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Cost Comparison Appraisal

Vutrisiran for treating hereditary transthyretin-related amyloidosis [ID5074] Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

COST COMPARISON APPRAISAL

Vutrisiran for treating hereditary transthyretin-related amyloidosis [ID5074]

Contents:

The following documents are made available to stakeholders:

Access the final scope and final stakeholder list on the NICE website.

1. Company submission from Alnylam

2. Clarification questions and company responses

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

• a. Cardiomyopathy UK

• b. UK ATTR Amyloidosis Patients’ Association (UKATPA)

• c. National Amyloidosis Centre

• d. NHS England

4. NICE medicines optimisation team (MOT) report

5. Expert responses to questions from the NICE technical team from:

• a. Professor Marianna Fontana, Professor of Cardiology – clinical expert, nominated by Alnylam

• b. Professor Julian Gillmore, Centre Head and Research Lead - nominated by National Amyloidosis Centre

6. External Assessment Report prepared by PenTAG:

• a. Main report

• b. Appendix

7. External Assessment Group response to factual accuracy check of EAR

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: cost-comparison

Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074] Document B Company evidence submission

October 2022

Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

© Alnylam (2022). All rights reserved

Contents

List of tables .......................................................................................................................... 5 List of figures ........................................................................................................................ 6 List of abbreviations .............................................................................................................. 7 B.1 Decision problem, description of the technology and clinical care pathway ................... 10 B.1.1 Decision problem ................................................................................................... 10 B.1.2 Description of the technology being evaluated ....................................................... 17 B.1.3 Health condition and position of the technology in the treatment ............................ 18 B.1.3.1 Disease overview ............................................................................................ 19 B.1.3.2 Clinical presentation and staging ..................................................................... 20 B.1.3.3 Epidemiology of hATTR amyloidosis in the UK ............................................... 21 B.1.3.4 Burden of disease ........................................................................................... 21 B.1.3.4.1 Clinical burden ......................................................................................... 21 B.1.3.4.2 Patient burden: Health-related quality of life (HRQoL) .............................. 21 B.1.3.4.3 Caregiver burden ...................................................................................... 21 B.1.3.4.4 Economic burden ..................................................................................... 22 B.1.3.5 Clinical pathway of care, unmet need and place of vutrisiran in therapy .......... 22 B.1.3.5.1 Overview .................................................................................................. 22 B.1.3.5.2 Clinical pathway of care ............................................................................ 23 B.1.3.5.3 Current therapies ...................................................................................... 24 B.1.3.5.4 Unmet need .............................................................................................. 26 B.1.3.5.5 Vutrisiran .................................................................................................. 28 B.1.4 Equality considerations .......................................................................................... 31 B.2 Key drivers of the cost effectiveness of the comparator(s) ............................................ 32 B.2.1 Clinical outcomes and measures ........................................................................... 32 B.2.1.1 Stopping and starting of patisiran .................................................................... 36 B.2.2 Resource use assumptions .................................................................................... 36 B.2.2.1 Relevance to the decision problem for vutrisiran ............................................. 36 B.3 Clinical effectiveness .................................................................................................... 38 B.3.1 Identification and selection of relevant studies ....................................................... 39 B.3.2 List of relevant clinical effectiveness evidence ....................................................... 39 B.3.3 Summary of methodology of the relevant clinical effectiveness evidence ............... 40 B.3.3.1 HELIOS-A study design .................................................................................. 42 B.3.3.1.1 External placebo control arm .................................................................... 43 B.3.3.1.2 Patisiran reference comparator arm ......................................................... 43 B.3.3.1.3 Patient selection criteria ........................................................................... 44 B.3.3.1.4 Assessments ............................................................................................ 47 B.3.3.1.5 Blinding .................................................................................................... 48 B.3.3.1.6 Endpoints ................................................................................................. 49 B.3.4 Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence .................................................................................................... 49 B.3.4.1 HELIOS-A overview .................................................................................... 49

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B.3.4.2 HELIOS-A sample size determination ......................................................... 49 B.3.4.3 HELIOS-A study hypotheses ....................................................................... 50 B.3.4.4 HELIOS-A statistical analyses ..................................................................... 50 B.3.5 Critical appraisal of the relevant clinical effectiveness evidence ............................. 51 B.3.6 Clinical effectiveness results .................................................................................. 52 B.3.6.1 Change in serum TTR levels through Month 18 .............................................. 52 B.3.6.2 Main clinical endpoint included in the cost-effectiveness analysis of patisiran (HST10): change in PND score from baseline to Month 18 ......................................... 53 B.3.6.3 HELIOS-A primary endpoint: change in mNIS+7 from baseline at Month 18 ... 53 B.3.6.4 Post hoc within-study comparison of patisiran and vutrisiran in HELIOS-A...... 54 B.3.7 Subgroup analysis ................................................................................................. 56 B.3.8 Meta-analysis ......................................................................................................... 56 B.3.9 Indirect and mixed treatment comparisons ............................................................. 56 B.3.10 Adverse reactions ................................................................................................ 59 B.3.11 Conclusions about comparable health benefits and safety ................................... 61 B.3.12 Ongoing studies ................................................................................................... 63 B.4 Cost-comparison analysis ............................................................................................. 64 B.4.1 Changes in service provision and management ..................................................... 64 B.4.1.1 Place of administration .................................................................................... 64 B.4.1.2 Administration-related resource use ................................................................ 64 B.4.1.3 Posology ......................................................................................................... 64 B.4.2 Cost-comparison analysis inputs and assumptions ................................................ 65 B.4.2.1 Features of the CCA ....................................................................................... 65 B.4.2.1.1 Time horizon ............................................................................................ 65 B.4.2.1.2 Patient characteristics and posology ........................................................ 65 B.4.2.1.3 Drug administration .................................................................................. 66 B.4.2.1.4 Premedication .......................................................................................... 66 B.4.2.1.5 Time on treatment .................................................................................... 66 B.4.2.1.6 Discount rate ............................................................................................ 67 B.4.2.2 Costs in the CCA ............................................................................................. 67 B.4.2.2.1 Intervention and comparators’ acquisition costs ....................................... 68 B.4.2.2.2 Intervention and comparators’ healthcare resource use and associated costs ........................................................................................................................ 68 B.4.2.3 Adverse reaction unit costs and resource use ................................................. 72 B.4.2.4 Miscellaneous unit costs and resource use ..................................................... 72 B.4.2.5 Clinical expert validation .................................................................................. 72 B.4.2.6 Uncertainties in the inputs and assumptions ................................................... 75 B.4.3 Base-case results .................................................................................................. 77 B.4.4 Sensitivity and scenario analyses .......................................................................... 79 B.4.4.1 One-way sensitivity analyses .......................................................................... 79 B.4.4.2 Scenario analyses ........................................................................................... 80 B.4.5 Subgroup analysis ................................................................................................. 81 B.4.6 Interpretation and conclusions of economic evidence ............................................ 82

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B.5 References ................................................................................................................... 83 B.6 Appendices ................................................................................................................... 88 Appendix C: Summary of product characteristics (SmPC) and UK public assessment report ........................................................................................................................................... 89 C1.1 SmPC ..................................................................................................................... 89 C1.2 UK public assessment report .................................................................................. 89 Appendix D: Identification, selection and synthesis of clinical evidence .............................. 90 D1.1 Identification and selection of relevant studies ........................................................ 90 D1.2 Participant flow in the relevant randomised controlled trials .................................... 97 D1.3 Quality assessment for each trial ............................................................................ 98 D1.4 APOLLO trial relevant information ........................................................................ 100 D1.5 NMA methodology ................................................................................................ 102 Appendix E: Subgroup analysis ........................................................................................ 104 Appendix F: Adverse reactions ......................................................................................... 105 Appendix G: Cost and healthcare resource identification .................................................. 106 Appendix H: Price details of treatments included in the submission .................................. 107 H1.1 Price of intervention .............................................................................................. 107 H1.2 Price of comparators and subsequent treatments ................................................. 107 Appendix I: Checklist of confidential information ............................................................... 108 Appendix J: Comparison of vutrisiran versus placebo in HELIOS-A across all secondary endpoints .......................................................................................................................... 109 J1.1 HELIOS-A key secondary endpoint: change in Norfolk QoL-DN from baseline at Month 18 ................................................................................................................... 109 J1.2 Key secondary endpoints at Month 18 ............................................................... 109 J1.2.1 Change in 10-MWT from baseline at Month 18 ........................................... 110 J1.2.2 Change in R-ODS from baseline at Month 18 ............................................. 110 J1.2.3 Change in mBMI from baseline at Month 18 ............................................... 111 J1.3 Binary analysis: mNIS+7 and Norfolk QoL-DN at Month 18 ............................... 111 Appendix K: Time on treatment in the CCA ....................................................................... 114

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List of tables

Table 42: Details of intervention costs, including concomitant medicines, for each formulation used in the model .............................................................................................................. 107 Table 43: Details of comparators and subsequent treatment costs, including concomitant medicines, for each formulation used in the model ............................................................ 107 Table 44: HELIOS-A: Month 18 efficacy results ................................................................ 110 Table 45: Fit statistics of parametric models to patisiran and vutrisiran time-on-treatment data ................................................................................................................................... 114 Table 46: Model parameters for parametric functions to extrapolate patisiran and vutrisiran time on treatment curves ................................................................................................... 114 List of figures

Figure 1: Pathophysiology of hATTR amyloidosis ............................................................... 20 Figure 2: Clinical pathway of care for patients with hATTR amyloidosis with polyneuropathy in the UK ............................................................................................................................. 24 Figure 3: Comparison of time requirements for treatment with vutrisiran and patisiran ........ 30 Figure 4: HELIOS-A secondary endpoint: change in serum TTR levels through Month 18 .. 53 Figure 5: HELIOS-A primary endpoint: mNIS+7 change from baseline at Month 18 ............ 54 Figure 6: Diagram of evidence network assessing vutrisiran and patisiran .......................... 56 Figure 7: OWSA tornado plot .............................................................................................. 80 Figure 8: PRISMA diagram ................................................................................................. 96 Figure 9: Consort diagram of patient flow in HELIOS-A ....................................................... 98 Figure 10: HELIOS-A key secondary endpoint: Norfolk QoL-DN change from baseline at Month 18 ........................................................................................................................... 109 Figure 11: HELIOS-A secondary endpoint: 10-MWT change from baseline at Month 18 ... 110 Figure 12: HELIOS-A secondary endpoint: R-ODS change from baseline at Month 18 ..... 111 Figure 13: HELIOS-A secondary endpoint: mBMI change from baseline at Month 18 ....... 111 Figure 14: HELIOS-A binary analysis: Reversal in neuropathy impairment from baseline at 18 months*[†] ...................................................................................................................... 112 Figure 15: HELIOS-A binary analysis: Improvement in Norfolk QoL-DN from baseline at 18 months*[†] ........................................................................................................................... 113 Figure 16: Vutrisiran and patisiran time on treatment ........................................................ 115

Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

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List of abbreviations

Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

© Alnylam (2022). All rights reserved

Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

© Alnylam (2022). All rights reserved

Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

© Alnylam (2022). All rights reserved

B.1 Decision problem, description of the technology and

clinical care pathway

B.1.1 Decision problem

The submission covers the full marketing authorisation of vutrisiran, namely, for the treatment of adults with hereditary transthyretin-mediated (hATTR) amyloidosis with stage 1 or stage 2 polyneuropathy.[1]

The submission covers the full population for the comparator, patisiran, as recommended by NICE in Highly Specialised Technology guidance (HST)10,[2] which is identical to the population indicated for treatment with vutrisiran.

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Table 1: The decision problem

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AE, adverse event; ATTR, transthyretin amyloidosis; CHMP, committee for Medicinal Products for Human Use; EMA, European Medicines Agency; EU, European Union; FAP, familial amyloid polyneuropathy; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; HCP, healthcare professional; HRQoL, health-related quality of life; HST, Highly Specialised Technology guidance; IRR, infusion-related reaction; IV, intravenous; MHRA, Medicines and Healthcare products Regulatory Agency; NAC, National Amyloidosis Centre; NHS, National Health Service; NMA, network meta-analysis; PAS, Patient Access Scheme; Q3M, quarterly; Q3W, once every 3 weeks; SC, subcutaneous; SmPC, Summary of Product Characteristics; TTR, transthyretin; UK, United Kingdom.

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B.1.2 Description of the technology being evaluated

In appendix C include the Summary of Product Characteristics or information for use, and the UK public assessment report, scientific discussion or drafts.

Table 2: Technology being evaluated

CHMP, Committee for Medicinal Products for Human Use; DHSC, Department of Health and Social Care; EC, European Commission; EU, European Union; GalNAc, N -acetylgalactosamine; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; MHRA, Medicines and Healthcare products Regulatory Agency; mRNA, messenger ribonucleic acid; PAS, Patient Access Scheme; Q3M, quarterly; RNAi, ribonucleic acid interference; SC, subcutaneous; siRNA, small interfering ribonucleic acid; TTR, transthyretin; UK; United Kingdom.

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

treatment

Hereditary transthyretin-mediated (hATTR) amyloidosis

• hATTR amyloidosis is a rare, inherited, rapidly progressive, debilitating, and fatal disease caused by misfolded transthyretin (TTR) that accumulates as amyloid deposits in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract.[18-21]

• From disease onset, the multiple disease manifestations of hATTR amyloidosis impose a substantial burden on patients,[22,23] caregivers,[24,25] and healthcare resources.[24,26-28] This burden increases over time as the rapid progression of sensorimotor neuropathy symptoms leads to increasing disability, ultimately resulting in complete loss of ambulation and confinement to a wheelchair, and death.[22]

• The multiple disease manifestations (motor, sensory and autonomic) in hATTR amyloidosis with polyneuropathy are associated with a profound and rapid worsening of HRQoL, starting from the early stages of the disease.[20,23,29]

• hATTR amyloidosis with polyneuropathy has a considerable effect on patients’ independence, dignity, and their ability to work, take part in family and social life, and carry out daily activities.[2]

Current treatment options and clinical pathway of care

• Patisiran is the current standard of care and is considered as the first-choice therapy for treatment-eligible patients with hATTR amyloidosis with polyneuropathy in England, with an estimated market share greater than ***. The only other NICEapproved therapy, inotersen, is rarely used due to limitations with its safety and efficacy profiles, as evidenced by real-world clinical experience.[3 ]

• Amongst current NICE-recommended therapies for hATTR amyloidosis with polyneuropathy, patisiran is the only therapy that has been shown to halt polyneuropathy progression or improve polyneuropathy and HRQoL relative to patients’ pre-treatment baseline in a substantial proportion of patients.[6,30,31] Nevertheless, there are still remaining unmet medical needs for patients who receive treatment with patisiran. Specifically, patisiran has limitations associated with its frequent dosing (every 3 weeks [Q3W]) and intravenous (IV) administration, which places added burden on patients, caregivers, healthcare providers (HCPs), and the NHS. IV administration of patisiran also carries the potential for IRRs and infusion-related complications, which can have serious implications for patients.

• • A summary of the burden for patients, caregivers, HCPs, and the NHS regarding patisiran use is provided in B.1.3.5.4 Unmet need.

Unmet Need

• Additional treatment options are needed that:

  • Have efficacy comparable to that of patisiran in reducing TTR levels, halting or reversing polyneuropathy, and improving HRQoL.

  • o Offer a favourable safety profile with no anticipated need for patient monitoring.

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• Have the ability to reduce treatment burden and time requirements for patients, HCPs, and caregivers by offering administration that is minimally invasive, simplified, and less frequent, relative to the current standard of care.

Vutrisiran

• Vutrisiran is indicated for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy.[1]

• Vutrisiran has demonstrated a comparable efficacy profile to patisiran. o Compared to patisiran, vutrisiran demonstrated non-inferior reduction of serum TTR in HELIOS-A in a pre-specified statistical comparison.[4]

  • In agreement with the observation of similar pharmacodynamic activity in lowering serum TTR, which is the causative agent in the disease process of hATTR amyloidosis, a post hoc analysis of the vutrisiran and patisiran arms in HELIOS-A demonstrated comparable efficacy in clinical outcomes at Month 18. This analysis was noted by the CHMP in their assessment report which concluded that comparable efficacy was demonstrated.[12] The post hoc analysis was additionally noted to demonstrate comparable efficacy between patisiran and vutrisiran in the MHRA orphan drug report for vutrisiran.[13]

  • Similarly, a network meta-analysis (NMA) that compared vutrisiran and patisiran using data from both available pivotal clinical trials for these medicines (APOLLO and HELIOS-A) reaffirmed comparable clinical efficacy regarding ambulatory ability, polyneuropathy impairment, and HRQoL.[14]

• Compared to patisiran, which is administered via IV infusion Q3W, vutrisiran offers the benefit of less frequent dosing and less burdensome administration, through fixed-dose subcutaneous (SC) injection administered quarterly (Q3M).[1] The effects of this change in administration not only decrease the time-related burdens of treatment, but also increase safety for patients by obviating the risks associated with IV infusion including IRRs.

Anticipated place of vutrisiran in therapy

• Based on input from clinical experts and the advantages that vutrisiran provides versus patisiran, vutrisiran is expected to supplant patisiran as the standard of care and to be considered in all treatment-eligible patients with hATTR amyloidosis with polyneuropathy as the first-choice therapy.[3]

• In view of the intended use of vutrisiran by clinicians, the body of evidence showing clinical efficacy comparable to that of patisiran, the advantages of its subcutaneous dosing, and the proposed confidential patient access scheme (PAS), vutrisiran is likely to provide similar or greater health benefits at a similar or lower cost than those provided by patisiran in the identical patient population.

B.1.3.1 Disease overview

hATTR amyloidosis is an inherited, autosomal dominant, progressive, debilitating disease caused by the accumulation of amyloid fibrils consisting of both variant and wild-type TTR.[18,32] It is a multisystem disease with heterogeneous clinical presentation that includes sensory, motor, and autonomic (e.g., diarrhoea, sexual dysfunction, orthostatic intolerance) polyneuropathy and cardiomyopathy, with the potential involvement of other organ systems as well.[18,31-33]

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Primarily produced in the liver, TTR functions as a transport protein for thyroxine and vitamin A.[18,34] TTR is a tetrameric protein composed of four monomers.[18] In the case of transthyretin-mediated (ATTR) amyloidosis, the tetrameric protein destabilises into unstable monomers and TTR fragments that can misfold and form amyloid fibril deposits in multiple organs, including the peripheral nervous system, heart, and GI tract, leading to cellular injury and organ dysfunction with corresponding clinical manifestations (Figure 1).[18,19,32,35]

Figure 1: Pathophysiology of hATTR amyloidosis

==> picture [389 x 85] intentionally omitted <==

----- Start of picture text -----
TTR tetramer TTR fragments and Misfolded aggregation-prone Amyloid oligomers
full-length monomers monomers and fragments and fibril formation
Proteolysis
and dissociation Misfolding Aggregation
----- End of picture text -----

hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; TTR, transthyretin. Source: Hawkins et al, 2015[18] ; Kittleson et al, 2020[36] ; Koike and Katsuno, 2019[37]

B.1.3.2 Clinical presentation and staging

The main clinical features of hATTR amyloidosis were presented to NICE in Section B of the company submission for HST10.[2] Table 3 provides an overview of two of the most widely used clinical staging systems in hATTR amyloidosis with polyneuropathy.[22] The familial amyloid polyneuropathy (FAP) staging system was originally developed to classify the disease based largely on the patient’s ability to ambulate.[38] In the UK Summary of Product Characteristics (SmPC), vutrisiran is indicated for the treatment of adult patients with hATTR amyloidosis with stage 1 or stage 2 polyneuropathy, as defined by FAP stage.[1] The polyneuropathy disability (PND) score is based on both sensory and motor impairment, and the associated impact on ambulation.[39] Higher scores on each of the staging systems are indicative of greater disease severity.[40]

Table 3: Clinical staging in hATTR amyloidosis

*hATTR amyloidosis with peripheral neuropathy was historically referred to as FAP or TTR-FAP.[22] FAP, familial amyloid polyneuropathy; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; PND, polyneuropathy disability. Source: Coutinho et al, 1980[38] ; Suhr et al, 1994[39]

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B.1.3.3 Epidemiology of hATTR amyloidosis in the UK

Clinical experts from the NAC have informed Alnylam that they estimate there are *** patients with hATTR amyloidosis with polyneuropathy in England.[3] In the Medicines and Healthcare products Regulatory Agency (MHRA) Orphan Drug Assessment Report for vutrisiran, an estimate of 235 patients with hATTR amyloidosis with polyneuropathy in Great Britain is suggested.[13]

B.1.3.4 Burden of disease

B.1.3.4.1 Clinical burden

In the absence of effective disease-modifying therapy, hATTR amyloidosis is a progressive, debilitating, and ultimately fatal disease.[41-43] hATTR amyloidosis imposes a substantial burden from the time of disease onset, with patients presenting with peripheral neuropathy (sensory and motor), autonomic neuropathy, GI impairment, cardiomyopathy, nephropathy, and/or ocular involvement.[22] Rapid progression of sensorimotor neuropathy symptoms leads to increased disability over time.[22] Progressive peripheral and autonomic neuropathy can also lead to inanition, causing infection or starvation.[16] Inanition is a leading cause of mortality in patients with hATTR amyloidosis with polyneuropathy.[44] Median survival from the time of diagnosis in hATTR amyloidosis with polyneuropathy has been found to be 4.7 years,[45] and survival from the time of symptom onset can range from 3 to 15 years.[46]

B.1.3.4.2 Patient burden: Health-related quality of life (HRQoL)

hATTR amyloidosis has a considerable effect on patients’ independence, dignity, and their ability to work, take part in family and social life, and carry out daily activities.[2] Symptomatic patients have a reduced HRQoL at disease onset compared with the general, healthy population.[23] Significant impairments in HRQoL, measured using the Norfolk QoL – Diabetic Neuropathy (Norfolk QoL-DN) and EQ-5D assessment tools, have been observed in patients with hATTR amyloidosis compared to age-matched controls across a wide range of age groups (18 to 34 years, 35 to 49 years, 50 to 64 years, and 65 years and older).[23] HRQoL impairment worsens over time, as evidenced by a significant relationship between worsening scores on the Norfolk QoL-DN questionnaire and increasing duration of symptoms among symptomatic patients with hATTR amyloidosis.[29,47] The progressive worsening of HRQoL begins early in the disease course, with rapid deterioration in all five domains of the Norfolk QoL-DN score (activities of daily living, physical function/large fibre neuropathy, small-fibre neuropathy, symptoms, and autonomic neuropathy) observed over time for patients in FAP stages 1 and 2.[29] The initial worsening in Norfolk QoL-DN score is 9.12 points per year of symptom duration on average, until HRQoL impairment would be predicted to reach a maximum (i.e., worst possible level of impairment) after approximately 19 years.[47] In addition, the Rasch-built Overall Disability Score (R-ODS), which measures the degree of limitations on everyday activities and social participation, has also been shown to decrease in patients with hATTR amyloidosis.[4] Importantly, patisiran and vutrisiran have both been shown to maintain or improve HRQoL in patients with hATTR amyloidosis (B.3.6 Clinical effectiveness results).[4,6]

B.1.3.4.3 Caregiver burden

The polyneuropathy caused by hATTR amyloidosis progressively limits patients’ autonomy, impairing their ability to perform activities of daily living, and impacts their HRQoL substantially.[22,23] As polyneuropathy progresses, patients may lose the ability to walk unaided and become wheelchair-bound or bedridden and increasingly dependent on others for care.[22] Caregiver burden (resulting from this dependence of patients on others for care) typically affects an older population that may be struggling with health issues of their own,

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including age-related physical and cognitive declines, chronic illness, and some level of disability.[48]

In a cross-sectional online survey of caregivers (n=36) for patients with hATTR amyloidosis that included UK caregivers and was piloted and reviewed by the UK Amyloidosis Research Consortium (ARC), providing practical and emotional care was found to take an average 5.8 and 4.1 hours, respectively, per day.[49] Additionally, it was shown caregivers had significantly higher anxiety and depression compared to the matched general population.[49] The impact of hATTR amyloidosis on caregiver QoL has also been evaluated in a cross-sectional, noninterventional survey of adult patients (n=60) with hATTR amyloidosis and nonpaid caregivers (n=32) in Spain and the US.[25] The mean age for caregivers was 57.0 years in the US and 52.8 years in Spain, and the majority of caregivers in both countries were spouses or partners of affected patients.[25] On average, caregivers reported spending more than 45 hours per week caring for patients and had a mean Zarit Burden Interview (ZBI) score of 34.3, which is comparable to the caregiver burden reported in Alzheimer disease.[25] The survey reported particularly poor QoL among caregivers who also have the disease.[24,25]

These data suggest that caregivers for patients with hATTR amyloidosis in the UK face high levels of burden, and thus treatments that decrease this burden of care are needed.

B.1.3.4.4 Economic burden

Healthcare costs

In the NICE appraisal of patisiran (HST10), UK-specific healthcare resource utilisation (HCRU) costs for patients with hATTR amyloidosis according to PND score were estimated by a Delphi panel to be ***************************************************************************** **********************************************************[2] These costs did not include the use of

disease modifying therapies and were centred around polyneuropathy-related costs to the NHS and PSS.[2] The observation of comparable clinical effectiveness between vutrisiran and patisiran suggests a similar disease trajectory and, by extension, similar HCRU needs for managing disease manifestations (as reflected by different possible disease states) in patients receiving either therapy. However, it is important to note that patisiran, relative to vutrisiran, is associated with added costs due the requirement for more frequent administration, the need for complex IV administration, and required premedications.

B.1.3.5 Clinical pathway of care, unmet need and place of vutrisiran in therapy

B.1.3.5.1 Overview

Patisiran is the current standard of care and is considered the first-choice therapy for all treatment-eligible patients with hATTR amyloidosis with polyneuropathy in England. Patisiran is currently the only NICE recommended therapy in the UK that halts or reverses the progression of polyneuropathy relative to pre-treatment baseline in a substantial proportion of patients and significantly improves HRQoL from pre-treatment baseline in patients with hATTR amyloidosis with polyneuropathy.[6]

The only other NICE recommended therapy for patients with hATTR amyloidosis with polyneuropathy, inotersen, is rarely used in the UK, due to challenges encountered by clinicians in their real-world clinical experience with inotersen.[3] There are also safety issues associated with inotersen that include special warnings and contraindications on the UK product label.[50]

Although patisiran is currently the standard of care for hATTR amyloidosis with polyneuropathy, the administration profile of patisiran, which is weight-based and includes an IV infusion once every 3 weeks (Q3W), necessitates a time-consuming administration

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procedure (approximately *** hours), In addition, it requires premedication to reduce infusion related reactions (IRRs) and patient monitoring for IRRs by HCPs during and after treatment.[10] The IV infusion of patisiran also places a strain on the National Amyloidosis Centre (NAC), which is the setting for initial infusions, and NHS homecare delivery services for subsequent infusions.

Thus, there is a need for a treatment option with:

• Comparable efficacy as patisiran in halting or reversing polyneuropathy and improving HRQoL.

• A dosing scheme that is not weight-based to minimise dosing errors.

• A favourable safety profile (without IRRs) with no need anticipated for patient monitoring.

• No requirement for premedications.

• The ability to reduce treatment burden and time requirements for patients, HCPs, and caregivers.

Vutrisiran provides comparable efficacy to patisiran (described in B.3.6 Clinical effectiveness results and B.3.9 Indirect and mixed treatment comparisons) but offers a less burdensome administration profile through its Q3M SC dosing. Based on its clinical profile and the proposed confidential PAS for vutrisiran, vutrisiran is likely to provide similar or greater health benefits at similar or lower cost than those provided by patisiran. Thus, vutrisiran is expected by UK clinicians to supplant patisiran,[3] decreasing the aforementioned burdens associated with patisiran, which will benefit patients, caregivers, HCPs, and the NHS.

B.1.3.5.2 Clinical pathway of care

A representation of the clinical pathway of care for patients with hereditary transthyretinmediated (hATTR) amyloidosis with polyneuropathy in the UK is presented in Figure 2.

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Figure 2: Clinical pathway of care for patients with hATTR amyloidosis with polyneuropathy in the UK

==> picture [452 x 439] intentionally omitted <==

hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; NAC, National Amyloidosis Centre; ULC, University College London; UK, United Kingdom. Source: Figure generated from communications with key opinion leaders.[3]

B.1.3.5.3 Current therapies

A summary of the NICE-recommended therapies for patients with hATTR amyloidosis with polyneuropathy in the UK is provided in Table 4.

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Table 4: Current therapies recommended in the UK for patients with hATTR

amyloidosis with polyneuropathy

ASO, antisense oligonucleotide; eGFR, estimated glomerular filtration rate; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; HST, highly specialised technology guidance; IV, intravenous; MoA, mechanism of action, ribonucleic acid interference; ROA, route of administration; siRNA, small interfering RNA; SC, subcutaneous; TTR, transthyretin; UK, United Kingdom; UPCR, urine protein to creatinine ratio. Note: inotersen is not considered an appropriate comparator due to the differences in contraindications, monitoring requirements, and market share, as outlined in the table.

Among current NICE-recommended products for hATTR amyloidosis with polyneuropathy, patisiran was shown to stabilise or improve patients’ polyneuropathy (measured using modified Neuropathy Impairment Score [mNIS]+7) and HRQoL (measured using Norfolk QoL-DN) relative to their own pre-treatment baseline.[6] Notably, inotersen was shown to only slow worsening of polyneuropathy from pre-treatment baseline (i.e., patients continue to

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experience neuropathy progression over time) on average and did not improve average HRQoL from pre-treatment baseline.[31,52]

In HST10 for patisiran, with regard to its efficacy profile, the NICE committee stated that:[2]

• “Clinical trial evidence shows that patisiran reduces disability and improves quality of life, by enabling patients to return to work, carry out daily activities, participate in a more active family and social life, and maintain their independence and dignity. There is also evidence suggesting that patisiran may provide long-term benefits by stopping the progression of amyloidosis and potentially reversing it.”

In contrast, in HST9 for inotersen, the NICE committee stated that:[51]

“Clinical trial evidence shows that inotersen slows progression of the disease considerably, although its long-term benefits are uncertain.”

In addition, inotersen is approved in the UK and EU with certain special warnings and precautions for use, in addition to multiple contraindications (Table 4),[53] that are not present in the UK and EU product label for patisiran.[10,11]

The differences in the clinical pathway positions of patisiran and inotersen are reflected in their market share. Alnylam estimates that the patisiran market share is currently greater than ***, which represents *********** from a level of *** market share in January 2022 (estimated based on communications with NAC clinicians).[3] This is especially notable considering that inotersen and patisiran were both appraised by NICE in 2019 and inotersen was recommended by NICE 3 months prior to patisiran.[2,51] The observation of a small and declining market share of inotersen suggests that it is plausible that no patients, or very few patients in the UK will be receiving inotersen in the near future.

B.1.3.5.4 Unmet need

Despite the status of patisiran as standard-of-care treatment in England for this condition, there continue to be unmet needs for patients with hATTR amyloidosis with polyneuropathy beyond the burdens for HCPs and the NHS in association with the use of patisiran.

Temporal burden

• A single treatment session with patisiran can take approximately *** hours (not including travel),[3] consisting of premedication administration (60 minutes prior to infusion), infusion (80 minutes), and the need for HCP-monitoring post-infusion for IRRs.[10,11]

• IV infusion is required every 3 weeks.[10,11]

• Patients currently need to visit the NAC in London for initial treatments, potentially requiring significant travel for patients with hATTR amyloidosis. The SmPC states that patisiran can be considered for delivery via homecare after at least three welltolerated infusions in a clinic.[10,11] Currently, all patients in the UK are moved to homecare for patisiran administration following treatment initiation at the NAC.

• Loss of time due to administration and/or travel requirements is inherently burdensome and may also result in productivity losses for working patients, as well as for caregivers accompanying patients at treatment sessions.

Health-related burden and requirement for premedication

• IV administration of patisiran carries the potential for IRRs and IV infusion-related complications at the site of the peripheral IV catheter, such as extravasation or phlebitis.

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• In clinical studies with patisiran as of July 12, 2022, ************************************** ************************************************************************************************* **************************************************************[54]

• To minimise the risk of IRRs, a premedication regimen is required every treatment session.

  • The premedication regimen includes an IV corticosteroid (dexamethasone 10 mg or equivalent), H1 blocker (diphenhydramine 50 mg, or equivalent [in clinical practice chlorphenamine 10 mg is used]), H2 blocker (ranitidine 50 mg, or equivalent [in clinical practice oral famotidine 20mg is used][3] ), and oral paracetamol.[10,11]

  • In the event of a shortage of any component of premedication, treatment would be severely compromised for patients with hATTR amyloidosis.

  • In addition, the premedication regimen itself carries its own risk of adverse effects. For example, fatigue or drowsiness from premedication can last up to 2 days.

• The weight-based dosing scheme for patisiran may also introduce a risk of medication errors. According to the FDA Adverse Events Reporting System (FAERS), ************************************************************************************* ************************************************************************************************* ************************************************************************************************* *******************************.

• In current conditions in which SARS-CoV-2 transmission risk may be heightened in healthcare environments, dosing of patisiran every 3 weeks may carry additional risks associated with healthcare interactions.

• Patients receiving patisiran can also be fragile and elderly, amplifying the potential burden of IRRs, other infusion-related complications, AEs associated with premedication, and increased exposure to healthcare settings.

Burden to HCPs and the NHS

After initial treatments, patients on patisiran are reliant on a robust homecare delivery service requiring the availability of HCPs trained to provide IV infusions. Alnylam notes that homecare delivery services in the UK are experiencing chronic long-term staff shortages, potentially jeopardising the administration of patisiran to patients in accordance with their ongoing Q3W treatment schedule, in view of the associated HCP time requirements. The European Medicines Agency (EMA) Committee for Orphan Drug Medicinal Products (COMP) and the MHRA Orphan Drug Designation Assessment Report for vutrisiran concluded that for treatment with patisiran, up to 10 hours of active HCP time is required per patient with hATTR amyloidosis per year.[13,55]

Similarly, the NAC has limited infusion capacity for patients with hATTR amyloidosis. In addition, the ability of the NAC to maintain infusion capacity is reliant on adequate HCP staffing. Alnylam notes chronic nurse staffing challenges in the UK NHS particularly as a result of the COVID pandemic;[56] thus, should there be a failure of homecare delivery in the UK, it is unlikely that the NAC could accommodate patisiran infusions for all patients affected.

Given the burden associated with patisiran treatment as described herein, there is need for a treatment for hATTR amyloidosis with polyneuropathy that provides comparable clinical benefit to patisiran, but with a less burdensome administration profile for patients and the UK healthcare system.

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B.1.3.5.5 Vutrisiran

Vutrisiran is an siRNA therapeutic comprising a synthetic, chemically modified, doublestranded siRNA covalently linked to a ligand containing three N-acetylgalactosamine (GalNAc) residues.[57] Employing the same mechanism of action as patisiran, vutrisiran is an siRNA molecule designed to promote the catalytic degradation of both variant and wild-type TTR mRNA, which, in turn, decreases the production of both variant and wild-type TTR protein.[57-59] This activity results in reduced serum TTR protein levels and reduced TTR protein deposits in tissues.[57,59,60] Such reductions are crucial to halting polyneuropathy of hATTR amyloidosis, as shown in the APOLLO trial of patisiran.[6,10] Therefore, like patisiran, treatment with vutrisiran is disease modifying as it targets and improves the underlying disease and its clinical manifestations.[10,61]

While the biological activity and clinical efficacy of vutrisiran are comparable to those of patisiran (detailed fully in B.3.6 Clinical effectiveness results and B.3.9 Indirect and mixed treatment comparisons), its novel delivery mechanism represents an advance within the broader treatment landscape. In particular, vutrisiran makes use of enhanced stabilisation chemistry (ESC), a term that refers to chemical modifications designed to increase the metabolic stability of the medicinal substance, which allows for infrequent (Q3M) dosing (Table 5).[61] In addition, covalent linkage of the medicinal substance to a ligand containing three GalNAc residues allows rapid and specific delivery of vutrisiran to hepatocytes. While patisiran employs lipid-nanoparticle technology to target liver tissue, the use of ESC-GalNAc technology by vutrisiran enables targeting of liver tissue and comparable biological effects on TTR reduction, while also being administered SC and less frequently.

Table 5: ESC-GalNAc platform versus lipid nanoparticles

ASGPR, asialoglycoprotein receptor; ESC, enhanced stabilisation chemistry; GalNAc, N-acetylgalactosamine; IV, intravenous; LNP, lipid nanoparticle; Q3M, quarterly; Q3W, every 3 weeks; RNA, ribonucleic acid; SC, subcutaneous; siRNA, small interfering RNA.

Source: Cullis and Hope, 2017[62] ; Brown et al, 2020[63] ; Springer and Dowdy, 2018[64]

The benefits resulting from the ESC-GalNAc platform utilised by vutrisiran versus the lipid nanoparticle technology utilised by patisiran, for patients, caregivers, HCPs, and the healthcare system, are described in Table 6.

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Table 6: Benefits of vutrisiran over patisiran

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AE, adverse event; HCRU, healthcare resource use; IRR, infusion-related reaction; IV, intravenous; Q3W, every 3 weeks; Q3M, every 3 months; SC, subcutaneous.

Source: ONPATTRO (patisiran) Summary of Product Characteristics[11] ; AMVUTTRA (vutrisiran) Summary of Product Characteristics[1]

Figure 3 compares the time burden associated with a single treatment with patisiran or vutrisiran, including the duration of travel time to the NAC and the length of time for which a patient may be impacted by treatment fatigue or AEs from premedication.

Figure 3: Comparison of time requirements for treatment with vutrisiran and patisiran

==> picture [482 x 168] intentionally omitted <==

IRR, infusion related reaction; IV, intravenous; NAC, National Amyloidosis Centre; SC, subcutaneous. Source: Figure generated from communications with key opinion leaders.[3]

The benefits that the vutrisiran administration profile provides compared to patisiran have been noted by the EMA COMP and the MHRA Orphan Drug Designation Assessment Report for vutrisiran.[13,55] Recognition of this benefit was based in large part on the observation of strong positive feedback from patients with hATTR amyloidosis treated with vutrisiran compared with patients treated with patisiran during the 18-month randomised treatment period of the pivotal phase 3 trial of vutrisiran, HELIOS-A, as well as highly positive feedback about vutrisiran from patients who switched from patisiran to vutrisiran during the extension phase of the HELIOS-A trial.[55]

Overall, the aforementioned advantages of vutrisiran over patisiran are expected to reduce the burdens of treatment previously presented by patisiran, for patients and caregivers, in addition to HCPs and the NHS:

Decreased temporal burdens

• Vutrisiran significantly decreases the frequency of treatment.

• The total time required for treatment with vutrisiran (<5 minutes) is significantly less than for treatment with patisiran (approximately *** hours).

Decreased health-related burdens

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• SC vutrisiran administration obviates the risk of IRRs.

• There is no premedication requirement for vutrisiran, which removes the risk of premedication-associated fatigue or drowsiness, potentially lasting up to 2 days with patisiran. Elimination of premedication requirements also removes the risk that components of premedication regimens would not be available, as required for appropriate patient care with patisiran, due to shortages caused or exacerbated by future COVID waves.

• The fixed dosing of vutrisiran eliminates the need to calculate and administer an appropriate dose for each patient on the basis of body weight, a potential source of medication errors in the administration of patisiran.

• By minimising the amount of time patients spend in healthcare settings to receive treatment, vutrisiran would support efforts to ensure minimal COVID/iatrogenic disease transmission in a highly vulnerable population.

Decreased burdens to HCPs and the NHS

• Healthcare systems would systematically benefit as vutrisiran would reduce/eliminate the burden and cost associated with IV delivery of care (e.g., infusion chair time, nurse time, and homecare). The reduced burden would also contribute to alleviating system staffing pressures.

• Vutrisiran would free up capacity for IV infusion services that could be provided to other patients.

• Vutrisiran decreases the time requirements for HCPs due to its less frequent administration and shorter time required to perform a single administration.

B.1.4 Equality considerations

The use of vutrisiran in the UK is not expected to raise any issues related to equality given its clinical comparability with patisiran and the committee’s note on equality considerations with patisiran in HST10. In HST10, the following was stated regarding equality:[2]

“The committee noted the potential equality issue raised by clinical experts and the company, and recognised that specific mutations were more common in some ethnic groups in the UK. It also considered whether the age of onset of the condition raised particular issues of equality. The committee concluded that its recommendations apply equally, regardless of age or ethnicity, so a difference in disease prevalence in different age and ethnic groups does not in itself represent an equality issue.”

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B.2 Key drivers of the cost effectiveness of the

comparator(s)

B.2.1 Clinical outcomes and measures

Patisiran, the comparator in the company evidence submission, was recommended by NICE in HST10 as a treatment for the population specified in the decision problem for this appraisal.[2]

In HST10, the committee concluded that the outcomes measured in patisiran’s pivotal trial, APOLLO, likely captured most of the aspects of the condition important to people with hATTR amyloidosis. The committee considered APOLLO endpoints beyond those directly incorporated in the cost-effectiveness model, including mNIS+7, Norfolk QoL-DN, and serum TTR levels, when concluding that the evidence showed that patisiran offers considerable benefit for patients and that in addition to stopping disease progression, patisiran has the potential to reverse it.[2] Table 7 provides a summary of the relevant clinical outcomes included in the NICE appraisal of patisiran.

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Table 7: Clinical outcomes and measures appraised in published NICE guidance for patisiran

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EQ-5D-3L, EuroQol-5 dimension 3-level; EQ-5D-5L, EuroQol-5 dimension 5-level; HST, highly specialised technology; ICER, incremental cost-effectiveness ratio; LY, life year; mNIS+7, modified Neuropathy Impairment Score +7; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; NT-proBNP, N ‑ terminal pro ‑ B ‑ type natriuretic peptide; PND, polyneuropathy disability; QALY, quality-adjusted life year.

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B.2.1.1 Stopping and starting of patisiran

The CEA included treatment discontinuation for patients who entered PND stage IV, in addition to incorporating a time-on-treatment (ToT) discontinuation curve (Kaplan–Meier curve) from APOLLO data, meaning patients had some probability of stopping treatment at any time based on the ToT curve. The committee suggested that including both stopping rules simultaneously could overestimate stoppage of patisiran.[2] However, after recognising that treatment discontinuation rates in APOLLO were very low and subsequently had minimal impact on the treatment discontinuation in the model, resulting in minimal effects on the incremental cost-effectiveness ratio (ICER), the committee accepted the company’s approach to modelling treatment discontinuation.[2]

B.2.2 Resource use assumptions

For the CEA for patisiran appraised in HST10, a Delphi panel approach was used to determine the resource use by the NHS and Personal Social Services Research Unit (PSSRU) for UK patients with hATTR amyloidosis. This investigation stratified resource use and associated per-cycle costs by PND score and NT-proBNP levels. The NICE appraisal committee concluded that there were some uncertainties in these resource use assumptions which would be incorporated into decision making.[2]

The key economic drivers of the patisiran CEA in HST10 were:

• Patisiran list price

• Annual cost of patisiran

  • Estimated using cost per dose of patisiran and relative dose intensity (RDI), which provided a measure of actual doses taken in practice. The RDI was calculated to be 0.97 based on the number of doses administered as a proportion of scheduled doses in APOLLO.

• Administration costs

  • Administration of patisiran was considered comparable with complex chemotherapy IV infusion and was accordingly estimated to cost £301 per treatment (NHS Reference Costs [2016/2017]).[65]

  • The eligibility for patients to undergo homecare infusions was unknown at the time of the appraisal. Therefore, the model assumed all infusions were administered at the NAC.

• Health-state costs

  • Per-cycle costs were assigned for each health state defined by the combination of PND score and NT-proBNP category (less than 3000 pg/mL or equal to or greater than 3000 pg/mL). The costs were based on generic drug use, and use of NHS and PSSRU resources. One-off costs were also assigned for patients transiting into each PND score category.

• AE costs

• Miscellaneous costs

• End-of-life costs

B.2.2.1 Relevance to the decision problem for vutrisiran

In terms of relevance to the decision problem for vutrisiran, the observation of comparable clinical effectiveness between vutrisiran and patisiran as shown by comparable reductions in

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serum TTR levels to patisiran through Month 18 in HELIOS-A (Figure 4),[4] the within trial post hoc analysis from HELIOS-A (Table 16), and the NMA (B.3.9 Indirect and mixed treatment comparisons) suggests a similar disease trajectory and, by extension, similar HCRU needs for managing disease manifestations (as reflected by different possible disease states) in patients receiving either therapy. Given the expectation of similarity in terms of such costs, the current economic analysis submission is a cost-comparison model without health states—this submission does not include health-state-specific HCRU and associated costs.

Therefore, state-specific HCRU estimates and associated costs from the patisiran submission (HST10) are not relevant for this submission. The only HCRU differences expected between vutrisiran and patisiran are from their different routes of administration and the need for premedication with patisiran, which are conservatively accounted for in this cost-comparison model. For this reason, AE, miscellaneous, and end-of-life costs were not included in the current submission for vutrisiran.

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B.3 Clinical effectiveness

The comparable clinical efficacy of vutrisiran and patisiran supports a cost-comparison analysis for the appraisal of vutrisiran.

Trials that assessed vutrisiran and patisiran

• Pivotal phase 3 studies have assessed the safety and efficacy of vutrisiran (technology being evaluated) and patisiran (comparator technology) in hATTR amyloidosis with polyneuropathy. HELIOS-A assessed the efficacy and safety of vutrisiran, and APOLLO assessed the efficacy and safety of patisiran.

  • The vutrisiran-HELIOS-A evidence base included important outcomes also considered in the previous patisiran-APOLLO evidence base, including the primary outcome, change from baseline in mNIS+7, the key secondary outcome, change from baseline in Norfolk QoL-DN score, reduction of serum TTR levels, and other important exploratory outcomes.[4,6]

  • HELIOS-A randomised patients with hATTR amyloidosis with polyneuropathy to receive vutrisiran or patisiran (reference arm). Prespecified primary and secondary endpoint analyses, excluding the analysis of serum TTR reduction, compared vutrisiran to the APOLLO placebo group as an external control. A pre-specified non-inferiority analysis compared percent serum TTR reduction between the vutrisiran and patisiran arms.[4]

  • APOLLO randomised patients with hATTR amyloidosis with polyneuropathy to receive patisiran or placebo. Primary and secondary endpoint analyses involved comparison of the patisiran and placebo arms.[6]

Vutrisiran and patisiran provide comparable clinical efficacy

• Vutrisiran was shown to achieve comparable reductions in serum TTR levels to patisiran through Month 18 in HELIOS-A, as demonstrated by a prespecified statistical noninferiority analysis.[4]

• Post hoc analyses (Table 16) compared the HELIOS-A vutrisiran and patisiran arms on multiple outcomes at Month 18 of the study. In these analyses, vutrisiran and patisiran showed numerically comparable efficacy against clinical manifestations of hATTR amyloidosis with polyneuropathy, as noted by the EMA CHMP in their assessment report for vutrisiran,[12] and in the MHRA Orphan Drug Designation Assessment Report for vutrisiran.[13] These post hoc findings are consistent with the observation of comparable reductions in serum TTR and can be explained by the shared mechanism of action between patisiran and vutrisiran.

• • An NMA (B.3.9 Indirect and mixed treatment comparisons) of vutrisiran and patisiran using data from both available pivotal clinical trials for these medicines (HELIOS-A and APOLLO) demonstrated their comparable efficacy in all three measures evaluated:[14]

  • Likelihood of maintenance or improvement from baseline to Month 18 in PND score, a clinical outcome assessing both sensory as well as motor impairment and the associated impact on ambulation (which was used to define health states in the CEA model submitted for patisiran [HST10][2] ), indicating comparable benefit in terms of halting or reversing worsening of functional disability in patients with hATTR amyloidosis.

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• Change from baseline to Month 18 in the primary outcome of both pivotal studies, mNIS+7, which measures the totality of the sensorimotor and autonomic polyneuropathy (postural blood pressure [PBP]) in hATTR amyloidosis, indicating comparable benefits in terms of polyneuropathy impairment in patients with hATTR amyloidosis.

• Change from baseline to Month 18 in the key secondary outcome of both pivotal studies, Norfolk QoL-DN, indicating comparable benefits in HRQoL in patients with hATTR amyloidosis.

B.3.1 Identification and selection of relevant studies

See appendix D for full details of the process and methods used to identify and select the clinical evidence relevant to the technology being evaluated.

• Systematic literature reviews (SLRs) of relevant clinical and non-clinical evidence pertaining to predefined interventions for the treatment of adults with hATTR amyloidosis to support upcoming Health Technology Assessment (HTA) submissions for vutrisiran were conducted (searches were initially run in October 2021 and an update was executed in July 2022).

• A total of 1,697 unique records (+570 records in the update) were identified in the clinical and non-clinical SLRs combined, of which 273 (+92) full-text publications were screened using predefined PICOS criteria, resulting in:

  • 133 records for inclusion in the clinical SLR, representing 32 unique studies

  • Seven records for inclusion in the non-clinical SLR, representing four unique studies/analyses

  • No CCAs were identified in the non-clinical SLR

B.3.2 List of relevant clinical effectiveness evidence

A summary of the pivotal study (HELIOS-A) that demonstrated the clinical effectiveness of vutrisiran is provided in Table 8. In HELIOS-A, patients were randomised 3:1 to receive vutrisiran or patisiran.[4] In this pivotal trial, the clinical efficacy of vutrisiran was compared against an external placebo group from the APOLLO trial of patisiran in patients with hATTR amyloidosis with polyneuropathy.[6] A patisiran arm was included in HELIOS-A as a benchmark for comparing reductions in serum TTR between vutrisiran and patisiran. This within-study patisiran arm also allowed post hoc efficacy and safety comparisons between vutrisiran and patisiran, as well as validation of the use of the external control group from APOLLO for pre-specified efficacy comparisons in HELIOS-A (discussed further in B.3.3.1.2 Patisiran reference comparator arm).

The APOLLO study was reviewed by NICE in the appraisal of patisiran (HST10).[2] It is summarised in appendix D.

Table 8: Clinical effectiveness evidence; pivotal vutrisiran trial

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10-MWT, 10-metre walk test; hATTR, hereditary transthyretin-mediated amyloidosis; HRQoL, health-related quality of life; IV, intravenous; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; Q3M, quarterly; Q3W, once every 3 weeks; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; PND, polyneuropathy disability; R-ODS, Rasch-built Overall Disability Score; SC, subcutaneous; TTR, transthyretin.

B.3.3 Summary of methodology of the relevant clinical effectiveness evidence

A summary of the clinical methodologies used to assess vutrisiran is provided in Table 9.

Table 9: Comparative summary of trial methodology

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10-MWT, 10-metre walk test; BL, baseline; FAP, familial amyloid polyneuropathy; hATTR, hereditary transthyretinmediated amyloidosis; HST, Highly Specialised Technology guidance; HRQoL, health-related quality of life; IV, intravenous; KPS, Karnofsky Performance Scale; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; NIS, neuropathy impairment score; NIS-W, Neurological impairment score-weakness; Q3M, quarterly; Q3W, once every 3 weeks; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score; SC, subcutaneous; TTR, transthyretin.*APOLLO trial data was included in an NMA of vutrisiran and patisiran (B.3.9 Indirect and mixed treatment comparisons).[†] The term ‘FAP’ has historically been used to describe hATTR amyloidosis with polyneuropathy.[68,69] Thus, the patient populations in APOLLO and HELIOS-A had the identical hereditary condition, namely hATTR amyloidosis with polyneuropathy.

B.3.3.1 HELIOS-A study design

HELIOS-A was a phase 3, randomised, open-label, multicentre, global study to evaluate the efficacy and safety of vutrisiran over 18 months in patients with hATTR amyloidosis with polyneuropathy.[70] The study had two arms: a vutrisiran treatment arm and a patisiran treatment arm (reference arm).[70] Patients in HELIOS-A were randomised 3:1 to receive vutrisiran 25 mg SC Q3M or patisiran 0.3 mg/kg IV infusion Q3W for 18 months.[70] Randomisation was stratified by TTR genotype (V30M versus non-V30M) and baseline NIS score (<50 versus ≥50).[70]

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B.3.3.1.1 External placebo control arm

The placebo arm of the APOLLO study (NCT01960348), a phase 3 study that evaluated the efficacy and safety of patisiran in patients with hATTR amyloidosis, was used as an external control for the HELIOS-A study.[70] Specifically, the APOLLO placebo arm served as the prespecified comparator group for all primary and secondary endpoint analyses, excluding the analysis of serum TTR reduction. APOLLO enrolled a similar patient population to HELIOS-A and incorporated similar endpoints.[6]

Based on International Conference on Harmonisation (ICH), EMA, and FDA guidelines, an external comparison is an appropriate clinical study design for diseases occurring in small populations, when the natural history of the disease course is well understood.[71-73] The natural history of hATTR amyloidosis has been well-characterised in several large randomised controlled clinical trials (RCTs), including the APOLLO study, as well as observational natural history studies.[6,20,30,74 ]

Importantly, these studies all demonstrate similar rates of disease progression, despite having been conducted at substantially different points in time and in patients with varying disease characteristics across a range of geographies. Therefore, whilst the HELIOS-A and APOLLO trial populations were largely similar (as the inclusion criteria were very similar for both studies), any differences in baseline characteristics between the HELIOS-A and APOLLO populations do not invalidate the approach of using the placebo arm of APOLLO as the external control for vutrisiran in HELIOS-A. In view of the available data, there is no basis to expect that a different trend in mNIS+7 would have been observed in a placebo group in HELIOS-A, had one been included, and the placebo arm of the APOLLO study was therefore deemed an appropriate external control for the HELIOS-A study.

Use of an external placebo comparator in HELIOS-A was necessary due to ethical considerations preventing the inclusion of a within-trial placebo arm. According to the scientific recommendations of the EMA and the ICH, a study design involving a within-study placebo group would be unethical in a context where there are other therapeutic alternatives available that are known to prevent irreversible morbidity. In fact, as of mid 2022, no product in development for hATTR amyloidosis is being studied in a placebo-controlled trial (www.ClinicalTrials.gov). This includes the study of eplontersen in patients with hATTR amyloidosis with polyneuropathy by Ionis Pharmaceuticals, which is a phase 3, open-label trial,[75] as well as the ATTRibute-PN clinical trial (NCT04418024, NCT04882735) of acoramidis (AG10) in patients with ATTR amyloidosis with polyneuropathy, which was recently withdrawn by the sponsor.[76,77] The ATTRibute-PN trial was originally designed as a placebo-controlled trial but that design was withdrawn because “after a careful review of the currently available treatments worldwide for patients with ATTR-polyneuropathy, Eidos has made the decision to halt the current study design.” The ATTRibute-PN trial was then redesigned as a single-arm study.[76,77] In February 2022, the ATTRibute-PN trial was cancelled altogether.[76,77] This decision highlights the practical and ethical issues with conducting placebo-controlled trials in hATTR amyloidosis.

B.3.3.1.2 Patisiran reference comparator arm

The patisiran reference arm in the HELIOS-A study served as a benchmark for assessing whether TTR reduction with vutrisiran is noninferior to that seen with patisiran.[70] The sample size for the patisiran arm also provided >90% power to establish noninferiority of vutrisiran compared to patisiran with respect to TTR reduction at Month 18, assuming that both interventions have a similar effect on TTR reduction. As previously noted, this analysis was specified as a secondary endpoint.[70] At the request of the EMA and to support health technology assessment submissions, the patisiran reference comparator arm was also used for post hoc comparisons of mNIS+7, Norfolk QoL-DN, and 10-metre walk test (MWT) between vutrisiran and patisiran,[70] and data from the patisiran reference arm of HELIOS-A Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

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were also included in an NMA of patisiran, vutrisiran, and placebo.[14] The patisiran reference arm also provided a within-study comparison of safety outcomes for patisiran and vutrisiran. Finally, inclusion of a patisiran reference arm helped to validate use of the external control group from APOLLO for efficacy comparisons in HELIOS-A (by allowing assessment of the similarity of response to patisiran treatment between the HELIOS-A and APOLLO populations, as an indicator of comparability between these two populations).

It was not possible to perform a formal within-trial analysis for noninferiority of mNIS+7 results with vutrisiran versus patisiran in HELIOS-A because the trial could not be powered for this endpoint. An adequately powered, formal, direct noninferiority comparison between vutrisiran and patisiran based on mNIS+7 would require a study with a sample size of approximately 400 patients; recruiting a study population of such size would have been neither viable nor ethical in this rare, orphan disease where the estimated European prevalence is approximately 1/100,000.[55]

For APOLLO, the full trial population of 225 patients were enrolled in the study from December 2013 to January 2016. The APOLLO trial experience indicates that the time required to recruit a larger cohort of approximately 400 patients, to power a noninferiority comparison of mNIS+7 results between vutrisiran and patisiran, would have been infeasibly long. This issue would have been further exacerbated by the potentially reduced pool of eligible clinical trial participants after the APOLLO and NEURO-TTR trials had been completed, and by the increasing availability of patisiran and inotersen in clinical practice in various countries (thereby reducing the attractiveness of participating in trials of investigational therapies) at the time of enrolment for the HELIOS-A trial.

B.3.3.1.3 Patient selection criteria

Eligibility criteria of the HELIOS-A study are presented in Table 10. The eligibility criteria for APOLLO are provided in appendix D.

Table 10: HELIOS-A: Eligibility criteria

• Inclusion criteria • 18 to 85 years of age • PND score ≤IIIb • hATTR amyloidosis with documented • KPS ≥60% TTR variant • Willing and able to comply with the study

• • NIS of 5 to 130 requirements and provide written informed consent

• Exclusion criteria • Prior liver transplant or likely to undergo • Major surgery within the preceding 3 liver transplant during study treatment months or planned during study period treatment period

• • Known other (non-hATTR) forms of • Active infection requiring systemic amyloidosis antiviral, antiparasitic, or antimicrobial

• • Clinical evidence of leptomeningeal therapy that will not be completed prior to study drug dosing

• amyloidosis

• • NYHA Class >II • Malignancy within the past 2 years, except for basal or squamous cell

• • ALT and/or AST >1.5× ULN reference carcinoma of the skin or carcinoma in

• range situ of the cervix that has been

• • Total bilirubin >ULN (>1.5 ULN in

  • PND score ≤IIIb

  • • KPS ≥60% • Willing and able to comply with the study requirements and provide written informed consent

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ALT, alanine transaminase; ANC, absolute neutrophil count; AST, aspartate aminotransaminase; eGFR, estimated glomerular filtration rate; GalNAc, N-acetylgalactosamine; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; INR, international normalised ratio; KPS, Karnofsky performance status; LLN, lower limit of normal; MDRD, Modification of Diet in Renal Disease; NIS, Neuropathy Impairment Score; NYHA, New York Heart Association; PND, polyneuropathy disability; SC, subcutaneous; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TTR, transthyretin; ULN, upper limit of normal.

Sources: Alnylam Data on File. HELIOS-A 18-Month Clinical Study Report, 2022[78] ; Adams et al, 2022[4]

Key demographic and baseline characteristics for patients enrolled in the HELIOS-A trial and patients in the placebo arm of the APOLLO trial are presented in Table 11. Demographic and baseline characteristics were widely overlapping and clinically comparable across treatment groups.

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Table 11: HELIOS-A: Key demographic and baseline characteristics (safety and efficacy population)

hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; FAP, familial amyloid polyneuropathy; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; V30M, valine-to-methionine at position 30. *North America: USA, Canada; Western Europe: Belgium, France, Germany, Greece, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom; Rest of world: Argentina, Australia, Brazil, Bulgaria, Cyprus, Japan, Korea, Malaysia, Mexico, Taiwan, Turkey.[†] In the APOLLO study, NYHA class was classified as I through IV, without the option to

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categorise patients as having "no heart failure"; thus, patients classified as NYHA class I in APOLLO included both those without heart failure and those with heart failure who had no symptoms during ordinary physical activity. Source: Alnylam Data on File. HELIOS-A 18-Month Clinical Study Report, 2022[78] ; Adams et al, 2022[4] ; APOLLO Clinical Study Report.[79]

B.3.3.1.4 Assessments

The primary endpoint of the HELIOS-A study is based on mNIS+7, which assesses the progression of the motor and the sensory aspects of polyneuropathy, as well as some autonomic manifestations, such as postural hypotension, and correlates with both FAP and PND scores.[20] The mNIS+7 assessment scale ranges from 0 to 304 points. A score of zero equates to absence of polyneuropathy and the upper bound represents a maximally affected individual. Therefore, a negative change versus a patient’s own baseline represents neurologic improvement.[5,58,74]

A consensus report of the international Peripheral Nerve Society (PNS) defined a 2-point change as the minimal clinically important difference (MCID) for scores on the original NIS assessment (from which the mNIS+7 assessment is derived).[80] At present, MCID has not been defined for the mNIS+7 assessment used in APOLLO and HELIOS-A; however, given the rationale in the PNS consensus report and precedents in trials using NIS-LL and NIS+7 (i.e., other assessments derived from the NIS) as endpoints, a similar threshold of 2 points could be reasonably applied to mNIS+7.

In addition to mNIS+7, Norfolk QoL-DN was used in the HELIOS-A study to measure HRQoL,[5] R-ODS was used to measure the degree of limitations on everyday activities and social participation,[5] 10-MWT was used to measure gait speed,[70] and mBMI was used to measure nutritional status and wasting as an indicator of autonomic neuropathy.[70] All were secondary endpoints, with Norfolk-QoL-DN serving as the key secondary endpoint. Table 12 provides a summary of the assessments included in post hoc comparisons of patisiran and vutrisiran in HELIOS-A, including the directionality of measure and the MCID (results of post hoc analysis are provided in Table 16).

Table 12: Summary of assessments in HELIOS-A used for pos hoc comparison of patisiran and vutrisiran

10-MWT, 10-metre walk test; mBMI, modified body mass index; MCID, minimal clinically important difference; mNIS+7, modified Neuropathy Impairment Score +7; Norfolk QoL-DN, Norfolk Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score.

• The Norfolk QoL-DN score assesses 35 measures of symptoms and functional impairment related to nerve function, with higher scores indicating worse HRQoL.[5] An MCID of 8.8 points has recently been reported in the literature for Norfolk QoLDN.[81] Norfolk QoL-DN has also been demonstrated to correlate with FAP stages.[47]

• The R-ODS is a 24-item scale used to assess the ability to perform everyday activities, with a lower score indicating worsening disability.[5] The MCID of the R-ODS has not yet been reported in the literature. However, an analysis of data from APOLLO and the phase 2 patisiran OLE study indicated that the R-ODS is a reliable and valid measure of activity and social participation limitations in patients with hATTR amyloidosis.[83]

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• The 10-MWT measures the time taken to walk 10 metres without assistance from another person (although ambulatory aids such as canes as walkers are permitted).[70] The numerical output of the test is the patient’s walking speed in metres per second. At each time point, the test is performed on two separate occasions approximately 24 hours apart but not more than 7 days apart, with positive change values corresponding to improvement.[58,70] Among older adults, including those with mobility disabilities and subacute stroke survivors, a mean increase of 0.05 m/s represents a small meaningful change in gait speed while an increase of 0.10 m/s represents a substantial clinically meaningful change, based on distribution and anchor-based approaches.[82]

• mBMI is calculated as the product of BMI (weight in kilograms divided by the square of height in metres) and serum albumin (g/L).[70] mBMI is a measure of inanition/wasting, which is a leading cause of death in patients with hATTR amyloidosis.[44] While no MCID for mBMI has been established in hATTR amyloidosis, decreases in mBMI are associated with the presence of autonomic neuropathy and resulting malnutrition, which when severe, is a predictor of mortality.[84]

Quantification of serum TTR reduction in the HELIOS-A trial served as a secondary endpoint to compare the activity of patisiran and vutrisiran in a pre-specified non-inferiority analysis. PND score change from baseline was also evaluated in the trial as an exploratory endpoint, to assess polyneuropathy impairment and ambulation.

• Reductions in serum TTR are indicative of clinical efficacy, as TTR accumulation in tissues and organ systems leads to clinical manifestations of the disease.

• An improvement in PND score is indicative of improved ambulatory function. A finding of “no change” in PND score reflects preservation of ambulatory function and therefore a halting of advancing disease impairment, which is also a highly clinically meaningful outcome in this progressively disabling disease.

B.3.3.1.5 Blinding

As the HELIOS-A trial was an open-label study, data integrity was maintained by measures and strategies, including data access restrictions, designed to prevent or minimise potential unintentional biases during the conduct of the study.[78] These measures and strategies included the following:[78]

• Personnel performing mNIS+7 component assessments did not reference any previous assessments in order to minimise the potential for knowledge of prior assessments to influence subsequent assessments.

• Norfolk QOL-DN questionnaires were completed by the patients themselves without any assistance, to minimise potential for study personnel to influence interpretation of and responses to questionnaire items. Study personnel reviewed general instructions with patients and checked questionnaires for completeness only.

• mNIS+7 results were evaluated by certified, qualified personnel, who did not have access to the patients’ treatment assignments.

• Primary clinical research representatives and clinical operations staff did not have access to any mNIS+7 or Norfolk QoL-DN data in the electronic data capture system before the Month 9 primary analysis (Month 9 assessment served as the primary endpoint for the United States Food and Drug Administration and select other regulatory bodies; the EMA and MHRA retained Month 18 as the primary endpoint for analysis).

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• Primary clinical research and clinical operations study team representatives and study sites did not have access to pharmacodynamic (PD) or pharmacokinetic (PK) data or analyses based on actual treatment groups before the Month 9 primary analysis.

All other data, including treatment assignment, remained otherwise unrestricted to study members, given the open-label design and differences between study treatment administration methods.[78]

B.3.3.1.6 Endpoints

Efficacy outcomes for HELIOS-A are summarised in Table 9.

The safety and tolerability of vutrisiran in patients with hATTR amyloidosis with polyneuropathy were assessed through the surveillance and recording of AEs including serious adverse events (SAEs), recording of concomitant medication, physical examination, electrocardiogram (ECG) findings, laboratory tests, and measurements of vital signs, weight, and height.[70]

B.3.4 Statistical analysis and definition of study groups in the

relevant clinical effectiveness evidence

B.3.4.1 HELIOS-A overview

The modified intent-to-treat (mITT) population of the HELIOS-A study was defined as all randomised patients who received any amount of study drug.[70] The safety population was defined as all randomised patients who received any amount of study drug, grouped according to the treatment actually received.[70] For efficacy analyses, patients were analysed according to the treatment to which they were randomised.[58] The TTR per-protocol (PP) population was defined as the set of mITT population patients with a non-missing serum TTR assessment at baseline and ≥1 trough serum TTR assessment associated with adequate treatment compliance between Month 6 and Month 18.

HELIOS-A used the placebo group from the APOLLO study as an external control for efficacy analyses. Patient-level data from HELIOS-A were compared with patient-level data from APOLLO for these analyses. Analysis models compared vutrisiran (HELIOS-A) and the placebo group from APOLLO.[78,85]

A mixed-effects model for repeated measures (MMRM) was the default analysis for most continuous efficacy endpoints at Month 18 unless otherwise specified.[78] Maximum percentage reduction and mean percentage reduction from baseline in serum TTR over 18 months, and mean percentage reduction from baseline in serum TTR at steady state between Month 6 and Month 18 were summarised using descriptive statistics.[78]

B.3.4.2 HELIOS-A sample size determination

Enrolment of approximately 160 patients was planned for the HELIOS-A study.[86] The sample size was chosen to enable an adequate characterisation of the long-term safety profile, as well as the efficacy of vutrisiran in this patient population.

This sample size was chosen based on power analyses using data from the APOLLO trial. Specifically, for mNIS+7 change from baseline at 9 months, the observed mean (±standard deviation [SD]) was 15 ± 17 points for the placebo group from the APOLLO study. A mean change of 0 points from baseline was assumed for the vutrisiran group, resulting in >90% power to establish superiority over placebo at the target sample size using a 2-sided t-test

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with a significance level of 0.05. For the Norfolk QoL-DN total score change from baseline at 9 months, the observed mean (±SD) was 11.5 ± 19.2 points for the placebo group from the APOLLO study. By assuming a mean change of -4 points for the vutrisiran group, it was determined that the target sample size resulted in >90% power to establish superiority over placebo using a 2-sided t-test with a significance level of 0.05. The sample size chosen also provided >90% power to establish noninferiority of vutrisiran compared to patisiran in terms of percent reduction in serum TTR, assuming that vutrisiran and patisiran have a similar effect on TTR reduction.

For safety, a sample size of >100 patients on vutrisiran was considered to be able to provide reasonable assurance that the true cumulative 1-year incidence of an adverse drug event is no greater than 3% when that event is not observed during the trial.

B.3.4.3 HELIOS-A study hypotheses

For most inferentially-evaluated efficacy endpoints, the null hypothesis for the superiority comparison of vutrisiran vs placebo was defined as follows:

• H0: No difference between vutrisiran and placebo (APOLLO): difference (vutrisiran – placebo) = 0

• For the TTR percent reduction endpoint, the null hypothesis for the noninferiority comparison of vutrisiran vs patisiran was defined as follows:

  • H0: Vutrisiran is inferior to patisiran: difference in median TTR reduction (vutrisiran – patisiran) ≤ -10%

B.3.4.4 HELIOS-A statistical analyses

Statistical analyses used to evaluate outcomes in the HELIOS-A trial are summarised in Table 13.

Table 13: Analysis of primary and secondary endpoints in HELIOS-A

10-MWT, 10-metre walk test; BL, baseline; mBMI, modified body mass index; mITT, modified intent-to-treat; MMRM, mixed-effects model for repeated measures; mNIS+7, modified Neuropathy Impairment Score +7; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score; TTR, transthyretin; TTR PP, TTR perprotocol.

See appendix D for details of participant numbers and participant flow in HELIOS-A.

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B.3.5 Critical appraisal of the relevant clinical effectiveness

evidence

Results from the HELIOS-A trial are presented in this submission to demonstrate the clinical effectiveness of vutrisiran for patients with hATTR amyloidosis. These data were published in a peer-reviewed scientific journal in July 2022.[4] Table 14 presents quality assessment results for HELIOS-A. A similar table is provided for APOLLO in appendix D.

Table 14: Quality assessment results for HELIOS-A

Appendix D provides a detailed quality assessment for the HELIOS-A trial.

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B.3.6 Clinical effectiveness results

Demonstration of the comparable efficacy of vutrisiran and patisiran to support a cost-comparison analysis

• Vutrisiran was shown to reduce serum TTR levels with pharmacodynamic activity similar to that of patisiran through Month 18 in HELIOS-A, as demonstrated by a prespecified statistical noninferiority analysis.[4]

• In a post hoc analysis (Table 16) of primary and secondary endpoints assessed at Month 18, comparable outcomes with regard to clinical manifestations of hATTR amyloidosis with polyneuropathy were observed between the patisiran and vutrisiran arms in HELIOS-A, as expected based on the finding of similar pharmacodynamic activity between these two therapies. This was noted to demonstrate comparable clinical efficacy between patisiran and vutrisiran in the CHMP assessment report of vutrisiran,[12] which was also noted in the MHRA Orphan Drug Designation Assessment Report for vutrisiran.[13]

• Similarly, an NMA that compared vutrisiran and patisiran using data from both pivotal clinical trials for these medicines (APOLLO and HELIOS-A) reaffirmed comparable clinical efficacy regarding ambulatory ability, polyneuropathy impairment, and HRQoL (B.3.9 Indirect and mixed treatment comparisons).[14]

Clinical efficacy of vutrisiran versus external placebo

• Vutrisiran significantly improved neuropathy versus external placebo and halted the progression of polyneuropathy (as measured by mNIS+7) relative to pretreatment baseline through 18 months of treatment.[4]

• Vutrisiran significantly improved HRQoL compared with external placebo at Month 18 and halted the worsening of HRQoL (as measured by Norfolk-QoL-DN) relative to pre-treatment baseline through 18 months of treatment.[4]

• A significantly greater proportion of patients treated with vutrisiran experienced reversal in neuropathy impairment (mNIS+7) and improvement in HRQoL (Norfolk QoL-DN) from baseline through Month 18 compared with those treated with placebo.[78]

• Clinically and statistically significant benefits were observed for vutrisiran versus external placebo through 18 months of treatment for all other secondary endpoints, including 10-MWT, R-ODS, and mBMI,[4] indicating treatment benefits in terms of ambulatory ability, ability to perform activities of daily living, and nutritional status.

B.3.6.1 Change in serum TTR levels through Month 18

Vutrisiran demonstrated noninferiority compared to within-study patisiran in terms of PD activity, as the median treatment difference in TTR percent reduction from baseline (vutrisiran – patisiran) was 5.28% (95% CI, 1.17 to 9.25), the lower limit of which was above the prespecified noninferiority margin of -10%.[4,78] The time-averaged trough TTR percent reduction from baseline through Month 18 was 84.7% for vutrisiran and 80.6% for patisiran. Patients in the vutrisiran arm achieved sustained reduction in serum TTR levels comparable to patients in the patisiran arm.[4,78] The mean (SD) steady-state serum TTR reduction from baseline through Month 18 (Week 81) was 88% (16%) for the vutrisiran arm and 86% (10%) for the patisiran arm.[4,78]

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Figure 4: HELIOS-A secondary endpoint: change in serum TTR levels through Month 18

==> picture [417 x 218] intentionally omitted <==

SE, standard error; TTR, transthyretin. Source: Adams et al, 2022[4]

B.3.6.2 Main clinical endpoint included in the cost-effectiveness analysis of patisiran (HST10): change in PND score from baseline to Month 18

At Month 18 in HELIOS-A, change in PND score from baseline (improved, no change, or worsened) was assessed (Table 15).[85] Similar trends in maintenance or improvement in PND score are evident for patisiran and vutrisiran. The comparable efficacy of vutrisiran and patisiran regarding PND score change from baseline has also been demonstrated via NMA (B.3.9 Indirect and mixed treatment comparisons).

Table 15: Change in PND score for patisiran and vutrisiran

Source: HELIOS-A Clinical Study Report[79,85]

B.3.6.3 HELIOS-A primary endpoint: change in mNIS+7 from baseline at Month 18

At Month 18, the LS mean change from baseline in mNIS+7 was significantly more favourable for the vutrisiran arm compared with the APOLLO placebo arm, with a treatment difference of −28.55 (p<0.0001; Figure 5).[4] The LS mean change from baseline at Month 18 was −0.46 for the vutrisiran arm, where a negative value indicates overall improvement compared to baseline, while the LS mean change from baseline at Month 18 was 28.09 for the placebo arm, where a positive value indicates overall worsening compared to baseline.[4] In APOLLO, patisiran also demonstrated significant benefit versus placebo when considering LS mean change from baseline in mNIS+7.[6] The comparable efficacy of vutrisiran and

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patisiran regarding mNIS+7 change from baseline has been demonstrated via post hoc analyses of data from HELIOS-A (Table 16) and via NMA (B.3.9 Indirect and mixed treatment comparisons).

Figure 5: HELIOS-A primary endpoint: mNIS+7 change from baseline at Month 18

==> picture [452 x 160] intentionally omitted <==

*Number of evaluable patients.[†] Data presented at Month 9 obtained from the completed Month 9 primary analysis. CI, confidence interval; LS, least squares; mNIS+7, modified Neuropathy Impairment Score+7; SE, standard error. Source: Adams et al, 2022[4]

Vutrisiran also demonstrated statistically significant benefit compared to placebo for all secondary endpoints in HELIOS-A. These are presented in appendix J.

B.3.6.4 Post hoc within-study comparison of patisiran and vutrisiran in HELIOS-A

A post hoc analysis of key efficacy endpoints at Month 18 was conducted using MMRM to compare treatment outcomes between the vutrisiran and patisiran groups within the HELIOS-A trial.[12] Overall, the vutrisiran arm showed similar results to the within-study patisiran arm of the HELIOS-A trial (Table 16).[12] From baseline to Month 18, the LS mean difference between the vutrisiran and patisiran arms of the HELIOS-A trial was −1.46 (95% CI −7.36, 4.43) for change in mNIS+7, −1.6 (95% CI −8.6, 5.4) for change in Norfolk QOLDN, 0.034 (95% CI −0.064, 0.132) for change in 10-MWT, 14.2 (95% CI −21.9, 50.3) for mBMI, and 0.1 (95% CI −2.0, 2.2) for change in R-ODS.[12]

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Table 16: Post hoc within-study comparison of the vutrisiran and patisiran arms of the HELIOS-A trial at Month 18

10-MWT, 10-metre walk test; CI, confidence interval; LS, least squares; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score+7; Norfolk QOL-DN, Norfolk Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score; SD, standard deviation; SEM, standard error of the mean. Source: CHMP Assessment Report[12]

These differences between vutrisiran and patisiran were neither statistically nor clinically significant. In terms of clinical significance, the mean difference between vutrisiran and patisiran was well below the MCID that has been reported in the literature for all measures where such a threshold has been established (mNIS+7: 2 points; Norfolk-QoL-DN, 8.8 points; 10-MWT, 0.10 m/s).

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B.3.7 Subgroup analysis

Subgroup analyses are not presented as vutrisiran provides clinical benefits comparable to those of patisiran in the full indicated population, which is identical to the population indicated for patisiran in HST10.[2]

B.3.8 Meta-analysis

As no further phase 3 RCTs studying the efficacy and safety of vutrisiran for patients with hATTR amyloidosis with polyneuropathy were found, no meta-analysis was conducted.

B.3.9 Indirect and mixed treatment comparisons

In appendix D, full details of the methodology for the NMA are included. A copy of the NMA report is included with the submission.

To further assess the relative efficacy of vutrisiran and patisiran using a comprehensive set of data from pivotal trials, an NMA was conducted that included the two arms from HELIOSA (vutrisiran and patisiran) and the 2 arms from APOLLO (patisiran and placebo), as depicted in Figure 6.[14] The NMA assessed the efficacy of vutrisiran and patisiran across three key outcomes of hATTR amyloidosis with polyneuropathy, in line with the anticipated indication for vutrisiran: PND score, mNIS+7, and Norfolk QoL-DN score.

Figure 6: Diagram of evidence network assessing vutrisiran and patisiran

==> picture [261 x 163] intentionally omitted <==

Overall, the NMA found that the estimated likelihood of achieving improvement or no change in PND score from baseline to Month 18 was comparable for vutrisiran and patisiran. Improving or stabilizing PND score (i.e., avoiding worsening of PND score) is of clear clinical value, as the normal natural history of polyneuropathy of hATTR amyloidosis is marked by progressive disability, and each change in PND score category represents a concrete, marked change in ambulatory status. Therefore, the results of the NMA provide further evidence of similar clinical efficacy for vutrisiran and patisiran on the outcome of ambulatory ability. This finding was consistent between an analysis involving imputation of missing data (Table 17 and Table 18) and an analysis considering observed data only (Table 19 and Table 20). The analysis method involving imputation assumes missing patient data to be indicative of worsening in PND score, while the method using observed data does not consider missing data as part of the analysis.

Estimated differences between patisiran and vutrisiran in terms of the magnitude of their effect on mNIS+7 score change from baseline were also not clinically meaningful (Table 21), based on an MCID threshold of 2 points. This finding substantiates the similar efficacy of

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vutrisiran and patisiran in treating polyneuropathy in patients with hATTR amyloidosis. The estimated median difference in Norfolk QoL-DN score change between patisiran and vutrisiran was also small and not clinically meaningful based on an 8.8-point MCID threshold,[81] indicating that vutrisiran and patisiran have comparable efficacy on the outcome of HRQoL in patients with hATTR amyloidosis (Table 22).

In summary, the results of this NMA across all outcomes analysed demonstrate comparable clinical efficacy for patisiran and vutrisiran when considering key outcome measures used to assess patients with hATTR amyloidosis with polyneuropathy.

Table 17: Pairwise risk ratios between treatments for achieving the binary outcome of improvement or no change (vs. worsening) in PND score using imputed data*

• *Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; RR, risk ratio.

Table 18: Pairwise odds ratios between treatments for achieving the binary outcome of improvement or no change (vs. worsening) in PND score using imputed data*

• *Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; OR, odds ratio.

Table 19: Pairwise risk ratios between treatments for achieving the binary outcome of improvement or no change (vs. worsening) in PND score using observed data*

• *Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; RR, risk ratio

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Table 20: Pairwise odds ratios between treatments for achieving the binary outcome of improvement or no change (vs. worsening) in PND score using observed data*

*Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; OR, odds ratio.

Table 21: Pairwise comparison between treatments on mNIS+7 score*

*Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; mNIS+7, modified Neuropathy Impairment Score +7.

Table 22: Pairwise comparison between treatments on Norfolk QoL-DN score*

*Treatment arm listed in column represents reference group for each pairwise comparison. CrI, credible interval; Norfolk QoL-DN, Norfolk Quality of Life-Diabetic Neuropathy.

Uncertainties in the indirect and mixed treatment comparisons

This NMA benefits from high-quality data from RCTs that have comparable study populations and use identical outcome measures. Notably, HELIOS-A and APOLLO had the same inclusion/exclusion criteria. In addition, the binary outcome of improvement or no change in PND score and the continuous outcome of mNIS+7 and Norfolk QOL-DN score were assessed in the two trials based on the same definitions and assessment timeframe. The overall comparability across the two RCTs served as the foundation for assessing comparative efficacy via this NMA.

The results of this study should be considered in light of its limitations. First, the evidence network was sparse (i.e., only one trial per link), which did not allow reliable estimation of the potential between-study variance using a random-effects model. Second, a non-trivial proportion of patients in HELIOS-A and APOLLO had missing PND score, mNIS+7, and/or Norfolk QOL-DN scores.

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no change in PND scores by treatment arm: a non-responder imputation (NRI) analysis and analysis considering only observed data, without any imputation. The NRI method results in conservative estimates of the percentage of patients with improvement or no change in PND score in all treatment arms in the evidence network, since it imputes all missing data as a worsening of PND score. In contrast, the approach using observed data only assumes a random pattern of missing data and results in less conservative estimates of the percentage of patients achieving the outcome of interest in all treatment arms in the evidence network.

The treatment efficacy of vutrisiran and patisiran, respectively, relative to placebo on the binary outcome of achieving improvement or no change in PND score was estimated to be slightly stronger when using an NRI approach, due to higher rates of missingness observed in the placebo arm than in the vutrisiran and patisiran arms. Nonetheless, irrespective of the approach used to handle missing data, the estimated likelihood of achieving improvement or no change in PND score was highly similar for vutrisiran vs. patisiran (risk ratio [95% CI]: ***************** NRI, ; observed data, ******************. The robustness of this finding to different assumptions about missing data, together with the known correlation of both mNIS+7 and Norfolk-QoL-DN scores with ambulatory status in hATTR amyloidosis, suggests that uncertainties related to the impact of missing data do not alter the conclusion that vutrisiran and patisiran provide comparable efficacy on the outcomes of ambulatory ability, polyneuropathy impairment, and HRQoL in hATTR amyloidosis with polyneuropathy.

B.3.10 Adverse reactions

• At 18 months, vutrisiran was well tolerated, with no safety signals relating to laboratory values, low discontinuation rates, and no serious safety concerns.[78]

• Vutrisiran and patisiran have comparable safety and tolerability in patients with hATTR amyloidosis; however, there is a risk of IRRs associated with the IV infusion of patisiran, which is obviated by the SC administration of vutrisiran.

Through 18 months of treatment in HELIOS-A, vutrisiran was well tolerated and the majority of AEs were mild or moderate in severity, comparable to safety outcomes for patisiran assessed in HELIOS-A and APOLLO.[78,79] In HELIOS-A, there were no treatment-related discontinuations or deaths with either vutrisiran or patisiran.[78] AEs were consistent with the underlying disease pathology, informed by observations of the APOLLO placebo arm.[78] No safety signals in laboratory values were identified, and no hepatic safety concerns were observed.[78] Summaries of the safety results and most common AEs from HELIOS-A and APOLLO are provided in Table 23 and Table 24.

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Table 23: Summary of safety results at Month 18 for patisiran and vutrisiran from HELIOS-A

AE, adverse event; SAE, serious adverse event. *External placebo group was from the APOLLO trial. Source: Adams et al, 2022[4]

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Table 24: AEs (≥10%) in any treatment group at Month 18: HELIOS-A

AE, adverse event; IRR, infusion-related reaction; UTI, urinary tract infection. *External placebo group was from the APOLLO trial. Source: Adams et al, 2022[4] ; Alnylam Data on File. HELIOS-A 18-Month Clinical Study Report, 2022[78]

Based on the collective data from APOLLO and HELIOS-A, it can be seen that both patisiran and vutrisiran provide comparable and acceptable safety and tolerability profiles for patients with hATTR amyloidosis with polyneuropathy. AEs observed with both agents were consistent with the underlying disease pathology, informed by observations of the APOLLO placebo arm.[78] A standout grouping of AEs that should be noted are IRRs in patisirantreated patients. In contrast to patisiran, which is administered via IV infusion, Vutrisiran is administered via the SC route, and therefore, the potential for IRRs is obviated, as observed in the HELIOS-A trial.

B.3.11 Conclusions about comparable health benefits and safety

• Vutrisiran has shown a comparable efficacy and safety profile to patisiran in patients with hATTR amyloidosis with polyneuropathy.

• Vutrisiran was shown to reduce serum TTR levels with pharmacodynamic activity similar to that of patisiran through Month 18 in HELIOS-A, as demonstrated by a prespecified statistical noninferiority analysis.[4]

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• In a post hoc analysis (Table 16) of primary and secondary endpoints assessed at Month 18, comparable outcomes with regard to clinical manifestations of hATTR amyloidosis with polyneuropathy were observed between the patisiran and vutrisiran arms in HELIOS-A, as expected based on the finding of similar pharmacodynamic activity between these two therapies. This analysis was noted to demonstrate comparable clinical efficacy between patisiran and vutrisiran in the CHMP assessment report of vutrisiran,12 which was also noted in the MHRA Orphan Drug Designation Assessment Report.[13]

• Similarly, an NMA that compared vutrisiran and patisiran using data from both pivotal clinical trials for these medicines (APOLLO and HELIOS-A) reaffirmed comparable clinical efficacy regarding ambulatory ability, polyneuropathy impairment, and HRQoL.[14]

In the HELIOS-A trial, vutrisiran was shown to be an efficacious treatment for patients with hATTR amyloidosis with polyneuropathy, with demonstrated benefits over external placebo in terms of all primary and secondary endpoints, covering the full range of clinical and humanistic impacts of this disease.[4]

A prespecified within-study noninferiority analysis of serum TTR reduction for vutrisiran and patisiran in HELIOS-A demonstrated that vutrisiran and patisiran had similar pharmacodynamic activity as measured by reduction of serum TTR levels over 18 months.[4] This finding provides a biological basis for the comparable clinical benefits of these siRNA therapeutics, as reductions in serum TTR decrease TTR deposition in tissues and organs, which is responsible for the clinical manifestations of hATTR amyloidosis.[18,19,32,35] As expected in view of their similar pharmacodynamic activity, a post hoc analysis of key efficacy parameters using MMRM for the within-study comparison of the vutrisiran and patisiran arms of the HELIOS-A study showed similar results for these two siRNA therapies in terms of change in polyneuropathy involvement (mNIS+7), quality of life (Norfolk QoLDN), gait speed/ambulatory ability (10-MWT), nutritional status (mBMI), and disability (RODS). These analyses have supported conclusions made in the CHMP Assessment Report and the MHRA Orphan Drug Designation Assessment Report for vutrisiran that patisiran and vutrisiran had comparable results in clinical endpoints in HELIOS-A.[12,13]

Furthermore, a comparison of vutrisiran and patisiran via an NMA that considered data from both pivotal clinical trials for these therapies, HELIOS-A and APOLLO, further supports their comparable clinical effectiveness. The NMA, which assessed key outcomes of hATTR amyloidosis with polyneuropathy (change in PND score, mNIS+7 and Norfolk-QoL-DN), was developed in line with NICE methods for assessing comparative effectiveness through indirect comparisons. These outcomes were all assessed in HST10 for patisiran.[2]

PND score change from baseline in APOLLO was the main outcome measure that informed the patisiran cost-effectiveness model in HST10.[2] NMA of this endpoint, which reflects a change in ambulatory function and thereby a broader change in disease status, across HELIOS-A and APOLLO showed similar outcomes between vutrisiran and patisiran in terms of the likelihood of maintenance or improvement of PND score.[14] This indicates that vutrisiran is comparable to patisiran when considering the primary clinical outcome that was included in the CEA used to assess patisiran.

NMA of mNIS+7 and Norfolk QOL-DN, which are reflective of polyneuropathy impairment and HRQoL respectively, across HELIOS-A and APOLLO once again showed similar treatment effects between vutrisiran and patisiran, further establishing the comparable clinical effectiveness of these siRNA therapies.

Both vutrisiran and patisiran showed acceptable safety profiles for patients with hATTR amyloidosis with polyneuropathy. Additionally, due to its SC administration, vutrisiran

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eliminates the risk of IRRs associated with the IV route of administration required for patisiran.

In addition to providing similar efficacy and acceptable safety, vutrisiran offers advantages over patisiran in terms of less frequent dosing and less burdensome administration, through fixed-dose SC injection every 3 months with no requirement for drug monitoring. In contrast, patisiran is administered more frequently (Q3W), dosing is weight-based, and administration involves IV infusion, which requires premedication to reduce the risk of IRRs as well as monitoring of patients for IRRs.[10] The advantages of vutrisiran are be expected to yield benefits over patisiran, including avoidance of the risk of IV administration-related AEs or weight-based dosing errors, reduced travel and time demands for patients and caregivers, reduced HCRU, and lower burden to the NHS. Consistent with these expectations, the EMA COMP has recognised that vutrisiran offers meaningful benefit to patients in terms of reduced treatment burden, based on survey data from the HELIOS-A trial demonstrating patients’ preference for treatment with vutrisiran over patisiran.[55] The patient preference for vutrisiran over patisiran based on the HELIOS-A survey was also noted in the MHRA Orphan Drug Designation Assessment Report for vutrisiran.[13]

Vutrisiran is expected to represent a step-change in the management of hATTR amyloidosis with polyneuropathy in the UK. Specifically, NAC clinicians ************************************ ******************************************************************************************************* and ****************************************************************************************, have informed Alnylam that they foresee vutrisiran supplanting patisiran as the standard of care for patients with hATTR amyloidosis with polyneuropathy in the UK. This view was echoed by NAC expert feedback received during the scoping of the present appraisal.

In view of its intended use and the body of evidence showing clinical efficacy similar to that of patisiran (with further advantages related to SC administration), the benefits of vutrisiran are demonstrated in a cost-comparison analysis presented in B.4 Cost-comparison analysis.

B.3.12 Ongoing studies

The open-label extension study of HELIOS-A is currently ongoing. However, Alnylam does not anticipate that data from this study will provide additional evidence for vutrisiran in the next 12 months for the condition being appraised.

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B.4 Cost-comparison analysis

B.4.1 Changes in service provision and management

B.4.1.1 Place of administration

The NAC provides the only highly specialised service for patients with amyloidosis in England and all patients with hATTR amyloidosis with polyneuropathy will have treatment initiated by clinicians at the NAC.

Vutrisiran is administered SC Q3M. The first dose of vutrisiran is expected to be administered by an HCP at the NAC, with subsequent doses expected to be administered by a nurse practitioner in a home-care setting, every three months.[1,3]

Patisiran, the comparator in the company submission, is administered IV Q3W. The SmPC for patisiran states that patients can be considered for home administration of patisiran after at least 3 well-tolerated infusions at the clinic.[10,11] Following treatment initiation, all patisiran patients in England receive subsequent doses via Lloyds clinical homecare by a nurse practitioner in a home-care setting, every three weeks.

Assumptions and inputs regarding the administration of patisiran or vutrisiran at home or in clinical settings in the cost-comparison analysis (CCA), based on current practices and expectations regarding place of administration, are summarised in B.4.2.1 Features of the CCA, and associated costs to NHS are summarised in B.4.2.2 Costs in the CCA.

B.4.1.2 Administration-related resource use

Vutrisiran is administered via SC injection and is supplied in a pre-filled syringe.[1] Patisiran is supplied in a vial and is intended for IV infusion.[10,11] The time and cost requirements for IV administration versus SC administration are significant. Infusion with patisiran takes approximately 80 minutes, which includes two separate stages of infusion: an initial slowrate 15-minute infusion followed by infusion at an increased rate for the remainder of the session.[10,11]

Due to the differences in route of administration, there are additional healthcare resource requirements associated with patisiran. Specifically, due to the risk of IRRs from the IV administration of patisiran, a premedication regimen administered 60 minutes prior to patisiran infusion is required.[10,11] This is associated with additional costs and time requirements for HCPs. Due to the risks of IRRs with patisiran, there is also a need for HCPs to monitor patients during and after patisiran infusion.[10,11]

Altogether, the time requirements for HCPs for the administration of patisiran are understood to exceed *** hours,[3] whereas total administration time for vutrisiran is estimated to be less than 5 minutes.

B.4.1.3 Posology

Vutrisiran

The recommended dose of vutrisiran is 25 mg administered via SC injection once every 3 months.[1]

Patisiran

The recommended dose of patisiran is 0.3 mg per kg body weight administered via IV infusion once every 3 weeks. Dosing is based on actual body weight. For patients weighing ≥100 kg, the maximum recommended dose is 30 mg.[11]

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B.4.2 Cost-comparison analysis inputs and assumptions

B.4.2.1 Features of the CCA

The objective of the CCA was to evaluate the costs associated with using vutrisiran or patisiran to treat patients with hATTR amyloidosis with polyneuropathy from a UK NHS perspective.

To perform this comparison, a CCA model was developed in Microsoft Excel[®] . The model compares the costs associated with the use of vutrisiran or patisiran for treating patients with hATTR amyloidosis with polyneuropathy in the UK over a 5-year period. The model incorporates acquisition costs, posology, administration frequency and type, premedication requirements, and treatment discontinuation rates. The general features of the CCA are summarised in Table 25.

Table 25: Features of the CCA model for vutrisiran vs. patisiran

CCA, cost-comparison analysis; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; IV, intravenous; Q3M, quarterly; Q3W, once every 3 weeks; SC, subcutaneous.

B.4.2.1.1 Time horizon

The base-case time horizon used in the CCA is 5 years. Five years was selected as an adequate time horizon to demonstrate differences in the costs associated with patisiran and vutrisiran, in alignment with recently published NICE cost-comparison appraisals that used the same time horizon (TA734 and TA803),[15,16] and given that key aspects of treatment administration that may impact cost are either time-invariant (e.g., monitoring requirements, dose frequency) or are likely to reach a “steady state” (e.g., site of administration) as early as the second dose of treatment. Time horizons of 2 and 10 years are additionally provided as scenario analyses in the CCA.

B.4.2.1.2 Patient characteristics and posology

Based on the HELIOS-A trial and the prescribing label for vutrisiran,[1] this CCA assumes one unit (25 mg) as the required dose of vutrisiran per administration, with administration required four times annually.

The mean number of patisiran vials used per patient per administration in the CCA was based on historical UK-specific data on administration of patisiran from Lloyds Pharmacy Clinical Homecare.[87] The vast majority of UK patients are represented in this estimation since, as noted in B.4.1.1 Place of administration, almost all UK patients receive patisiran via

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Lloyds Clinical Homecare following treatment initiation at the NAC. Alnylam understands the estimation from Lloyds is based on deliveries made for the purpose of a nurse visit to perform drug infusion and thus is representative of infused vials. ******************************* *********************************************************************************************************

********************** . This figure is therefore included in the CCA as the mean number of vials of patisiran used per administration.

Alnylam believes that this is the most robust estimate available for patisiran vial utilisation in the UK, since it reflects an independently generated estimate of current real-world utilisation in the UK population, with the vast majority of UK patients captured.

An additional scenario analysis is included where estimated mean patisiran vials used per administration is based on the bodyweight distribution observed in patients in HELIOS-A.

B.4.2.1.3 Drug administration

Different drug administration profiles are used in the CCA for vutrisiran and patisiran. Based on clinician input, the initial SC administration for vutrisiran in the CCA is assumed to be at the NAC, with all subsequent administrations occurring at home.[3] Vutrisiran is assigned an administration frequency of four times per year, based on its Q3M dosing regimen.

Based on the patisiran SmPC, it is assumed that patients receive three initial IV infusions of patisiran at the NAC, while all subsequent infusions are administered via homecare.[10,11] Patisiran is administered Q3W;[10,11] accordingly, in the model, it is assigned an administration frequency of 17.39 times per year.

B.4.2.1.4 Premedication

The extra costs associated with the premedication regimen required for patisiran must also be considered in the CCA. As described in B.4.1.2 Administration-related resource use, a premedication regimen is required prior to IV infusion of patisiran to reduce the risk of IRRs.[10,11] The SC administration profile of vutrisiran obviates requirement for premedication to minimise IRR risk.[1] The cost of premedication is incorporated for every infusion of patisiran.

B.4.2.1.5 Time on treatment

In the CCA, time on treatment (ToT) represents time to discontinuation of treatment from all causes excluding death. ToT was assumed to be equivalent for both vutrisiran and patisiran based on the rate of patient discontinuation in HELIOS-A and on input from clinical experts at the NAC.[3]

To compare extrapolations of ToT in HELIOS-A for vutrisiran and patisiran, Kaplan–Meier (KM) treatment discontinuation curves were generated from observed data in the HELIOS-A trial from baseline to Month 18. Based on these curves, parametric models were generated to extrapolate ToT across the 5-year time horizon. Akaike information criterion (AIC) and Bayesian information criterion (BIC) estimators were used to evaluate the relative quality (i.e., fit) of the parametric models considered, namely Exponential, Weibull, Log-Normal, Log-Logistic, Gompertz, and Gamma. Based on AIC and BIC estimators, the Exponential parametric function was selected to model ToT for both patisiran and vutrisiran in the CCA. After 5 years, estimates for the proportion of patients on treatment are very similar across treatment arms (91.98% for vutrisiran and 91.94% for patisiran). Therefore, ToT for patisiran was set as equal to ToT for vutrisiran in the base-case analysis.

A scenario analysis is included in the CCA where patisiran ToT is extrapolated from patisiran discontinuation data in HELIOS-A. Further details regarding the determination of ToT in the CCA are provided in appendix K.

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B.4.2.1.6 Discount rate

In the NICE user guide for submitting single technology cost-comparison assessments, it is stated that discounting of costs is not normally required for cost comparison. Accordingly, the discount rate is set to zero in the base-case scenario.

B.4.2.2 Costs in the CCA

Costs in the CCA include drug acquisition costs and costs for healthcare resource utilisation. Healthcare resource utilisation costs include costs for administration and the required premedication regimen for patisiran. Drug acquisition costs reflect a proposed simple discount PAS for vutrisiran and the approved simple discount PAS for patisiran.

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B.4.2.2.1 Intervention and comparators’ acquisition costs

A summary of the acquisition costs for vutrisiran and patisiran is provided in Table 26.

Table 26: Acquisition costs of the intervention and comparator technologies per patient

VAT, value-added tax. *Acquisition costs do not incorporate time on treatment.

£********* is the cumulative cost of acquisition of vutrisiran over 5 years. †£********** is the cumulative cost of acquisition of patisiran over 5 years.

B.4.2.2.2 Intervention and comparators’ healthcare resource use and

associated costs

The costs associated with HCRU for vutrisiran and patisiran in the CCA are summarised in Table 27. These include costs for home and in-clinic (NAC) SC administration for vutrisiran and home and in-clinic (NAC) IV administration and premedication for patisiran. The cost of IV administration of patisiran at home in the CCA is assumed to be equal to administration cost at the NAC. A scenario analysis that includes home administration costs equal to 125% and 150% of the cost of administration at the NAC is also provided, as added costs for homecare are estimated to be incurred in real-world practice.

In appendix G, a description of how relevant cost and HCRU data for England were identified is provided.

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Table 27: Summary of healthcare resource use and costs

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HCP, healthcare professional; HRG, Healthcare Resource Group; IV, intravenous; MIMS, Monthly Index of Medical Specialties; NAC, National Amyloidosis Centre; NHS, National Health Service; PSSRU, Personal Social Services Research Unit; SC, subcutaneous; UK, United Kingdom. *Resource costs for the full time horizon (5 years) do not incorporate time on treatment.

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Premedication dosage and associated costs for a single administration of patisiran (as used to inform the total unit cost of premedication listed in Table 27) are presented in Table 28.

Table 28: Patisiran premedication costs

B.4.2.3 Adverse reaction unit costs and resource use

AEs observed in the HELIOS-A trial for patisiran and vutrisiran were generally similar,[4] and were therefore not incorporated into the CCA as a simplifying assumption to facilitate decision-making. It is noted that IV administration of patisiran, but not SC administration of vutrisiran, is associated with the risk of IRRs, so this assumption of similar safety profiles for both therapies could be regarded as conservative. As explained above, costs associated with the premedication regimen required for patisiran to reduce the risk of IRRs are incorporated into the CCA.

B.4.2.4 Miscellaneous unit costs and resource use

All costs related to the CCA have been described.

B.4.2.5 Clinical expert validation

In 2022, Alnylam Pharmaceuticals solicited expert opinion to validate the current clinical pathway for hATTR amyloidosis with polyneuropathy, how vutrisiran would be positioned in the current clinical pathway of care, and key modelling approaches, inputs, and assumptions from a clinical perspective for the economic analysis of vutrisiran. The criteria for selecting clinical experts consisted of ensuring clinicians:

• Were members of the amyloidosis highly specialised service at the NAC at the Royal Free Hospital, London.

• Were responsible for the treating patients with hATTR amyloidosis with polyneuropathy with existing NICE recommended therapies, patisiran and inotersen.

• Had been investigators in the HELIOS-A study programme, to obtain their insights into how vutrisiran would be utilised in the current clinical pathway based on their hands-on experience using vutrisiran in HELIOS-A.

Two UK-based clinical experts meeting all of these criteria were approached to participate in web-based interviews: ******************************************************************************* ************************************************************ and ***************************************

• ************************************************. Both clinical experts agreed to these interviews.

In total, three interviews (17[th] March, 12[th] September and 20[th] September) were conducted, lasting between 30–60 mins each and both clinical experts attended all three interviews.

Both clinicians are investigators on ongoing studies for Alnylam and other competitor manufacturers and products. They have served as congress speakers for Alnylam as well as competitor manufacturer and products

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The information provided by Alnylam and verbalised during interviews as background for discussion consisted of:

• An overview of the HELIOS-A study and its results.

• Alnylam’s estimation of the time and burden associated with IV administration of patisiran, where clinical expert validation was sought.

• Alnylam’s estimation of the benefits offered by vutrisiran relative to patisiran, where clinical expert validation was sought.

Feedback on key model inputs and assumptions as discussed in these interviews are summarised in Table 29.

Table 29: Clinical validation

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hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; HCP, healthcare professional; IV, intravenous; NAC, National Amyloidosis Centre; SC, subcutaneous; SmPC, Summary of Product Characteristics; Q3M, quarterly; Q3W, once every 3 weeks; UK, United Kingdom.

B.4.2.6 Uncertainties in the inputs and assumptions

The CCA is aligned with the approved UK and EU product labels for patisiran and the expected product label for vutrisiran in terms of administration practices.[1,10,11] Modelling choices and assumptions made in the CCA are presented in Table 30.

Table 30: Assumptions in the CCA

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IV, intravenous; NAC, National Amyloidosis Centre; NHS, National Health Service; SC, subcutaneous; ToT, time on treatment UK, United Kingdom.

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B.4.3 Base-case results

Results from base-case analysis from the CCA are presented in Table 31. The total costs for 5 years of treatment in England, including drug acquisition costs, drug administration costs, and patisiran premedication costs, with ToT incorporated, are £******* for vutrisiran and £******* for patisiran. A cost differential of £****** between the two treatments shows vutrisiran to be a cost-saving option for the treatment of patients with hATTR amyloidosis with polyneuropathy.

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Table 31: Results from base-case analysis

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B.4.4 Sensitivity and scenario analyses

B.4.4.1 One-way sensitivity analyses

To evaluate the sensitivity of model results to variation in input parameters, a series of oneway sensitivity analyses (OWSA) were performed where key model parameters were varied one at a time around their base-case values. The 95% CI was approximated by setting high and low values as the base case ± 1.96 times the standard error (SE). When the SE was not available, 10% of base-case value was used to approximate the SE. High and low values used in the OWSA are presented in Table 32.

Table 32: Values used in OWSA

IV, Intravenous; OWSA, one-way sensitivity analysis; SC, subcutaneous. *Patients not receiving vutrisiran or patisiran at home are assumed to continue at the NAC.

Changes in incremental costs with changes in each parameter are ranked and summarised in Table 33 and depicted in Figure 7. As can be seen, the model was most sensitive to changes in the cost of IV infusion of patisiran in homecare settings. In contrast, if the cost of SC administration of vutrisiran is modified in the CCA, the outcome on total cost is significantly less impacted.

Table 33: Ranked OWSA incremental cost variations

IV, intravenous; OWSA, one-way sensitivity analysis; SC, subcutaneous. *Patients not receiving vutrisiran or patisiran at home are assumed to continue at the NAC.

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Figure 7: OWSA tornado plot

==> picture [459 x 203] intentionally omitted <==

IV, intravenous; OWSA, one-way sensitivity analysis; SC, subcutaneous. *Patients not receiving vutrisiran at home are assumed to continue at the NAC.

B.4.4.2 Scenario analyses

Scenario analyses have been included to provide additional information beyond what is presented in the base-case analysis. These include scenarios modelling variations from the base case with respect to mean patisiran vial usage per administration, ToT for patisiran, costs associated with IV infusion of patisiran at home, and time horizon.

Patisiran vial usage

A separate analysis for patisiran vial usage is included, where the average required number of vials per administered dose is estimated at ****, based on the weight distribution of the total patient population of HELIOS-A.

Patisiran ToT

In the base-case analysis, patisiran ToT is assumed to be equal to vutrisiran ToT, which was estimated based on extrapolation from data on patient discontinuation of vutrisiran in HELIOS-A.[78] A separate scenario analysis was conducted where patisiran ToT was estimated based on extrapolation from data on patisiran discontinuation in HELIOS-A.[78] In addition, a scenario analysis where ToT is not included for either patisiran or vutrisiran is included. Summaries of ToT extrapolations for patisiran and vutrisiran from HELIOS-A data are provided in appendix J.

Cost of IV administration at home

The cost for IV administration of patisiran is assumed to be the same irrespective of being administered at the NAC or in a homecare setting. Nonetheless, performing IV infusions in a homecare setting can incur additional costs to the NHS, and these costs can vary regionally. Additionally, the model currently accounts only for the IV infusion cost (£470.81) and no other auxiliary costs associated with IV infusion treatment. For example, the costs to supply and maintain infusion pumps for patisiran is a significant cost that is not included in the model. In the absence of accessible micro costing data on these auxiliary services, scenarios are modelled to account for these additional costs by adjusting the base-case infusion cost structure by +25% and +50% in two scenario analyses.

Additional time-horizons

Scenarios modelling the cost comparison of vutrisiran versus patisiran over time horizons of 2 and 10 years are provided. A 2-year time horizon (to present cost outcomes over a time Company evidence submission template for Vutrisiran for treating hereditary transthyretinrelated amyloidosis [ID5074].

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period similar to that of the HELIOS-A trial follow-up) and a 10-year time horizon (to estimate longer term cost outcomes) were modelled in scenario analyses.

Results of scenario analyses

Results of the scenario analyses are presented in Table 34.

Table 34: Vutrisiran CCA model scenario analysis results

IV, intravenous; NAC, National Amyloidosis Centre; ToT, time on treatment.

B.4.5 Subgroup analysis

Subgroup analyses were not included in the CCA.

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B.4.6 Interpretation and conclusions of economic evidence

As evidenced in B.3 Clinical effectiveness, the clinical efficacy of vutrisiran is comparable to that of patisiran for the treatment of patients with hATTR amyloidosis with polyneuropathy. However, due to vutrisiran’s SC Q3M administration versus patisiran’s IV Q3W administration, vutrisiran offers benefits for patients, caregivers, and the NHS.

Given the comparable efficacy and in keeping with NICE guidance for evaluating technologies using a CCA, a CCA has been conducted that simulated the treatment and treatment-administration costs of vutrisiran and patisiran over a 5-year time horizon in the base case. This analysis was conducted from a UK NHS perspective with all model inputs representing and comparing current clinical practice for patisiran and expected clinical practice for vutrisiran. Results from the base-case analysis over 5 years of treatment with vutrisiran demonstrate cumulative cost-savings of £****** compared to treatment with patisiran. These cost savings are attributable to the reduced cost for administration for vutrisiran (£38,589) and the lack of premedication costs (£827). Notably, the less frequent and less burdensome SC administration profile of vutrisiran is associated with an estimated £39,416 reduction in non–acquisition-related costs per patient compared to patisiran. Results from the OWSA showed that variability in model parameters had effects on the estimated difference in costs between vutrisiran and patisiran, but none resulted (on either end of range) in total costs that favour the use of patisiran

In the additional scenario analyses presented, vutrisiran was consistently found to demonstrate cost-savings compared to patisiran, including when vial consumption estimates for patisiran from HELIOS-A were used.

Considering that vutrisiran is expected to supplant patisiran, resulting in reduced costs and treatment burden while maintaining comparable clinical efficacy, vutrisiran should be regarded as a preferable substitute for patisiran for the treatment of patients with hATTR amyloidosis with polyneuropathy in England. The introduction of vutrisiran represents a stepchange in the clinical management of hATTR amyloidosis with polyneuropathy, imparting positive impacts on patients, HCPs, and caregivers, while also reducing financial costs and burdens currently borne by the NHS.

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B.5 References

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47. Vinik EJ, Vinik AI, Paulson JF, et al. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2014;19(2):104-114.

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52. Brannagan TH, Wang AK, Coelho T, et al. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. 2020;27(8):1374-1381.

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58. Adams D, Tournev IL, Taylor MS, et al. HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at the Peripheral Nerve Society (PNS) Annual Meeting, Virtual, June 12-13 and 25-27,, 2021.

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59. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.

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• https://clinicaltrials.gov/ct2/show/NCT03997383. Accessed August 4 2021.

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B.6 Appendices

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Appendix C: Summary of product characteristics (SmPC) and UK public assessment report

C1.1 SmPC

The MHRA SmPC is included with the submission in the references package.

C1.2 UK public assessment report

The UK public assessment report is included with the submission in the references package.

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Appendix D: Identification, selection and synthesis of

clinical evidence

D1.1 Identification and selection of relevant studies

Accompanying this submission is the SLR report.

The overall objective of the SLRs is to support HTA submissions for vutrisiran in the treatment of hATTR amyloidosis with polyneuropathy. They have been designed to identify all relevant clinical and non-clinical evidence (e.g., economic evaluations, HCRU, costs, and utilities) for the use of vutrisiran, patisiran, inotersen, or tafamidis in the treatment of adult patients with hATTR amyloidosis. The searches have been designed to be sensitive to the overall condition and to identify all relevant hATTR amyloidosis literature.

The clinical SLR identified clinical trials, including RCTs, open-label extensions of RCTs, and single-arm clinical trials, as well as observational studies that assessed and reported the clinical efficacy of relevant hATTR amyloidosis treatments. Safety data from included studies was also captured.

The non-clinical SLR identified published economic analyses (including CEAs, CCAs, etc), as well as studies that reported healthcare cost or resource utilisation estimates and/or utilities pertinent to hATTR amyloidosis and its treatments.

The process of study identification was divided into searches of bibliographic databases, to identify published studies, and non-database search methods, to identify in-process, unpublished, or grey literature. The searches were conducted systematically and transparently in accordance with international standards, including the CRD and NICE guidance.[95,96] Taking into account that publications could include populations with diverse hATTR phenotypes (polyneuropathy, cardiomyopathy, and mixed), a broad search and screening strategy was used to capture all relevant evidence. For vutrisiran HTA submissions, the focus is on hATTR amyloidosis with polyneuropathy.

The original SLRs searched for evidence to October 2021. An update was executed in July 2022.

Electronic database searches

Bibliographic databases were searched from database inception using predefined search strategies. Two search strategies were employed: one focused on retrieving clinical evidence and another designed to capture economic and HRQoL evidence. A search narrative for each SLR, describing the rationale behind the search terms and filters used, is reported in the appendix.[97] The basic search strategy structure was:

• Clinical: ((search terms for familial amyloidosis) AND (search terms for inotersen OR tafamidis OR patisiran OR vutrisiran) AND (search filters for interventional study designs)

• Non-clinical: ((search terms for familial amyloidosis) AND (search terms for inotersen OR tafamidis OR patisiran OR vutrisiran) AND (search terms for resource use (economics or costs) OR search terms for HRQoL or utilities))

The following bibliographic databases were searched separately for each SLR:

• MEDLINE[®] , 1946–present (OVID)

• MEDLINE In-Process & Other Non-Indexed Citations (OVID)

• MEDLINE Epub Ahead of Print (OVID)

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• Embase, 1980–present (OVID)

• PsycINFO, 1806–present (OVID)

• Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley)

• Cochrane Database of Systematic Reviews (CDSR) (Wiley)

• PubMed (NLM) – e-publications only

• International Network of Agencies for Health Technology Assessment Database (INAHTA)

In addition to those set out above, the following bibliographic databases and web-based resources were also searched for the non-clinical SLR:

• Econlit, 1886–present (EBSCOHost)

• CEA Registry (CEVR)

• EconPapers within Research Papers in Economics (RePEc)

• EuroQol website

• NHS Economic Evaluation Database (EED)

• ScHARR Health Utilities Database (HUD)

Manual searches

In addition to bibliographic databases, several non-database sources were also searched.

Conference data

Abstract books from the following conferences were hand-searched from 2019 to 2022 to identify relevant data for both SLRs:

• European ATTR (EU ATTR) Amyloidosis Meeting

• International Symposium on Amyloidosis – International Society of Amyloidosis (ISA)

• Peripheral Nerve Society (PNS) Annual Meeting

To supplement the hand-searching for relevant conference data, conference abstracts were further identified through searches of:

• Embase, 1980–present (OVID)

• Conference Proceedings Citation Index-Science (CPCI-S), 1990–present (Web of Science, Clarivate Analytics)

• International Society for Pharmacoeconomic and Outcomes Research (ISPOR) Presentation Database (non-clinical search only)

Bibliographic searches for conference data from these databases were date limited from 2019 to the date of the searches (original: October 2021; update: July 2022) to align with the inclusion criteria for hand-searched conference data.

HTA organizations

The following websites were hand-searched to identify any relevant guidelines/technology appraisals and any nested economic evaluations:

• The National Institute for Health and Care Excellence (NICE)

• Scottish Medicine Consortium (SMC)

• Canadian Agency for Drugs and Technologies in Health (CADTH)

Guidelines or technology appraisals meeting inclusion criteria were checked to identify any potentially relevant studies.

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Trial registries

The following trials registries and platforms were searched to identify studies for the clinical SLR:

• ClinicalTrials.gov

• EU Clinical Trials Register

• International Clinical Trials Registry Platform (ICTRP)

Manual bibliography review

Bibliographies of relevant systematic reviews or meta-analyses were hand-searched for applicable primary publications. No relevant studies were identified that were not already captured by the other searches.

Study selection

Two levels of screening (title–abstract and full-text screening) using predefined Population, Intervention, Comparator, Outcome, and Study design (PICOS) criteria were performed during study selection. PICOS criteria for the clinical and non-clinical SLRs are listed in Table 35 and Table 36, respectively.

Title–abstract screening was conducted independently by two researchers using Covidence systematic review software. At the onset of the screening phase, both researchers pilottested the inclusion criteria on a subset of records to ensure consistency between researchers and reliability of study selection. The Covidence software offers the option of “yes/no/maybe” for article inclusion. Records that are designated as "Maybe" at the title– abstract screening stage are advanced to full-text screening. Records were advanced to fulltext screening in case of doubt by either researcher. No records were excluded at title– abstract screening due to insufficient information.

The full-text publications of records that progressed through title–abstract screening were retrieved for further review. As with title–abstract screening, screening of full-text publications was conducted by two independent researchers using Covidence systematic review software. The same inclusion and exclusion criteria used in title–abstract screening were applied during full-text screening.

Disagreements between both researchers were resolved through discussion or, if necessary, by consulting a third researcher. Studies were excluded if they did not meet the inclusion criteria; if they presented preliminary results in abstract form only; or if they were duplicate publications, narrative reviews, editorials, or letters. The study selection results are presented in a PRISMA flow chart (Figure 8).

Table 35. Study selection (PICOS) criteria for the clinical SLR

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10-MWT, 10-metre walk test; AE, adverse event; FAP, familial amyloid polyneuropathy; hATTR, hereditary transthyretin-mediated amyloidosis; KPS, Karnofsky Performance Status; mBMI, modified Body Mass Index; mNIS+7, modified Neuropathy Impairment Score+7; NIS, Neuropathy Impairment Score; NIS-LL, Neuropathy Impairment Score– Lower Limb; Norfolk QOL-DN, Norfolk Quality of Life–Diabetic Neuropathy; NT-proBNP, N-terminal prohormone B-type natriuretic peptide; PND, polyneuropathy disability; RCT, randomized, controlled trial; R-ODS, Rasch-built Overall Disability Score; SAE, serious adverse event; SLR, systematic literature review; TTR, transthyretin.

*Relevant systematic reviews were searched for unique studies but not included.

Table 36. Study selection (PICOS) criteria for the non-clinical SLR

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DALY, disability-adjusted life year; hATTR, hereditary transthyretin-mediated amyloidosis; HUI, Health Utilities Index; ICER, incremental cost-effectiveness ratio; LY, life year; MRI, magnetic resonance imaging; QALY, quality-adjusted life year; SLR, systematic literature review; WPAI, Work Productivity and Activity Index. *The SLR searches identified HCRU and cost evidence regardless of region. At the screening stage, studies with no UK data were excluded with a reason (i.e., non-UK data).

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Figure 8: PRISMA diagram

==> picture [452 x 519] intentionally omitted <==

HCRU, healthcare resource use; SLR, systematic literature review.

• *Systematic reviews were hand-searched for relevant studies but were not included in the SLRs.

• **Five of the seven records were also included in the clinical SLR.

• †Costs were only reported in the two economic evaluations identified for inclusion.

• ‡Two of the three records reporting HCRU were the two economic evaluations identified for inclusion. §Two of the six records reporting utilities were the two economic evaluations identified for inclusion.

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Complete reference lists of included and excluded studies are provided in the SLR report.

Summary of trials used for indirect or mixed treatment comparisons

Table 37 provides a summary of the trials used for NMA of patisiran and vutrisiran.

Table 37: Summary of the trials used to carry out the NMA of patisiran and vutrisiran

comparisons

The trials included in the NMA of patisiran and vutrisiran included similar populations which are presented in Table 11 for HELIOS-A and appendix D1.4 for APOLLO. The outcomes for both trials were identical and are provided in Table 8 for HELIOS-A and appendix D1.4 for APOLLO. Outcomes for comparison were based on the clinical outcomes used to assess patisiran, the comparator, in HST10,[2] in addition to the primary and key secondary outcomes of both studies, mNIS+7 and Norfolk QoL-DN, which assess polyneuropathy and HRQoL in patients with hATTR amyloidosis.

Methods of analysis of studies included in the indirect or mixed treatment comparison

Methodology for the NMA is provided in appendix D1.5.

Risk of bias of studies included in indirect or mixed treatment comparisons

Quality assessments for HELIOS-A and APOLLO are provided in appendix D1.3.

D1.2 Participant flow in the relevant randomised controlled trials

A total of 164 patients were enrolled and randomised to receive vutrisiran (n=122) or patisiran (n=42); 77 patients were included in the external placebo arm from APOLLO.[58] At Month 18, a total of 5 (4.1%) patients in the vutrisiran arm had discontinued study drug (1 due to an unrelated AE, 2 due to death of the patient unrelated to study treatment, 1 due to physician decision for a patient who did not comply with study visits and was considered lost to follow-up, and 1 due to withdrawal of consent to treatment by the patient).[78] In the patisiran arm, 4 (9.5%) patients had discontinued study drug at Month 18 (1 due to an unrelated AE and 3 due to the death of the patient unrelated to study treatment).[78]

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Figure 9: Consort diagram of patient flow in HELIOS-A

==> picture [370 x 344] intentionally omitted <==

Patient flow in HELIOS-A trial. Modified intent-to-treat population (mITT): all patients who were randomised and received at least one dose of the study drug. †Total number of patient discontinuations at the end of 18 months. In both the patisiran and vutrisiran groups, 1 patient discontinued due to suspected or confirmed diagnosis of COVID-19 or due to the impact of the global COVID-19 pandemic, reported in addition to the primary reason for treatment discontinuation. There were two deaths due to COVID-19, one in each treatment arm. Taken from Adams et al, 2022[4]

D1.3 Quality assessment for each trial

Table 38: Quality assessment of HELIOS-A trial

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10-MWT, 10-metre walk test; AE, adverse event; hATTR, hereditary transthyretin-mediated amyloidosis; IRS, Interactive Response System; IV, intravenous; mITT, modified intent-to-treat; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; Q3M, quarterly; Q3W, once every 3 weeks; NIS, neuropathy impairment score; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score; SC, subcutaneous; TTR, transthyretin.

Table 39: Quality assessment of APOLLO trial

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IRS, interactive response system; ITT, intention to treat.

D1.4 APOLLO trial relevant information

The eligibility criteria for APOLLO are provided in Table 40.

Table 40: APOLLO eligibility criteria

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• Birth control: Female and male patients of child-bearing age or with partners of such age agreed to use 2 methods of birth control during the study and for 75 days after the last dose

• • Willingness to comply with protocol schedule; written informed consent

• Exclusion criteria • Prior liver transplant or planned to undergo liver transplant during the study period • Known cause of sensorimotor or autonomic neuropathy (e.g., autoimmune disease, monoclonal gammopathy, etc.) not related to hATTR amyloidosis

• • Primary amyloidosis or leptomeningeal amyloidosis • Type I diabetes • Type II diabetes for ≥5 years • Vitamin B12 below LLN • Untreated hypo- or hyperthyroidism • Major surgery within the past 3 months or major surgery planned during any point of the study period

• • Active Hepatitis B or C, or HIV infection • Active infection requiring systemic antiviral or antimicrobial therapy that was not completed prior to first dose of study drug administration

• • Malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated

• • NYHA heart failure classification of >2 • Acute coronary syndrome within the past 3 months • Uncontrolled cardiac arrhythmia or unstable angina • Known history of alcohol abuse or daily, heavy alcohol consumption (females: more than 14 units of alcohol per week; males: more than 21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer])

• • Investigational agent or device within 30 days of anticipated study drug administration or 5 half-lives of the investigational drug, whichever was longer

• • Participated in a clinical study with antisense oligonucleotide (3-month washout period prior to start of APOLLO study drug administration)

• • Currently taking tafamidis, doxycycline, or TUDAC (14-day washout period prior to start of APOLLO study drug administration)

• • Currently taking diflunisal (3-day washout period prior to start of APOLLO study drug administration)

• • Prior severe reaction to liposomal product or a known hypersensitivity to oligonucleotides or any component of patisiran

• • Unable to take required premedications • Anticipated survival <2 years (opinion of investigator) • Considered unfit • Under legal protection

• Concomitant medications

  • Any investigational agent other than patisiran

  • Tafamidis

  • Diflunisal

  • Doxycycline/TUDCA

• Corticosteroids other than those administered as premedications prior to the dose of patisiran, those used to treat an infusion reaction, or topical or inhaled corticosteroids. However, for patients with chronic inflammatory disorders (eg, asthma, rheumatoid arthritis, etc.), systemically administered steroids were permitted provided that: 1) the dose was <20 mg/day prednisone or equivalent if administered chronically, or 2) for doses ≥20 mg/day, administration was limited to no more than 5 consecutive days. -

• Additionally, an intra articular injection of a corticosteroid was also permitted.

• Abbreviations: ALT: alanine transaminase; ANC: absolute neutrophil count; AST: aspartate transaminase; CMAP: compound muscle action potential; FAP: familial amyloidotic polyneuropathy; HIV: human immunodeficiency virus; INR: international; KPS: Karnofsky performance status; LLN: lower limit of normal; NCS: nerve conduction study; NIS: Neuropathy Impairment Score; NYHA: New York Heart Association; PND: Polyneuropathy Disability Score; SNAP: sensory nerve action potential; TTR: transthyretin; ULN: upper limit of normal. Source: APOLLO Clinical Study Report[79] , Adams et al. 2018[6]

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Table 41: Clinical effectiveness evidence; pivotal patisiran trial

10-MWT, 10-metre walk test; hATTR, hereditary transthyretin-mediated amyloidosis; HRQoL, health-related quality of life; IV, intravenous; mBMI, modified body mass index; MHRA, Medicines and Healthcare products Regulatory Agency; mNIS+7, modified Neuropathy Impairment Score +7; Q3M, quarterly; Q3W, once every 3 weeks; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; R-ODS, Rasch-built Overall Disability Score; SC, subcutaneous; TTR, transthyretin.

D1.5 NMA methodology

A fixed-effects Bayesian NMA was conducted to estimate the relative efficacy of different treatments according to the guidance from the Decision Support Unite (DSU) and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Indirect Treatment Comparisons Good Research Practices Task Force.[98,99] Given a sparse evidence network that consists of a very limited number of studies relative to the number of treatments, e.g., only one trial per link as for the NMA considered here, a fixed-effect model is preferred. The reason for this preference is that the between-study variance in a randomeffect model cannot be appropriately estimated when there is only one study per link, such that the results (i.e., posterior distributions) generated via random-effects modelling are unreliable.[99] Therefore, a fixed-effects model was used in this analysis.

The Bayesian NMA was conducted using the Markov chain Monte Carlo (MCMC) method with non-informative priors for parameters of interest. The probabilities of achieving improvement or no change in PND score were modelled as a binary outcome using logit link. The mean changes from baseline in mNIS+7 and Norfolk QoL-DN scores were modelled as

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continuous variables. The models were run with three chains and 50,000 iterations per chain (with 5,000 adaptation and 50,000 burn-in iterations). Five thousand posterior samples per chain were generated using a thinning factor of 10 and were used to estimate posterior statistics.

For the binary outcome of improvement or no change vs. worsening in PND score, treatment effects were estimated as risk ratio (RR) and odds ratio (OR) for achieving improvement or no change with a given treatment relative to placebo. For mNIS+7 and Norfolk QoL-DN scores, treatment effects were estimated as differences between a given treatment and placebo in terms of mean change from baseline to study endpoints. As applicable, median RRs, ORs, and treatment differences versus placebo (drawn from posterior distributions) and the corresponding 95% credible intervals (CrI) were reported.

This NMA was performed to assess the comparative efficacy of vutrisiran and patisiran. Two RCTs, HELIOS-A and APOLLO, were included in the network. Specifically, two randomised treatment arms from APOLLO (patisiran and placebo) and two randomised treatment arms from the HELIOS-A trial (vutrisiran and patisiran) were included in this NMA. In the primary analysis of the HELIOS-A trial, a prespecified external placebo control from the APOLLO trial was used to establish the efficacy of vutrisiran relative to placebo in primary and secondary efficacy analyses. The use of an external placebo control (rather than including a within-trial placebo control arm) for the HELIOS-A trial is deemed necessary to assess the benefit of vutrisiran vs. placebo (i.e., supportive care measures) in this rare disease area due to the ethical concern for ensuring that patients not receiving the investigational therapy were on a proven active treatment (i.e., patisiran in this case) for hATTR amyloidosis. However, the inclusion of the direct link between vutrisiran and the external placebo arm (APOLLO) in the NMA network would result in a duplication of the placebo arm of APOLLO in the network (as this arm is already included via linkage to patisiran in APOLLO), which would inflate the sample size and lead to artificially increased precision of the treatment effect estimates. Therefore, the external placebo arm used in the HELIOS-A study was not included in this NMA. The effect of vutrisiran relative to placebo is established via the indirect link through patisiran within the NMA.

All analyses were implemented using the statistical software R and Just Another Gibbs Sampler (also known as JAGS).

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Appendix E: Subgroup analysis

Subgroup analyses are not presented.

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Appendix F: Adverse reactions

There are no additional data to present regarding AEs outside of what is presented in B.3.10 Adverse reactions.

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Appendix G: Cost and healthcare resource identification

The non-clinical SLR identified published economic analyses, as well as studies that reported healthcare cost or resource utilisation estimates. HST10 was identified in this search.

Healthcare resource costs were identified by searching relevant UK clinical databases. For administration costs, the 2020/2021 NHS national tariff workbook was used to identify the cost associated with complex chemotherapy (HRG code: SB13Z), which was assumed to be a relevant cost for the complex IV administration of patisiran at the NAC. This was also conservatively estimated to be the cost of IV administration of patisiran at home. This same NHS code was used to account for the cost of infusion of patisiran in HST10.[2] The cost of SC administration of vutrisiran at the NAC was based on 2020/2021 NHS national tariff workbook costs for specialist nursing (HRG code: N10AF).[89] The cost of SC administration of vutrisiran at home was estimated to be represented by the cost of the hourly wage (1 hour) of a community based nurse, identified via PSSRU-published costs.[90] The acquisition costs for the premedication components required for patisiran were sourced from the MIMS database.[91-94]

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Appendix H: Price details of treatments included in the submission

H1.1 Price of intervention

Table 42: Details of intervention costs, including concomitant medicines, for each formulation used in the model

SC, subcutaneous.

H1.2 Price of comparators and subsequent treatments

Table 43: Details of comparators and subsequent treatment costs, including concomitant medicines, for each formulation used in the model

IV, intravenous.

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Appendix I: Checklist of confidential information

Included with the submission is the Checklist of confidential information.

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Appendix J: Comparison of vutrisiran versus placebo in HELIOS-A across all secondary endpoints

J1.1 HELIOS-A key secondary endpoint: change in Norfolk QoL-DN from baseline at Month 18

At Month 18, the LS mean change from baseline in Norfolk QoL-DN was −1.2 for the vutrisiran arm, indicating patients maintained their baseline level of HRQoL, while the LS mean change from baseline for the placebo arm was 19.8, indicating overall worsening compared to baseline, for a treatment difference of −21.0 (p<0.0001; Figure 10).[4]

Figure 10: HELIOS-A key secondary endpoint: Norfolk QoL-DN change from baseline at Month 18

==> picture [452 x 162] intentionally omitted <==

*Number of evaluable patients.[†] Data presented at Month 9 obtained from the completed Month 9 primary analysis. CI, confidence interval; LS, least squares; Norfolk QoL-DN, Quality of Life-Diabetic Neuropathy; SE, standard error. Source: Adams et al, 2022[4]

J1.2 Key secondary endpoints at Month 18

Significant treatment effects were observed in the vutrisiran arm relative to the APOLLO external placebo arm for all other secondary endpoints at Month 18, demonstrating durable and clinically significant improvement across a range of measures that assess changes in how patients feel or function (R-ODS [level of disability in performing activities of daily living/social participation], 10-MWT [ambulatory ability/gait speed], and mBMI [nutritional status]) (Table 44).[4]

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Table 44: HELIOS-A: Month 18 efficacy results

10-MWT, 10-metre walk test; BL, baseline; CI, confidence interval; LS, least squares; m/s, metres/second; mBMI, modified body mass index; R-ODS, Rasch-built Overall Disability Score; SE, standard error. Source: Adams et al, 2022[4] Note: For 10-MWT, R-ODS, and mBMI, a numerical increase represents a favourable outcome.

J1.2.1 Change in 10-MWT from baseline at Month 18

Ambulatory ability, as assessed by 10-MWT, was stable compared to baseline for the vutrisiran arm, with a LS mean change from baseline to Month 18 of −0.024 m/s. In the placebo arm, the LS mean change from baseline to Month 18 was −0.264 m/s, where a negative value indicates overall worsening compared to baseline, for a treatment difference of 0.239 (p<0.0001) (Figure 11).[4]

Figure 11: HELIOS-A secondary endpoint: 10-MWT change from baseline at Month 18

==> picture [430 x 157] intentionally omitted <==

*Number of evaluable patients.[†] Data presented at Month 9 obtained from the completed Month 9 primary analysis. 10-MWT; 10-metre walk test; CI, confidence interval; LS, least squares; SE, standard error. Source: Adams et al, 2022[4]

J1.2.2 Change in R-ODS from baseline at Month 18

Ability to perform daily activities and participate in social activities, as assessed by R-ODS, was stable compared to baseline for the vutrisiran arm, with a LS mean change from baseline to Month 18 of −1.5. In the placebo arm, the LS mean change from baseline to

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Month 18 was −9.9, indicating overall worsening compared to baseline, for a treatment difference of 8.4 (p<0.0001) (Figure 12).[4]

Figure 12: HELIOS-A secondary endpoint: R-ODS change from baseline at Month 18

==> picture [452 x 166] intentionally omitted <==

*Number of evaluable patients.[†] Data presented at Month 9 obtained from the completed Month 9 primary analysis. CI, confidence interval; LS, least squares; R-ODS, Rasch-built Overall Disability Score; SE, standard error. Source: Adams et al, 2022[4]

J1.2.3 Change in mBMI from baseline at Month 18

At Month 18, the LS mean change from baseline in nutritional status, as assessed by mBMI, was 25.0 for the vutrisiran arm, indicating improvement compared to baseline, while the LS mean change from baseline for the placebo arm was −115.7, indicating overall worsening compared to baseline, for a treatment difference of 140.7 (p<0.0001) (Figure 13).[4]

Figure 13: HELIOS-A secondary endpoint: mBMI change from baseline at Month 18

==> picture [452 x 163] intentionally omitted <==

*Number of evaluable patients.[†] Data presented at Month 9 obtained from the completed Month 9 primary analysis. CI, confidence interval; LS, least squares; mBMI, modified body mass index; SE, standard error. Source: Adams et al, 2022[4]

J1.3 Binary analysis: mNIS+7 and Norfolk QoL-DN at Month 18

A binary outcomes analysis was conducted to compare the proportion of patients with a change of <0 points from baseline to Month 18 in mNIS+7 (i.e., improvement in neuropathy)

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between the vutrisiran arm and the APOLLO placebo arm.[78] In the vutrisiran arm, 48.3% of patients showed an improvement in neuropathy (change from baseline in mNIS+7 <0) at Month 18 compared to 3.9% of patients in the APOLLO placebo arm (OR 22.9 [95% CI 6.8, 76.9], p<0.0001) (Figure 14).[78]

Figure 14: HELIOS-A binary analysis: Reversal in neuropathy impairment from baseline at 18 months[†]*

==> picture [338 x 189] intentionally omitted <==

*HELIOS-A patients with missing post-baseline values due to COVID-19 (including values on or after onset of a serious COVID-19 AE) were excluded from the analysis. Assessments after initiation of local standard treatment for hATTR amyloidosis were treated as missing.[†] Patients included in analysis: vutrisiran (n=118) and placebo (APOLLO) (n=77). CI, confidence interval; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; mNIS+7, modified Neuropathy Impairment Score+7.

Source: Alnylam Pharmaceuticals. Data on File. HELIOS-A 18-Month Clinical Study Report, 2022[78]

A binary analysis was also conducted to compare the proportion of patients with a change of <0 points from baseline to Month 18 in Norfolk QoL-DN (i.e., improvement in HRQoL) between the vutrisiran arm and the APOLLO placebo arm.[78] In the vutrisiran arm, 56.8% of patients showed an improvement in HRQoL (change from baseline in Norfolk QoL-DN <0) at Month 18 compared to 10.4% of patients in the APOLLO placebo arm (OR 11.3 [95% CI 5.0, 25.7], p<0.0001) (Figure 15).[78]

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Figure 15: HELIOS-A binary analysis: Improvement in Norfolk QoL-DN from baseline at 18 months[†]*

==> picture [339 x 197] intentionally omitted <==

*HELIOS-A patients with missing postbaseline values due to COVID-19 (including values on or after onset of a serious COVID-19 AE) were excluded from the analysis. Assessments after initiation of local standard treatment for hATTR amyloidosis were treated as missing.[†] Patients included in analysis: vutrisiran (n=118) and placebo (APOLLO) (n=77). CI, confidence interval; hATTR amyloidosis, hereditary transthyretin-mediated amyloidosis; Norfolk QoL-DN, Norfolk Quality of Life–Diabetic Neuropathy; QoL, quality of life. Source: Alnylam Pharmaceuticals. Data on File. HELIOS-A 18Month Clinical Study Report, 2022[78]

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Appendix K: Time on treatment in the CCA

Table 45: Fit statistics of parametric models to patisiran and vutrisiran timeon-treatment data

AIC, Akaike information criterion; BIC, Bayesian information criterion.

Table 46: Model parameters for parametric functions to extrapolate patisiran and vutrisiran time on treatment curves

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Figure 16: Vutrisiran and patisiran time on treatment

==> picture [414 x 242] intentionally omitted <==

==> picture [414 x 241] intentionally omitted <==

KM, Kaplan–Meier; ToT, time on treatment.

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Single technology appraisal

[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis

Company response to clarification questions

October 2022

This document contains confidential information.

[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

Preamble

Alnylam would like to express our sincere appreciation for the prompt review by the External Assessment Group (EAG) of our cost-comparison submission for vutrisiran for treating hereditary transthyretin-related (hATTR) amyloidosis. We have addressed each of the questions to the best of our abilities in the time available, and would be pleased to provide any additional information that may be required. We wish to note that some of our responses contain commercial-in-confidence information that has been marked accordingly.

Response to clarification questions

1. Please provide the full reference for the information received from Lloyds Pharmacy Clinical Homecare regarding the mean number of vials used per patient per administration for patisiran. In particular:

• The information in the exact format supplied by Lloyds

Response: The base-case estimate of **** patisiran vials per patient in the company submission (CS) was a mean value calculated directly by LloydsPharmacy Clinical Homecare, and provided to Alnylam in a confidential email in September 2022. Although LloydsPharmacy also provided detailed data to Alnylam, these data are not at the level of individual patients, but rather at the level of patisiran vials delivered. To address the EAG’s request to the best of our ability, we are providing the detailed data in an Excel file accompanying this response ( ID5074 LloydsPharmacy patisiran data CIC.xlsx ). We request that the contents of this file be treated as commercial in confidence.

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

The Excel file contains two worksheets:

• Sheet1: raw data for delivered vials

• Sheet2: summary counts

We are forwarding this Excel file as supplied by LloydsPharmacy with only the following changes by Alnylam:

• Revising the filename for clarity

• Addition of confidentiality messages

• Deletion of two columns from Sheet1 ( Document No. and Location Code ) to avoid the inclusion of any identifying information (e.g., about location of vial delivery) that could break patient confidentiality

In the Excel file, vial quantities that are negative values represent patisiran vials shipped out for delivery; these deliveries are made for the purpose of a nurse visit to infuse the patient and thus are equivalent to infused vials. Vial quantities that are positive values represent vial returns (for unknown reasons).

In Sheet1, the Posting Date column gives the month and year of delivery made for the purpose of a nurse visit and patient infusion. Other column headings are selfexplanatory.

• The number of patients and administrations of drug that are contained within the records

Response: As explained above, the data provided to Alnylam by LloydsPharmacy preclude identifying individual patients, so cannot be used to estimate the number of patients. However, Alnylam understands that each row in Sheet1 with a negative value in the Quantity column represents a single delivery made for the purpose of a nurse visit to infuse a single patient, which is equivalent to an administration. Thus, these records contain 1996 administrations.

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

• The standard deviation around the mean number of vials

Response: Because the records do not identify individual patients, it is not possible to calculate mean or standard deviation (SD) number of vials per patient. Instead, we are submitting another version of the LloydsPharmacy dataset showing our calculation of mean (SD) vials across administrations ( ID5074 LloydsPharmacy patisiran data Alnylam calculations CIC.xlsx ), as explained in our response to the following question.

• How the mean number of vials (and standard deviation) varied within the time period covered (Sept 2021 to Aug 2022); preferably as a monthly breakdown

Response: We have provided the requested monthly breakdown in Sheet2 of the Excel file ID5074 LloydsPharmacy patisiran data Alnylam calculations CIC.xlsx so that the EAG can directly assess how these values varied over time. Note that the calculation of numbers in columns A–H of this worksheet was performed by LloydsPharmacy, while the numbers in columns K–M were calculated by Alnylam. Column A ( Row Labels ) indicates the month and year within the overall time period covered by the LloydsPharmacy data. Across the full time period covered, the mean (SD) number of vials per administration was estimated at **** (****).

2. Please provide full details of the calculation for the average number of vials required per patient for patisiran based on the HELIOS-A weight distribution including a list (preferably in Excel) of the individual patient weights from the trial.

Response: As presented in Section B.4.4.2 of the CS, a scenario analysis for patisiran vial usage is included in the submitted cost-comparison analysis whereby the average required number of patisiran vials per administered dose is set at ****, estimated from the bodyweight distribution of the total patient population of HELIOS-A (i.e., patients in both treatment arms).

The estimated average of **** patisiran vials was calculated as follows:

1. For each patient, we retrieved the bodyweight at baseline from the HELIOS-A database.

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

2. We calculated vial usage for different bodyweight categories using the number of required vials for patients within each category according to the posology instructions in the product label,[1] as shown in Table 1.

Table 1: Patisiran vial requirements by bodyweight category

Source: ONPATTRO Summary of Product Characteristics[1]

3. We defined five categories of bodyweight and calculated the number and percentage of patients in HELIOS-A within each category, as shown in Table 2.

4. We derived the weighted average vial consumption by calculating the sum-product of the percentage of patients and vials required, yielding **** vials as shown in Table 2.

Table 2: Bodyweight distribution of all patients in HELIOS-A and estimated average patisiran vial consumption for scenario analysis

*Value within each bodyweight category is calculated as the percentage of patients multiplied by the number of vials required; total is the sum of these products.

• †Per the ONPATTRO Summary of Product Characteristics1

In the timeframe available for this response, we were unable to verify whether we are permitted to provide NICE with a list of the individual patient weights from HELIOS-A without violating patient confidentiality and the terms of the participants’ informedconsent agreements. Given these privacy concerns, we hope that the details of the calculations provided above will adequately address the EAG’s question.

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

3. Please provide the RIS file for the Endnote library references.

Response: We provided the RIS file of references in the EndNote library for the CS on Wednesday 19 October 2022.

4. Please provide additional details for the calculation of differences in serum TTR levels.

Response: The following sections provide detailed explanations of the calculations of (A) between–treatment-arm differences in reduction of serum transthyretin (TTR) trough levels, and (B) within-arm reduction from baseline in steady-state peak TTR levels.

A. Noninferiority analysis of median treatment difference in TTR percent reduction (trough) from baseline (vutrisiran – patisiran)

As explained in Section B.3 of the CS, the HELIOS-A trial included as a secondary endpoint a pre-specified noninferiority analysis to compare the activity of patisiran and vutrisiran on serum TTR reduction. Calculations were pre-defined in HELIOS-A per the trial’s statistical analysis plan (SAP).

Time-averaged trough TTR percent reduction through Month 18 was defined as the average trough TTR percent reduction (i.e., percent reduction based on TTR levels measured before study-drug dose administration on the day of a post-baseline visit) relative to baseline during the Month 6–18 interval (the steady-state period for both vutrisiran and patisiran). Note that the term “trough reduction” in this context refers to the least extent of pharmacodynamic activity/TTR reduction from baseline (i.e., TTR reduction that is furthest from complete) during the interval between doses.

The analysis population for this endpoint was the TTR per-protocol population, defined as all patients in the modified intent-to-treat (mITT) population who had a nonmissing TTR assessment at baseline and ≥1 trough TTR assessment between Month 6 (Week 24) and Month 18 (Week 72) that met the following criteria (which were required for inclusion of a post-baseline TTR assessment in the analysis):

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

• At the study visit at which the TTR assessment took place, the assessment had to have been performed before administration of study drug.

• The assessment must not have been performed after initiation of local standard treatment for hATTR amyloidosis (as was allowed, per investigator judgment, for patients who remained in the HELIOS-A study after discontinuing study drug).

• The patient had to have received their complete, planned study-drug administration at the treatment visit approximately 12 weeks before the study visit at which the TTR assessment took place ( for patients in the vutrisiran arm, in alignment with the vutrisiran dosing schedule ) or at the treatment visit approximately 3 weeks before the study visit at which the TTR assessment took place ( for patients in the patisiran arm, in alignment with the patisiran dosing schedule ).

• For patients in the vutrisiran arm: The patient had to have received their complete, planned study-drug administration at 2 consecutive planned treatment visits before the study visit at which the TTR assessment took place, to ensure steady state pharmacodynamics.

The treatment difference between vutrisiran and patisiran in TTR percent reduction from baseline was calculated per the following three-step process:

• Step 1: Time-averaged trough TTR percent reduction from baseline was calculated as follows for each patient:

  • The patient’s baseline TTR level was defined as the average serum TTR level across all TTR measurements performed on study (i.e., after enrolment) for that patient, including those from any unscheduled visits, before the date and time of the patient’s first dose of study treatment.

  • The patient’s TTR percent reduction from baseline was calculated by determining the percentage reduction from baseline for each trough TTR assessment (i.e., TTR assessment before study-drug dose administration on the day of a study visit) performed for the patient between Months 6 and 18, and then calculating the average percentage reduction from baseline across all of these assessments;

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

for the purposes of this calculation, only trough TTR assessments that met the criteria for inclusion in the analysis, as described above, were considered.

• Step 2: Group median time-averaged trough TTR percent reduction from baseline was calculated for each treatment arm using the Hodges-Lehmann method[2] for estimation of a 1-sample median (pseudomedian):

  • Inputs used were individual-patient–level estimates of time-averaged trough TTR percent reduction from baseline (calculated as described above) for the treatment arm of interest.

  • The outputs from this step were the time-averaged trough TTR percent reduction results of 84.7% from baseline for vutrisiran and 80.6% from baseline for patisiran, as reported in Section B.3.6.1 of the CS.

• Step 3: Median difference between treatment arms in terms of time-averaged trough TTR percent reduction from baseline was calculated using the Hodges-Lehmann method[2] for estimation of a 2-sample median difference:

  • Inputs used were individual-patient–level estimates of time-averaged trough TTR percent reduction from baseline (calculated as described above) for each treatment arm.

  • The analysis was stratified by previous TTR stabiliser use (yes vs. no); values within each stratum were first aligned by the within-stratum 1-sample HodgesLehmann median, and the 95% confidence interval (CI) for the median difference between the vutrisiran and patisiran groups was then calculated.

  • The output from this step was the median treatment difference (vutrisiran – patisiran) of 5.28% (95% CI, 1.17 to 9.25) in TTR percent reduction from baseline, as reported in Section B.3.6.1 of the CS.

As pre-specified in the HELIOS-A SAP and stated in the primary publication for the study (Adams et al. 2022[3] ), noninferiority of vutrisiran vs. patisiran was to be declared if the lower limit of the 95% CI for the median difference in TTR percent reduction between treatment arms (vutrisiran – patisiran) was greater than –10%. Note that the

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

convention used for reporting analysis results was that reductions from baseline were assigned a positive value (e.g., an 80% reduction from baseline would be indicated by an analysis output of “80%”, while a 20% increase from baseline would be indicated by an analysis output of “–20%”); thus, the pre-specified noninferiority margin of –10% reflects a scenario in which the percent TTR reduction from baseline was less pronounced (by 10 percentage points) in the vutrisiran arm vs. the patisiran arm. Therefore, the lower limit of the 95% CI for the median treatment difference, (+)1.17, was above the prespecified noninferiority margin of –10%.[3]

B. Descriptive analysis of steady-state peak TTR percent reduction from baseline through Month 18

In addition to the noninferiority analysis of trough TTR percent reduction described above, our CS and the primary publication[3] report results of a descriptive analysis of steady-state peak TTR percent reduction from baseline through Month 18. The latter analysis provides an estimate of the TTR percent reduction seen when the

pharmacodynamic effects of the treatment of interest have reached their maximum level within the dosing interval, for a dosing interval during the steady-state phase of treatment. Note that the term “peak reduction” in this context refers to the greatest extent of pharmacodynamic activity/TTR reduction from baseline (i.e., reduction that is closest to complete) during the interval between doses.

The analysis population for steady-state peak TTR percent reduction was the mITT population, defined as all randomised patients who received any amount of study drug; patients were analysed according to the treatment to which they were randomised.

The within-treatment steady-state peak TTR percent reduction from baseline was calculated per the following two-step process:

• Step 1: Steady-state peak TTR percent reduction from baseline was calculated for each patient, as follows:

  • The patient’s baseline TTR level was defined as the average serum TTR level across all TTR measurements performed on study for that patient, including

Company response to EAG clarification questions This document contains confidential information.

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[ID5074] Vutrisiran for treating hereditary transthyretin-related amyloidosis: A Single Technology Appraisal

those from any unscheduled visits, before the date and time of the patient’s first dose of study treatment.

• In the vutrisiran arm, each patient’s peak TTR percent reduction was calculated by determining the percentage reduction from baseline to TTR assessment at study week 66.

• In the patisiran arm, each patient’s peak TTR percent reduction was calculated by determining the percentage reduction from baseline to TTR assessment at study month 18.

• Step 2: Descriptive statistics on steady-state peak TTR percent reduction from baseline through Month 18 were calculated by treatment arm, as follows:

  • Per-patient results as calculated above were used as inputs to calculate the mean (SD) of peak TTR percent reduction from baseline across all patients in the treatment arm of interest.

  • The outputs from this step were the mean (SD) steady-state peak serum TTR reduction results of 88% (16%) from baseline for the vutrisiran arm and 86% (10%) from baseline for the patisiran arm, as reported in the CS and by Adams et

    • al. 2022 (see Supplementary Table S4 in the publication).[3]

References

1. Medicines and Healthcare products Regulatory Agency (MHRA). ONPATTRO (patisiran) Summary of Product Characteristics. Amsterdam, Netherlands: Alnylam Netherlands B.V.; 01 January 2021.

2. Hodges JL, Jr., Lehmann EL. Rank methods for combination of indepdendent experiments in analysis of variance. Annals of Mathematical Statistics. 1962;33(2):482-497.

3. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2022:1-9.

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Streamlined Cost Comparison Appraisal

Vutrisiran for treating hereditary transthyretin-related amyloidosis [ID5074] Patient Organisation Submission

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