Single Technology Appraisal

Risankizumab for previously treated moderately to severely active Crohn's disease [ID3986] Committee Papers

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

Contents:

The following documents are made available to stakeholders:

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

Pre-technical engagement documents

1. Company submission from Abbvie

2. Clarification questions and company responses

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

• Crohns and Colitis UK

4. External Assessment Report prepared by Peninsula Technology Assessment Group (PenTAG)

5. External Assessment Report – factual accuracy check

Post-technical engagement documents

6. Technical engagement response from company

7. Technical engagement responses and statements from experts:

• a. Dr Mark Samaan – clinical expert, nominated by AbbVie ’

• b. Ms Kamila Kingstone – patient expert, nominated by Crohn s and Colitis UK

8. External Assessment Group critique of company response to technical engagement prepared by Peninsula Technology Assessment Group (PenTAG)

• 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

Risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

Document B

Company evidence submission

June 2022

Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

© AbbVie (2022). All rights reserved

Contents

Tables and figures

Table 1: The decision problem .............................................................................................. 10 Table 2: Technology being appraised ................................................................................... 11 Table 3: Overview of disease severity measures for CD ...................................................... 14 Table 4: Clinical effectiveness evidence – ADVANCE (pivotal induction study) ................... 29 Table 5: Clinical effectiveness evidence – MOTIVATE (pivotal induction study) .................. 29 Table 6: Clinical effectiveness evidence – FORTIFY (pivotal maintenance study) ............... 30 Table 7: Definitions of analysis sets – ADVANCE and MOTIVATE ...................................... 33 Table 8: Definitions of analysis sets – FORTIFY SS1 .......................................................... 35 Table 9: Comparative summary of trial methodology ........................................................... 38 Table 10: Primary and secondary efficacy endpoints in ADVANCE, MOTIVATE and FORTIFY trials ...................................................................................................................... 45

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Figure 4: Proposed treatment pathway including risankizumab for CD in the UK ................ 25 Figure 5: Trial design for ADVANCE and MOTIVATE .......................................................... 32 Figure 6: Trial design for FORTIFY (Sub Study 1) ................................................................ 36 Figure 7: Network diagram of included induction studies in a CCF population ..................... 85 Figure 8: Network diagrams of included maintenance studies in a CCF population: (A) risankizumab and ustekinumab; (B) adalimumab, infliximab and vedolizumab .................... 85 Figure 9: Network diagram of included induction studies in a BF population ....................... 86 Figure 10: Network diagrams of included maintenance studies in a BF population: (A) risankizumab and ustekinumab; (B) adalimumab and vedolizumab ..................................... 86 Figure 11: Proportion of subjects receiving placebo during maintenance phase in CDAI clinical remission ................................................................................................................... 96 Figure 12: Decision tree structure: Induction phase ........................................................... 125 Figure 13: Long-term model structure: Maintenance and post-maintenance phases ......... 127 Figure 14: Proposed treatment pathway including risankizumab for CD in the UK ............ 132 Figure 15: Example of calibration process for standard-dose RZB in the CCF population* 147 Figure 16: Cost-effectiveness acceptability curves in the CCF population ......................... 188 Figure 17: Cost-effectiveness acceptability curves in the BF population ............................ 189 Figure 18: Tornado diagram for risankizumab vs ustekinumab in the CCF population ...... 191 Figure 19: Tornado diagram for risankizumab vs adalimumab 160/80 biosimilar in the CCF population ........................................................................................................................... 192 Figure 20: Tornado diagram for risankizumab vs infliximab IV biosimilar in the CCF population ........................................................................................................................... 193 Figure 21: Tornado diagram for risankizumab vs infliximab SC in the CCF population ...... 194 Figure 22: Tornado diagram for risankizumab vs ustekinumab in the BF population ......... 195 Figure 23: Tornado diagram for risankizumab vs vedolizumab IV in the BF population ..... 196 Figure 24: Tornado diagram for risankizumab vs vedolizumab SC in the BF population ... 197

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Abbreviations

Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

© AbbVie (2022). All rights reserved

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

B.1.1 Decision problem

The full marketing authorisation for risankizumab is expected to be for the treatment of

************************************************************************************************ ************************************************************************************************ ***********************************************. The submission covers the technology’s expected full marketing authorisation for this indication.

The decision problem addressed is consistent with the National Institute for Health and Care Excellence (NICE) final scope for this appraisal, as outlined in Table 1.

The submission specifically addresses the clinical efficacy and safety, the comparative effectiveness and cost-effectiveness of the licensed doses (i.e., risankizumab 600 mg intravenous [IV] induction, followed by 360 mg subcutaneous [SC] maintenance every 8 weeks [Q8W]) for the treatment of moderately to severely active Crohn’s disease (CD), in people aged 16 years and over.

Risankizumab currently holds marketing authorisation in the UK for treating moderateto-severe plaque psoriasis as well as for the treatment of active psoriatic arthritis. Risankizumab received a recommendation from both NICE (NICE TA596) and the SMC (SMC2196) for treating moderate-to-severe plaque psoriasis. A recommendation from the SMC (SMC2459) and NICE (ID1399) has been received for risankizumab, alone or in combination with methotrexate (MTX), for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to one or more disease-modifying antirheumatic drugs (1, 2).

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Table 1: The decision problem

Abbreviations: ADA, adalimumab; BF, biologic failure; BSC, best supportive care; Bio-IR, biologic inadequate response/intolerance; CD, Crohn’s disease; CCF, conventional care failure; IFX, infliximab; NA, not applicable; RZB, risankizumab; TNF, tumour necrosis factor; UST, ustekinumab; VDZ, vedolizumab.; † Subjects who had an inadequate response or intolerance to conventional therapy (defined as one or more of the following: aminosalicylates, oral locally acting steroids [e.g., budesonide, beclomethasone], systemic corticosteroids [prednisone or equivalent], or immunomodulators). This population may include patients who had received biologic therapy in the past but stopped therapy based on reasons other than inadequate response (IR) or intolerance (e.g., change in reimbursement coverage, well-controlled disease); ‡ Subjects with documented intolerance or inadequate response (either failure to respond to induction treatment, or loss of response to maintenance therapy) to one or more biologics for CD (infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and/or ustekinumab).

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B.1.2 Description of the technology being evaluated

Details of the technology being appraised in the submission, including the mechanism of action, expected marketing authorisation, indications, method of administration, dosing and related costs, are provided in Table 2. The draft summary of product characteristics (SmPC) for risankizumab is provided in Appendix C (3, 4).

Table 2: Technology being appraised

Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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Abbreviations: EMA, European Medicines Agency; IgG1, immunoglobulin G1; IL, interleukin; IV, intravenous; MHRA, Medicines and Healthcare products Regulatory Agency; MoA, mechanism of action; nM, nanomolar; OBD, on-body device; PAS, patient access scheme; PASLU, Patient Access Schemes Liaison Unit; Q8W, every 8 weeks; SC, subcutaneous; Th, T helper cell.

Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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

B.1.3.1 Disease overview

CD is a chronic relapsing systemic inflammatory bowel disease (IBD) that can cause inflammation and mucosal ulceration to the entire gastrointestinal tract (from the mouth to the anus), but most commonly affects the distal small intestine. Inflammation involves the whole thickness of the bowel wall (14, 15). The pathogenesis of CD involves the complex interaction of immunological, microbiological, environmental and genetic factors (14, 16, 17). Presenting symptoms can be heterogeneous and insidious. Symptoms commonly experienced by people with CD include abdominal pain, diarrhoea, fatigue, weight loss, and blood or mucus in stools (17, 18). Individuals typically suffer from recurrent relapses, with acute exacerbations interspersed with periods of remission (19-21). The symptoms of CD can significantly adversely affect individuals’ lives, negatively impacting educational achievements, work productivity, mental health and quality of life (22-27). In addition, disease symptoms can also lead to extensive use of health services for disease management (24-26, 28). Timely intervention is required to promote mucosal healing and reduce long-term complications (29, 30). Inadequate treatment of mucosal inflammation leads to disease progression and increased likelihood of surgery (31).

Typically, CD severity is classified using clinical assessments which assess symptoms, including the Crohn’s Disease Activity Index (CDAI), the patient reported outcomes 2-item (PRO2) and the Harvey Bradshaw Index (HBI) scores as well as endoscopic assessments (i.e., Simple Endoscopic Score for Crohn’s Disease [SESCD]) (32-36). An overview of the selected measures of disease severity frequently utilised in clinical trials and for the purposes of this submission are presented in Table 3 (for more details, see Appendix N).

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Table 3: Overview of disease severity measures for CD

Abbreviations: AP, abdominal pain; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; PRO2, patient reported outcomes 2-item; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency.

B.1.3.2 Disease burden

Epidemiology

Based on data from the Office of National Statistics, the total English population ≥16 years of age was estimated to be 46,911,788 in mid-2020 (43). The prevalence of CD in the UK in 2021 was 0.35 and 0.44 in males and females, respectively (44); given the latest population estimates (45), this leads to an estimated 185,668 people aged 16 and over in the England with CD. Approximately 40% of people with CD in the UK are estimated to have moderately to severely active disease at any time post diagnosis (46, 47). The estimated total prevalent number of people with moderate-to-severe CD in England based on this was approximately 74,267 in 2022.

In 2021, there were approximately 6,708 diagnosed incident cases of CD (a rate of 9 cases per 100,000) (48). Most individuals are diagnosed between 17 and 40 years of age, with incidence peaking at 14.9 per 100,000 person years in this age category in England (48). Although there has been a slight decrease in the incidence of CD in adults in the UK, the incidence is increasing in people aged <17 years of age (48).

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Symptoms of CD

The manifestations of CD vary from person to person, can change over time, and flare up during relapses (19-21, 49). The life expectancy of people with CD is slightly reduced when compared with the unaffected individuals (14, 44, 50, 51), with excess mortality mainly due to gastrointestinal causes linked to CD. Therefore, symptom management and minimisation of the impact of CD on quality of life are key considerations for disease management.

The symptoms of CD result from inflammation and commonly include the development of abdominal pain and distension, fever, weight loss, tiredness or fatigue, and clinical signs of bowel obstruction or diarrhoea with passage of blood or mucus, or both (14, 17, 18). Scar tissue can also develop, causing obstruction and the development of strictures, abscesses and/or fistulas (abnormal connections between the inflamed intestine and other areas). These complications are major causes of morbidity and can lead to surgery in up to 80% of people with CD (52, 53).

Due to the systemic nature of CD, individuals may also experience a broad range of extraintestinal manifestations (EIMs) as a result of abnormal immunological response (Figure 2) (14, 54). Up to 40% of people with CD develop dermatological, rheumatological, ocular and hepatic EIMs. In addition, CD is also commonly associated with cardiovascular disease, hepatic disorders, infections, gastrointestinal (GI) disorders and nutritional disorders (54-58). Psychological disorders are also more prevalent in people with CD compared with matched controls; 60% of people with CD have been reported to experience mental health problems, such as depression and anxiety, when symptoms are active (26, 27, 59). Issues with mental health are typically greater in individuals with more active or severe disease (27, 60), and may result in poor treatment compliance and risk of relapse (61).

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Figure 2: Major extraintestinal manifestations for CD

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Source: Image adapted from Baumgart et al. (2012) (14).

Health-related quality of life in individuals with CD

The symptoms of CD can have a substantial negative impact on individuals’ functioning, daily activities, wellbeing, ability to work and health-related quality of life (HRQoL) (23-25). In one study of people with moderate-to-severe CD, 41% had problems with or were unable to perform usual activities, 7% had difficulties washing and dressing, and 14% reported problems with mobility (62). Fatigue has been reported in up to 43% of people with CD (63). The fatigue, pain, and anxiety and depression experienced by people with CD may all contribute to the impact of the disease on quality of life (QoL) and ability to perform daily activities (62, 64). Additionally, increased disease activity has been reported to negatively affect individuals’ feelings about relationships, with individuals experiencing embarrassment and feeling socially restricted as a result of symptoms (60).

Loss of productivity

CD also negatively affects the educational achievements and work productivity of individuals (22). In a study of the long-term impact of CD and ulcerative colitis (UC) on the career aspirations, opportunities and choices of individuals aged 16–25 in the UK, 67% (n=91) reported that their IBD had delayed or was delaying their education and/or training, while 69% (n=91) felt IBD prevented them from reaching their full educational potential (22). Similarly, 40% (n=744) of individuals assessed stated that CD prevented them from pursuing their preferred job of choice, 57% (n=1,314) had to reduce working hours due to CD, and 54% (n=744) reported that CD had an impact on their career progression (22). The negative effect of CD on careers translates into Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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a perceived loss of earning for individuals (22). In a retrospective analysis of people with IBD (N=233), 50% of employed people with CD had some loss of employment days, with a median loss of earnings of £299[a] over a 6-month period (65). Similarly, significantly higher loss of productivity costs has been reported for the caregivers of people with CD aged ≤18 years compared with controls, highlighting that the indirect costs of CD can extend to caregivers (66).

Economic burden of CD

In 2006, IBD treatment cost the NHS in excess of £700 million per year (67). The medical requirements of people with CD place a significant burden on healthcare resources, with the average annual cost of care for treating CD in the UK estimated to be £6,156 per person[b] (68). CD is associated with higher rates of primary care visits and emergency attendances compared with matched controls (26). In 2019–2020, there were 139,303 finished consultant episodes and 128,692 hospital admissions related to CD in England (28). Additionally, many people with CD require surgery, which contributes to their healthcare resource use (HCRU); the risk of surgery five and 10 years after diagnosis of CD has been reported to be 33.3% and 46.6%, respectively (18, 52, 69). Higher costs for treatment, adverse events and complications are associated with individuals in relapse or experiencing flare-up compared with those in remission (total cost: £10,513 versus £1,800 for relapse versus remission) (68), while worsening disease severity is associated with increasing healthcare costs (65).

B.1.3.3 Treatment aims and clinical guidelines

Aim of treatment

CD is not medically or surgically curable. Treatment choices rely on clinical judgement and individual preference (35). The aim of medical treatment in CD has been focused on maintaining a symptom-free remission state whilst controlling inflammation, reducing risk of complications, and minimising surgery to preserve the patient’s nutritional independence by maintaining sufficient intestinal luminal length. Whilst surgical rates have decreased over time in the era of biologic therapies, surgery is still required in significant proportion of individuals with CD, with up to 8 in 10 people with

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CD requiring surgery at some point in their lives (69-71). In addition, approximately 25% of people with CD who undergo surgery will require additional surgery within 5 years of the first surgery (72). From an individual perspective, people with CD considered abdominal pain and bowel movement urgency the most important symptoms when prioritising disease control (73).

The use of both clinical and endoscopic treatment targets can facilitate effective disease control on a long-term basis (35). Endoscopic outcomes, such as mucosal healing, are now recognised as an important treatment target (35, 74, 75). The evolution of treatment goals from a focus on symptom control to also include endoscopic improvements is based on available evidence that mucosal healing is associated with better long-term outcomes, such as reduced risk of relapse, decreased hospitalisation rates, steroid-free remission in follow-up examination, resection free intervals and improved HRQoL (76, 77). There is increasing evidence of the benefits of mucosal healing in reducing future relapse rate (78). Additionally, people with CD with mucosal healing have a decreased risk of penetrating complications (i.e., development of fistulae) and probability of surgery as compared with those with severe ulcerations (77).

Recently updated guidance by the British Society of Gastroenterology (BSG) recognises the importance of mucosal healing, as measured by endoscopy, as a target for individuals and clinicians (35). Furthermore, evidence- and consensus-based recommendations from The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) (74) and STRIDE-II (75) programs recommended treatment targets for the management of IBD. In addition to short-term treatment targets of symptomatic response and remission, endoscopic response, normalised QoL and absence of disability were recognised as long-term treatment targets.

Disease management guidance

The treatment guidelines that are considered relevant for moderately to severely active CD in UK clinical practice are listed below:

• Crohn’s disease: management (NICE guidance, NG129) (53)

• BSG consensus guidelines on the management of IBD in adults (35)

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• European Crohn's and Colitis Organisation Guidelines on Therapeutics in Crohn's Disease: Medical Treatment (79)

In England, current NICE guidance (NG129) for adults recommends initial pharmacotherapy with conventional care to induce remission (initial presentation or during a flare-up), which typically includes corticosteroids (e.g., prednisolone) or aminosalicylates, typically followed by immunomodulators (IMM), such as azathioprine, to induce remission. IMM can also be given in addition to corticosteroids in the presence of continued inflammatory exacerbations (Figure 3) (53). Of note, aminosalicylates are rarely used in UK clinical practice (80) and other treatment guidelines do not recommend their use for CD (35, 79).

The treatment pathway based on NICE management guidance (53), including the typical biologic therapy sequence observed in UK clinical practice, is presented in Figure 3.

Figure 3: Treatment pathway based on CD management guidance by NICE

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Abbreviations: CC, conventional care; CD, Crohn’s disease; IR, inadequate response/treatment failure; TNF, tumour necrosis factor. Figure adapted from NICE guidance. Source: Crohn’s disease: management (NG129). 2019. NHS England, Clinical Commissioning Policy. 2020 (53). † Biosimilars are also available; The only approved biologic therapy for use in children and adolescents (>6–17 years old) with moderate-to-severe CD (53). ‡ TNF-alpha contraindicated people with CD are considered as part of the biologic failure population, in line with CEM and BIM. The majority (69%) of the TNF-alpha contraindicated population were expected to have failed a prior biologic (81) and analyses presented are split between the CC failure and biologic failure populations. Note: For paediatric patients, enteral nutrition or steroids are generally used for mild disease. For severe disease,

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stronger immunosuppressive add-on therapies with stronger immunosuppressive medications, such as azathioprine and methotrexate, are used (82).

For adults, biologic medicines are introduced if there is a poor response to initial therapy with conventional care, if the therapy is not tolerated, or is contraindicated. For individuals with moderate-to-severe CD who have an inadequate response, are intolerant or are contraindicated to conventional care, TNF-alpha inhibitors (adalimumab, infliximab [both have biosimilars available]) and an interleukin 12/23 inhibitor (ustekinumab) are available as biologic treatment options.

For individuals who have biologic failure (those treated with a biologic therapy and subsequently have a loss of response, an inadequate response or are intolerant) ustekinumab or vedolizumab (an integrin α4β7 inhibitor) are the therapy options. Ustekinumab and vedolizumab are also the therapy options when TNF-alpha inhibitors are contraindicated (Figure 3) (53).

NICE recommend starting biologic treatment with the least expensive option, and that clinicians, after 12 months of treatment with a biologic therapy, assess individuals to determine if they are responding and should continue on the same therapy (53). The use of biologic therapies is beneficial but may be associated with loss of response in almost half of individuals within the first year (83), requiring dose escalation or therapy change, subsequently limiting the treatment options for clinicians and people with CD. The BSG guidance recommends that the choice between TNF-alpha inhibitor treatment, ustekinumab and vedolizumab should be made on an individual basis, considering individual preference, cost, likely adherence, safety data and speed of response to the drug (35).

For children and adolescents with CD, the treatment aim is to manage symptoms and ensure normal growth velocity in children. Enteral nutrition or steroids are generally induction treatments for all disease severity, with subsequent use of stronger immunosuppressive medications, such as azathioprine and methotrexate, to maintain remission (82). TNF-alpha inhibitors (infliximab, adalimumab) are the only biologic therapies licensed for those aged 6-17 years (53). For children and adolescents who have failed all these treatments, there is no alternative licensed therapy.

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Ultimately, clinical management depends on disease activity, site, behaviour of disease (inflammatory, fistulising or stricturing), response to previous treatments, sideeffect profiles of treatments and extra-intestinal manifestations, such as uveitis and arthritis, and patient preference (35, 53, 84).

Surgery is another treatment option for people with CD (53); the most common reasons for surgery include poor response to drug or nutritional treatment, strictures, fistulas and delayed growth in children as result of adequate control of inflammation. The benefits of surgery can include relief from pain, reduction of symptoms (e.g., diarrhoea, vomiting and fatigue), and reduction or cessation of treatments which may cause side effects (71). However, surgery is not curative, and use of biologic therapies may still be required (85).

In general, guidance from the BSG aligns with the NICE guidance presented before, with people with CD starting treatment on conventional care and progressing to biologic therapies if the disease is not adequately controlled with conventional care (35). The BSG guidance also recommends early use of biologic therapies in individuals with adverse prognostic factors.

Dosing of biologic therapies

Dosing of currently available biologic treatments requires induction therapy, where the drug is administered at a higher dose initially to reduce inflammation and improve CD symptoms (i.e., achieve remission). Following induction, a standard dose is administered at regular intervals to maintain control of the disease. People with moderately to severely active CD who experience loss of response to a particular TNFalpha inhibitor are advised to reduce the interval between maintenance doses or escalate the dose before switching to another TNF-alpha inhibitor (86-88). Similarly, there is clinical flexibility for dose escalation for other classes of biologics (i.e., IL-12/23 [ustekinumab] and integrin α4β7 [vedolizumab] inhibitors) as per their respective SmPCs (89, 90). Specifically, ustekinumab may be initiated at a standard dose (Q12W) or a higher dose (Q8W), and both ustekinumab and vedolizumab may be escalated from the standard dose (Q12W and Q8W, respectively) to a higher dose during treatment (Q8W and Q4W, respectively) (89, 90). Feedback from clinical

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experts indicates that dose escalation may be necessary in 30% and 92.5% of individuals receiving vedolizumab or ustekinumab, respectively (80).

B.1.3.4 Unmet need

As CD is a chronic condition which needs to be managed throughout the individual’s lifetime, there is a significant unmet need for treatments in CD. Priorities include improved and sustained efficacy, including improved sustained corticosteroid-free remission.

CD is not always adequately controlled by currently available conventional and biologic therapies; it is estimated that there are approximately 4,000 people in the UK that have had an inadequate response to all currently available conventional and biologic therapies[c] (46). Approximately 50% of people with moderately to severely active CD do not respond to or cannot tolerate conventional treatment (46). Although advanced biologic therapies offer additional treatment options, individuals may still experience disease flares resulting in the appearance or worsening of disease symptoms such as abdominal pain and fatigue, which may require a dose escalation, therapy change or treatment with additional therapies, such as corticosteroids (83, 9194). Furthermore, response to biologic therapy is often not sustained over time. Based on an international online survey (Canada, France, Germany, Italy, Spain, UK and USA) of individuals with CD, the response to biologic therapy is often not sustained over time, with loss of response to prior treatment reported in 69% of individuals (81).

TNF-alpha inhibitor treatments for CD (i.e., infliximab, adalimumab [including their biosimilars]) are commonly associated with therapy failure. Up to 30% of individuals do not respond to TNF-alpha inhibitor therapy (primary non-responders) and almost half of individuals who experience a benefit with these drugs will lose clinical benefits within the first year, requiring dose escalation or therapy change (secondary loss of response) (83). Moreover, people with CD who lose response to a specific TNF-alpha inhibitor have a lower chance of responding to a second TNF-alpha inhibitor (95). Primary loss of treatment response is also an issue with other classes of biologic therapies. A loss of response rate of approximately 30% at 52 weeks has been

c Figure estimated before the introduction of ustekinumab. Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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reported for vedolizumab (integrin α4β7 inhibitor) and ustekinumab (IL-12/23 inhibitor) (92, 94).

In addition to loss of response, another key limitation of existing treatments is their association with adverse side effects leading to potential increased HCRU and costs. For example:

• Long-term exposure to corticosteroids (often used alongside biologic therapies) results in an increased risk of numerous adverse events, including infection, psychological disturbances, diabetes, hypertension and osteoporosis (96); current BSG guidance does not recommend their long-term use (35).

• TNF-alpha inhibitors are associated with an increased risk of malignancy, demyelination and infection, including tuberculous infection (83, 89, 92).

• The development of anti-drug antibodies are associated with a loss of response (89, 97). The rates of anti-drug antibody development with TNF-alpha inhibitors are high and, consequently, are often given in combination with IMMs (e.g., azathioprine, mercaptopurine, methotrexate) to prevent anti-drug antibody formation (98). TNFalpha inhibitor anti-drug antibody rates of 28.5% and 62.8% have been reported for adalimumab and infliximab, respectively (98). Additionally, the use of thiopurines (e.g., azathioprine) is associated with a risk for the development of lymphoma, nonmelanoma skin cancer, liver inflammation bone marrow suppression and severe infections (99-102).

B.1.3.5 Risankizumab for the treatment of CD

Risankizumab is a humanised antibody which inhibits binding of the IL-23 proinflammatory cytokine to the IL-23 receptor complex. By blocking IL-23 from binding to its receptor, risankizumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines (10-12, 92). Increasing experimental and genetic evidence points to a fundamental role for IL-23 in driving inflammatory bowel disease, including CD (5).

In line with the NICE recommendations for the clinical pathway in moderate-to-severe CD as detailed in Section B.1.3.3, the proposed UK treatment pathway including

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risankizumab for CD is depicted Figure 4, the proposed positioning for risankizumab is equivalent to that of ustekinumab.

The positioning of risankizumab is in line with the expected marketing authorisation for CD, which is expected to be for the treatment of ************************************************************************************************ ************************************************************************************************ ***********************************************. Therefore, risankizumab is expected to provide an additional treatment option in UK clinical practice for people with moderateto-severe CD who are suitable for biologic therapy (Figure 4, green outline box). Risankizumab will also provide an additional treatment option for individuals with incomplete response to other biologic therapies (Figure 4, yellow outline box).

Risankizumab is a new class of biologic with a novel mode of action that selectively targets IL-23. Given that up to 50% of people with moderate-to-severe CD do not respond to, or cannot tolerate conventional treatment (46) and approximately 30% of individuals will lose response to biologic therapy within the first year of treatment (83, 92, 94) (previously discussed in Section B.1.3.4), risankizumab fulfils and important unmet need by providing an additional biologic therapy option for the management of individuals with CD.

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Figure 4: Proposed treatment pathway including risankizumab for CD in the UK

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Abbreviations: CD, Crohn’s disease; IR, inadequate response/treatment failure; TNF, tumour necrosis factor. Figure adapted from NICE guidance. Source: NICE. Crohn’s disease: management (NG129). 2019. NHS England, Clinical Commissioning Policy. 2020. (53). † Biosimilars are also available; The only approved biologic therapy for use in children and adolescents (>6–17 years old) with moderate-to-severe CD (53). ‡ TNF-alpha contraindicated people with CD are considered as part of the biologic failure population, in line with CEM and BIM. The majority (69%) of the TNF-alpha contraindicated population were expected to have failed a prior biologic (81) and analyses presented are split between the CC failure and biologic failure populations. Note: For paediatric patients, enteral nutrition or steroids are generally used for mild disease. For severe disease, stronger immunosuppressive add-on therapies, such as azathioprine, are used (82).

B.1.4 Equality considerations

No equality issues associated with the use of risankizumab in this indication have been identified or are foreseen.

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B.2 Clinical effectiveness

Evidence for risankizumab in moderately-to-severely active CD

The Phase 3 pivotal induction studies (ADVANCE, MOTIVATE) and maintenance study (FORTIFY) provide the evidence for risankizumab for the treatment of moderately to severely active CD.

• ADVANCE and MOTIVATE were Phase 3, multicentre, randomised, double-blind, 12week induction studies which evaluated the efficacy and safety of risankizumab (600 mg or 1,200 mg IV at weeks 0, 4 and 8) versus placebo in subjects aged ≥16 years with moderately-to-severely active CD.

• ADVANCE enrolled subjects with either inadequate response/intolerance to prior biologic therapy (Bio-IR) or with inadequate response/intolerance to conventional therapy (non-Bio-IR) for CD, whereas MOTIVATE enrolled subjects with only a documented inadequate response or intolerance to ≥1 biologic therapy/therapies for CD (Bio-IR).

  • Subjects in the risankizumab treatment arms who did not achieve PRO2 (SF/APS) clinical response[†] at Week 12 were re-randomised 1:1:1 to receive risankizumab 1,200 mg IV, risankizumab 360 mg SC or risankizumab 180 mg SC. Subjects in the placebo arm who did not achieve PRO2 (SF/APS) clinical response[†] at Week 12 of Induction Period 1 received risankizumab 1,200 mg IV during the 12-week Induction Period 2

• FORTIFY is a Phase 3, multicentre, partially randomised, double-blind, placebocontrolled, 52-week maintenance study with an ongoing open-label (OL) extension which evaluated the efficacy and safety of risankizumab in subjects with moderately-toseverely active CD. The study enrolled subjects who achieved SF/APS clinical response[†] at the last visit of induction (Induction Period [Week 12] or Induction Period 2 [Week 24]) for ADVANCE or MOTIVATE.

  •  Subjects who achieved SF/APS clinical response[†] to 12 weeks of IV risankizumab induction (either at Week 12 or 24) from ADVANCE and MOTIVATE and a Baseline induction eligibility SES-CD of ≥6 (≥ 4 for isolated ileal disease) were re-randomised in a 1:1:1 ratio to receive risankizumab at either 180 mg SC Q8W or 360 mg SC Q8W, or to receive placebo SC Q8W (referred to as placebo SC [withdrawal][‡] ).

Definition of subpopulations of interest

The naming conventions used to describe the populations of interest in the pivotal risankizumab clinical trials in CD (Bio-IR and non-Bio-IR) are different from naming conventions used in previous TAs for this indication (conventional care failure [CCF] and biologic failure [BF]). Definitions of the specific populations are as follows:

• Non-Bio-IR: Subjects who had an inadequate response or intolerance to conventional therapy.[§] This population may also include subjects who had received biologic therapy in the past but stopped therapy based on reasons other than inadequate response (IR) or intolerance (e.g., change in reimbursement coverage, well-controlled disease); however, the majority of subjects (>**%) had not received a prior biologic therapy (103). This population is analogous to the CCF population which has been described in previous submissions.[¶]

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• Bio-IR: Subjects with documented intolerance or IR (either failure to respond to induction treatment, or loss of response to maintenance therapy) to one or more biologics for CD (infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and/or ustekinumab). This population is analogous to the BF population which has been described in previous submissions.[¶]

Consequently, the Bio-IR and non-Bio-IR naming conventions are used in the context of the risankizumab clinical trials only, whilst through the remainder of the submission (i.e., the NMA and cost-effectiveness model), CCF and BF are used for consistency with previous appraisals.

Efficacy

• Treatment with risankizumab in the induction (risankizumab 600 mg IV) and maintenance (risankizumab 360 mg SC) studies were superior to placebo for the coprimary endpoints of clinical remission (CDAI or PRO2 [SF/APS][††] ) and endoscopic response.[‡‡]

• In the induction studies, symptomatic improvements were seen as early as Week 4 and mucosal improvement (measured by SES-CD) observed at Week 12 after treatment with risankizumab 600 mg IV.

• For risankizumab maintenance, symptomatic and mucosal improvements were also observed after 52 weeks of treatment. Outcomes indicative of mucosal healing, specifically ulcer-free endoscopy[§§] and the composite endpoint of deep remission[¶¶] were achieved by approximately 30% of subjects receiving risankizumab 360 mg SC.

• Subjects treated with risankizumab 600 mg IV in ADVANCE and MOTIVATE had significantly improved HRQoL (EQ-5D-5L) as early as 4 weeks and at Week 12 when compared with placebo.

Safety

• Across the risankizumab induction (ADVANCE and MOTIVATE) and maintenance (FORTIFY) studies, no new safety risks were identified, and the overall safety profile was consistent with the known safety profile of risankizumab in the management of psoriasis.

Indirect treatment comparisons

• In the absence of head-to-head clinical trial evidence for risankizumab versus other biologic therapies, an indirect treatment comparison was performed. Overall, the indirect treatment comparison (ITC) results indicate that that risankizumab has similar efficacy compared with other biologics across most clinically relevant outcomes, in both CCF and BF populations.

Conclusion

• Risankizumab is an innovative therapy that is associated with significant symptomatic, clinical and mucosal improvements from as early as Week 4 versus placebo, with similar improvements observed over the 52-week SC maintenance phase. Risankizumab is also well tolerated. In an ITC, risankizumab has similar efficacy compared with other biologics across the majority of clinically relevant outcomes, in both CCF and BF populations.

† For this submission, only CDAI outcomes are presented as the cost-effectiveness model utilises CDAI outcomes to define CD health states (i.e. PRO2 [SF/APS] outcomes are not used in the model) and CDAI outcomes facilitate Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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indirect treatment comparisons with previous trials of treatments for CD (104, 105). Overall, the results for PRO2 [SF/APS] and CDAI outcomes were similar for risankizumab in CD. Consequently, all PRO2 (SF/APS) outcomes, including the co-primary endpoint of PRO2 [SF/APS] clinical remission and endoscopic response, are presented in Appendix M; ‡ Subjects re-randomised to receive placebo are referred to as the placebo SC (withdrawal) group as these subjects previously received risankizumab in the induction studies and have subsequently had it withdrawn for the maintenance study (i.e., re-randomised to placebo); § Defined as one or more of the following: aminosalicylates, oral locally acting steroids [e.g., budesonide, beclomethasone], systemic corticosteroids [prednisone or equivalent], or immunomodulators; ¶ Clinicians at an expert advisory board (80) have also concluded that the non-Bio-IR and Bio-IR populations in the risankizumab clinical trials are analogous to the CCF and BF populations, respectively; †† Ulcer-free endoscopy defined as SES-CD ulcerated surface subscore of 0 in subjects with SES-CD ulcerated surface subscore ≥1 at baseline of the induction study, as scored by a central reviewer; CDAI clinical remission defined as CDAI <150; ‡‡ Endoscopic remission is defined as SES-CD ≤4 and at least a 2 point reduction versus baseline of the induction study and no subscore greater than 1 in any individual variable, as scored by a central reviewer.

B.2.1 Identification and selection of relevant studies

A systematic literature review (SLR) was conducted to identify all relevant clinical evidence on the efficacy and safety of risankizumab and relevant comparators for the treatment of people aged ≥16 years with moderate-to-severe CD. An overview of the methodology, including search strategy, PRISMA flow diagram, list of included studies and list of excluded studies at full paper review is provided in Appendix D.

B.2.2 List of relevant clinical effectiveness evidence

A summary of the clinical effectiveness evidence for risankizumab is provided in Table 4, Table 5 and Table 6.

The primary data for risankizumab CD in this submission is taken from clinical study reports (CSRs) and published manuscripts. At the time of submission, only data from the CSRs were deemed commercial in confidence.

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Table 4: Clinical effectiveness evidence – ADVANCE (pivotal induction study)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CD, Crohn’s disease; CSR, clinical study report; IV, intravenous; non-Bio-IR, conventional therapy inadequate response/intolerance.

Table 5: Clinical effectiveness evidence – MOTIVATE (pivotal induction study)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CD, Crohn’s disease; CSR, clinical study report; IV, intravenous.

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Table 6: Clinical effectiveness evidence – FORTIFY (pivotal maintenance study)

Abbreviations: CD, Crohn’s disease; CSR, clinical study report; Q8W, every 8 weeks; SC, subcutaneous. † SF/APS clinical response defined as ≥ 30% decrease in average daily stool frequency (SF) and/or ≥ 30% decrease in average daily abdominal pain score (APS) and both not worse than Baseline of the induction study.

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

B.2.3.1 Comparative summary of trial methodology

The Phase 3 pivotal induction studies (ADVANCE, MOTIVATE) and maintenance study (FORTIFY) provide the evidence for risankizumab for the treatment of moderately-to-severely active CD in people aged 16 years and older.

B.2.3.1.1 Induction studies (ADVANCE and MOTIVATE)

ADVANCE and MOTIVATE were Phase 3, multicentre, randomised, double-blind induction studies which evaluated the efficacy and safety of risankizumab (600 mg or 1,200 mg IV Q4W) versus placebo in subjects with moderately-to-severely active CD aged 16 years and older. ADVANCE enrolled subjects with inadequate response or intolerance to prior biologic therapy (Bio-IR), or with inadequate response or intolerance to conventional therapy (non-Bio-IR). MOTIVATE enrolled subjects with a documented inadequate response or intolerance to ≥1 biologic therapy/therapies for CD (Bio-IR). These populations were defined as following:

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• Bio-IR population: Included subjects with documented inadequate response or intolerance to one or more biologics for CD (infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and/or ustekinumab) (refer to Appendix M for full definition).

• Non-Bio-IR population: included subjects who had an inadequate response or intolerance to conventional therapy (defined as one or more of the following: aminosalicylates, oral locally acting steroids [e.g., budesonide, beclomethasone], systemic corticosteroids [prednisone or equivalent], or immunomodulators). This population included subjects who had received biologic therapy in the past but stopped therapy based on reasons other than inadequate response or intolerance (e.g., change in reimbursement coverage, well-controlled disease), however, the majority of subjects had not received a prior biologic therapy (refer to Appendix M for full definition).

The percent of subjects with exposure, including intolerance or inadequate response, to ustekinumab was to be no more than 20% in the ADVANCE and MOTIVATE.

In ADVANCE and MOTIVATE, subjects received placebo IV or risankizumab IV (600 mg or 1,200 mg) at weeks 0, 4, and 8. The final study visit was at Week 12 (Induction Period 1). Subjects who did not achieve a clinical response during Induction Period 1 were re-randomised to receive a further 12 weeks of induction treatment (Induction Period 2) (Figure 5).

An overview of the analysis sets and contributing subject populations is presented in Table 7, with the two induction periods detailed as follows:

• Induction Period 1: After a screening period of up to 35 days, subjects were randomised in a 2:2:1 (ADVANCE; Figure 5) or 1:1:1 ratio (MOTIVATE; Figure 5) into risankizumab 1,200 mg IV, risankizumab 600 mg IV or placebo IV arms for the 12-week Induction Period 1, with subjects in all arms receiving treatment at Week 0, 4 and 8. Visits for clinical evaluation occurred at Baseline, and Weeks 4, 8, and 12, or premature discontinuation.

• Induction Period 2: Subjects in risankizumab treatment arms who did not

  • achieve PRO2 (SF/APS) clinical response (see Table 11 for definition) at Week 12 were re-randomised 1:1:1 to receive risankizumab 1,200 mg IV, risankizumab 360

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mg SC or risankizumab 180 mg SC (see Figure 5 for more details). Subjects in the placebo arm who did not achieve PRO2 (SF/APS) clinical response at Week 12 of Induction Period 1 received risankizumab 1,200 mg IV during the 12-week Induction Period 2 (Figure 5).

Study duration for ADVANCE and MOTIVATE was up to 49 weeks (comprised of 5 weeks screening, up to 24 weeks’ treatment and a 20-week follow up for subjects who discontinued and did not go on to enter FORTIFY. Subjects who achieved PRO2 (SF/APS) clinical response at the last visit of Induction Period 1 (Week 12) or Induction Period 2 (Week 24) in ADVANCE or MOTIVATE were enrolled in the FORTIFY maintenance study (see B.2.3.1.2).

Figure 5: Trial design for ADVANCE and MOTIVATE

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Abbreviations: DC, discontinuation; IR, inadequate response/intolerance; IV, intravenous; R, randomisation / response; RZB, risankizumab; RR, re-randomisation; SC, subcutaneous. † Subjects were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE). Colours refer to trial population flow in FORTIFY (see Figure 6)

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Table 7: Definitions of analysis sets – ADVANCE and MOTIVATE

Abbreviations: ITT, intention to treat; PBO, placebo; RZB, risankizumab; SA, safety analysis; SES-CD, Simple Endoscopic Score for Crohn’s Disease.

B.2.3.1.2 Maintenance study (FORTIFY)

FORTIFY is a Phase 3, multicentre, partially randomised, double-blind, placebocontrolled, 52-week maintenance study with an ongoing OL extension which evaluated the efficacy and safety of risankizumab in subjects with moderately-to-severely active CD aged 16 years and older. The study enrolled subjects who achieved PRO2 (SF/APS) clinical response (defined as 30% decrease in average daily SF and/or ≥30% decrease in average daily AP score and both not worse than Baseline of induction study) at the last visit of induction (Induction Period [Week 12] or Induction Period 2 [Week 24]) for ADVANCE or MOTIVATE.

FORTIFY consists of 3 sub-studies. This submission presents the results from FORTIFY Sub-study 1 (SS1)[d] , which was a 52-week randomised, double-blind, placebo-controlled maintenance study. FORTIFY SS1 had a randomised portion and non-randomised portion. An overview of the analysis sets and contributing subject populations is presented in Table 8 and the trial design is presented in Figure 6.

 FORTIFY SS1 randomised responders: Included all subjects from ADVANCE and MOTIVATE who had a clinical response to induction treatment with IV risankizumab (either during Induction Period 1 or Induction Period 2) and a

d Sub-Study 2 was a 52-week randomised, exploratory maintenance study of 2 different dosing regimens (TDM vs clinical assessment for dose escalation) and is not presented in this submission. Sub-Study 3 is an OL long-term extension for which data collection is still ongoing. Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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Baseline induction eligibility SES-CD of ≥6 (≥ 4 for isolated ileal disease) – denoted as the purple and dark blue populations in Figure 6).

• Subjects were re-randomised in a 1:1:1 ratio to receive either risankizumab 180 mg SC Q8W, risankizumab 360 mg SC Q8W or placebo SC Q8W. The placebo will henceforth referred to as placebo SC (withdrawal). This reflects the placebo ‘withdrawal’ arm as all subjects in this arm received and clinically responded to risankizumab IV during induction in ADVANCE and MOTIVATE.

  • The primary efficacy analysis included subjects with PRO2 (SF/APS) clinical response to IV risankizumab induction at Week 12 (Induction Period 1) or subjects who had an IR to placebo at Week 12 (Induction Period 1) and a subsequent response to IV risankizumab at Week 24 (Induction Period 2) (purple population in Figure 6).

  • Subjects who had an IR to IV risankizumab at Week 12 (Induction Period 1), and a subsequent response to IV risankizumab at Week 24 (Induction Period 2) were re-randomised but were not included in the primary efficacy analysis (dark blue population in Figure 6).

  • The main safety population (SA1) consisted of all randomised subjects who received at least 1 dose of study risankizumab.

• FORTIFY SS1 non-randomised responders: Included subjects with either PRO2 (SF/APS) clinical response to IV placebo at the end of Induction Period 1 or risankizumab 360mg/180mg SC induction treatment at the end of Induction Period 2 in ADVANCE or MOTIVATE.

  • Subjects who achieved a clinical response to IV placebo at the end of Induction Period 1 were assigned to continue receiving placebo SC in FORTIFY (referred to as ‘true’ placebo, as these subjects did not receive any risankizumab treatment in the induction or maintenance trials; turquoise population in Figure 6).

  • Subjects who achieved a clinical response to risankizumab 360mg/180mg SC induction treatment at the end of Induction Period 2 were assigned to continue to receive the same blinded study drug in FORTIFY (light blue populations in Figure 6).

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Table 8: Definitions of analysis sets – FORTIFY SS1

Abbreviations: APS, abdominal pain score; ITT, intention to treat; IV, intravenous; PROS, patient reported outcomes 2-item; RZB, risankizumab; SA, safety analysis; SC, subcutaneous; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; SS, sub study.

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Figure 6: Trial design for FORTIFY (Sub Study 1)

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Abbreviations: IR, inadequate response/intolerance; IV, intravenous; PBO, placebo; Q8W, every 8 weeks; R, response RZB, risankizumab; SC, subcutaneous; SSI, Sub Study 1. † Randomisation ratio for ADVANCE (2:2:1) and MOTIVATE (1:1:1); ‡ Any IR subjects at Wk24 did not enter FORTIFY; § FORTIFY Wk0 is the last dose of the induction period (i.e., either Wk12 or Wk24 of treatment).

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Subjects who demonstrated IR during FORTIFY SS1 received OL risankizumab rescue therapy starting at the Week 16 visit (up to 2 rescue therapy visits) based upon increased symptom activity and confirmation with objective markers of inflammation. Rescue therapy consisted of OL risankizumab at 1,200 mg IV as a single dose, followed by OL risankizumab 360 mg SC dosing Q8W. Please note, these subjects are not considered further in this submission as this population is not in line with the licensed indication.

Subjects who were taking corticosteroid therapy at the Week 0 visit of FORTIFY had their corticosteroid therapy tapered. If an Investigator believed that the steroid taper was not advisable for a particular subject, the sponsor Therapeutic Area Medical Director (TA MD) was consulted for evaluation and approval. The corticosteroid tapering schedule is available in Appendix M.3

For subjects who enrolled in FORTIFY SS1, Baseline was defined as the Baseline visit of the induction studies ADVANCE or MOTIVATE for efficacy analyses. For safety analyses, Baseline was defined as the last measurement prior to the first dose of study drug in ADVANCE or MOTIVATE.

Week 0 was defined as the first study visit in FORTIFY SS1. The final visit of ADVANCE or MOTIVATE (Week 12 or Week 24) was considered as the Week 0 visit of SS1.

Visits during FORTIFY SS1 occurred at Weeks 0, 8, 16, 24, 32, 40, 48 and 52/premature discontinuation. Subjects who discontinued from the study early or completed FORTIFY SS1 and did not continue into Sub-Study 3 had an additional 140 days of safety follow-up from the last dose administration of study drug.

The methodologies of ADVANCE, MOTIVATE and FORTIFY are summarised in Table 9.

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Table 9: Comparative summary of trial methodology

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Abbreviations: MP, mercaptopurine; ADA, adalimumab; AP, abdominal pain; APS, abdominal pain score; AZA, azathioprine; Bio-IR, biologic inadequate response/intolerance; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; CRA, clinical research associate; EQ-5D-5L, EuroQoL five dimensions five levels; FCP, faecal calprotectin; Hct, haematocrit; hs-CRP, high-sensitivity C-reactive protein; IFX, infliximab; IR, inadequate response; IRT, Interactive Response Technology; MTX, methotrexate; non-Bio-IR, conventional therapy inadequate response/intolerance; RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; TA MD, Therapeutic Area Medical Director; TNF, tumour necrosis factor; TPMT, thiopurine methyltransferase; UST, ustekinumab; VDZ, vedolizumab.

† All eligible scores excluded the presence of narrowing component and were confirmed by a central reader (once cap of subjects was reached (no more than 85 in ADVANCE and no more than 58 in MOTIVATE); subjects with a SES-CD of <3 were enrolled as an experimental subset (results from this population are excluded from this submission); ‡ intolerance included patients with a known TPMT genetic mutation or low activity; § Permitted pre-medication included with diphenhydramine hydrochloride and acetaminophen (or equivalents); ¶ Examples of such vaccines included but were not limited to the following: live attenuated influenza, herpes zoster (e.g., Zostavax[®] ), rotavirus, varicella (chicken pox), smallpox, yellow fever. †† An endoscopy performed before the Screening visit, independently of the study, may have been used as the Screening endoscopy, with the approval of the AbbVie TA MD, if the following conditions were met: 1. Biopsy confirmation of the diagnosis was available according to section "Biopsy During Endoscopy" below, as applicable, 2. The endoscopy took place within 45 days prior to Baseline visit, 3. The endoscopy was recorded in a video format as the endoscopic eligibility will be determined by the central reviewers; ‡‡ The final CDAI for all other visits was calculated once the Hct value was received from the central lab. If the Hct was missing due to technical issues, the Hct value from the preceding visit may have been used.

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B.2.3.2 Trial endpoints

The co-primary and secondary endpoints for the ADVANCE, MOTIVATE and FORTIFY studies are presented in Table 10. Definition and interpretation of these endpoints are defined in Table 11.

Two protocols were used in the studies, a US protocol and an OUS protocol due to regional differences in regulatory requirements, which resulted in two co-primary endpoints which differ based on the clinical measures described in Table 10.

The main body of this submission only presents results for CDAI outcomes, given that CD clinical trials have historically used this measure, and this is consistent with the outcomes reported in both the ustekinumab and vedolizumab clinical trials for CD (35, 104, 105). CDAI outcomes are also used to define health states in the costeffectiveness model (the model does not utilise the PRO2 [SF/APS] outcomes), also aligning with previous CD NICE submissions (46, 47).

Although CDAI is not commonly used as a measure to assess disease severity in UK clinical practice, it is the most frequently utilised measure used in clinical trials for this indication (35, 104, 105). However, CDAI has some relevance to the HBI, a commonly used measure of disease severity in the UK, given that both disease severity measures share several common items for disease measurement (32). For completeness the PRO2 (SF/APS) outcomes are included in Appendix M (M.2 for ADVANCE and MOTIVATE and M.4 for FORTIFY).

From hereon, endpoints are defined as per Table 11 unless stated otherwise.

Table 10: Primary and secondary efficacy endpoints in ADVANCE, MOTIVATE and FORTIFY trials

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Abbreviations: APS, abdominal pain score; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; EQ-5D5L, EuroQoL five dimensions five levels; IBDQ, Inflammatory Bowel Disease Questionnaire; OUS, outside of the United States; PRO2, patient reported outcomes 2-item; SF, stool frequency; SF-36, short form 36-item.

Table 11: Definition of disease-specific endpoints used in ADVANCE, MOTIVATE and FORTIFY

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Abbreviations: AP, abdominal pain; APS, abdominal pain score; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; IBDQ, Inflammatory Bowel Disease Questionnaire; PRO2, patient reported outcomes 2-item; SESCD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; VAS, visual analogue scale. † CDAI clinical remission is an outcome used in the NMA base case analyses and the trial definition aligns with the NMA definition. CDAI clinical response is also assessed in the NMA, but the outcome is named ‘CDAI-100 response’ in the NMA analyses; both CDAI clinical response and CDAI-100 response have the same definitions. See Section B.2.9.1.4 for the definition of outcomes used in the NMA; ‡ FORTIFY used induction study Baseline values as Baseline; § Endpoints only applicable to FORTIFY.

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B.2.3.3 Baseline characteristics and demographics

The baseline characteristics from the induction (ADVANCE, MOTIVATE) and maintenance (FORTIFY) trials are summarised in Table 12. The baseline demographics and clinical characteristics of subjects were well balanced between the treatment groups in each trial and were generally similar across studies.

For the induction studies (ADVANCE, MOTIVATE), the mean age of subjects across the study arms ranged from 38.3 to 40.2 years in the risankizumab 600 mg IV arm and 37.1 to 39.3 years in the placebo IV arm. Across the induction studies, mean disease duration ranged from 9.0 to 10.9 years in the risankizumab 600 mg IV arm and 8.2 to 12.5 years in the placebo IV arm. Similar baseline characteristics were observed for the maintenance study (FORTIFY); the mean age of subjects was 37.0 in the risankizumab 360 mg SC arm and 38.0 years in the placebo SC (withdrawal) arm, while mean disease duration was 9.3 years in the risankizumab 360 mg SC arm and 9.6 years in the placebo SC arm. Of note, the risankizumab CD studies enrolled subjects aged 16 to 80 years, with those aged <18 years representing approximately 1% of subjects in each study.

Across the trial arms of the induction studies (ADVANCE, MOTIVATE), disease severity baseline characteristics were reflective of moderately-to-severely active CD (mean CDAI scores of 310.7 to 319.6, mean SES-CD scores of 13.8 to 15.0, mean SF scores of 5.8 to 6.4, and mean AP scores of 1.8 to 1.9 [see Appendix N.1 for interpretation of disease severity scores]). Disease severity baseline characteristics were broadly similar for the maintenance study (FORTIFY [mean CDAI scores of 307.4 to 308.9, mean SES-CD scores of 14.0 to 14.3, mean SF scores of 5.8 to 5.9, and mean AP scores of 1.8 to 1.9]).

With regard to treatment history, the proportion of subjects with corticosteroid and immunomodulator use at baseline across the induction studies (ADVANCE, MOTIVATE) ranged from 28.6% to 36.4% and 18.8% to 26.2%, respectively. For the maintenance study (FORTIFY), similar results were observed for corticosteroid (29.8– 31.1%) and immunomodulator (24.4–28.4%) use. A substantial proportion of the subjects enrolled in the risankizumab studies were treatment refractory, having failed more than one previous biologic therapy (ADVANCE, [30%], MOTIVATE [52%] and

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FORTIFY [36%]). Across the studies, the majority of subjects with previous biologic therapy failure had failed TNF-alpha inhibitor therapy (ADVANCE, [94–100%], MOTIVATE [93–97%] and FORTIFY [89–97%]).

B.2.3.4 Expert elicitation/opinion

UK clinical and health economic expert opinion was sought to support the submission for risankizumab in people with moderate-to-severe CD, with expert opinion collected at a virtual advisory board meeting, via virtual ‘round table’ discussions, ****************. AbbVie approached eight experts (six clinicians and two health economic experts), who all participated. The criteria for selecting suitable experts were expertise and experience of treating CD in the UK (clinician) and specialised technical expertise in economic evaluation and health technology assessment (health economic expert).

Experts were provided with pre-read material prior to the advisory board which contained a CD disease overview, UK epidemiological data, methods for assessing disease severity and activity, current UK treatment landscape, risankizumab product information and clinical trial data, and risankizumab health economic model information. All information provided to the experts was consistent with the evidence provided in this submission. UK clinical and health economic expert opinion was also sought during development of this submission. Expert opinion was gathered through review of the submission document by four clinical and one health economic expert. The criteria for selecting suitable experts were the same as previously described.

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Table 12: Characteristics of participants in the studies across treatment groups (ITT1A population)

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Abbreviations: AP, abdominal pain; Bio-IR, biologic inadequate response/intolerance; BMI, body mass index; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; IV, intravenous; PBO, placebo; RZB, risankizumab; SC, subcutaneous; SD, standard deviation; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; TNF, tumour necrosis factor; WHO, World Health Organization.

†Bio-IR population; ‡generic name (WHO 2018Q1); §for FORTIFY, baseline refers to baseline of the induction study; ¥Data reported for randomised subjects only from FORTIFY SS1;[†† ] The placebo SC (withdrawal) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy in ADVANCE or MOTIVATE and were randomised to receive placebo in FORTIFY.

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

B.2.4.1 Definitions of subject population analysis sets

Definitions of the subject population analysis sets of the induction (ADVANCE, MOTIVATE) and maintenance (FORTIFY) studies are provided in Section B.2.3.1 Table 7 and Table 8, respectively. All analyses of co-primary endpoints were performed using the ITT1A analysis set, while all analyses of secondary endpoints were performed using the ITT analysis set. The subject numbers comprising each data set are presented in Appendix D.2.

B.2.4.2 Statistical analysis

A summary of the statistical analysis plan for each of the ADVANCE, MOTIVATE and FORTIFY trials is provided in Table 13. For all studies, a multiple testing procedure was used to provide strong control of the type 1 error rate at alpha = 0.05 (2-sided) across analyses comparing each risankizumab dose level to placebo with respect to the co-primary endpoints and ranked secondary endpoints.

For ADVANCE and MOTIVATE, a sequence of hypothesis testing for the co-primary endpoints was utilised, followed by the ranked secondary endpoints and started with each of the co-primary endpoints using alpha of 0.025 (2-sided) for each dose compared with placebo. If both co-primary endpoints achieved statistical significance within a dose level, continued testing followed a pre-specified weight of alpha allocation between the single hypothesis within the family as well as between the families of hypotheses across the doses. Additionally, for ADVANCE, the analysis of co-primary efficacy endpoints was performed in the bio-IR and non-bio-IR populations.

For FORTIFY, a sequence of hypothesis testing for the co-primary endpoints of risankizumab 360 mg SC dose versus placebo using alpha of 0.05 (2-sided) was utilised, followed by testing the co-primary endpoints of risankizumab 180 mg SC dose versus placebo using alpha of 0.05 (2-sided). If both co-primary endpoints achieved statistical significance for both dose levels, continued testing of the ranked secondary endpoints for 360 mg and 180 mg followed a pre-specified weight of alpha allocation

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between the single hypothesis within the family as well as between the families of hypotheses across the doses.

For ADVANCE, MOTIVATE and FORTIFY, secondary efficacy endpoints were divided into two groups. The first group included ranked secondary endpoints, which were ranked by clinical importance. Statistical significance was assessed at the prespecified alpha level (two-sided) in ranked endpoint order until the significant level exceeded the pre-specified alpha level. No additional statistically significant treatment differences could be declared if the preceding ranked endpoint failed to achieve the pre-specified alpha level. The second group includes all other additional secondary variables.

B.2.4.3 Participant flow in the relevant randomised controlled trials

See Appendix D for details of participant flow.

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Table 13: Summary of statistical analysis approach in ADVANCE, MOTIVATE and FORTIFY

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Abbreviations: APS, abdominal pain score; Bio-IR, biologic inadequate response/intolerance; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CMH, Cochran– Mantel–Haenszel; non-Bio IR, conventional therapy inadequate response/intolerance; NRI, non-responder imputation; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; NRI-NC, NRI with no special data handling for missing due to COVID-19; OUS, outside of the United States; PRO2, patient reported outcomes 2-item; RZB, risankizumab; SF, stool frequency.

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B.2.5 Critical appraisal of the relevant clinical effectiveness evidence

A summary of quality assessment results for the risankizumab trials is provided in Table 14. A complete quality assessment for each trial is provided in Appendix D.

Table 14: Quality assessment results for parallel group RCTs

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B.2.6 Clinical effectiveness results of the relevant studies

The clinical benefits of risankizumab versus placebo have been demonstrated in two pivotal induction studies (ADVANCE, MOTIVATE) and one pivotal maintenance study (FORTIFY). The results from the maintenance study (FORTIFY) support continued maintenance treatment with risankizumab 360 mg SC in subjects with clinical response to risankizumab IV induction treatment (106, 107).

• Key results for risankizumab induction studies (ADVANCE and MOTIVATE)

• In both ADVANCE and MOTIVATE, symptomatic improvements were seen as early as Week 4 and mucosal improvement measured by SES-CD observed at Week 12 after treatment with risankizumab 600 mg IV. Risankizumab 600 mg IV was superior to placebo for the co-primary endpoints of clinical remission (CDAI or PRO2 [SF/APS][†] ) and endoscopic response (106).

• In ADVANCE, when compared with placebo, risankizumab 600 mg IV also

  • demonstrated beneficial treatment effects for subjects in the subgroups of biologic inadequate response/intolerance (Bio-IR) or inadequate response/intolerance to conventional therapy (non-Bio-IR) for CDAI clinical remission and endoscopic response (38, 39, 106).

• Subjects treated with risankizumab 600 mg IV in ADVANCE and MOTIVATE had significantly improved HRQoL as early as 4 weeks and at Week 12 when compared with placebo (38, 39).

• Key results for risankizumab maintenance study (FORTIFY)

• In the overall study population for FORTIFY, risankizumab 360 mg SC was superior to placebo SC (withdrawal) for the co-primary endpoints of clinical remission (CDAI) or (PRO2 [SF/APS][†] ) and endoscopic response (107).

• When compared with placebo SC (withdrawal), risankizumab 360 mg SC also demonstrated beneficial treatment effects for subjects with biologic inadequate response/intolerance (Bio-IR) or inadequate response/intolerance to conventional therapy (non-Bio-IR) for CDAI clinical remission and endoscopic response (107).

• More than one third of subjects (39%) treated with risankizumab 360 mg SC achieved endoscopic remission at Week 52 when compared with those who received placebo SC (withdrawal) (107)

† For this submission, only CDAI outcomes are presented as the cost-effectiveness model utilises CDAI outcomes to define CD health states (i.e. PRO2 [SF/APS] outcomes are not used in the model) and CDAI outcomes facilitate indirect treatment comparisons with previous trials of treatments for CD (104, 105). Overall, the results for PRO2 [SF/APS] and CDAI outcomes were similar. The co-primary endpoint of PRO2 [SF/APS] clinical remission and endoscopic response is presented in Appendix M.

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This section presents the results from the risankizumab induction and maintenance studies. As previously discussed in Section B.2.3.2, for this submission, CDAI outcomes are presented across the three pivotal trials (ADVANCE, MOTIVATE, FORTIFY) as this endpoint facilitates indirect treatment comparisons with previous trials of treatments for CD (104, 105) and the cost-effectiveness model utilises CDAI outcomes to define CD health states (i.e., PRO2 [SF/APS] outcomes are not used in the model) in alignment with previous CD NICE submissions (46, 47).

For completeness, the co-primary endpoint of PRO2 [SF/APS] clinical remission is presented in Appendix M (Section M.2 for ADVANCE and MOTIVATE and Section M.4 for FORTIFY). Co-primary endpoints which included CDAI clinical remission or PRO2 (SF/APS) clinical remission, in addition to endoscopic response, were both superior to placebo in the induction and maintenance studies.

A key point to highlight regarding the outcomes from the risankizumab induction and maintenance studies is that they are based on data obtained from subjects aged 16 to <18 years old and adult subjects. This approach was deemed appropriate given the low overall proportion of subjects aged 16–17 years in the risankizumab studies (approximately 1% across the studies) and expert clinical opinion. Based on expert clinical opinion of the populations enrolled in the risankizumab studies, treatment response to risankizumab was expected to be similar between the 16–18-year-old and adult populations if treatment history was comparable between the groups (i.e., bionaïve or treatment refractory) (80). The 16–17-year-old and adult populations in the risankizumab studies show a similar pattern of treatment response, albeit this comparison is based on treatment response observed in a low number of subjects aged 16–17 years (see Appendix E). In addition, evidence highlighting the efficacy of TNF-alpha inhibitors in paediatric subjects is available in several trials, and results are generally consistent with observations from previous trials of adults with moderate-tosevere CD (109-112)[e] .

Note that risankizumab data are presented for the anticipated licensed doses only (600 mg IV induction dose from ADVANCE and MOTIVATE, and 360 mg SC maintenance

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dose from FORTIFY). All study outcome definitions have been previously described in Section B.2.3.2. Study outcomes are also defined in the footnotes of the results tables in the following sections.

The primary data for risankizumab CD in this submission is taken from clinical study reports (CSRs) and published manuscripts. At the time of submission, only data from the CSRs were deemed commercial in confidence.

B.2.6.1 ADVANCE

B.2.6.1.1 Co-primary efficacy outcome: Proportion of subjects with CDAI clinical remission and/or endoscopic response at Week 12

In ADVANCE, the co-primary endpoints of clinical remission (CDAI and PRO2 [SF/APS]) and endoscopic response were met for the risankizumab 600 mg IV arm when compared with the placebo IV arm (38, 106). At Week 12, a significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved the co-primary endpoint of CDAI clinical remission versus the placebo IV arm (45.2% vs 24.6%, respectively; p<0.001) (Table 15). Additionally, a clear treatment effect was demonstrated in non-Bio-IR and Bio-IR populations, with a greater proportion of subjects achieving CDAI clinical remission and a larger effect size noted in the nonBio-IR population compared with the Bio-IR population (Table 15). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 15).

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Table 15: CDAI clinical remission at Week 12 (NRI-C) – total and by prior biologic failure status (ADVANCE ITT1A population)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; non-Bio-IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab. Source: ADVANCE CSR (38), D’Haens et al (2022) (106). Notes: CDAI clinical remission defined as CDAI <150 † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each stratum, 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

At Week 12, a statistically significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved endoscopic response compared with the placebo IV arm (40.3% vs 12.0%, respectively; p<0.001) (Table 16). Additionally, a clear treatment effect was demonstrated in the non-Bio-IR and Bio-IR populations, with a greater proportion of subjects achieving endoscopic response and a larger effect size noted in the non-Bio-IR population compared with the Bio-IR population (Table 16). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 16).

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Table 16: Endoscopic response at Week 12 (NRI-C) - total and by prior biologic failure status (ADVANCE ITT1A population)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CI, confidence interval; CMH, Cochran–Mantel– Haenszel; ITT, intention to treat; IV, intravenous; non-Bio IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease. Source: ADVANCE CSR (38), D’Haens et al (2022) (106). Notes: endoscopic response defined as decrease in SES-CD >50% from baseline (or for subjects with isolated ileal disease and a baseline SES-CD of 4, ≥2-point reduction from baseline).

† 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each stratum, 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-1; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for both the US-specific and OUS protocols.

B.2.6.1.2 Secondary efficacy outcomes - ADVANCE

B.2.6.1.2.1 CDAI clinical response at Week 4 and Week 12

Significant improvements in CDAI clinical response were observed as early as Week 4, with 40.8% of subjects in the risankizumab 600 IV mg arm versus 25.2% of subjects in the placebo IV arm achieving CDAI clinical response (p<0.001) (38, 106) (Table 17).

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Table 17: Achievement of CDAI clinical response at Week 4 (NRI-C) (ADVANCE ITT1A population)

Abbreviations: CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab Source: ADVANCE CSR (38), D’Haens et al (2022) (106). Notes: CDAI clinical response defined as reduction of CDAI ≥100 points from baseline. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each stratum, 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Endpoint achieved statistical significance based on the pre-specified graphical testing procedure for both the US-specific and OUS protocols.

At Week 12, a statistically greater proportion of subjects in the risankizumab 600 mg IV arm achieved CDAI clinical response compared with placebo (59.7% vs 36.7%, respectively; p<0.001) (38, 106) (Table 18). A clear treatment effect was demonstrated in both the non-Bio-IR and Bio-IR populations, with a greater proportion of subjects achieving CDAI clinical response and effect size observed in the non-Bio-IR population (Table 18). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 18).

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Table 18: Summary of achievement of CDAI clinical response at Week 12 (NRI-C) (ADVANCE ITT1A population)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; non-Bio IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab. Notes: CDAI clinical response defined as reduction of CDAI ≥100 points from baseline. Source: ADVANCE CSR (38), D’Haens et al (2022) (106). † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each stratum, 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Endpoint achieved statistical significance based on the pre-specified graphical testing procedure for both the US-specific and OUS protocols; †† 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19.

B.2.6.1.2.2 Endoscopic remission at Week 12

A significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved endoscopic remission at Week 12 versus the placebo IV arm (24.2% vs 9.1%, respectively; p<0.001) (38, 106) (Table 19). A clear treatment effect was demonstrated in the non-Bio-IR and Bio-IR populations, with a greater proportion of subjects achieving endoscopic remission and larger effect size noted in the non-Bio-

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IR population (Table 19). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 19).

Table 19: Achievement of endoscopic remission at Week 12 (NRI-C) (ADVANCE ITT1A population)

Abbreviations: Bio-IR, biologic inadequate response/intolerance; CI, confidence interval; CMH, Cochran–Mantel– Haenszel; ITT, intention to treat; IV, intravenous; non-Bio IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease. Source: ADVANCE CSR (38), D’Haens et al (2022) (106). Notes: Endoscopic remission defined as SES-CD ≤4 and at least a 2-point reduction versus baseline and no subscore greater than 1 in any individual variable, as scored by a central reviewer. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [0, 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each stratum, 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Endpoint achieved statistical significance based on the pre-specified graphical testing procedure for both the US-specific and OUS protocols; †† 95% CI for difference calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19.

B.2.6.1.2.3 EQ-5D-5L at Week 4 and Week 12

The risankizumab 600 mg IV arm was associated with statistically significant improvements in EQ-5D-5L at Week 4 and Week 12 compared with the placebo IV arm (38). For EQ-5D-5L Index Value scores, subjects in the risankizumab 600 mg IV

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arm had a greater improvement from baseline (least squares [LS] mean) when compared with the placebo IV arm at Week 4 () and Week 12 () (Table 20). Similar results were observed for EQ-5D visual analogue scale (VAS) scores; subjects in the risankizumab 600 mg IV arm had a greater improvement from baseline (LS mean) when compared with the placebo IV arm at Week 4 () and Week 12 () (Table 20).

Table 20: Change from baseline in EQ-5D-5L at Weeks 4 and 12 (MMRM) (ADVANCE ITT1A population)

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----- Start of picture text -----
Parameter Within Group Change from Baseline Between Group Difference vs Placebo
Timepoint N Missing Baseline Visit LS LS [95% CI] SE P-value
Treatment due to Mean Mean Mean Mean
COVID-19
EQ-5D-5L Index Value
Week 4
RZB 600 *** * ***** ***** ***** ***** ************** ****** *****
mg IV
Placebo IV *** * ***** ***** ***** - - - -
Week 12
RZB 600 *** * ***** ***** ***** ***** ************** ****** ******
mg IV
Placebo IV *** * ***** ***** ***** - - - -
EQ-5D VAS
Week 4
RZB 600 *** * **** **** **** *** ********** **** ******
mg IV
Placebo IV *** * **** **** *** - - - -
Week 12
RZB 600 *** * **** **** **** *** *********** **** ******
mg IV
Placebo IV *** * **** **** *** - - - -
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Abbreviations: CI, confidence interval; EQ-5D-5L, EuroQol 5 dimensions 5 levels; ITT, intention to treat; IV, intravenous; LS, least squares; MMRM, Mixed-Effect Model Repeat Measurement; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SE, standard error; VAS, visual analogue scale. Source: ADVANCE CSR (38). Notes: MMRM is the Mixed-Effect Model Repeat Measurement with the categorical fixed effects of treatment, visit and treatment-by-visit interaction, stratification factors (Number of prior biologics failed [0, 1, >1] and baseline steroid use [Yes, No]), and the continuous fixed covariates of baseline measurements included in the model. An unstructured covariance matrix is used.

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B.2.6.1.3 Other outcomes

Outcomes for change from Baseline in IBDQ Total Score at Week 12 in the ITT1A population are presented in Appendix M.

B.2.6.1.4 Conclusion – ADVANCE

ADVANCE demonstrated significant clinical benefits associated with risankizumab 600 mg IV compared with placebo IV in a population of Bio-IR and non-Bio-IR subjects with moderately to severely active CD. Risankizumab 600 mg IV was superior to placebo IV for the co-primary endpoints of clinical remission (CDAI) and endoscopic response (38, 106). Furthermore, significant improvements in CDAI clinical response were seen as early as Week 4 for risankizumab 600 mg IV compared with placebo IV and was maintained over 12 weeks. Significant improvements in HRQoL were also seen with risankizumab 600 mg IV compared with placebo IV from as early as Week 4.

B.2.6.2 MOTIVATE

B.2.6.2.1 Co-primary efficacy outcome: Proportion of subjects with CDAI clinical remission at Week 12 and proportion of subjects with endoscopic response at Week 12

In MOTIVATE, the co-primary endpoints of clinical remission (CDAI) and endoscopic response were met for the risankizumab 600 mg IV arm when compared with the placebo IV arm (39, 106). At Week 12, a significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved the co-primary endpoint of CDAI clinical remission versus the placebo IV arm (42.0% vs 19.8%, respectively; p<0.001) (Table 21). Additionally, a clear treatment effect was demonstrated in both the ≤1 prior biologics failed and >1 prior biologics failed populations, with a greater proportion of subjects achieving CDAI clinical remission and a larger effect size noted in the ≤1 prior biologics failed population (Table 21). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 21).

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Table 21: CDAI clinical remission at Week 12 (NRI-C) – total and by prior biologic failure status (MOTIVATE ITT1A population)

Abbreviations: CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab. Source: MOTIVATE CSR (39), D’Haens et al (2022) (106). Notes: CDAI clinical remission defined as CDAI <150. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [≤ 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each subgroup, 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

At Week 12, a statistically significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved endoscopic response compared with the placebo IV arm (28.8% vs 11.2%, respectively; p<0.001) (Table 22). Additionally, a clear treatment effect was demonstrated in the ≤1 prior biologics failed and >1 prior biologics failed populations, with a greater proportion of subjects achieving endoscopic response and a larger effect size noted in the ≤1 prior biologics failed population (Table 22). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 22).

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Table 22: Endoscopic response at Week 12 (NRI-C) – total and by prior biologic failure status (MOTIVATE ITT1A population)

Abbreviations: CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID19; RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease. Source: MOTIVATE CSR (39), D’Haens et al (2022) (106). Notes: Endoscopic response defined as decrease in SES-CD >50% from baseline (or for subjects with isolated ileal disease and a baseline SES-CD of 4, ≥2-point reduction from baseline).

† 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [≤ 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each subgroup, 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

B.2.6.2.2 Secondary efficacy outcomes - MOTIVATE

B.2.6.2.2.1 CDAI clinical response at Week 4 and Week 12

Significant improvements in CDAI clinical response were observed as early as Week 4, with 36.6% of subjects in the risankizumab 600 IV mg arm versus 20.9% of subjects in the placebo IV arm achieving CDAI clinical response (p=0.001) (39, 106) (Table 23).

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Table 23: Achievement of CDAI clinical response at Week 4 (NRI-C) (MOTIVATE ITT1A population)

Abbreviations: CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID19; RZB, risankizumab. Source: MOTIVATE CSR (39), D’Haens et al (2022) (106). Notes: CDAI clinical response defined as reduction of CDAI ≥100 points from baseline. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [≤ 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each subgroup, 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

At Week 12, approximately 60% of subjects in the risankizumab 600 mg IV arm achieved CDAI clinical response (39, 106). A significantly greater proportion of subjects in the risankizumab 600 mg arm achieved CDAI clinical response at Week 12 versus the placebo IV arm (59.5% vs 30.0%, respectively; p<0.001) (Table 24).

Table 24: Achievement of CDAI clinical response at Week 12 (NRI-C) (MOTIVATE ITT1A population)

Abbreviations: CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab. Source: MOTIVATE CSR (39), D’Haens et al (2022) (106). Notes: CDAI clinical response defined as reduction of CDAI ≥100 points from baseline. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [≤ 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each subgroup, 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

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B.2.6.2.2.2 Endoscopic remission at Week 12

A significantly greater proportion of subjects in the risankizumab 600 mg IV arm achieved endoscopic remission at Week 12 versus the placebo IV arm (19.4% vs 4.3%, respectively; p<0.001) (39, 106) (Table 25).

Table 25: Achievement of endoscopic remission at Week 12 (NRI-C) (MOTIVATE ITT1A population)

Abbreviations: CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SES-CD, Simple Endoscopic Score for Crohn’s Disease. Source: MOTIVATE CSR (39), D’Haens et al (2022) (106). Notes: Endoscopic remission defined as SES-CD ≤4 and at least a 2-point reduction versus baseline and no sub-score greater than 1 in any individual variable, as scored by a central reviewer. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § Across the strata, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (Number of prior biologics failed [≤ 1, > 1] and baseline steroid use [Yes, No]) for the comparison of two treatment groups. Within each subgroup, 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol.

B.2.6.2.2.3 EQ-5D-5L at Week 4 and Week 12

The risankizumab 600 mg IV arm was associated with statistically significant improvements in EQ-5D-5L from as early as Week 4 and also at Week 12 compared with the placebo IV arm (39). For the EQ-5D Index Value scores, subjects in the risankizumab 600 mg IV arm had a greater improvement from baseline (LS mean) when compared with the placebo IV arm at Week 4 (*************************************)

and Week 12 (*************************************) (Table 26). Similar results were observed for EQ-5D VAS scores; subjects in the risankizumab 600 mg arm had a greater improvement from baseline (LS mean) when compared with the placebo IV arm at Week 4 (**********************************) and Week 12 (***********************************) (Table 26).

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Table 26: Change from Baseline in EQ-5D-5L at Week 4, Week 12 (MMRM) (MOTIVATE ITT1A population)

==> picture [452 x 370] intentionally omitted <==

----- Start of picture text -----
Parameter Within Group Change from Baseline Between Group Difference vs
Timepoint Placebo
Treatment N Missing due Baseline Visit LS LS [95% CI] SE P-value
to COVID- Mean Mean Mean Mean
19
EQ-5D-5L Index Value
Week 4
RZB 600 *** * ***** ***** ***** ***** ************** ****** *****
mg IV
Placebo IV *** * ***** ***** ***** - - - --
Week 12
RZB 600 *** * ***** ***** ***** ***** ************** ****** *****
mg IV
Placebo IV *** * ***** ***** ***** - - - -
EQ-5D VAS
Week 4
RZB 600 *** * **** **** **** *** ********** **** *****
mg IV
Placebo IV *** * **** **** *** - - - -
Week 12
RZB 600 *** * **** **** **** *** *********** **** ******
mg IV
Placebo IV *** * **** **** **** - - - -
----- End of picture text -----

Abbreviations: CI, confidence interval; EQ-5D-5L, EuroQol 5 dimensions 5 levels; ITT, intention to treat; IV, intravenous; LS, least squares; MMRM, Mixed-Effect Model Repeat Measurement; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SE, standard error; VAS, visual analogues scale.

Source: MOTIVATE CSR (39). Notes: MMRM is the Mixed-Effect Model Repeat Measurement with the categorical fixed effects of treatment, visit and treatment-by-visit interaction, stratification factors (Number of Prior Biologics Failed (<= 1, > 1) and Baseline Steroid Use (Yes, No), and the continuous fixed covariates of baseline measurements included in the model.

B.2.6.2.3 Other outcomes

Outcomes for change from Baseline in IBDQ Total Score at Week 12 in the ITT1A population are presented in Appendix M.

B.2.6.2.4 Conclusion – MOTIVATE

MOTIVATE demonstrated significant clinical benefits associated with risankizumab 600 mg IV compared with placebo IV in a population of Bio-IR subjects with moderately

to severely active CD (39, 106). In line with the results of ADVANCE, risankizumab

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remission and endoscopic response. Furthermore, significant improvements in CDAI clinical response were seen as early as Week 4 for risankizumab 600 mg IV compared with placebo IV and maintained over 12 weeks. Significant improvements in HRQoL were also seen with risankizumab 600 mg IV compared with placebo IV from as early as Week 4.

B.2.6.3 FORTIFY

B.2.6.3.1 Primary efficacy outcome: Proportion of subjects with CDAI clinical remission and/or endoscopic response at Week 52

In FORTIFY, the co-primary endpoint of CDAI clinical remission and endoscopic response for the risankizumab 360 mg SC arms compared with the placebo SC (withdrawal) arm were met (40, 107). At Week 52, a significantly greater proportion of subjects in the risankizumab 360 mg SC arm achieved the co-primary endpoint of CDAI clinical remission (CDAI <150) versus the placebo SC (withdrawal) (52.2% vs 40.9%, respectively; p=0.005) (Table 27). Additionally, a greater proportion of subjects achieved CDAI clinical remission in the non-Bio-IR population compared with the BioIR population (Table 27). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 27).

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Table 27: CDAI clinical remission at Week 52 (NRI-C) – total, by prior biologic failure status and last risankizumab induction dose (FORTIFY ITT1A population)

Abbreviations: APS, abdominal pain score; Bio-IR, biologic inadequate response/intolerance; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; non-Bio IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; RZB, risankizumab; SC, subcutaneous; SF, stool frequency. Source: FORTIFY CSR (40), Ferrante et al (2022) (107). Notes: CDAI clinical remission defined as CDAI <150. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § For overall population, 95% CI for adjusted difference and p- value are calculated according to the CMH test adjusted for strata (endoscopic response at Week 0 [yes or no], SF/APS clinical remission status at Week 0 [yes or no] and last IV dose during risankizumab induction periods [1200 mg or 600 mg]) for the comparison of 2 treatment groups. Within each subgroup (i.e. prior biologic failure status and last risankizumab induction dose), 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US protocol; †† The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomised to receive placebo in the maintenance study.

At Week 52, a significantly greater proportion of subjects in the risankizumab 360 mg SC arm achieved the co-primary endpoint of endoscopic response versus the placebo SC (withdrawal) arm (46.5% vs 22.0%, respectively; p<0.001) (Table 28). Additionally, a clear treatment effect was demonstrated in both the non-Bio-IR and Bio-IR

populations, with a greater proportion of subjects achieving endoscopic response and

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a larger effect size noted in the non-Bio-IR population compared with the Bio-IR population (Table 28). Overall, a consistent treatment effect was observed in the overall and prior biologic failure populations (Table 28).

Table 28: Endoscopic response at Week 52 (NRI-C) – total, by prior biologic failure status and last risankizumab induction dose (FORTIFY ITT1A population)

Abbreviations: APS, abdominal pain score; Bio-IR, biologic inadequate response/intolerance; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; IV, intravenous; non-Bio IR, conventional therapy inadequate response/intolerance; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; NS, not significant; RZB, risankizumab; SC, subcutaneous; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency. Source: FORTIFY CSR (40), Ferrante et al (2022) (107). Notes: Endoscopic response defined as decrease in SES-CD >50% from induction study baseline (or for subjects with isolated ileal disease and an induction study baseline SES-CD of 4, ≥2-point reduction from induction study baseline). † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § For overall population, 95% CI for adjusted difference and p- value are calculated according to the CMH test adjusted for strata (endoscopic response at Week 0 [yes or no], SF/APS clinical remission status at Week 0 [yes or no] and last IV dose during risankizumab induction periods [1200 mg or 600 mg]) for the comparison of 2 treatment groups. Within each subgroup (i.e. prior biologic failure status and last risankizumab induction dose), 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Co-primary endpoint achieved statistical significance based on the pre-specified graphical testing procedure for the US and OUS protocol; †† The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomised to receive placebo in the maintenance study.

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B.2.6.3.2 Secondary efficacy outcomes

B.2.6.3.2.1 Endoscopic remission at Week 52

More than one third of subjects (39%) treated with risankizumab 360 mg SC achieved endoscopic remission at Week 52 when compared with those who received placebo SC (withdrawal) (12.8%; nominal p-value <0.001) (40, 107) (Table 29).

Table 29: Achievement of endoscopic remission at Week 52 (NRI-C) (FORTIFY ITT1A population)

Abbreviations: APS, abdominal pain score; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; NS, not significant; RZB, risankizumab; SC, subcutaneous; SF, stool frequency. Source: FORTIFY CSR (40), Ferrante et al (2022) (107). Notes: Endoscopic remission defined as SES-CD ≤4 and at least a 2-point reduction versus baseline and no subscore greater than 1 in any individual variable, as scored by a central reviewer.

† 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § For overall population, 95% CI for adjusted difference and p- value are calculated according to the CMH test adjusted for strata (endoscopic response at Week 0 [yes or no], SF/APS clinical remission status at Week 0 [yes or no] and last IV dose during risankizumab induction periods [1200 mg or 600 mg]) for the comparison of 2 treatment groups. Within each subgroup (i.e. prior biologic failure status and last risankizumab induction dose), 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there are no missing data due to COVID-19; ¶ Did not achieve statistical significance (NS) based on the pre-specified graphical testing procedure for the US-specific protocol; †† The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomised to receive placebo in the maintenance study.

B.2.6.3.2.2 CDAI clinical response at Week 52

A greater proportion of subjects in the risankizumab 360 mg SC arm achieved CDAI clinical response (reduction of CDAI ≥100 points from baseline of the induction study) at Week 52 versus the placebo SC (withdrawal) arm (61.6% vs 48.2%, respectively; nominal p-value=0.002) (40, 107) (Table 30).

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Table 30: Achievement of CDAI clinical response at Week 52 (NRI-C) (FORTIFY ITT1A population)

Abbreviations: APS, abdominal pain score; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; ITT, intention to treat; NRI-C, Non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19; NS, not significant; RZB, risankizumab; SC, subcutaneous; SF, stool frequency. Source: FORTIFY CSR (40), Ferrante et al (2022) (107). Notes: CDAI clinical response defined as reduction of CDAI ≥100 points from baseline of the induction study. † 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there are missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19; ‡ Risk difference = (risankizumab – placebo). Adjusted difference is calculated based on the CMH test; § For overall population, 95% CI for adjusted difference and p-value are calculated according to the CMH test adjusted for strata (endoscopic response at Week 0 [yes or no], SF/APS clinical remission status at Week 0 [yes or no] and last IV dose during risankizumab induction periods [1200 mg or 600 mg]) for the comparison of 2 treatment groups. Within each subgroup (i.e. prior biologic failure status and last risankizumab induction dose), 95% CI for difference are calculated using normal approximation to the binomial distribution. The calculations are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or nonresponder imputation only if there are no missing data due to COVID-19; ¶ Did not achieve statistical significance (NS) based on the pre-specified graphical testing procedure for the US-specific protocol; †† The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy and were randomised to receive placebo in the maintenance study.

B.2.6.3.2.3 EQ-5D-5L at Week 52

For the EQ-5D-5L Index Value scores, subjects in the risankizumab 360 mg SC arm had a similar improvement from baseline of the induction study (LS mean) at Week 52 when compared with the placebo SC (withdrawal) arm (40) (Table 31). Comparing the change from baseline scores between treatment arms, there was no significant difference in EQ-5D-5L Index Value scores between the risankizumab 360 mg SC arm and placebo SC (withdrawal) arm at Week 52 (*********************************) (Table 31).

For the EQ-5D VAS scores, subjects in the risankizumab 360 mg SC arm had a numerically greater, non-significant improvement from baseline (LS mean) at Week 52 when compared with the placebo SC (withdrawal) arm (Table 31). Comparing the change from baseline scores between treatment arms, there was no significant

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difference in EQ-5D VAS scores between the risankizumab 360 mg SC arm and placebo SC (withdrawal) arm at Week 52 (***********************************) (Table 31).

Table 31: Change from Baseline in EQ-5D-5L at Week 52 (MMRM) (FORTIFY ITT1A population)

Abbreviations: CI, confidence interval; EQ-5D-5L, EuroQol 5 dimensions 5 levels; ITT, intention to treat; LS, least squares; MMRM, Mixed-Effect Model Repeat Measurement; RZB, risankizumab; SC, subcutaneous; SE, standard error; VAS, visual analogue scale.

Source: FORTIFY CSR (40).

† 95% CI for within group LS Mean and 95% CI for LS Mean in treatment difference and p-value are calculated according to the ANCOVA with strata (endoscopic response at Week 0 [yes or no], clinical remission status at Week 0 [yes or no] and last IV dose during risankizumab induction periods [1200 mg or 600 mg]) and induction baseline EQ-5D-5L and Week 0 EQ-5D-5L as covariates for the comparison of two treatment groups.

B.2.6.3.3 Other outcomes

Additional outcomes for the ITT1A population are listed below and are presented in Appendix M.

• CDAI clinical remission at Week 52 among subjects with CDAI clinical remission at Week 0

• Ulcer-free endoscopy at Week 52

• Deep remission

• Change from Baseline of the Induction Study in IBDQ Total Score at Week 52

• The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) change from baseline at Week 52

• SF remission Week 52

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• AP remission Week 52

• CDAI clinical remission and endoscopic response Week 52

• Change from Baseline of the Induction Study in SF-36 Physical Component Summary Score at Week 52

• Exposure-adjusted occurrence of CD-related hospitalisations from Week 0 to 52

• Achievement of steroid-free remission, endoscopic remission and response

B.2.6.3.4 Conclusion - FORTIFY

The results of FORTIFY SS1 demonstrate that subjects with a clinical response to 12 weeks of induction risankizumab continue to benefit from treatment with risankizumab 360 mg SC in a maintenance phase (40, 107). The re-randomised responder with withdrawal placebo design for FORTIFY permitted subjects with previous risankizumab exposure from the induction studies to be randomised to the maintenance placebo SC (withdrawal) arm. Consequently, there was prolonged efficacy observed in the placebo SC (withdrawal) arm for symptomatic endpoints in the maintenance study (further discussed in Section B.2.12.2.1). Despite this, the coprimary endpoints of CDAI clinical remission and endoscopic response both met statistical significance for the risankizumab 360 mg SC arm compared with the placebo SC (withdrawal) arm. In addition, these results were achieved in a notably treatment refractory population, with approximately 36% of subjects in both treatment arms having failed more than one previous biologic therapy. When compared with placebo SC withdrawal, risankizumab 360 mg SC also demonstrated beneficial treatment effects for CDAI clinical remission and endoscopic response in subjects who were BioIR or non-Bio-IR. In addition, subjects who received risankizumab 360 mg SC achieved greater responses for objective outcomes (nominal p-values only), including endoscopic remission and ulcer-free endoscopy when compared with placebo SC (withdrawal).

B.2.7 Subgroup analysis

Across the risankizumab CD studies (ADVANCE, MOTIVATE, FORTIFY), preplanned and post-hoc subgroup analyses were conducted. Those relevant to the submission are outlined in Table 32; results are presented in Appendix E.

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Table 32: Pre-planned and post-hoc subgroup analyses

Abbreviations: NA, not applicable; TNF, tumour necrosis factor; UST, ustekinumab.

In addition to the subgroups outlined in Table 32, a post-hoc analysis of outcomes by CD location was conducted. In the analysis, treatment with induction or maintenance risankizumab was shown to be effective versus placebo in all CD locations except where CD was limited to the ileum. However, the subgroup with ileal CD represents a small proportion of the total trial study population such that no meaningful conclusions can be drawn from this analysis.

B.2.8 Meta-analysis

A comprehensive network meta-analysis (NMA) was conducted instead of a metaanalysis of RCTs as the absence of head-to-head data prevented a standard metaanalysis from being performed. This enabled comparisons with other biologic therapies included in the NICE scope and allowed for more precise estimates of treatment effects to be calculated when compared with a naive comparison of trials (see Section B.2.9).

B.2.9 Indirect and mixed treatment comparisons

B.2.9.1 Methodology

Full details of the methodology for the indirect/mixed treatment comparison are provided in Appendix D. A brief overview of the methodology is presented in Section B.2.9.1.3.

B.2.9.1.1 Analysis scope

As discussed in Section B.2.1, an SLR was conducted to identify all relevant clinical evidence on the efficacy and safety of risankizumab and potential comparators for the treatment of people with moderate-to-severe active CD. In the absence of head-tohead RCTs between all comparators specified in the NICE scope, an NMA was

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performed to assess the relative efficacy of risankizumab compared with relevant comparators (adalimumab, infliximab, ustekinumab, vedolizumab) in adults with moderate-to-severe CD who experienced CCF or BF. The non-Bio-IR and Bio-IR populations in the risankizumab clinical trials are considered analogous to the CCF and BF populations, respectively (see Section B.2 summary for more details). The methodology of the SLR that identified studies used in the NMAs is described in Appendix D.

B.2.9.1.2 Study selection for the NMA

As described in Appendix D, a total of 281 records met the inclusion criteria of the clinical SLR, reporting on 69 original studies. After applying the inclusion/exclusion criteria, 16 unique trials reported by 30 records were included for analysis in the NMA. A list of all studies excluded from the NMA (including reason for exclusion) is available in Appendix D.1.2.2.

The interventions and doses of interest included in the NMAs for the induction and maintenance phases are presented in Appendix D. For each of the interventions, only licensed UK doses were included in the analysis. A summary of the trials used to conduct the NMA is presented in Table 33.

Table 33: Summary of trials used in the NMA

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Abbreviations: ADA, adalimumab; CSR, clinical study report; IFX, infliximab; NMA, network meta-analysis; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab. † CSR data used in NMA.

CDAI outcomes were the outcomes of interest for the NMA as they facilitate comparison with comparator therapies and are used in the cost-effectiveness model (see Section B.2.3.2 for further details). In general, outcomes were assessed after an induction phase of 4 to 12 weeks and a maintenance phase of 44 to 60 weeks (see Appendix D for more details).

For CDAI outcomes, CDAI clinical remission and CDAI clinical response (CDAI-100) were assessed for induction trials, while CDAI clinical remission was assessed for the maintenance trials (Table 34).

Table 34: Trials reporting CDAI outcomes used in the NMA

Abbreviations: BF, biologic failure; CCF, conventional care failure; CDAI, Crohn’s Disease Activity Index; NMA, network meta-analysis.

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B.2.9.1.3 Summary of trials included in the NMA

A summary of the trials included in the base case and sensitivity analysis NMAs as well as the reporting of outcomes from each study considered for inclusion is detailed in Appendix D.

B.2.9.1.4 Overview of NMA methodology

A Bayesian NMA approach was selected to accomplish the study objective using an evidence base of published RCTs. Binary outcomes were modelled with a binomial likelihood and either a logit or risk difference (RD) link (as recommended by NICE decision support unit [DSU] technical support document [TSD] 2 (122, 123)). The feasibility of the NMAs based on the included RCTs was assessed (for full details on methodology and feasibility assessment, see Appendix D). In addition, an RD NMA methodology was used in the base case analysis (for more detail, refer to Section B.2.9.3 and Appendix D).

The maintenance network was separated into two networks based on biologic halflife, induction duration, and study heterogeneity, grouping risankizumab and ustekinumab together, and analysing other therapies (adalimumab, infliximab and vedolizumab) in a separate network (for further details, see Section B.2.9.3.2). Given the general data sparsity, a fixed effects (FE) framework was used in the base case analysis to avoid producing credible intervals that did not pass validity. In addition, given the similar deviance information criteria (DIC) values between the FE and random effect (RE) models, the FE model was preferred since it is easier to interpret (as recommended by NICE DSU TSD 2 (122)). The rationale for selecting this approach is further described in Appendix D. The impacts of the RE models on the cost-effectiveness results were investigated in a scenario analysis (see Section B.3.11.3).

For each combination of outcome and NMA, league tables of the relative effect estimate for all possible pair-wise comparisons are presented.

Additional results for base case analysis are presented in Appendix P:

• Relative effect estimates for each relevant comparator versus placebo on the RD scale

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• Predicted absolute outcomes for each treatment

• Surface Under the Cumulative RAnking (SUCRA) values for each treatment[f]

Outcomes assessed include CDAI clinical remission and CDAI-100 response (see Table 35 for definitions). The definitions used in the NMA for CDAI clinical remission and CDAI-100 response align with those used in the risankizumab CD studies (see Section B.2.3.2). The NMA presents results for CDAI outcomes as CD clinical trials have historically used this measure, and this is consistent with the trial outcomes reported for both ustekinumab and vedolizumab, the most recently approved biologic therapies for CD (35, 104, 105).

Table 35: Outcomes assessed in the NMA

Abbreviations: CDAI, Crohn’s disease activity index; NMA, network meta-analysis.

B.2.9.1.4.1 Sensitivity analysis methodology

In the RE sensitivity analysis, the methodology remains the same as that described for the base case analysis (see Section B.2.9.1.4) except that an RE model was used instead of an FE model.

B.2.9.1.5 NMA networks

The treatment networks for the studies included in the base case analyses for the CCF and BF populations are presented in the following sections. In all networks, placebo was included as the common comparator.

B.2.9.1.5.1 CCF population

The CCF population network diagrams created in the induction and maintenance phases are presented in Figure 7 and Figure 8, respectively.

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Figure 7: Network diagram of included induction studies in a CCF population

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Abbreviations: ADA, adalimumab; CCF, conventional care failure; IFX, infliximab; PBO, placebo; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab.

Figure 8: Network diagrams of included maintenance studies in a CCF population: (A) risankizumab and ustekinumab; (B) adalimumab, infliximab and vedolizumab

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Abbreviations: ADA, adalimumab; CCF, conventional care failure; IFX, infliximab; PBO, placebo; QxW, every x weeks; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab.

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B.2.9.1.5.2 BF population

The BF population network diagrams for the induction and maintenance phases are presented in Figure 9 and Figure 10, respectively.

Figure 9: Network diagram of included induction studies in a BF population

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Abbreviations: ADA, adalimumab; BF, biologic failure; PBO, placebo; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab.

Figure 10: Network diagrams of included maintenance studies in a BF population: (A) risankizumab and ustekinumab; (B) adalimumab and vedolizumab

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Abbreviations: ADA, adalimumab; BF, biologic failure; PBO, placebo; QxW, every x weeks; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab.

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B.2.9.2 Results

The following sections report results from the NMA for CDAI outcomes which have been used to inform the economic model. The results are reported as RD with credible intervals (CrI). Please note that ‘significance’ in these results is defined by CrIs not crossing zero; these analyses should not be interpreted in a frequentist manner.

B.2.9.2.1 Base case analysis – induction CDAI clinical remission

B.2.9.2.1.1 CCF population

Table 36 presents the base case NMA CDAI clinical remission results for induction risankizumab versus comparators in a CCF population.

The results show that the RD for risankizumab versus placebo is significant (************************) and comparable with the rest of the comparators (adalimumab 80/40, vedolizumab IV, ustekinumab, adalimumab 160/80, infliximab) as the CrIs cross zero; the second column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., an RD of ***** for the comparison versus placebo means there is a ***** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger RD.

Table 36: Results for CDAI clinical remission in CCF induction NMA (FE model)

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B.2.9.2.1.2 BF population

Table 37 presents the base case NMA CDAI clinical remission results for induction risankizumab versus comparators in a BF population.

The results show that the RDs for risankizumab versus placebo, vedolizumab IV and ustekinumab are significant (vs placebo: ************************; vs vedolizumab IV: ************************; vs ustekinumab: *******************) and comparable for the rest of the comparators (adalimumab 80/40 and adalimumab 160/80) as the CrIs cross zero; the first column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., an RD of ***** for the comparison versus placebo means there is a ***** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger RD.

Table 37: Results for CDAI clinical remission in BF induction NMA (FE model)

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B.2.9.2.2 Base case analysis – induction CDAI-100 clinical response

B.2.9.2.2.1 CCF population

Table 38 presents the base case NMA CDAI-100 clinical response results for induction risankizumab versus comparators in a CCF population.

The results show that the RD for risankizumab versus placebo is significant (************************ ) and comparable with the rest of the comparators (vedolizumab IV, adalimumab 80/40, adalimumab 160/80, ustekinumab, infliximab) as the CrIs cross

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zero; the fourth column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., an RD of ***** for the comparison versus placebo means there is a ***** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger RD.

Table 38: Results for CDAI-100 clinical response in CCF induction NMA (FE model)

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B.2.9.2.2.2 BF population

Table 39 presents the base case NMA CDAI-100 clinical response results for induction risankizumab versus comparators in a BF population.

The results show that the RDs for risankizumab versus placebo, vedolizumab IV, ustekinumab and adalimumab 160/80 are significant (vs placebo: ************************; vs vedolizumab: ************************; vs ustekinumab ************************; vs adalimumab 160/80: ************************) and comparable with adalimumab 80/40 as the CrIs cross zero; the first column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., an RD of ***** for the comparison versus placebo means there is a ***** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger RD.

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Table 39: Results for CDAI-100 response in BF induction NMA (FE model)

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B.2.9.2.3 Base-case analysis – maintenance CDAI clinical remission

B.2.9.2.3.1 CCF population (risankizumab and ustekinumab)

Table 40 presents the base case NMA CDAI clinical remission results for maintenance risankizumab versus comparators (ustekinumab) in a CCF population.

The results show that the efficacy of risankizumab is comparable with the rest of the comparators (placebo, ustekinumab (Q12W, ustekinumab Q8W) as the CrIs cross zero; the third column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., an RD of ***** for the comparison versus placebo means there is a **** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger RD.

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Table 40: Results for CDAI clinical remission in CCF maintenance NMA (risankizumab and ustekinumab network) (FE model)

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B.2.9.2.3.2 CCF population (infliximab, adalimumab and vedolizumab)

Table 41 presents the base case NMA CDAI clinical remission results for the maintenance network containing infliximab, adalimumab and vedolizumab in a CCF population. Most treatments were superior to placebo with the exception of VDZ300/Q4W and VDZ108/Q2W, for which the credible intervals for each comparison crossed zero. The rest of the comparisons did not indicate superiority of any one treatment with the exception of ADA40/QW which appeared to have a significantly greater probability of remission than VDZ108/Q2W (), VDZ300/Q4W () and IFX5/Q8W (**********************).

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Table 41: Results for CDAI clinical remission in CCF maintenance NMA (infliximab, adalimumab and vedolizumab network) (FE model)

B.2.9.2.3.3 BF population (risankizumab and ustekinumab)

Table 42 presents the base case NMA CDAI clinical remission results for maintenance risankizumab versus comparators (ustekinumab) in a BF population.

The results show that the risk difference for risankizumab versus placebo is significant (vs placebo: ***********************) and comparable with the rest of the comparators (UST90/Q12W, UST90/Q8W) as the credible intervals cross zero; the second column of the league table shows these results. A positive value indicates a comparison in favour of risankizumab, e.g., a risk difference of ***** for the comparison versus placebo means there is a ***** greater absolute probability of remission in patients on risankizumab versus placebo. Darker colours indicate a larger risk difference.

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Table 42: Results for CDAI clinical remission in BF maintenance NMA (risankizumab and ustekinumab network) (FE model)

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B.2.9.2.3.4 BF population (infliximab, adalimumab and vedolizumab)

Table 43 presents the base case NMA CDAI clinical remission results for the maintenance network containing adalimumab and vedolizumab in a BF population. All treatments were superior to placebo. All comparators (with the exception of placebo) were comparable in efficacy to one another.

Table 43: Results for CDAI clinical remission in BF maintenance NMA (adalimumab and vedolizumab network) (FE model)

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B.2.9.2.4 RE model results

Results for the NMAs conducted using a RE model are presented in Appendix P. Overall, the RE NMA results were similar to the FE models although there were larger CrIs across most comparisons, which is to be expected as the RE NMA incorporates between-study differences in its efficacy estimates.

B.2.9.3 Uncertainties in the indirect and mixed treatment comparisons

B.2.9.3.1 RD NMA method

The NMAs used in this submission utilised the RD method, which was used in this instance as it is recommended where baseline risk-adjusted models are deemed inappropriate due to lack of convergence or face validity (122).

Like baseline risk adjustment, RD NMA is also recognised as valid framework by NICE (DSU TSD2, Section 3.7 (122)). It has been used in publications and prior submissions to NICE (125, 126). Cameron et al. (2018) (127) found that the use of an NMA on the RD scale represents a viable alternative approach to account for the presence of cross-study differences in placebo response rates. Per NICE DSU TSD2 (123, 128), RD NMA could be used as an alternative method to log-odds NMA when there are imbalances in the number of studies with low placebo response rates across pairwise contrasts in the network. The RD model code utilised was adapted from Dias et al. (2018) (123), which was based on modelling frameworks by Warn et al. (2002) (129).

In TA521, RD was used to adjust for cross-trial differences (125). Rather than calculating relative effects as ratios (such as odds ratios produced by traditional logitlink NMA frameworks), absolute probabilities of treatment response were subtracted across interventions in RD models, minimising potential impacts of overly low or high placebo efficacy. This may help minimise bias when there are imbalances in the number of studies with low placebo response rates across pairwise contrasts in the network. TA521 concluded that baseline-risk adjusted models and risk difference NMAs should yield less biased estimates of effect than the unadjusted NMA analyses on the relative scale.

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attractive option to minimise impacts of placebo heterogeneity on NMA-produced treatment effect estimates.

Criticism of RD models stems from potential model instability, leading to lack of convergence and sensitivity to starting values (127). However, the RD models in the CD NMA analysis in this submission converged and had appropriate fit. Appropriate vague prior distributions were utilised which corresponded to the RD scale. Starting values were utilised which are dispersed across the probability space.

In summary, the RD models addressed placebo rate variation of the sort observed in the biologic CD trials, yielded reasonable estimates, passed diagnostic tests based on their convergence and fit, are accepted by NICE, have been used in prior submissions, and have appeared in the published academic literature.

B.2.9.3.2 Use of two separate networks for the maintenance NMA

Two separate networks for the maintenance NMAs were used in order to reduce the heterogeneity in the placebo arms of the maintenance studies. Risankizumab and ustekinumab were grouped in one network (rather than a single network with adalimumab, infliximab and vedolizumab) as both are IL inhibitors and have longer half-lives. This mitigates the maintenance placebo heterogeneity issue as placebo heterogeneity is greatly reduced in the IL inhibitor network and the direct comparability of risankizumab and ustekinumab greatly improves. There was a clear differentiation in placebo efficacy in maintenance trials, with risankizumab and ustekinumab having placebo remission rates sustained notably longer than other comparators in the NMA, likely due to differences in half-lives and the long-term effects on the pathological process of ustekinumab and risankizumab when compared with the other comparators in the NMA. Placebo arms in the maintenance studies are not comparable because subjects who entered the maintenance phase were initially selected for their ability to respond to the intervention in the induction phase. Due to the long half-lives of risankizumab and ustekinumab, it is likely that their residual treatment effect (carried over from the induction phase) during the maintenance trials impacted the placebo group for longer than the other comparators. This is illustrated in Figure 11[g] , where

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the proportion of subjects receiving placebo in the maintenance period and achieving remission is prolonged for risankizumab and ustekinumab when compared with adalimumab and vedolizumab.

Figure 11: Proportion of subjects receiving placebo during maintenance phase in CDAI clinical remission

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Abbreviations: ADA, adalimumab; CDAI, Crohn’s Disease Activity Index; RZB, risankizumab; UST, ustekinumab; VDZ, vedolizumab.

In addition, the induction periods varied across the different treatments with ustekinumab and risankizumab having the longest (8 weeks and 12 weeks, respectively), further contributing to the residual treatment effect in the maintenance phase. Therefore, adalimumab, infliximab and vedolizumab were grouped together in a separate network to risankizumab and ustekinumab.

B.2.9.3.3 Potential for network inconsistency

In the network diagrams contained in B.2.9.1.5, there are loops that can show inconsistency in the following populations, phases and efficacy outcomes:

• BF induction CDAI clinical remission, formed by GAIN (110) and Watanabe et al. (2012) (120) for ADA160/80, ADA80/40 and PBO

• CCF maintenance CDAI clinical remission (non-IL-23 comparators), formed by GEMINI 2 (105) and Watanabe et al. (2020) (121) for VDZ300/Q8W, VDZ300/Q4W and PBO

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• BF maintenance CDAI clinical remission (non-IL-23 comparators), formed by GEMINI 2 (105) and Watanabe et al. (2020) (121) for VDZ300/Q8W, VDZ300/Q4W and PBO

The test of the consistency assumption was conducted on each outcome’s unadjusted logit-link selected model using the FE or RE unrelated mean effects (UME) model. The presence of inconsistency in each network was assessed by comparing the model fit and heterogeneity between each set of consistency (unadjusted logit-link NMA) and inconsistency (UME) models, which are summarised in Table 44 and Table 45.

Table 44: Model fit between consistency and inconsistency models, induction

Abbreviations: BF, biologic failure; CCF, conventional care failure; CDAI, Crohn’s Disease Activity Index; CR, clinical response, Dbar, overall residual deviance; DIC, deviance information criteria; FE, fixed effects model; NMA, network meta-analysis; UME, unrelated mean effects model.

Table 45: Model fit between consistency and inconsistency models, maintenance

Abbreviations: ADA, adalimumab; BF, biologic failure; CCF, conventional care failure; CDAI, Crohn’s Disease Activity Index; Dbar, overall residual deviance; DIC, deviance information criteria; FE, fixed effects model; IFX, infliximab; NMA, network meta-analysis; RZB, risankizumab; UME, unrelated mean effects model; UST, ustekinumab; VDZ, vedolizumab

In all assessed networks, the posterior means of the residual deviance (Dbar) and the

DIC were very similar between the NMA and UME models (Table 44 and Table 45), suggesting lack of evidence for inconsistency in these networks. A difference in DIC values of ≥4 suggests there is no evidence of difference in model appropriateness (130).

B.2.9.4 Conclusion

Risankizumab was found to have broadly comparable efficacy with the rest of the comparators in the NMA, with the exception of placebo, where risankizumab was superior. The NMA results for the CCF population generally show comparable efficacy

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for risankizumab versus other comparators, while the results for the BF population generally favour risankizumab. The results of the NMA remained consistent regardless of the NMA model type used (i.e., FE or RE model).

B.2.10 Adverse reactions

Summary

• In ADVANCE and MOTIVATE, induction with risankizumab 600 mg IV for 12 weeks was generally well tolerated

  • The overall incidence of treatment-emergent adverse events (TEAEs) during the 12week induction period was similar between the risankizumab 600 mg IV and placebo IV treatment arms (56.3% vs 56.5% in ADVANCE and 47.6% vs 66.2% in MOTIVATE)

  • The rates of serious AEs (SAEs), severe AEs and AEs leading to discontinuation were numerically higher in the placebo IV arm than the risankizumab 600 mg IV arm[†]

• Two deaths occurred during induction (ADVANCE), both of which were in the placebo IV arm. No deaths occurred in the risankizumab 600 mg IV arm.

•  In FORTIFY, risankizumab 360 mg SC as maintenance treatment for 1 year was generally well tolerated  The incidence of TEAEs was 72.1% in the risankizumab 360 mg SC arm and 73.4% in the placebo SC (withdrawal) arm

• The percentage of subjects with SAEs, severe AEs and AEs leading to discontinuation were comparable in risankizumab 360 mg SC and placebo SC (withdrawal) arms

• There were no deaths reported during the maintenance study

•  Across the induction and maintenance studies, no new safety risks were identified, and the overall safety profile was consistent with the known safety profile of risankizumab in the management of psoriasis

• The rates of SAEs, severe AEs and AEs leading to discontinuation were numerically higher in the placebo IV arm, with most events related to underlying CD.

The primary data for risankizumab CD in this submission is taken from clinical study reports (CSRs) and published manuscripts. At the time of submission, only data from the CSRs were deemed commercial in confidence.

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All AEs described were considered treatment-emergent and summarised using Medical Dictionary for Regulatory Activities (MedDRA[®] ), Version 23.1 primary system organ class and preferred term.

B.2.10.1 ADVANCE and MOTIVATE

B.2.10.1.1 Treatment-emergent adverse events

An overview of treatment-emergent adverse events (TEAEs) is provided for the SA1 population (which included all subjects who received at least 1 dose of risankizumab during Induction Period 1 of ADVANCE and MOTIVATE) in Table 46. As mentioned in Section B.2.6, results are presented for the anticipated licensed doses of risankizumab only. A summary of TEAEs occurring in ≥5% of subjects in either the risankizumab 600 mg IV treatment group or the placebo IV treatment group is presented in Table 47.

Table 46: Overview of TEAEs and deaths during Induction Period 1 by n (%) of subjects – ADVANCE and MOTIVATE SA1 population

Abbreviations: IV, intravenous; PBO, placebo; RZB, risankizumab; SA, safety analysis; SC, subcutaneous; SF, stool frequency; SS, sub study; TEAE, treatment-emergent adverse event. Source: ADVANCE CSR (38), MOTIVATE CSR (39), D’Haens et al (2022) (106). Note: TEAEs for the 12-Week Induction Period are defined as events that begin either on or after the first dose of the study drug in the 12-Week Induction Period and until the first dose of study drug in the FORTIFY study if the subject is enrolled into FORTIFY or until first dose of study drug in Induction Period 2 if the subject is enrolled into

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Induction Period 2, or within 140 days after the last dose administration of the study drug in 12-Week Induction Period if the subject does not participate in FORTIFY or the Induction Period 2.

Table 47: TEAEs reported in ≥5% of subjects in either treatment group or during Induction Period 1, by n (%) of subjects – ADVANCE and MOTIVATE SA1 population

Abbreviations: AE, adverse event; IV, intravenous; MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable; PBO, placebo; RZB, risankizumab; SA, safety analysis; SC, subcutaneous; TEAE, treatmentemergent adverse event. Source: D’Haens et al (2022) (106). Note: TEAEs for the 12-Week Induction Period are defined as events that begin either on or after the first dose of the study drug in the 12-Week Induction Period and until the first dose of study drug in the FORTIFY study if the subject is enrolled into FORTIFY or until first dose of study drug in Induction Period 2 if the subject is enrolled into Induction Period 2, or within 140 days after the last dose administration of the study drug in 12-Week Induction Period if the subject does not participate in FORTIFY or the Induction Period 2.

B.2.10.1.2 AEs of special interest

A summary of AEs of special interest that were reported during Induction Period 1 of ADVANCE and MOTIVATE (SA1 population) is presented in Table 48.

Table 48: Overview of TEAEs of special interest during Induction Period 1 by n (%) of subjects – ADVANCE and MOTIVATE SA1 population

Abbreviations: IV, intravenous; TEAE, treatment-emergent adverse event. Source: D’Haens et al (2022) (106).

Note: For n (%), subjects are counted once in each row, regardless of the number of events they may have had. AEs of special interest were defined based on prevalence in the moderately to severely active CD population, customary concerns with injected immunoglobulin products, the immunomodulatory activity of risankizumab, or

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regulatory interest. These AEs of special interest were identified using standard MedDRA queries (SMQ) and company MedDRA queries (CMQ).

B.2.10.2 FORTIFY

B.2.10.2.1 Treatment-emergent adverse events

An overview of TEAEs is provided for the SA1 population of Sub-study 1[h] (which included all subjects who received at least 1 dose of risankizumab during FORTIFY) in Table 49. In FORTIFY, TEAEs were defined as events that begin either on or after the first dose of the study drug in Sub-Study 1 and within 140 days after the last dose administration of the study drug or until the first dose of study drug in Sub-study 3[i] if the subject was enrolled into Sub-Study 3. As mentioned in Section B.2.6, results are presented for the anticipated licensed doses of risankizumab only. A summary of TEAEs occurring in ≥5% of subjects in either the risankizumab 360 mg SC treatment group or the placebo SC treatment group is presented in Table 50.

Table 49: Overview of TEAEs and all deaths, by n (%) of subjects – randomised subjects, FORTIFY SA1 population

Abbreviations: PBO, placebo; RZB, risankizumab; SC, subcutaneous; TEAE, treatment-emergent adverse event. Source: FORTIFY CSR (40), Ferrante et al (2022) (107).

† Data reported for randomised subjects only from FORTIFY SS1;[‡ ] The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy in ADVANCE or MOTIVATE and were randomised to receive placebo in FORTIFY.

h FORTIFY consists of 3 sub-studies. This submission presents the results from FORTIFY Sub-study 1 (SS1), which was a 52-week randomised, double-blind, placebo-controlled maintenance study. i Sub-study 3 is an OL long-term extension for which data collection is still ongoing. Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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Table 50: TEAEs reported in ≥5% of subjects in either treatment group – randomised subjects, FORTIFY SA1 population

Abbreviations: AE, adverse event; IV, intravenous; MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable; PBO, placebo; RZB, risankizumab; SA, safety analysis; SC, subcutaneous; TEAE, treatmentemergent adverse event. †Data reported for randomised subjects only from FORTIFY SS1; ‡ The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy in ADVANCE or MOTIVATE and were randomised to receive placebo in FORTIFY. Source: Ferrante et al (2022) (107). Note: Cells that are marked NA indicate that this AE was not reported in ≥5% of subjects in either arm of that trial. Note: Subjects are counted once in each row, regardless of the number of events they may have had. For subjects receiving risankizumab rescue therapy (see Section B.2.3.1.2), all events happening after receiving risankizumab rescue therapy are presented regardless of the previous treatments. Adverse events happening before receiving risankizumab rescue therapy are presented in their original treatment arm.

B.2.10.2.2 AEs of special interest

A summary of AEs of special interest that were reported during FORTIFY (SA1 population) is presented in Table 51.

Table 51: Overview of TEAEs of special interest by n (%) of subjects – randomised subjects FORTIFY SA1 population

Abbreviations: CMQ, Company MedDRA query; MedDRA, Medical Dictionary for Regulatory Activities; PBO, placebo; RZB, risankizumab; SA, safety analysis; SC, subcutaneous; SMQ, Standardized MedDRA query; TEAE, treatment-emergent adverse event. The withdrawal (placebo SC) arm consisted of subjects who achieved SF/APS clinical response to IV risankizumab induction therapy in ADVANCE or MOTIVATE and were randomised to receive placebo in FORTIFY. Source: FORTIFY CSR (40), Ferrante et al (2022) (107). Note: Subjects are counted once in each row, regardless of the number of events they may have had. For subjects receiving risankizumab rescue therapy (see Section B.2.3.1.2), all events happening after receiving risankizumab rescue therapy are presented regardless of the previous treatments. Adverse events happening before receiving risankizumab rescue therapy are presented in their original treatment arm. AEs of special interest were defined based on prevalence in the moderately to severely active CD population, customary concerns with injected immunoglobulin products, the immunomodulatory activity of risankizumab, or regulatory interest. These AEs of special interest were identified using standard MedDRA queries (SMQ) and company MedDRA queries (CMQ).

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B.2.10.3 Additional studies

For the pooled safety analysis provided in Section B.2.10.4.1.1, data from a Phase 2 induction trial of risankizumab in subjects with moderate-to-severe CD were pooled with safety data from the risankizumab Phase 3 induction trials (ADVANCE, MOTIVATE). The Phase 2 induction study (M15-993 [NCT02031276]) was a randomised, double-blind, placebo-controlled phase 2 study which enrolled subjects with moderate-to-severe CD at 36 referral sites in North America, Europe and southeast Asia (131).

Eligible subjects were aged 18–75 years, with a diagnosis of CD for at least 3 months, assessed as moderate-to-severe CD at screening, defined as a CDAI of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for subjects with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Subjects could have had previous treatment with one or more TNF-alpha inhibitors or vedolizumab. Subjects previously treated with ustekinumab were excluded, as were subjects who had received any other biologic agent (including agents targeting integrins) within 8 weeks or five half-lives before randomisation. Subjects continued stable doses of oral corticosteroids, oral 5- aminosalicylates, azathioprine, mercaptopurine, methotrexate and antibiotics throughout the trial if they were on these at the start. Subjects were randomised 1:1:1 to receive risankizumab 200 mg IV (n=41), risankizumab 600 mg IV (n=41), or placebo IV (n=39) via an interactive response system to a double-blind investigational product and stratified by previous exposure to TNF-alpha inhibitors (yes vs no). Subjects received their assigned treatment by intravenous infusion at weeks 0, 4 and 8. Subjects were followed through Week 12 every 4 weeks. The primary outcome was clinical remission in the pooled risankizumab dose groups, defined by a CDAI <150 at Week 12. Secondary outcomes (all evaluated at Week 12) including clinical response (defined by either CDAI <150 or a CDAI reduction from baseline of ≥100), endoscopic remission (CDEIS score of ≤4; ≤2 for subjects with isolated ileitis), endoscopic response (>50% CDEIS reduction from baseline), mucosal healing (absence of mucosal ulceration), and deep remission (clinical remission and endoscopic remission).

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Comparing the placebo IV and risankizumab 600 mg IV groups, AEs (82% vs 76%, respectively), severe AEs (23% vs 7%), AEs leading to discontinuation (15% vs 2%) and SAEs (31% vs 7%) were higher in the placebo IV arm. The most common AE was nausea and most common SAE was worsening of underlying CD. No deaths occurred.

B.2.10.4 Overview of safety from the pivotal induction and maintenance trials

Induction with risankizumab 600 mg IV for 12 weeks was generally well tolerated. In both ADVANCE and MOTIVATE, the overall incidence of AEs during the 12-week induction period was similar among all treatment arms. The rates of SAEs, severe AEs and AEs leading to discontinuation were numerically higher in the placebo IV arm, with most events related to underlying CD. Across both studies, the most frequently reported AEs in ≥5.0% of subjects in the risankizumab arm were headache and nasopharyngitis, whereas the most common AEs in the placebo IV arm were CD (worsening of CD), abdominal pain, nausea and headache.

Additionally, risankizumab 360 mg SC as maintenance treatment for 1 year was generally well tolerated. The most common AEs (≥5.0%) in the risankizumab 360 mg SC arm was CD (worsening of CD), nasopharyngitis, arthralgia, headache, abdominal pain and nausea. The percentage of subjects with SAEs and AEs leading to discontinuation were comparable in risankizumab 360 mg SC and placebo SC (withdrawal) arms. Across the induction and maintenance studies, no new safety risks were identified and the overall safety profile was consistent with the known safety profile of risankizumab in the management of psoriasis (132). For the risankizumab doses presented in this submission (600 mg IV and 360 mg SC [i.e., in line with anticipated licensing]), two deaths occurred during induction (ADVANCE); both of these were in the placebo IV arm. One death was reported in the risankizumab 1,200 mg IV arm in ADVANCE (data for this arm have not been reported in the submission as this is a non-licensed dose) and was caused by acute respiratory failure due to invasive squamous cell carcinoma of the left lung. This event was considered by the investigator to be unrelated to the study drug. There were no deaths reported during maintenance study.

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B.2.10.4.1.1 Pooled safety data

The Placebo-Controlled 12-Week Induction Period Safety Analysis Set provides an integrated safety assessment across the placebo-controlled 12-Week Induction Periods of the Phase 2 (M15-993 [NCT02031276]) and Phase 3 studies (ADVANCE, MOTIVATE) (132). This analysis set provides a robust assessment of risankizumab 600 mg IV induction treatment. As there is only one maintenance trial for risankizumab safety data, FORTIFY (Sub-Study 1); there are no pooled results to present for maintenance risankizumab. Results of the main safety population for maintenance risankizumab is presented in Section B.2.10.2.

In the induction period (Placebo-Controlled 12-Week Induction Period Safety Analysis Set), the percentage of subjects with AEs was lower in the risankizumab 600 mg IV group compared to the placebo IV group (***** vs *****, respectively) (Table 52). The rates of SAEs, severe AEs, and AEs leading to study drug discontinuation were lower in the risankizumab 600 mg IV groups compared with the placebo IV group. One death was reported in the risankizumab 1,200 mg IV group, and 2 deaths were reported in the placebo group (deaths previously summarised in Section B.2.10.4). Overall, there was no apparent dose-relationship on AE rates between the 600 mg risankizumab IV doses.

Table 52: Overview of most frequent treatment-emergent adverse - Placebo-Controlled 12-Week Induction Period Safety Analysis Set

Abbreviations: IV, intravenous; RZB, risankizumab; SSA, study size adjusted; TEAE, treatment-emergent adverse event. Source: Risankizumab Summary of Clinical Safety (132).

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In the induction period using the same safety analysis set, the most common AEs (≥5.0%) in the risankizumab 600 mg IV group were headache and nasopharyngitis, whereas the most common AEs in the placebo IV group were CD, abdominal pain, nausea and headache (Table 53). Overall, CD (worsening of CD) was the most common AE in the placebo IV group and occurred more frequently than in the risankizumab 600 mg IV group.

Table 53: Most frequent adverse events reported in ≥5% of subjects - PlaceboControlled 12-Week Induction Period Safety Analysis Set

Abbreviations: IV, intravenous; MedDRA, Medical Dictionary for Regulatory Activities; RZB, risankizumab; SSA, study size adjusted; TEAE, treatment-emergent adverse event. Source: Risankizumab Summary of Clinical Safety (132).

AEs of special interest

Pooled analysis of AESIs, namely serious infections, active tuberculosis, lymphoma, hypersensitivity and skin reactions, for the induction trials are presented in Table 54.

As there is only one maintenance trial for risankizumab safety data, FORTIFY (SubStudy 1), there are no pooled AESI results to present for maintenance risankizumab. AESIs for the main safety population for maintenance risankizumab is presented in Section B.2.10.2.2, Table 51.

During the induction period (Placebo-Controlled 12-Week Induction Period Safety Analysis Set) and the maintenance period (FORTIFY Safety Population), percentages and rates AESIs were generally comparable between the risankizumab induction (risankizumab 600 mg IV) and maintenance (risankizumab 360 mg SC) groups and placebo groups (Table 54 and Table 51). Notable differences include a higher rate of serious infection reported in the placebo group versus the risankizumab 600 mg IV

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group during the induction period (***% vs ***%). For the maintenance phase, the rate of serious infections was similar between the risankizumab 360 mg SC and placebo SC groups.

Table 54: Overview of treatment-emergent adverse events of special interest - Placebo-Controlled 12-Week Induction Period Safety Analysis Set

Abbreviations: IV, intravenous; RZB, risankizumab; SSA, study size adjusted. Source: Risankizumab Summary of Clinical Safety (132). † Injection site reaction area of safety interest category contains infusion-related PTs.

B.2.11 Ongoing studies

In addition to the Phase III pivotal trials (ADVANCE, MOTIVATE, FORTIFY), a further OL head-to-head study is underway (SEQUENCE, M20-259; the estimated primary completion date is September 2023) to demonstrate the clinical effectiveness of risankizumab versus ustekinumab when sequenced after TNF-alpha inhibitor therapy for the treatment of CD (133).

B.2.12 Interpretation of clinical effectiveness and safety evidence

B.2.12.1 Principal (interim) findings from the clinical evidence highlighting the clinical benefits and harms of the technology

Approximately 50% of people with moderate-to-severe CD do not respond to, or cannot tolerate conventional treatment (46). Biologic therapies offer an option for treating these individuals; however, these treatments may be associated with a loss of response. Up to 30% of individuals do not respond to TNF-alpha inhibitor therapy (primary non-responders) and almost half of individuals who experience a benefit with these drugs will lose clinical benefits within the first year, requiring dose escalation or therapy change (secondary loss of response) (83). Other biologic therapies with different mechanisms of action are also associated with a primary loss of response,

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with a loss of response rate of approximately 30% at 52 weeks reported for vedolizumab (integrin α4β7 inhibitor) and ustekinumab (IL-12/23 inhibitor) (92, 94).

From a safety perspective, TNF-alpha inhibitors are associated with an increased risk of malignancy and infection, including tuberculous infection (83, 89, 92). In order to prevent immunogenicity, a high percentage of individuals treated with TNF-alpha inhibitors are on combination therapy, often for long periods of time (e.g., IMM and corticosteroids), leading to an increased risk of developing severe infections and cancer, including lymphoma and non-melanoma skin cancer (101, 134-136). These issues highlight the need for the development of new treatment modalities for people with moderately to severely active CD, both with and without prior biologic treatment failure.

Risankizumab is a new class of biologic with a novel mode of action that selectively targets IL-23 which provides an additional biologic therapy option for the management of individuals with CD. Based on the innovative nature of risankizumab and potential to address an unmet clinical need for patients it was granted a Promising Innovative Medicine (PIM) designation by the MHRA in November 2021. Risankizumab subsequently received an Early Access to Medicines Scheme (EAMS) positive final scientific opinion from the MHRA in April 2022 for the treatment of moderately to severely active CD in both adult patients and adolescent patients (aged 16-17 years) who have had an inadequate response, lost response or are not suitable for currently licensed treatments.

Efficacy of risankizumab

The clinical benefits of risankizumab versus placebo have been demonstrated in two pivotal induction studies (ADVANCE and MOTIVATE) and one pivotal maintenance study (FORTIFY). The risankizumab CD studies are the first Phase 3 induction trials completed in CD to include the novel and stringent co-primary endpoints of clinical remission, using both the traditional CDAI score and the newer patient reported outcomes of SF and APS, and endoscopic response. Co-primary endpoints are novel to IBD; they represent a stringent combination of clinical symptom and endoscopic endpoints which ensure that clinical improvement is accompanied by an objective improvement of the gut mucosa which is important to achieve in CD and is associated

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with improved long-term outcomes (e.g., reduced risk of relapse, decreased hospitalisations rates, steroid-free remission, and fewer bowel resections) (77, 78, 137). However, co-primary endpoints are a more difficult target to achieve when compared with a single primary outcome.

These endpoints reflect a paradigm shift in CD treatment where demonstrable healing of the mucosa, as assessed through endoscopy is associated with improved long-term outcomes (previously described), is now considered a major treatment objective in clinical trials and clinical practice (29, 138, 139). In addition, current guidance by the BSG recognises the importance of different treatment goals, with a recent focus on endoscopic outcomes, such as mucosal healing (absence of macroscopic mucosal inflammation or ulceration), in addition to controlling clinical symptoms (35). The endpoints assessed within and the subsequent results obtained from ADVANCE, MOTIVATE and FORTIFY align with these emerging treatment goals.

The results from the ADVANCE and MOTIVATE induction studies support the use of risankizumab 600 mg IV as either a biologic therapy for people with moderate-tosevere CD who have failed or are unsuitable for conventional care, or those that have already failed one or more biologics. Overall, risankizumab 600 mg IV was superior to placebo for the co-primary endpoints of CDAI clinical remission and endoscopic response for both the US and OUS protocols.

The majority of key secondary endpoints were statistically significant for risankizumab 600 mg IV versus placebo, symptomatic improvements seen as early as Week 4 and mucosal improvement measured by SES-CD observed at Week 12. Clinical response and clinical remission (defined by CDAI) were seen at Week 4, with statistically significant differences observed for the risankizumab 600 mg IV versus placebo. Continued improvements in CDAI clinical response were seen at Week 12, with greater efficacy and treatment differences relative to those at Week 4. Endoscopic remission at Week 12 was statistically significant in the risankizumab 600 mg IV arm versus placebo. As early as Week 12, approximately 1 in 5 subjects treated with risankizumab achieved the stringent endpoint of endoscopic remission; these results are indicative of the early endoscopic improvement associated with risankizumab treatment.

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The results from the maintenance study (FORTIFY) support continued maintenance treatment with risankizumab 360 mg SC in subjects with clinical response to risankizumab IV induction treatment. The co-primary endpoints of CDAI clinical remission and endoscopic response met statistical significance for the risankizumab 360 mg SC arm.

Importantly, approximately 29% of subjects achieved the composite endpoint of deep remission (CDAI clinical remission [CDAI <150] and endoscopic remission [SES-CD ≤ 4 and at least a 2-point reduction versus baseline and no subscore greater than 1 in any individual variable, as scored by a central reviewer]) after maintenance treatment with risankizumab compared with placebo (10%). Control of clinical symptoms and endoscopic outcomes, such as mucosal healing, are recognised as important targets for treatment of CD by the BSG (35). These outcomes are associated with improved long-term outcomes, including reduced risk of disease progression, surgery or hospitalisation (77, 78, 137). Additionally, maintenance with risankizumab 360 mg SC was associated with a greater rate of steroid-free clinical remission and steroid-free endoscopic remission and response when compared with the placebo SC arm at Week 52 (Appendix M). These results suggest that risankizumab may facilitate reduced corticosteroid use which may be beneficial to individuals with CD given the harmful side effects of long-term corticosteroid use (140).

Durable treatment effect

Evidence from across the pivotal CD trials indicates that risankizumab has a durable treatment effect in subjects with biologic inadequate response/intolerance (Bio-IR) or inadequate response/intolerance to conventional therapy (non-Bio-IR).

A substantial proportion of the subjects enrolled in the ADVANCE and MOTIVATE induction studies were treatment refractory, with 30% and 52% of subjects, respectively, having failed more than one previous biologic therapy. The risankizumab studies enrolled a more refractory population when compared with the other recently licensed biologic therapies, ustekinumab and vedolizumab.

Furthermore, the average disease duration was 9 and 12 years in ADVANCE and MOTIVATE, respectively. As CD is a progressive disease and disease duration

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correlates with accumulated bowel damage, the disease duration of subjects in the risankizumab studies further indicates the refractory nature of the populations enrolled (141). In addition, the use of centrally read endoscopic criteria for subject inclusion in the risankizumab studies (as compared with reliance on only clinical criteria for study entry [e.g., CDAI]) may have resulted in the inclusion of subjects with greater disease severity.

For induction (ADVANCE) and maintenance (FORTIFY) treatment with risankizumab, treatment effects were observed in Bio-IR and non-Bio-IR subjects, with treatment effects higher in the non-Bio-IR population as expected due to the treatment-refractory nature of the Bio-IR population (e.g., in ADVANCE, 42.5% and 48.9% of Bio-IR and non-Bio-IR subjects, respectively, achieved primary endpoint of CDAI clinical remission and endoscopic response). Another key feature of the risankizumab CD studies was the enrolment of subjects aged 16–17 years. This populations’ current choice of biologic therapies is limited to TNF-alpha therapies. Although the proportion of subjects aged 16–17 years enrolled across the studies was low at approximately 1%, this is broadly reflective of the proportion seen in UK clinical practice, according to expert clinical opinion (80). The evidence from the risankizumab CD studies has exhibited signs of efficacy and safety in subjects aged 16–17 years, and based on expert clinical opinion (80), the 16–17-year-old population was expected to have similar treatment response to an adult population if both populations have the same treatment history (i.e., bio-naïve or treatment refractory). Consequently, it can be expected that risankizumab will have similar clinical outcomes in the 16–17-year-old population as the adult population. Currently, only TNF-alpha inhibitors are licensed for use in 16–17-year-old population; a different class of biologic therapy for these individuals would provide an important treatment option. An epidemiology study in the UK indicated that the incidence of CD is increasing in people aged <17 years of age, which further underlines the need for additional treatment options in this population (48).

Safety of risankizumab

Induction with risankizumab 600 mg IV for 12 weeks (Induction Period 1) was generally well tolerated. In both ADVANCE and MOTIVATE, the overall incidence of AEs during

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the 12-week induction period was similar among all treatment arms. The rates of SAEs, severe AEs and AEs leading to discontinuation were numerically higher in the placebo IV arm, with most events related to underlying CD. These results are due to the impact of uncontrolled disease as a result of subjects not receiving any active treatment (other than the permitted background treatments [which includes immunomodulator therapies], see Section B.2.3). Across both studies, the most frequently reported AEs in ≥5.0% of subjects in the risankizumab 600 mg IV arm were headache and nasopharyngitis, whereas the most common AEs in the placebo IV arm were CD (worsening of CD), abdominal pain, nausea, and headache.

Additionally, risankizumab 360 mg SC as maintenance treatment for 1 year was generally well tolerated. The most common AEs (≥5.0%) in the risankizumab 360 mg SC arm was CD (worsening of CD), nasopharyngitis, arthralgia, headache, abdominal pain, and nausea. The percentage of subjects with SAEs and AEs leading to discontinuation were comparable in risankizumab 360 mg SC and placebo SC (withdrawal) arms. Across the induction and maintenance studies, no new safety risks were identified, and the overall safety profile was consistent with the known safety profile of risankizumab.

Based on the limited number of anti-drug antibody-positive subjects, no apparent impact of immunogenicity on risankizumab exposure was observed (see Appendix M). The occurrence of anti-drug antibody-positive subjects in individuals treated with risankizumab 360 mg SC maintenance therapy was 0.9%. The anti-drug antibodies associated with risankizumab were not associated with changes to clinical response, similar to that observed for ustekinumab (90). This compares favourably with vedolizumab, where anti-drug antibodies are associated with increased clearance of vedolizumab and lower rates of clinical remission, and TNF-alpha inhibitors, where anti-drug antibodies are associated with a loss of response (89, 97). The rates of antidrug antibody development with TNF-alpha inhibitors are high and, consequently, are often given in combination with immunosuppression (e.g., thiopurines) to prevent antidrug antibody formation (98). TNF-alpha inhibitor anti-drug antibody rates of 28.5% and 62.8% have been reported for adalimumab and infliximab, respectively (98). Additionally, the use of thiopurines is associated with a risk for the development of lymphoma, non-melanoma skin cancer and severe infections (98). Furthermore, Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986]

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combination therapy of TNF-alpha inhibitors and IMMs alters the safety profile of therapy and is associated with a higher risk of opportunistic infection and neoplasms such as lymphoma and non-melanoma skin cancer (142).

For AEs of special interest (serious infections, active tuberculosis, lymphoma, hypersensitivity, and injection site reaction), rates were generally comparable for the risankizumab induction (risankizumab 600 mg IV) and maintenance doses (risankizumab 360 mg SC) versus placebo. Notable differences include a higher rate of serious infection reported in the placebo group versus the risankizumab 600 mg IV group in the during the induction period (***% vs ***%). For the maintenance phase, the rate of serious infections was similar between the risankizumab 360 mg SC and placebo SC groups (4.5% vs 3.8%). There were no cases of lymphoma recorded in the risankizumab induction or maintenance phase.

Indirect and mixed treatment comparisons

In the absence of head-to-head RCT between all comparators specified in the NICE scope, a series of NMAs were performed to assess the relative efficacy of risankizumab compared with relevant comparators (adalimumab, infliximab, ustekinumab, vedolizumab) in people with moderate-to-severe CD in CCF and BF populations. Risankizumab was found to have broadly comparable efficacy with the rest of the comparators in the NMA, with the exception of placebo, where risankizumab was superior. The NMA results for the CCF population generally show comparable efficacy for risankizumab versus other comparators, and the results for the BF population generally favour risankizumab. The results of the NMA remained consistent regardless of the NMA model type used (i.e., FE or RE model). (Note that the comparison with vedolizumab was not a head-to-head as this NMA was performed as two separate networks as explained in Section B.2.9.1).

Overall, the NMA results suggest that risankizumab is comparable with other biologics across most clinically relevant outcomes, in both CCF and BF patients.

Conclusion

Based on the evidence presented, risankizumab for the treatment of moderate-tosevere CD fulfils unmet medical needs in CD by providing a novel class of biologic Company evidence submission template for risankizumab for previously treated moderately to severely active Crohn's disease [ID3986] © AbbVie (2022). All rights reserved Page 113 of 227

treatment for people with moderately to severely active CD with or without prior biologic therapy failure. Risankizumab is associated with significant symptomatic, clinical and mucosal improvements from as early as Week 4 versus placebo, with similar improvements observed over the 52-week SC maintenance phase. Across the induction and maintenance studies, risankizumab was well tolerated and no new safety risks were identified. In addition, the overall safety profile was consistent with the known safety profile of risankizumab.

B.2.12.2 Strengths and limitations of the clinical evidence base for the technology

B.2.12.2.1 Internal validity

ADVANCE, MOTIVATE and FORTIFY were large, multinational, placebo-controlled, well-conducted and methodologically robust studies. The study entry criteria were relevant and appropriate. The risankizumab CD study programme enrolled a total of ** subjects at ** UK centres, with UK subjects representing ***%, ***% and ***% of the study populations in ADVANCE, MOTIVATE and FORTIFY, respectively.

The studies were placebo-controlled, as mandated by the Food and Drug Administration and EMA. The placebo design is similar to other recently approved biologics for moderate-to-severe CD, and this design facilitates indirect treatment comparison with multiple other comparator treatments through the placebo arms. Additionally, conventional care (i.e., immunomodulators, corticosteroids) was permitted in both the risankizumab and placebo treatment arms in the risankizumab CD trials, in line with the expected use of risankizumab in UK clinical practice. In line with anticipated licensing, risankizumab may be used in addition to conventional care; therefore, a placebo arm was used to estimate the added benefit of risankizumab on top of conventional care for moderate-to-severe CD.

The baseline demographics and clinical characteristics of subjects were well balanced between the treatment groups in each trial and were generally similar across studies. Across studies, the disease severity baseline characteristics were reflective of moderately to severely active CD (based on CDAI, SES-CD, SF, and AP scores).

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