in HDV RNA levels, and ALT

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normalisation, are at a reduced risk of developing complications of liver disease, such as HCC, cirrhosis, decompensation, and death (20,35,36,61).

The combined response composite endpoint sets a high bar for level of response, given it requires the fulfilment of two surrogate outcomes. When analysing the individual components of the combined response, of patients in the bulevirtide 2 mg treatment group achieved undetectable HDV RNA or a ≥2-log10 decline in HDV RNA levels at Week 48, compared to just in the delayed treatment arm ( ). With regards to ALT normalisation, of subjects achieved normal ALT levels at Week 48, compared to in the delayed treatment arm ( ) (59). In patients who demonstrated a >2-log10 reduction in HDV RNA, but failed to achieve the combined endpoint,

Figure 29). N; Figure 30),

(see Appendix N; (see Appendix (107). By

also taking into account the innovative mechanism of action of bulevirtide, the proportion of responders is predicted to increase further beyond Week 48. In this regard, data collection is still ongoing with MYR 301, with 96-week data expected to become available in .

Furthermore, at Week 48, the FibroScan[®] measurement of liver stiffness indicated that the bulevirtide 2 mg ( kPa) group had a significant decrease in liver stiffness from baseline compared to the delayed treatment group ( kPa) (59). In addition, an exploratory substudy of MYR 301 found that there was a strong correlation between HDV RNA and HDAg levels, which demonstrates that the number of infected hepatocytes reduced (80). As established by Farci et al . (2004), there is an association between fibrosis regression and a significant decrease in HDV viral load (103), which would suggest that patients responding to bulevirtide could experience an improvement in fibrosis and cirrhosis.

The multicentre, open-label, randomised supporting Phase 2 MYR 202 study further supports the efficacy and safety of bulevirtide, albeit over a shorter 24-week

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treatment period. Similar to MYR 301, the MYR 202 population represented a group with a poor prognosis, with 50.0% of patients cirrhotic at baseline, and 56.8% having failed prior IFN-based therapy (58).

The MYR 202 study assessed the efficacy and safety of bulevirtide in suppressing HDV replication in adults with CHD, in combination with TDF, over a shorter 24-week treatment period. The trial achieved its primary endpoint of an HDV RNA response at Week 24, which was observed in 53.6% of participants treated with bulevirtide 2 mg + TDF, compared to 3.6% of participants receiving TDF alone. Furthermore, treatment with bulevirtide 2 mg + TDF was associated with a statistically significantly higher proportion of participants achieving a combined response at Week 24 compared to TDF monotherapy (58).

In summary, bulevirtide has demonstrated unprecedented efficacy in a population of adults with CHD with compensated liver disease. Evidence from the MYR 301 and MYR 202 clinical studies demonstrates that treatment with bulevirtide results in a greater proportion of individuals achieving a combined response, HDV RNA decline or suppression, and ALT normalisation, compared to BSC or delayed treatment. The proposed population highlighted in the decision problem currently has no existing treatment options. Thus, as the only approved treatment for CHD, bulevirtide represents an important therapeutic option to address the rapid progression of the disease in this population and reduce the risk of developing severe liver-related complications including cirrhosis, HCC, decompensation and death.

B.2.7 Subgroup analysis

A pre-planned subgroup analysis of virologic and biochemical response was defined to greater characterise patient populations for whom bulevirtide could provide the greatest benefit. These endpoints were analysed in the same manner as the primary efficacy endpoint. The subgroups analysed were:

• People with cirrhosis (METAVIR fibrosis stage F4).

• People without cirrhosis (METAVIR fibrosis stage F0-F3).

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The proportion of patients demonstrating a combined response was consistent amongst patients with and without cirrhosis (59). At Week 48, of 23 subjects ( ) with cirrhosis showed a combined response, compared with of 24 subjects ( ) in the delayed treatment arm ( ). Similarly, of 26 subjects ( ) without cirrhosis also demonstrated a combined response, while of the 27 subjects without cirrhosis in the delayed treatment arm showed a combined response to treatment ( ) (See Table 82; Appendix E) (59).

Given the proposed positioning of bulevirtide, a post-hoc subgroup analysis was undertaken to greater characterize whether prior treatment with IFN-based therapy impacts response to bulevirtide. This subgroup was defined based on data from prior medication for which the preferred name includes the word ‘interferon’. The list of medications satisfying this condition are as follows:

• Peginterferon alfa-2a

• Peginterferon alfa-2b

• Interferon alfa-2b

• Interferon alpha

• Peginterferon

• Interferon

• Cepeginterferon alfa-2b

• Interferon alfa-2a

• Interferon beta-1b

Subgroup analyses suggests that the achievement of a combined response is consistent amongst IFN-based therapy naïve patients and those with prior IFNbased therapy exposure (99). At Week 48, subjects ( ) naïve to IFNbased therapy demonstrated a combined response, in comparison to

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subjects ( ) who had experienced prior IFN treatment. In the delayed treatment arm, only patients ( ) who experienced prior IFN-based therapy demonstrated a combined response, in comparison to no subjects in the IFN-based therapy-naïve subgroup (Table 83; Appendix E) (59). As highlighted in Section B.2.6.1, there was not expected to be any difference in the proportion of responders between the two subgroups, given that IFN-based therapy has a different mechanism of action to bulevirtide.

Results of the subgroup analyses are presented in Appendix E.

B.2.8 Meta-analysis

The objective of the meta-analysis was to conduct a relative efficacy and safety comparison of bulevirtide 2 mg monotherapy versus BSC or relevant comparators for CHD treatment (108).

A total of 19 studies from 63 publications were included in the SLR. Across these 19 studies, two studies evaluated bulevirtide 2mg as monotherapy, and one study each evaluated bulevirtide 2 mg in combination with TDF or PEG-IFN. For methods and results of the SLR, please refer to Appendix D1.1.

A comparison of bulevirtide 2 mg, either as a monotherapy or in combination with TDF, is available from the pivotal Phase 3 MYR 301 and Phase 2 MYR 202 clinical studies. MYR 301 compared bulevirtide 2 mg versus delayed treatment, while MYR 202 compared bulevirtide in combination with TDF against TDF alone. As highlighted in Section B.2.3.2, TDF is classified as an NA, and is recommended to manage the patients underlying HBV infection (13). NAs are commonly used medications in hepatitis D, as highlighted in the MYR 301 study, whereby 60.0% of patients

received concomitant antiviral treatment (69). The efficacy of TDF monotherapy and delayed treatment is assumed to be similar. Hence, these are marked under one treatment group, termed NA therapy (NAT; referred to previously as NA throughout the submission), in the forthcoming figures to form a comparator for meta-analysis (108).

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The DMA was performed using the Sidak–Jonkman [random effect] and MantelHaenszel methods [fixed effect] using Stata 17 (Version 17.0, StataCorp, College Station, Texas 77845 USA) (108).

Although we present the results of the DMA compared to NAs, this does not inform the economic model. Instead, data from the pivotal MYR 301 study was used in the economic analyses to inform the relative efficacy and safety of bulevirtide versus BSC. The economic model includes an extrapolation of clinical response data beyond the trial observation period, therefore use of the MYR 301 data ensured consistency of outcomes between different timepoints and between bulevirtide and BSC. Furthermore, whilst figures were generated based on the original NMA report and thus include reference to PEG-IFN, the text focuses on the comparison with BSC as this is relevant for the submission (108).

Further detail on the methodology and results of the DMA can be found in the accompanying NMA report (108).

B.2.8.1 Feasibility assessment

A feasibility assessment study for indirect comparisons of bulevirtide versus BSC was conducted. Table 24 presents the list of studies included in for the DMA basecase analyses (108).

Table 24: List of studies included in the DMA base-case

Key : BLV: bulevirtide; mg: milligram; NA: nucleos(t)ide analogue; µg: microgram; PO: per oral; SC: subcutaneous; TDF: tenofovir; WK: weekly.

Source : Adapted from Table 7, NMA report (108).

Table 25 highlights the differences across certain baseline characteristics collected in each of the studies confirmed in the DMA base-case analyses. Low heterogeneity was observed across the patient characteristics for MYR 202 and MYR 301 (108).

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Table 25: Patient characteristics of studies considered for DMA base-case

Key : ALT: alanine aminotransferase; HDV: hepatitis delta virus; IFN: interferon; RNA: ribonucleic acid. Source : Appendix B – feasibility assessment slides, NMA report (108).

B.2.8.2 Outcomes selected and assessed for analysis

The report of key outcomes at Week 48 in the included studies is summarised below in Table 26.

Table 26: Summary of outcomes reported across included studies at Week 48

Key : AE: adverse event; ALT: Alanine aminotransferase; HDV: hepatitis delta virus; mg: milligram; RNA: ribonucleic acid; SAE: serious adverse event

Notes : *≥2-log10 HDV RNA decline or undetectable;[T] TDF treatment in all arms for 24 weeks.

Source : Adapted from Table 10, NMA report (108).

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B.2.8.3 Results

B.2.8.3.1 Combined response at Week 48

A statistically higher proportion of patients treated with bulevirtide 2 mg experienced a combined response compared to NA monotherapy [OR: using SidikJonkman model; OR: using Mantel-Haenszel model] (Figure 14) (108).

Figure 14: Summary plot of meta-analysis for combined response at Week 48

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Key : BLV: bulevirtide; CI: confidence interval; DT: delayed treatment; mg: milligram; OR: odds ratio; TDF: tenofovir. Notes : In MYR 202, patients received bulevirtide for 24 weeks only, after which all treatment arms received TDF for 24 weeks. Source : Adapted from NMA report (108).

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B.2.8.3.2 Undetectable HDV RNA or reduction (≥2-log10) at Week 48

At Week 48, bulevirtide showed statistically better results compared to NAs [OR: using Sidik-Jonkman model; OR: using Mantel-Haenszel model] (Figure

15. (108).

Figure 15: Summary plot of meta-analysis for undetectable HDV RNA or reduction (≥2-log10) at Week 48

==> picture [481 x 306] intentionally omitted <==

Key : BLV: bulevirtide; CI: confidence interval; DT: delayed treatment; HDV: hepatitis delta virus; mg: milligram; OR: odds ratio; RNA: ribonucleic acid; TDF: tenofovir. Notes : In MYR 202, patients received bulevirtide for 24 weeks only, after which all treatment arms received TDF for 24 weeks. Source : Adapted from NMA report (108).

B.2.8.3.3 ALT normalisation at Week 48

At Week 48, a statistically significantly greater proportion of patients treated with bulevirtide 2 mg experienced ALT normalisation compared to NA treatment [OR: using Mantel-Haenszel model]. While the direction of the results for the SidikJonkman model was aligned to the results of the Mantel-Haenszel model, statistical significance was not reached [OR: using Sidik-Jonkman model] (Figure 16) (108).

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Figure 16: Summary plot of meta-analysis for ALT normalisation at Week 48

==> picture [475 x 321] intentionally omitted <==

Key : ALT: alanine aminotransferase; BLV: bulevirtide; CI: confidence interval; DT: delayed treatment; mg: milligram; OR: odds ratio; TDF: tenofovir.

Notes : In MYR 202, patients received bulevirtide for 24 weeks only, after which all treatment arms received TDF for 24 weeks. Source : Adapted from NMA report (108).

B.2.8.4 Conclusions

Overall bulevirtide 2mg monotherapy has statistically significantly better efficacy than

NA monotherapy in terms of the combined response (ALT normalisation and HDV RNA loss or ≥2-log10 reduction), HDV RNA response, and ALT normalisation at Week 48.

B.2.9 Indirect and mixed treatment comparisons

Not applicable.

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B.2.10 Adverse reactions

B.2.10.1 MYR 301

The safety and tolerability of bulevirtide for the treatment of adult CHD was evaluated as a secondary outcome in MYR 301. The SAS included all patients randomised to the delayed treatment group, or randomised to bulevirtide and received bulevirtide at least once after randomisation. AEs were coded with the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 (59).

A total of 150 subjects were enrolled for the Phase 3 MYR 301 study, of which 99 participants received at least one dose of bulevirtide. The remaining 51 participants randomised to the delayed treatment group did not receive bulevirtide before the data cut--off date for the Week 48 primary endpoint analysis. Few doses of the study drug were missed across both treatment groups (Table 27). The mean (SD) rate of compliance for bulevirtide up to Week 48 was similar for both active treatment arms: ( ) in the bulevirtide 2 mg group and ( ) in the bulevirtide 10 mg treatment group. There were some recorded protocol deviations related to treatment compliance, which have been previously described in Section B.2.4.1. The mean (SD) duration of treatment across the bulevirtide 2 mg and bulevirtide 10 mg treatment groups was ( ) weeks and ( ) weeks, respectively (59).

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Table 27: Missed doses of bulevirtide at Week 48 (SAS; MYR 301)

Key : BLV: bulevirtide; IQR: interquartile range; Q1: first quartile; Q3: third quartile; SAS: safety analysis set; SD: standard deviation. Notes : For the SAS, participants were analysed as treated (i.e., actual treatment). For one participant, number and proportion of missed doses are set to missing as discovery date was several months after expected Week 24 date. Source : Table 29, MYR 301 CSR (59).

B.2.10.1.1 Summary of adverse events

In total, treatment emergent adverse events (TEAEs) were reported in subjects ( ) during the first 48 weeks of the MYR 301 study, with TEAEs reported in participants ( ) in the bulevirtide 2 mg treatment group, less than the number seen in the bulevirtide 10mg group ( TEAEs in subjects). TEAEs related to bulevirtide were recorded in subjects ( ) in the bulevirtide 2 mg treatment group, compared to subjects ( ) in the bulevirtide 10 mg treatment arm. Adverse events were graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5 (109). Overall, the majority of TEAEs were Grade 1 (mild) or Grade 2 (moderate) in severity. A similar percentage of participants in each treatment group experienced any TEAEs Grade 3 or higher. No deaths occurred and there were no TEAEs reported which led to withdrawal from the study (59).

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Table 28: Overview of AEs (SAS; MYR 301)

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----- Start of picture text -----
Delayed BLV 2mg BLV 10mg Total
Treatment (n=150)
(n=49) (n=50)
(n=51)
Total number of AEs, n
Any AE, n (%)
Any TEAE, n (%)
Any serious TEAE, n (%)
Any TEAE leading to the
withdrawal of the study
medication, n (%)
Any TEAE leading to death,
n (%)
TEAE by severity, n (%)
Grade 1 (mild)
Grade 2 (moderate)
Grade 3 (severe)
Grade 4 (life-threatening or
disabling)
Grade 5 (death)
TEAE by causality, n (%)
Reasonable possibility
No reasonable possibility
Not applicable
----- End of picture text -----

Key : AE: adverse event; BLV: bulevirtide; TDF: TEAE: treatment emergent adverse event; SAS: safety analysis set. Notes : AEs were coded according to MedDRA Version 24.0. TEAEs began on or after the drug start up date up to 30 days after permanent discontinuation of the study drug, or led to premature study drug discontinuation. For the delayed treatment group, TEAEs began on or after the randomisation date up to the Week 48 visit date, or up to study discontinuation date if discontinued study before the Week 48 visit.

Source : Table 30, MYR 301 CSR (59).

B.2.10.1.2 Common adverse events

TEAEs that occurred in ≥5% of participants across any treatment group in the SAS are summarised in Table 29 (59).

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Table 29: AEs in ≥5% of patients in any treatment group (SAS; MYR 301)

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----- Start of picture text -----
AE by Preferred Term Delayed BLV 2mg BLV 10mg
Treatment (n=49) (n=50)
(n=51)
Subjects with any TEAE, n (%)
Vitamin D deficiency
Leukopenia
Thrombocytopenia
Headache
Pruritus
Fatigue
Lymphopenia
Neutropenia
Nausea
Eosinophilia
ALT increased
Anaemia
Arthralgia
Abdominal pain upper
Injection site reaction
Proteinuria
Nasopharyngitis
Injection site erythema
Asthenia
Abdominal pain
Injection site pruritus
AST increased
Injection site swelling
Sleep disorder
Hypertension
Bradycardia
----- End of picture text -----

Key : AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BLV: bulevirtide; SAS: safety analysis set; TEAE: treatment emergent adverse event.

Notes : Percentages are based on the number of participants treated with BLV. Source : Table 31, MYR 301 CSR (59).

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The most common Grade 3 TEAEs, experienced in >1 patient across the treatment groups, were and . was observed

in subjects ( ) subjects in the delayed treatment arm, subjects ( ) in the bulevirtide 2 mg treatment group, and subjects ( ) in the bulevirtide 10 mg treatment arm. was observed in the delayed treatment arm and bulevirtide 10 mg treatment group in subjects ( ) and

participants ( ) ) respectively. No Grade 4 TEAEs were recorded across the study groups (59).

B.2.10.1.3 Summary of serious adverse events

A similar percentage of participants experienced a serious adverse event (SAE) across each treatment group (Table 30). SAEs were observed in ( ) in the bulevirtide 10 mg and delayed treatment arms, and in ( ) within the bulevirtide 2 mg treatment arm. None of the SAEs were considered related to the study drug by investigators (59).

There were no SAEs reported for >1 participant in any of the treatment groups. participants experienced more than one SAE: in the delayed treatment group experienced and , and in the bulevirtide 2 mg treatment group experienced and (59).

Table 30: SAEs reported across any treatment group (SAS; MYR 301)

Key : BLV: bulevirtide; SAE: serious adverse event; SAS: safety analysis set. Notes : Percentages are based on the number of participants within each treatment group. Source : Table 33, MYR 301 CSR (59).

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B.2.10.1.4 Adverse events of special interest

The preferred terms for the AEs of interest were defined by selecting relevant preferred terms based on MedDRA Version 24.0 (59).

Increased bile salts

Bile salt elevations are mechanistically due to the binding of the NTCP receptor by bulevirtide. Per the study protocol, if an increase of total bile salts above ULN was both asymptomatic and judged by the investigator to be clinically insignificant, it was not reported as an AE, which was the case for the vast majority of bile salt increases over 48 weeks. Bile salts have been reported in the literature to be associated with skin conditions. Due to the effect of bulevirtide on increasing levels of bile salts, particular attention was paid to skin disorders, and the anaphylactic/anaphylactoid response. No participants experienced an anaphylactic reaction or anaphylactoid response. Whilst the bile salt levels in the bulevirtide 10 mg group were higher than the bulevirtide 2 mg group as expected, there was no clear correlation between the presence of pruritus and the levels of bile salts in either the bulevirtide 2 mg or bulevirtide 10 mg dose (59).

Hepatic Safety

In the MYR 301 SAS, potential hepatic flare AEs were experienced by a similar percentage of participants in the delayed treatment group ( ), the bulevirtide 2 mg treatment group ( ), and the bulevirtide 10 mg treatment group ( ). All potential hepatic flare AEs were

Grade 1 or Grade 2 in severity, and none resulted in discontinuation of the study drug (59).

The AEs meeting the definition of potential hepatic flare by treatment group were as follows:

 Delayed treatment group : ALT and aspartate aminotransferase (AST) increased ( ); and gamma-glutamyl transferase (GGT) increased ( ).

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 Bulevirtide 2 mg treatment group : ALT increased, hyperbilirubinemia, and blood bilirubin increased ( ); and AST increased and hepatic pain ( ).

• Bulevirtide 10 mg treatment group : ALT increased (

); hyperbilirubinemia and GGT increased ( );

and AST increased, blood bilirubin increased, and hepatic pain ( ) (59).

participants ( ) in the bulevirtide 2 mg treatment group and participants ( ) in the bulevirtide 10 mg treatment group had potential hepatic flares considered related to bulevirtide. Of these subjects, had the potential hepatic flare AE resolved and subject in the bulevirtide 10 mg group had an unresolved hepatic flare (59).

==> picture [29 x 12] intentionally omitted <==

----- Start of picture text -----
(59).
----- End of picture text -----

Eosinophilia

Eosinophil count increase was observed in in the delayed treatment arm and in the bulevirtide 10 mg treatment arm, while eosinophilia was reported across in the bulevirtide 2 mg group ( ) and the bulevirtide 10 mg group ( ). All eosinophilia AEs were Grade 1 in severity, and none resulted in discontinuation of the study drug (59).

Injection site reactions

At Week 48, injection site reaction AEs were experienced by subjects ( ) in the bulevirtide 2 mg treatment group and subjects ( )

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subjects in the bulevirtide 10 mg treatment group. The higher proportion with injection site reactions in the bulevirtide 10 mg treatment group is likely related to the additional daily injection required to receive this dosage. All injection site reaction AEs were Grade 1 or Grade 2 in severity, and none resulted in the discontinuation of the study drug (59).

Skin and subcutaneous disorders

Skin and subcutaneous disorder AEs were experienced in participants ( ) in the bulevirtide 2 mg treatment group, and in subjects ( ) in the bulevirtide 10 mg treatment group. Only participants ( ) in the delayed treatment arm reported a skin and subcutaneous disorder AE. All AEs were Grade 1 or Grade 2 in severity, and none resulted in the discontinuation of the study drug.

B.2.10.1.5 Study drug discontinuation

No TEAEs led to the discontinuation of the study drug (59).

B.2.10.1.6 Deaths

There were no deaths in MYR 301 as of the 48 week data cut-off (59).

B.2.10.2 MYR 202

The safety and tolerability of bulevirtide for the treatment of adults with CHD was evaluated as a secondary outcome in MYR 202. The SAS was defined as all patients who received at least one dose of bulevirtide. AEs were coded with MedDRA version 21.0 (58).

A total of 118 subjects were enrolled for the Phase 2 MYR 202 study, of which 90 subjects received at least one dose of bulevirtide (see Figure 8). At least one injection interruption was observed in 20 of 90 (22.2%) subjects, with 4 of 28 (14.3%) participants the bulevirtide 2 mg treatment arm experiencing injection interruptions, followed by 9 of 32 (28.1%) participants in the bulevirtide 5 mg group and 7 of 30 (23.3%) subjects in the bulevirtide 10 mg treatment arm. Despite this, all patients were compliant with bulevirtide according to the definition stated in the study protocol

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(unsatisfactory compliance was defined as missed study drug doses for three consecutive days or four missed doses over 28 days). In accordance with the treatment regimen specified in study design of MYR 202 (see Section B.2.3.2.2), the mean number of weeks of treatment with bulevirtide was 24.18 weeks (range: 18.9 – 36.7 weeks), while the mean duration of TDF exposure was 54.51 weeks (range: 18.9 – 61.6 weeks) in the three bulevirtide treatment groups (58).

B.2.10.2.1 Summary of adverse events

In total, 406 AEs were reported in 76 of 118 (64.4%) subjects in the MYR 202 study (Table 31). Most AEs were reported within the system organ class investigations, blood and lymphatic system disorders, general disorders and administration site conditions, and gastrointestinal disorders. The most common AEs (past conditions) were total bile acids increased, ALT increased, and AST increased (Table 32). Most AEs were of mild (Grade 1) to moderate (Grade 2) intensity, with only 23 AEs assessed as severe (Grade 3). There were no deaths recorded in the study (58).

Compared to TDF alone, there were more treatment-emergent AEs reported for participants receiving bulevirtide in all intervention groups and the number of AEs increased with increasing bulevirtide dose.

Table 31: Overview of AEs (SAS; MYR 202)

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Key : AE: adverse event; BLV: bulevirtide; TDF: tenofovir; SAE: serious adverse event; SAS: safety analysis set. Notes : Percentages are based on the number of participants within each treatment group. Source : Table 43, MYR 202 CSR (58).

B.2.10.2.2 Common adverse events

AEs that occurred in ≥10% of patients in any treatment group in the SAS are summarised below in Table 32. The most common AE reported across all the bulevirtide treatment groups was an increased in total bile acids (58). As highlighted in Section B.2.10.1, bile salt elevations are mechanistically due to the binding of the NTCP receptor by bulevirtide.

Table 32: Most common AEs reported by subjects treated with bulevirtide (SAS; MYR 202)

Key : AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; SAS: safety analysis set. Notes : Percentages are based on the number of participants treated with bulevirtide. Source : Table 45, MYR 202 CSR (58).

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B.2.10.2.3 Summary of serious adverse events

No SAEs were reported in the bulevirtide 2 mg + TDF treatment arm. One patient reported hepatic cirrhosis in the TDF monotherapy group, which was judged to be related to progression of the underlying disease (58).

B.2.10.2.4 Study drug continuation

Study drug discontinuation due to an AE was reported in one subject in the bulevirtide 5 mg treatment arm. The patient withdrew from the study and required hospitalisation after experiencing anaemia, which was judged as not related to bulevirtide. This SAE was assessed as life-threatening and was not resolved when the patient discontinued from the study (58).

B.2.10.2.5 Deaths

There were no deaths in the study (58).

B.2.11 Ongoing studies

MYR 301 is the pivotal trial for the treatment of CHD. Whilst the primary endpoint is based on interim 48-week data, an interim 96-week data cut is expected to be made available in . Depending on the timing of availability, this may be available to be submitted as new evidence during this technology appraisal which is expected to provide further evidence as to the optimal time to assess treatment response and demonstrate the continued benefits of ongoing treatment with bulevirtide over the longer-term.

In addition, the ongoing MYR 204 study is exploring the combination of PEG-IFN and bulevirtide as a potentially curative treatment option for patients with hepatitis delta (110).

B.2.12 Interpretation of clinical effectiveness and safety evidence

Bulevirtide is a novel, first-in-disease and first-in-class entry inhibitor used to treat CHD. Bulevirtide mimics the NTCP-binding domain, thereby selectively binding and inactivating NTCP, preventing HDV entry into host cells (1,2). In November 2021,

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bulevirtide received conditional marketing authorisation from the MHRA for the treatment of CHD in adults with compensated liver disease (8).

As the first approved treatment for HDV in Europe, clinical experts considered bulevirtide to be a step change in the treatment of CHD (31). Bulevirtide is designated as an orphan medication by the EMA and has also received PIM designation by the MHRA (26). Furthermore, experts consulted during the development of the EPAR agreed that there is an unmet medical need for bulevirtide, and that chronic HDV infected, or HDV-RNA positive adult patients with compensated liver cirrhosis would constitute a patient population in urgent need of treatment (3).

Bulevirtide specifically blocks viral entry by binding to NTCP, and as such, does not interfere with HDV viral replication or hepatocyte egress of the virus. Because of this, the observed declines in plasma HDV RNA during treatment with bulevirtide reflect a decline in the number of infected, virus-producing hepatocytes in the liver. By blocking the essential entry receptor, the de novo infection of liver cells is decreased, viral spread is inhibited, and the lifecycle of HDV is disrupted (111). This event is expected to lead to both reduced necroinflammation and HDV viral load decline by the same mechanism of prevention of new infections (59).

The efficacy and safety of bulevirtide in participants with CHD was investigated in the multicentre, open-label, randomised pivotal Phase 3 MYR 301 trial, as well as the supporting MYR 202 trial.

The MYR 301 population represented a group with particularly poor prognosis, with of patients cirrhotic at baseline, and having failed prior treatment with IFN-based therapy (59). Clinical experts suggested that the baseline characteristics observed were generalisable to patients currently seen in UK clinical practice (31). However, in a 2020 retrospective study by Spaan et al . found a lower median age of 36.0 years, a more relevant figure compared to MYR 301 based on study sites (78).

Overall, of patients in the bulevirtide 2 mg treatment group achieved a combined response at Week 48, compared to just in the delayed treatment arm

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( ) (59). Data from previous studies suggests that patients achieving undetectable HDV RNA or a ≥2-log10 decline in HDV RNA levels, and ALT normalisation, are at a reduced risk of developing complications of liver disease, such as HCC, cirrhosis, decompensation, and death (20,35,36,61).

The consensus from the 2019 EASL-AASLD Conference was that a decrease in HDV RNA by ≥2-log10 IU/mL from baseline might suffice as a primary endpoint for clinical trials for a maintenance treatment for CHD (25). However, alongside an improvement in virologic response, primary endpoints used to predict a clinical benefit in people with CHD should also provide an improvement in associated liver inflammation evident by a biochemical response. Therefore, as recommended by the FDA (53), a combined response was used as the primary endpoint for the MYR 301 study. The combined response composite endpoint sets a high bar for level of response, given it requires the fulfilment of two surrogate outcomes, one of which is a non-specific marker of liver inflammation. When analysing the individual components of the combined response, of patients in the bulevirtide 2 mg treatment group achieved undetectable HDV RNA or a ≥2-log10 decline in HDV RNA levels at Week 48, compared to just in the delayed treatment arm ( ) (59).

With regards to ALT normalisation, of subjects achieved normal ALT levels at Week 48, compared to in the delayed treatment arm (59). Furthermore, as shown in Appendix N, for patients who demonstrated a significant reduction in HDV RNA, but failed to achieve the combined endpoint,

(107). By also taking into

account the innovative mechanism of action of bulevirtide, whereby uninfected and newly formed hepatocytes are protected from new and re-infection, the proportion of responders is predicted to increase further beyond Week 48. In this regard, data collection is still ongoing with MYR 301, with 96-week data expected to become available in .

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Furthermore, at Week 48, the FibroScan[®] measurement of liver stiffness indicated that the bulevirtide 2 mg ( kPa) group had a significant decrease in liver stiffness from baseline compared to the delayed treatment group ( kPa) (59). In addition, an exploratory substudy of MYR 301 found that there was a strong correlation between HDV RNA and HDAg levels, which demonstrates that the number of infected hepatocytes reduced (80). As established by Farci et al . (2004), there is an association between fibrosis regression and a significant decrease in HDV viral load (103), which would suggest that patients responding to bulevirtide could experience an improvement in fibrosis and cirrhosis.

A multicentre, open-label, randomised supporting Phase 2 MYR 202 study further supports the efficacy and safety of bulevirtide, albeit over a shorter 24-week treatment period. Similar to MYR 301, the MYR 202 population represented a group with a poor prognosis, with 50.0% of patients cirrhotic at baseline, and 56.8% having failed prior therapy with IFN-based therapy (58).

The MYR 202 study assessed the efficacy and safety of bulevirtide in suppressing HDV replication in adults with CHD, in combination with TDF, over a shorter 24-week treatment period. The trial achieved its primary endpoint of an HDV RNA response at Week 24, which was observed in 53.6% of participants treated with bulevirtide 2 mg + TDF, compared to 3.6% of participants receiving TDF alone. Furthermore, treatment with bulevirtide 2 mg + TDF was associated with a statistically significantly higher proportion of participants achieving a combined response at Week 24 compared to TDF monotherapy (58).

In summary, bulevirtide has demonstrated unprecedented efficacy in a population of adults with CHD with compensated liver disease. Evidence from the MYR 301 and MYR 202 clinical studies demonstrates that treatment with bulevirtide results in a greater proportion of individuals achieving a combined response, HDV RNA decline or suppression, and ALT normalisation, compared to BSC or delayed treatment. The proposed population highlighted in the decision problem currently has no existing treatment options. Thus, as the only approved treatment for CHD, bulevirtide represents an important therapeutic option to address the rapid progression of the

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disease in this population, and reduce the risk of developing severe liver-related complications including cirrhosis, HCC, decompensation and death.

B.2.12.1 Strengths and limitations of the evidence base

Although HDV is the most severe form of viral hepatitis (10), no studies have been identified that provide utility values with HDV. The effect of bulevirtide on the HRQoL of people with HDV was assessed using EQ-5D-3L in the Phase 3 MYR 301 clinical study (see Section B.2.6.1). Baseline EQ-5D-3L scores did not differ between patients with and without liver cirrhosis, with a mean score of for non-cirrhotic patients and a score of for cirrhotic subjects. Clinical experts confirmed a difference of was an unexpected result (31). Furthermore, these findings are inconsistent with previous research which suggests that cirrhosis status in chronic hepatitis infection, including HBV monoinfection, negatively impacts patient QoL (104–106). As a result, base-case health state utilities are sourced from a metaanalysis of hepatitis B, and a statistical analysis of MYR 301 data.

Whilst it is acknowledged that the sample size for the Phase 3 MYR 301 study could be deemed small, CHD is considered to be an orphan disease in Europe (7). Due to difficulties in hepatitis delta screening and diagnosis, clinical studies of hepatitis delta often suffer from small sample sizes, which can make collecting statistically significant results for clinical outcomes challenging. MYR 301 represents the largest CHD clinical study to-date, with a larger population of patients recruited in comparison to the multicentre HIDIT-I and HIDIT-II studies used to investigate the efficacy and safety of PEG-IFN for CHD (76,112). Furthermore, despite an

acknowledgement of a small trial population, the EMA granted bulevirtide conditional marketing authorisation given the beneficial effect demonstrated by the available data, and in light of the limited treatment options and critical unmet needs associated with the disease (3).

Long-term liver disease complications of hepatitis delta are impractical targets for clinical trials, as they require a large number of participants followed for an extended period of time to demonstrate a clinical benefit (52). As a result, clinical trials for treatments for hepatitis rely on virologic and biochemical endpoints as surrogate

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markers that are likely to predict clinical benefit in people with CHD. According to the FDA’s guidance on developing treatments for CHD, and discussion from the 2019 EASL-AASLD Conference, surrogate endpoints should provide evidence for both a decline in virologic replication, and an improvement in associated liver inflammation evident by a biochemical response (25,53). The main surrogate endpoint used to predict clinical benefit, as recommended by the FDA, is combined response, or ‘the proportion of trial patients with undetectable serum HDV RNA (defined as undetectable HDV RNA [HDV RNA <LoD, where LoD=6 IU/mL] or decrease in HDV RNA by ≥2-log10 IU/mL from baseline) and ALT normalisation’ (53).

Data from the MYR 301 and MYR 202 studies shows a higher proportion of subjects treated with bulevirtide 2 mg demonstrated a combined response compared to BSC. As mentioned previously in this section, the consensus from the 2019 EASL-AASLD Conference was that decline in HDV RNA by ≥2-log10 IU/mL from baseline might suffice as a primary endpoint for clinical trials for a maintenance treatment for CHD (25). The use of a combined response as a primary endpoint, as recommended by the FDA (53), provides a more stringent definition of a responder, and subsequently makes this endpoint more difficult to achieve. Given the aforementioned difficulties in demonstrating an improvement in long-term liver disease complications in a clinical trial setting, a combined response represents a high bar for treatment efficacy.

B.2.12.2 Applicability of clinical evidence to practice

B.2.12.2.1 Patient characteristics

The population of MYR 301 represents a mixture of treatment naïve and experienced patients, with of patients having received prior therapy with IFN-based therapy. A similar rate of prior treatment with IFN-based therapy was observed in MYR 202 (56.8%). NICE guidelines recommend a trial of PEG-IFN for the treatment of adults with CHD (72). Feedback from clinical experts also suggests that most patients diagnosed with HDV have already tried IFN-based therapy, owing to a lack of other options (31). Therefore, prior use of IFN-based therapy in MYR 301 can be considered representative of UK clinical practice.

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Although neither of the relevant clinical studies included any UK study centres, there were study sites in Russia, Germany, Italy, and Sweden. Over half of patients (57%) in the pivotal MYR 301 study were recruited from Russia. EASL guidelines for the treatment of hepatitis B are considered to follow the rules of good clinical practice in Russia, and thus the treatment and management of CHD is likely to be aligned to UK clinical practice (see Section B.1.3.3).

While ALT normalisation was defined as ALT ≤ ULN by central laboratory, the cut-off value for the ULN was higher in Russia than the other participating countries, as outlined below:

• Russia: ≤31 U/L for females and ≤ 41 U/L for males.

• Others (Germany, Italy, and Sweden): ≤34 U/L for females and ≤ 49 U/L for males.

The EASL guidelines use a traditional cut-off value for the ULN at approximately 40 U/L (27). The definition adopted by Russia is more stringent and requires a greater decline in ALT levels in order to achieve the combined response endpoint. EASL guidelines are expected to be followed for the treatment and management of patients with CHD in Germany, Italy, and Sweden, which collectively contributed to almost half of the patients recruited for the pivotal MYR 301 clinical study.

Overall, as described in Section B.2.3.1, clinical experts generally agreed that the baseline characteristics of MYR 301 were reflective of the patients they expect to treat in clinical practice (31). However, in a 2020 retrospective study by Spaan et al . found a lower median age of 36.0 years, compared to the median age of years observed in the MYR 301 study (78). Given this data is UK specific, it can be considered a more appropriate figure for clinical practice.

B.2.12.2.2 Analysis sets

In consideration of the most appropriate analysis set for decision making, the FAS for MYR 301 (n = 150) is presented and the data for bulevirtide 2 mg and delayed

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treatment is used in the subsequent cost-effectiveness analysis. This analysis set includes all treated patients in the pivotal MYR 301 study.

B.2.12.2.3 Service provision

Treatment with bulevirtide should be initiated by a physician experienced in treating patients with HDV. Appropriate training should be given to the patients selfadministering the product to minimise the risk of the injection site reactions when injecting bulevirtide at home. No additional infrastructure or personnel is required, and therefore bulevirtide would fit in with current service provisions already set up within NHS England.

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B.3 Cost effectiveness

B.3.1 Published cost-effectiveness studies

An SLR was conducted to identify published cost-effectiveness analyses for bulevirtide or BSC for the treatment of CHD. The SLR methods are detailed in Appendix G. The identified studies are summarised in Table 33.

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Table 33: Summary list of published cost-effectiveness studies

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*Study reported efficacy in terms of ‘combined response rate’

Abbreviations: QALYs, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; CC, Compensated Cirrhosis; DC, Decompensated Cirrhosis; HCC, Hepatocellular Carcinoma; LT, Liver Transplantation; PEG-IFN, Pegylated interferon; SVR, Sustained Virologic Response; VR, Virologic Resistance.

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B.3.2 Economic analysis

The SLR of published cost-effectiveness studies identified that none of the studies addresses the decision problem presented in section B.1.1. A de novo costeffectiveness model was therefore developed to appraise the cost-effectiveness of bulevirtide as per the scope of this submission.

B.3.2.1 Patient population

The patient population included in the economic evaluation is defined as: adults with CHD who have compensated liver disease and evidence of significant fibrosis (METAVIR stage greater than or equal to F2), whose disease has responded inadequately to IFN-based therapy, or who are ineligible to receive IFN-based therapy due to intolerance or contraindication.

As discussed in Section B.1.1, the patient population included in the economic evaluation is different from the final scope issued by NICE and is narrower that the marketing authorization for bulevirtide.

B.3.2.2 Model structure

The cost-effectiveness model takes the form of a short-term decision tree for the first 72 weeks of treatment, followed by a Markov cohort model that follows patients through the lifetime of their disease. The Markov structure is presented in Figure 17. The model structure is similar to well established nature history models of HBV which have been adopted for previous economic evaluations of treatments of chronic HBV (TA173 (115), TA153 (115), TA154 (115), TA96 (115)) and more recently in other anti-viral treatments for chronic HCV (TA507 (116), TA499 (115)). The model structure was validated by an expert advisory board comprising clinical and health economic experts held in November 2021.

At baseline, patients are distributed across fibrosis stages and are assigned to treatment (bulevirtide or BSC). In the decision tree portion of the model, there are two efficacy assessments/continuation rules at Weeks 48 and 72 of treatment that determine whether the patient remains on treatment. The Week 48 assessment can

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be considered an early assessment of efficacy that evaluates achievement of a virologic (HDV-RNA undetectability or ≥2-log10 decline) while the Week 72 assessment can be considered a definitive assessment of both virologic and biochemical response (MYR 301 primary endpoint; composite response of HDVRNA undetectability or 2-log10 decline and ALT normalisation). Having these two continuation rules allows sufficient time for patients to achieve a clinical response (response rate was still increasing at Week 48 in MYR 301) while ensuring that patients who are not responding adequately to treatment do not incur ongoing treatment costs. This approach is also consistent with the current NICE guideline for assessment of response to PEG-IFN which states “ Consider stopping peginterferon alfa-2a if there is no decrease in HDV RNA after 6 months to 1 year of treatment. Otherwise, continue treatment and re-evaluate treatment response annually ”(72). Week 72 was considered appropriate as a final assessment timepoint based on extrapolations of the composite responder rate beyond 48 weeks which anticipate a peak at around 72 weeks (see section B.3.3.2).

Patients who fail to achieve virologic response at Week 48 are considered nonresponders and discontinue treatment. Those remaining on treatment are split into complete responders (patients who achieve both a virologic and biochemical response according to the MYR 301 primary endpoint) and partial responders (those who achieve a virologic response only). At Week 72, patients who fail to achieve a biochemical response are assumed to discontinue treatment leaving only complete responders on treatment going forwards. This can be considered a conservative approach, given that post-hoc analyses have shown that a large majority of patients who do not achieve the combined response primary endpoint have ALT within 1-2x ULN at Week 48 and are likely to have a significant clinical benefit (see Figure 29, Appendix N).

Patients progress through stages of fibrosis before developing cirrhosis. Cirrhotic patients remain asymptomatic or with limited symptoms (i.e. CC) before developing DCC. As chronic infection progresses, patients are at higher risk of developing HCC. Over the course of a simulation process, patients can achieve spontaneous or treatment-induced virologic responses (e.g., HBsAg seroconversion or HDV

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combined response endpoint) or develop liver complications (e.g. CC, DCC, HCC, or LT).

The model links the treatment response definitions to the slowing or stopping of disease progression. The MYR 301 combined response endpoint of HDV-RNA undetectability or ≥2-log10 decline and ALT normalisation (defined in the economic evaluation as complete responder) was linked to HDV disease management by assuming that a combination of improvement on virologic and inflammation biomarkers halts disease progression, leading to a reduction in HDV-related morbidity, mortality, healthcare resource utilisation (HCRU), costs and improvement in patient quality of life. It is assumed that achievement of biochemical response, i.e. ALT normalisation in addition to virologic response (defined as complete response in the economic evaluation) indicates that the liver is not showing any signs of inflammation and thus no disease progression would occur. The MYR 301 virologic response endpoint of HDV-RNA undetectability or ≥2-log10 decline (defined as partial responder in the economic evaluation) was linked to HDV disease management by assuming that an improvement on virologic biomarkers without ALT normalisation slows (but does not halt) disease progression (38).

Health state transitions for both responders and non-responders are illustrated in Figure 17. Complete responders can progress through stages F0 – F4 or regress from F4 to F3 or from F3-F2. Partial responders and non-responders can progress through F0-F4, but not regress. As with HBV, from all fibrosis stages, nonresponders can develop HCC. However, from CC (fibrosis stage 4 [F4]), both responders and non-responders can develop HCC or DCC. From the DCC state, patients may then move to the HCC state. Patients in the HCC state may undergo LT. There is a mortality risk associated with LT that may be due to either death during the operation or following the operation, or due to complications such as graft rejection. Patients who do not die due to LT within one year move to the post-liver transplant (PLT) state. For both responders and non-responders, beginning in F4 (CC), patients may transition to liver-related mortality at any time. While transitions between responders and non-responders are similar, responder patients progress slower than non-responders. As noted above, however, complete responders can

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also regress from F4 (CC) to F3 and from F3 to F2 while on treatment. This possibility to regress is established based on expert opinion and fibrosis regression observed in HBV mono-infected patients who are virologically supressed on HBVtreatment (103), (102). A summary of the definitions of responder, continuation rules and assumptions regarding disease progression is presented in Table 34.

Figure 17: Model structure

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Key: F0: fibrosis stage 0; F1: fibrosis stage 1; F2: fibrosis stage 2; F3: fibrosis stage 3; F4: fibrosis state 4 (compensated cirrhosis).

The analysis was conducted from the perspective of the NHS and personal social services in England and Wales, in line with current NICE guidelines (114). The basecase analysis thus considers only direct healthcare costs. Costs and outcomes are discounted at an annual rate of 3.5%, in line with the NICE reference case (114). Table 35 presents additional features of the current economic analysis and compares them to previous relevant NICE technology evaluations in CHB.

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Table 34: Summary of clinical assumptions in model

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Table 35: Features of the economic analysis

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cirrhosis, decompensated cirrhosis, HCC, liver transplant and postliver transplant), costs were based on large UK costing studies on hepatitis C (117), (117). Unit costs were sourced from the PSSRU, drug tariffs, hospital tariffs and Shepherd et al., 2006 (117).

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B.3.2.3 Intervention technology and comparators

The modelled intervention is Bulevirtide 2 mg once daily, as per its conditional marketing authorisation (8). Bulevirtide is an HBV/HDV entry inhibitor that binds and blocks the jointly used NTCP receptor on liver cells. It misdirects HBV and coinfecting HDV to an unproductive pathway and prevents an infection of the cell. The recommended dose and treatment duration of bulevirtide is 2 mg once daily (every 24 hours ± 4 hours) by SC injection as monotherapy or in co-administration with a NA for treatment of underlying HBV infection (8).

The comparator in the cost-effectiveness model is BSC. BSC consists of current clinical practice for HDV patients and includes non-specific treatments and care. BSC is generally defined as symptomatic treatment, alongside treatment for the underlying hepatitis B. The definition of BSC was validated with leading clinicians in the UK.

B.3.3 Clinical parameters and variables

B.3.3.1 Baseline characteristics

None of the patients enrolled into MYR 301 were from the UK, thus baseline characteristics from the trial were not deemed generalisable to the UK population likely to receive bulevirtide. The baseline age and proportion male in the model were informed by a retrospective analysis of 107 patients with HBV/HDV coinfection attending an outpatient clinic in London, England (78). The baseline characteristics for the subgroup of patients with actively replicating HDV detectable HDV RNA and/or anti-HDV-IgM (n=46) were used to inform the model. This resulted in a baseline age of 35.1 years and a proportion of 58.7% males (78).

In line with the proposed positioning of bulevirtide, in patients with compensated liver disease, the model assumes that patients are distributed amongst health states F2F4 at baseline. In line with the NICE guideline for treatment with PEG-IFN (72), patients in F0-F1 would not be classed as severe enough to receive bulevirtide in clinical practice and thus these patients are not included at baseline. Patients in any of the advanced liver disease health states (DCC, HCC, LT, PLT) would not meet the

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eligibility criteria to initiate treatment and thus no patients are assumed to occupy these health states at baseline. A scenario analysis was explored where the baseline population was restricted to those in the F3-F4 health states only.

21 out of the 46 (46%) patients in the actively replicating HDV detectable HDV RNA and/or anti-HDV-IgM subgroup in Spaan et al., 2020 (78) were cirrhotic at baseline. This is used to inform the proportion of CC (F4) patients at baseline. Spaan et al., 2020 (78) did not provide the proportion of patients in the non-cirrhotic fibrosis stages (F0-F3) at baseline, thus the proportion of non-cirrhotic patients (54%) was reweighted using Romeo et al., 2009. Romeo et al ., 2009 provide a baseline split of patients by fibrosis stage (F0-F4) in a sample of 299 HDV patients (35). The baseline distribution of patients is reported in Table 36. The distribution applied in the scenario analysis where the baseline population is restricted to F3-F4 patients is reported in Table 37.

Table 36: Distribution of patients amongst fibrosis stages, model base-case

Table 37: Distribution of patients amongst fibrosis stages, scenario analysis

B.3.3.2 Clinical efficacy

Trial data

Key efficacy parameters for bulevirtide were sourced from the Phase 3 MYR 301 trial. MYR 301 is an on-going multicentre, open-label, randomised clinical trial assessing the efficacy and safety of bulevirtide in patients with CHD. The primary

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objective of the study is to evaluate the efficacy of bulevirtide administered subcutaneously for 48 weeks at a dose of 2 mg or 10 mg once daily for treatment of CHD in comparison to delayed treatment. Data from the 2 mg arm was used to inform the efficacy of bulevirtide in the model. The delayed treatment arm was used to inform the clinical efficacy of BSC. The MYR 301 data was restricted to the subgroup of patients who were IFN-experienced.

The key efficacy parameter in the model is the proportion of patients achieving combined response, that is virologic response (HDV-RNA undetectability or ≥2-log10 decline) and ALT normalisation. Patients who achieve this endpoint are categorised as ‘complete responders’ in the model. Patients who achieve virologic response, but fail to meet the ALT normalisation criteria, are defined as partial responders. The response rates for the combined response endpoint, as observed in MYR 301 are reported in Table 38. The modelled response rates applied in the base-case are reported in Table 39.

Table 38: Combined response rates observed in MYR 301, applied in model base-case

Table 39: Bulevirtide and BSC response rates, model base-case

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Week 48 Complete Responder Suboptimal Responder Non-responder

A scenario analysis was conducted where virologic response was selected as the definition of a complete responder. In this scenario, there are no partial responders. The trial outcomes for virologic response are reported in Table 40. The response rates applied in the scenario analysis are reported in Table 41.

Table 40: Virologic response rates observed in MYR 301, applied in scenario analysis

Table 41: Bulevirtide and BSC response rates, model scenario

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Extrapolation of trial data

Non-responders are assumed to discontinue treatment at 48 weeks, leaving complete responders and partial responders on treatment. Although the available follow-up data from MYR 301 are limited to 48 weeks, analysis of the individual patient data (IPD) indicates that response rates were still increasing at that timepoint. Therefore, the proportion of complete responders among those remaining on treatment past 48 weeks is expected to increase. The response rates for the 2mg bulevirtide and delayed treatment arms of MYR 301 up until week 48 were therefore extrapolated to estimate treatment response at weeks 72 and 96. This was done using the EMAX function with continuity correction in the R statistical package (119).

EMAX is a non-linear function that is widely used in the areas of dose-response or exposure-/concentration-response modelling. It is characterised by a monotone, concave response shape. Based on visual inspection of the pattern of observed response rates at weeks 4, 8, 16, 24 and 48, within each treatment group of MYR 301, the shape of the response rates was deemed appropriate to be fit with an EMAX function. Using the general property of the EMAX function and the observed data indicated a very good visual fit. The time course of the response rates was modelled separately for individuals by treatment groups, bulevirtide 2mg or delayed treatment. Specifically, a hyperbolic EMAX model was used in order to capture the rapid response rates observed during the earlier timepoints for some endpoints.

Using the treatment group level observed response rates at weeks 4, 8, 16, 24 and 48, a separate set of EMAX functions were estimated for both combined and virologic response. R software (version 4.1.2) was used for this purpose, with the package “DoseFinding” to estimate the response shape with the ‘fitMod’ function used to fit the model. Once the parameters of the response curve for each endpoint and treatment group were determined, the predicted response values at weeks 72 and 96 were derived. As there is no in-built function or option to handle continuity correction within the DoseFinding R package used for the extrapolation, we used an increasing response rate of 0.05% to 0.5% over the 7 visits from week 4 to week 48, when there is at least one 0% response. In such situations, we also added the small additional response to the non-zero response rate, as they should also be scaled up Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

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per the methodology of continuity correction. This overall approach helps us achieve the target of estimating some reasonable predicted values for Week 72 and 96 and is able to determine the upper and lower confidence intervals for response at these timepoints.

The primary limitation of using this method is that the estimated maximum response could become more than 100% over a longer period of follow-up time, particularly for endpoints with high response starting at earlier timepoints. However, this limitation does not impact the predictions over a reasonable follow-up time course, such as 72 or 96 weeks.

Using the EMAX model, we obtained regression parameters for each response endpoint, allowing us to calculate mean response at weeks 72 and 96 using the following equation:

==> picture [120 x 12] intentionally omitted <==

The coefficient values from the EMAX model as well as the predicted response rates are provided in Appendix O. Estimates of the mean for all parameters in the equation were estimated from the EMAX model. The � parameter in the equation is substituted with the value of the respective week i.e. 72 or 96. The extrapolated response rates at weeks 72 and 96 for the composite endpoint are reported in Table 42. The respective response rates for the virologic endpoint are reported in Table 43. These response rates are applied to both the bulevirtide and BSC arms in the basecase.

The removal of the MYR 301 extrapolated response rates was explored in a scenario analysis.

Table 42: Bulevirtide and BSC combined response, extrapolated timepoints

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Suboptimal Responder Non-responder Week 96 Complete Responder Suboptimal Responder Non-responder

Table 43: Bulevirtide and BSC virologic response, extrapolated timepoints

B.3.3.3 Natural history

For patients who are off-treatment or on BSC, disease progression is modelled through the natural history of HDV-infection. A pragmatic literature search was performed to identify natural history data in HDV. While multiple publications were identified, the data was heterogenous both for the time-period for which the natural history data were evaluated (for example, ranging from 1980s-2010s) and geographic focus. The population sizes of the identified studies were generally small, reflecting the orphan nature of the disease. Given the data limitations and heterogeneity in study designs, it was deemed appropriate to calculate the natural history HDV progression based on publications comparing disease progression in HDV/HBV co-infected individuals versus treated HBV mono-infected patients. This

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approach was validated with clinical experts at an advisory board, given the more robust data in HBV mono-infection and the well-established relationship of accelerated progression in HDV/HBV co-infected versus HBV mono-infected patients. Disease transition rates used in the model (with respective sources and calculations) are presented in Table 44 below.

Table 44: Fibrosis and liver disease transition rates

The model also takes into consideration an annual rate of HbsAg seroclearance. The rate of HbsAg seroclearance for patients on bulevirtide, as well as spontaneous clearance rate for patients off treatment, is informed by a published meta-analysis and is 1.13% (123). When adjusted to accommodate the 24-week cycle length, this results in a cycle probability of 0.52%. Patients who achieve HbsAg seroclearance are assumed to discontinue HDV treatment.

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B.3.3.4 Disease progression

A pragmatic literature review was completed to identify data regarding the MYR 301 combined response endpoint and its impact on disease progression. Farci et al., 2004 (103) established a relationship between a HDV-RNA 2-log10 decline and the reduction in risk of mortality. However, the study was not suitable for use in the model as the mortality data is not aligned with progression from any specific health state in the model.

A review of the existing natural history data identified relationships between HDVRNA undetectability and disease progression (38). Further, there are known relationships between ALT normalisation and disease progression from HBV monoinfection that can be considered for the HDV/HBV co-infection and HBV monoinfection relationship (65).

To provide robust estimates of the impact of HDV RNA undetectability on natural history data in HDV patients, a systematic literature review and meta-analysis was performed. A systematic literature review was first undertaken to identify cohort studies that reported relationships of HDV RNA negativity vs. positivity in terms of its impact on liver disease progression in chronic HDV patients. These data were then synthesised in a meta-analysis, where hazard ratios for specific liver disease progression events (i.e., any liver disease event, progression from CC to DCC, CC to HCC, etc.) were determined. The hazard ratios obtained from the meta-analysis are applied to partial (virologic) responders and are reported below. The effect when combined with the natural history transition rates (Table 44) results in disease progression transition rates for patients achieving sub-optimal (virologic) response as summarised in Table 46.

Table 45: Disease progression treatment hazard ratios, suboptimal responders

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Table 46: Fibrosis and liver disease transition rates amongst sub-optimal responders

The model assumes that complete responders (those who meet the composite endpoint of MYR 301) have no progression compared to partial or non-responders. The hazard ratios for complete responders are thus set to 0.001 in the model basecase. The effect when combined with the natural history transition rates (Table 44) results in disease progression transition rates for patients achieving combined response as summarised in Table 47.

Table 47: Disease progression treatment hazard ratios, complete responders

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Table 48: Fibrosis and liver disease transition rates amongst complete responders

In the absence of data on the reduction of progression from granular non-cirrhotic fibrosis stages (e.g., F0-F3), it was assumed that the hazard ratio from non-cirrhotic to cirrhotic disease was applied to sequential fibrosis stage transitions (e.g., F0 to F1, F1 to F2 and so forth).

B.3.3.5 Fibrosis regression

In addition to the reduction in disease progression due to treatment, there is the possibility that responding to treatment may induce a regression in liver fibrosis and cirrhosis for those achieving the combined response endpoint. In a previous study in HDV patients responding to PEG-IFN therapy, Farci et al., 2004 (103) reported regression in four of six patients with sustained biochemical response. These patients had active cirrhosis in their first three liver biopsies and an absence of fibrosis in their last liver biopsy. The authors concluded that there was an association between fibrosis regression and a significant decrease in HDV viral load (103). Marcellin et al., (2013) (102) also reported regression of cirrhosis for HBV monoinfected patients who experienced viral suppression while on treatment. In their study, 51% of patients were found to have fibrosis regression after five years (102). Expert opinion aligned with these findings that patients who respond to therapy and achieve the combined response endpoint could experience an improvement in cirrhosis/fibrosis due to treatment, and regress. The annual transition rates used in the model for fibrosis regression among combined responders are reported in the table below. The impact of removing fibrosis regression in responder patients was explored in a scenario analysis.

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Table 49: Fibrosis regression on treatment in responder patients

B.3.3.6 Treatment discontinuation

Treatment discontinuation is only incorporated for bulevirtide patients as BSC patients are not on active treatment.

Stopping rules

All patients begin treatment at the start of the model when classified according to their fibrosis stages. Treatment stopping rules for bulevirtide patients are the following: no response to treatment by Week 48, responders having HbsAg seroclearance; or, regardless of stage, disease progression. According to the approved SmPC (see Appendix C), “ treatment should be continued as long as associated with clinical benefit ”, so responders may continue treatment unless they achieve HbsAg seroclearance or discontinue therapy. Disease progression to DCC, HCC, LT, and PLT health states also results in the end of treatment.

The model thus includes a stopping rule at Week 48 which removes non-responders from active treatment with bulevirtide. Partial responders, who have achieved virologic response but not biochemical response at Week 48, are able to continue treatment until Week 72. If they do not achieve complete (composite) response by Week 72 then they are withdrawn from active treatment with bulevirtide. Discontinuing patients are assumed to be treated with BSC and no subsequent treatment acquisition costs are thus incurred.

Background discontinuation

In addition to treatment withdrawal due to lack of efficacy (response), the model also accounts for treatment withdrawal for any other reasons, based on rates observed in

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MYR 301. 1 out of 49 (2.04%) patients in the bulevirtide 2 mg group discontinued treatment in MYR 301. When converted to a 24-week probability, this results in a probability of 1.03% per model cycle.

B.3.3.7 Adverse events

Only moderate to severe adverse events occurring in ≥5% of patients were incorporated into the model. Adverse event rates for the bulevirtide arm were sourced from the 2 mg bulevirtide arm of MYR 301. For the BSC arm, rates were sourced from the delayed treatment arm of MYR 301. The adverse event rates for each arm are reported in the table below. The impact of adverse events is assumed to occur in the first cycle on in the model.

Table 50: Adverse event rates included in the model

B.3.3.8 Mortality

All-cause mortality is applied using a background mortality rate applied to all patients. The background mortality represents the risk of dying of any cause at a given age and is sourced from national life tables sourced from the Office for National Statistics (ONS) (125).

Liver-related excess mortality is applied from the PLT state onwards, to capture the mortality risk associated with severe liver disease. The excess mortality risk for patients in these health states was sourced from published literature and then converted to a 24-week probability of death to accommodate the model cycle length. The probabilities are reported below.

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Table 51: Liver-related mortality risk applied in the model

B.3.4 Measurement and valuation of health effects

Although the EQ-5D-3L was collected in the MYR 301 trial, the trial data was not deemed suitable for use in the model due to a lack of construct and content validity (see section B.3.4.1). Therefore, the core natural history health state utilities in the model, including the utility of non-responders, were obtained from a meta-analysis of the HBV literature (see section B.3.4.3). The model incorporates an incremental utility for complete responders which is derived from a regression analysis of the MYR 301 data.

B.3.4.1 Health-related quality-of-life data from clinical trials

The MYR 301 trial collected HRQoL data using the EQ-5D-3L, the Hepatitis Quality of Life Questionnaire (HQLQ) and the Fatigue Severity Scale at baseline, 24 weeks and 48 weeks. HRQoL data from the EQ-5D-3L is the preferred measure as this is a standardised and validated generic instrument and the preference elicitation is based on a time trade-off algorithm, in line with the NICE reference case (126).

MYR 301 provides the best available dataset for estimating the effect of bulevirtide on HRQoL, that is, the best estimate of the gain in utility associated with a treatment response for CHD patients. Therefore, these data were carefully explored and analysed in detail. Simple descriptive analyses can be subject to bias and so it is typically recommended that regression modelling is undertaken so that other variables can be controlled for (127).

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Utility data do not typically meet the assumptions of an ordinary least squares (OLS) regression model. For instance, EQ-5D values may be subject to censoring, clustering, non-linearity, heterogeneity of variance and may be non-normally distributed. Tobit models, on the other hand, are suited and have been extensively used (128) to examine data such as the EQ-5D where the distribution is effectively truncated (the highest score on EQ-5D is 1.0). Tobit regression models were used to explore the data and estimate the gain in utility for treatment responders at week 24 and week. Compared to baseline, moderate gains at week 48 were observed based on the analysis from the Tobit model (Table 52). The estimate for the gain in EQ-5D scores from the Tobit model are applied in the cost effectiveness model, differentiating responders from non-responders in the same health state.

However, the MYR 301 EQ-5D-3L data is not used for the core health state utilities in the base-case and utilities from the literature are used instead (see section B.3.4.3). The trial data was not deemed suitable for use in the model due to a lack of clinical validity. As discussed in Section B.2.6, and shown in Table 53, baseline data from the MYR 301 show that EQ-5D-3L is insensitive to objective differences between cHDV patients, such as patients with or without cirrhosis, which is clinically not plausible and against the large body of evidence in CHB and chronic HCV (74). In clinical practice, the progression of patients with hepatitis through fibrosis stages, cirrhosis and cancer is expected to further decrease their HRQoL.

The results in Table 53 also show the standard deviations around the mean scores which helps to illustrate that the EQ-5D-3L is a somewhat noisy measure in this sample.

Table 52: Regression analysis of 48-week MYR 301 utility values

==> picture [463 x 123] intentionally omitted <==

----- Start of picture text -----
OLS regression Tobit model around median
Estimate 95% CI p-value Estimate 95% CI p-value
Intercept
Baseline EQ-5D
Liver Cirrhosis
Composite
Responder
----- End of picture text -----

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Table 53. Mean baseline utility values from the MYR 301 trial, by compensated cirrhosis status

Abbreviations: CC, compensated cirrhosis; cHDV, chronic hepatitis D virus; NC, non-cirrhotic; SD, standard deviation; UK, United Kingdom

These findings may be driven by trial-specific factors, particularly low sample size in each health state (approximately 100 patients with usable data at Week 48, less than 50% of which had CC), possible impact of COVID-19 or rapid progression to CC among CHD patients not adequately controlled for. It is also possible that these results are driven by instrument specific factors, such as the EQ-5D-3L being insensitive to objective differences between CHD patients which would explain the lack of utility difference between non-cirrhotic (NC) and CC patients, or EQ-5D-3L not measuring important features of CHD.

The above-described uncertainties and limitations indicate two key issues with the MYR 301 EQ-5D-3L utility estimates:

• Lack of construct validity: No difference in EQ-5D-3L based utilities for NC and CC at baseline which lacks clinical validity and goes against a large body of literature in hepatitis;

• Lack of content validity: CHD causes fatigue, nausea and vomiting as key symptoms and these issues are not reflected in the descriptive system of the EQ-5D-3L so it is possible that they are not well measured. The presence or absence of these important symptoms may have an effect on the utility weights from EQ-5D-3L. Several studies in various diseases reported that EQ-5D-3L does not appropriately reflect differences in fatigue (129) (130).

The MYR 301 values are therefore not applied in the model base-case, but in a scenario analysis. The health-state utility values for the fibrosis stages in this

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scenario are reported in Table 54 below. CHB values are applied to all other health states as per the base case.

Table 54: Health state utility values applied for F0-F4 health states, model

scenario

B.3.4.2 Mapping

No mapping was undertaken for this economic evaluation.

B.3.4.3 Health-related quality-of-life studies

An SLR was conducted to identify studies reporting on the HRQoL of patients with CHD. Full details of the methodology and results of included studies are presented in Appendix H.

As described in Section B.3.4.1, the MYR 301 EQ-5D-3L data were not deemed suitable for the base-case health state utilities. No suitable CHD-specific health state utilities were identified in the SLR reported in Appendix H. The use of proxy conditions is feasible if utility values are available for another condition that is deemed to have a similar impact on HRQoL, then those utility values were sometimes assumed representative of the condition of interest. Based on

discussions with clinical experts, CHB and chronic HCV were deemed as the most suitable proxies as the three conditions affect the liver, among other organs, have the same transmission modes and similar disease progression paths – although at different velocities. An SLR and meta-analysis of health state utilities in CHB and chronic HCV were conducted. Full details of the meta-analysis methodology are provided separately (131). Clinical experts attending the UK advisory board stated

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states and thus the base-case health state utilities for non-responders are informed by the CHB meta-analysis. These values are reported in Table 55 (including the previous values for fibrosis states from Table 54). Utilities for responders are from the same source however they include the utility gain associated with response, as estimated by the tobit model median from the MYR 301 EQ-5D-3L utility analysis (Table 52).

The chronic HCV utilities were applied to the health states in a scenario analysis. These values are reported in Table 56.

Patients with more severe stages of disease (DC, HCC or PLT) were not included in MYR 301 and therefore no HRQoL data are available from the trial for these health states. The utilities for these health states were thus also informed by the CHB metaanalysis in the base-case and by the chronic HCV meta-analysis in a scenario analysis.

Table 55: Health state utility values by response status, model base case

Table 56: Health state utility values by response status, model scenario

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B.3.4.4 Adverse reactions

Utility decrements associated with adverse events were incorporated in the costeffectiveness model by multiplying the utility decrement by the incidence of the adverse event (Table 50) to determine a one-off value, applied in the first cycle of the model.

Table 57: Utility decrements associated with adverse events included in the model

Health-related quality-of-life data used in the cost-effectiveness analysis

Table 58: Summary of utility values for cost-effectiveness analysis

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

B.3.5 Cost and healthcare resource use identification,

measurement and valuation

Details of how relevant cost and healthcare resource data were identified are presented in Appendix I.

B.3.5.1 Intervention and comparators’ costs and resource use

B.3.5.1.1 Acquisition costs

The acquisition cost of bulevirtide once the PAS is applied is per pack of 30 vials of 2 mg powder for solution for injection. The recommended dose of bulevirtide is 2 mg once daily (every 24 hours ± 4 hours). This results in a cost of per 24-week model cycle.

The treatment acquisition costs are reported in Table 59. Bulevirtide is selfadministered, thus no drug administration costs are applied. Patients who are allocated to BSC do not receive active drug treatment for CHD and thus there are no drug acquisition costs applied for these patients.

Table 59: Drug acquisition costs applied in the model

B.3.5.1.2 Monitoring costs

Monitoring costs refer to the costs of monitoring the patient while they are treated with either Bulevirtide or BSC. The nature and frequency of each type of monitoring resource use was informed by clinical experts (n=3), who were asked to state the type and frequency of NHS activities that would take place each year for HDV patients at treatment initiation, during treatment and when off-treatment. The

Company evidence submission template for bulevirtide for treating chronic hepatitis D [ID3732]

© Gilead (2022) All rights reserved

frequency of monitoring resource use for bulevirtide patients is presented in Table 60 and in Table 61 for BSC patients.

Unit costs from the 2019/20 National schedule of NHS costs were then attached to the frequency of HCRU to derive total monitoring costs. Unit costs are reported in Table 62.

Table 60: Monitoring resource use for bulevirtide patients

Table 61: Monitoring resource use for BSC patients

Event Off Treatment (Frequency per year)