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Single Technology Appraisal

Rimegepant for treating or preventing migraine [ID1539]

Committee Papers

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NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

SINGLE TECHNOLOGY APPRAISAL

Rimegepant for treating or preventing migraine [ID1539]

Contents:

The following documents are made available to consultees and commentators:

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

Pre-technical engagement documents

1. Company submission from Pfizer

2. Clarification questions and company responses

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

• a. Association of British Neurologists headache and pain advisory group b. British Association for the Study of Headache

• c. The Migraine Trust

4. Evidence Review Group report prepared by BMJ TAG

5. Evidence Review Group report – factual accuracy check

Post-technical engagement documents

6. Technical engagement response from company

7. Technical engagement responses and statements from experts:

• a. David Kernick, GP – clinical expert, nominated by Teva UK

• b. Andy Bloor – patient expert, nominated by The Migraine Trust

• c. Deborah Sloan – patient expert, nominated by The Migraine Trust

8. Technical engagement responses from consultees and commentators:

• a. Association of British Neurologists Advisory Group on Headache and Pain

• b. British Association for the Study of Headache

• c. The Migraine Trust

• d. Novartis

• e. Teva

9. Evidence Review Group critique of company response to technical engagement prepared by BMJ TAG

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

Rimegepant for treating or preventing migraine [ID1539]

Document B

Company evidence submission

June 2022

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

Contents

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

© Pfizer (2022). All rights reserved

© Pfizer (2022). All rights reserved

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

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List of tables

Table 1: The decision problem ............................................................................................ 19 Table 2: Technology being appraised ................................................................................. 24 Table 3: ICHD Diagnostic Criteria for Migraine .................................................................... 26 Table 4: MOH Diagnosis Criteria ......................................................................................... 30 Table 5. Identified clinical effectiveness evidence: acute treatment of migraine with rimegepant .......................................................................................................................... 46 Table 6. Identified clinical effectiveness evidence: prevention of migraine with rimegepant 47 Table 7: Pivotal clinical effectiveness evidence for rimegepant ODT and oral tablet in the acute treatment of migraine................................................................................................. 51 Table 8: Pivotal clinical effectiveness evidence for rimegepant in the preventive treatment of migraine .............................................................................................................................. 55 Table 9: Summary of study design and methodology for eligible clinical studies evaluating rimegepant in acute treatment of migraine .......................................................................... 57 Table 10: Summary of outcomes for eligible clinical studies evaluating rimegepant in acute treatment of migraine .......................................................................................................... 59 Table 11: BHV3000-303, BHV3000-301, BHV3000-302 and BHV3000-201 (acute): Trial populations and statistical analyses .................................................................................... 61 Table 12: Overview of quality assessment of eligible randomised controlled trials that evaluated rimegepant for the acute treatment of migraine ................................................... 64 Table 13: Baseline demographics and disease characteristics across eligible clinical studies of rimegepant for the acute treatment of migraine ............................................................... 67 Table 14. Primary and secondary endpoint results for mITT participants in acute treatment studies BHV3000-303, BHV3000-301 and BHV3000-302 ................................................... 71 Table 15. Outcomes research endpoints for mITT participants in acute treatment studies BHV3000-303, BHV3000-301 and BHV3000-302 ............................................................... 74 Table 16: BHV-3000-201 - Absenteeism, Presenteeism, and Lost Productivity Time Over 52 Weeks ................................................................................................................................. 76 Table 17. A summary of the differences between the definitions of failure of prior treatment with ≥2 triptans in the pre-specified analyses from individual Phase 3 studies (Study BHV3000-303, Study BHV3000-301, Study BHV3000-302) and the post-hoc pooled analysis ........................................................................................................................................... 78 Table 18: Historical use of discontinued triptans mITT participants in Study BHV3000-301, Study BHV3000-302, and Study BHV3000-303 .................................................................. 78 Table 19: Baseline characteristics for mITT participants in acute treatment from studies BHV3000-303, BHV3000-301 and BHV3000-302 stratified by historical discontinuation of triptans ................................................................................................................................ 80 Table 20: Primary and secondary endpoint results for mITT participants in acute treatment from studies BHV3000-303, BHV3000-301 and BHV3000-302 stratified by historical discontinuation of triptans[a] .................................................................................................. 81

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Table 67: Results of the deterministic sensitivity analysis for rimegepant versus BSC acute treatment of migraine ........................................................................................................ 176 Table 68: Scenario analysis: rimegepant vs BSC (using Study BHV3000-201 MMD distribution option) acute treatment of migraine ................................................................. 178 Table 69: Summary of published cost-effectiveness studies informing the rimegepant prevention economic model .............................................................................................. 184 Table 70: Patient population considered in the economic model for migraine prevention .. 188 Table 71: Features of the rimegepant migraine prevention model ..................................... 192 Table 72: Summary of key parameters and sources informing the prevention model ........ 194 Table 73: Baseline patient characteristics, migraine prevention ........................................ 195 Table 74: Probability of response at 12 weeks in BHV3000-305 ....................................... 196 Table 75: Odds ratios for response at 12 weeks and corresponding probabilities ............. 196 Table 76: Predicted mean MMD ........................................................................................ 198 Table 77 Regression models for mapped EQ-5D-3L utility ................................................ 201 Table 78: Summary of utilities by monthly migraine day at model entry ............................ 201 Table 79: Drug unit costs for prevention ............................................................................ 204 Table 80: List of resource use and associated costs used in the prevention economic model ......................................................................................................................................... 206 Table 81: Mean HCRU by MMD (National Health and Wellbeing Survey) ......................... 206 Table 82 Summary of variables applied in the economic model in migraine prevention .... 209 Table 83: Key assumptions in the economic model in migraine prevention ....................... 211 Table 84: Base-case results prevention ............................................................................ 214 Table 85: Cost breakdown ................................................................................................ 214 Table 86: Probabilistic base-case results (migraine prevention) ........................................ 215 Table 87: Ranges for most influential parameters for rimegepant versus galcanezumab (migraine prevention) ........................................................................................................ 219 Table 88: Pairwise ICERs and NHB (rimegepant vs mAbs) for scenario analyses ............ 221

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List of figures

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Figure 25: Probabilistic cost-utility plane rimegepant vs galcanezumab ............................ 216 Figure 26: Probabilistic cost-utility plane rimegepant vs fremanezumab ............................ 217 Figure 27: Cost-effectiveness acceptability curves (migraine prevention).......................... 218 Figure 28: Tornado plot for rimegepant versus galcanezumab (migraine prevention)........ 219

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Abbreviations

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (2022). All rights reserved

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

© Pfizer (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 submission focuses on specific patient populations within the technology’s marketing authorisation, which will be referred to briefly as “acute migraine” and “migraine prevention” throughout. The proposed target populations are narrower than the marketing authorisation because of their relevance to NHS clinical practice. Based on expert clinical opinion obtained at UK advisory boards in 2022,[1] the proposed populations of acute migraine and migraine prevention are aligned with potential use in the current treatment pathway:

• Acute migraine: As an option for patients who have had inadequate symptom relief after trials of at least two triptans or in whom triptans are contraindicated or not tolerated; and have inadequate pain relief with NSAIDs and paracetamol. In the acute setting, rimegepant would not be used in patients in whom triptans are a suitable option; the unmet need is greater for patients in whom triptans are ineffective or are not appropriate due to safety and tolerability considerations.

• Migraine prevention: As an option for patients with episodic migraine who have at least four migraine days per month, but fewer than 15 headache days per month and have failed three or more preventive oral drug treatments. In the preventive setting, rimegepant would not be used in patients in whom traditional oral therapies are efficacious, nor would it be used until they have failed three preventive treatments, consistent with prior appraisals of the anti-CGRP mAbs.

The decision problem addresses the evidence separately for rimegepant used for acute migraine treatment or in the prevention setting. A summary of the decision problem addressed within this submission is presented in Table 1.

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Table 1: The decision problem

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B.1.2. Description of the technology being appraised

The summary of product characteristics (SmPC) has been included in Appendix C.

The technology being appraised (rimegepant) is described in Table 2.

Table 2: Technology being appraised

Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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

B.1.3.1. Overview of disease or condition

Migraine is a common, often disabling neurologic disease characterised by recurrent attacks of head pain that are typically unilateral, throbbing, and associated with a range of symptoms that may include photophobia, phonophobia, nausea, and vomiting.[14-16] Clinically, migraine attacks comprise four phases: the premonitory/prodrome, aura, headache, and postdrome.[17] Migraine is a complex disorder, susceptibility is affected by the interaction between multiple genetic and environmental factors.[9 ]

In addition to a higher prevalence in women, migraine attacks in women tend to be more frequent than those in men, and the attacks are more severe, have a longer duration, and are more challenging to treat.[18] Migraine prevalence appears to increase until 40 years of Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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age and then decline in older adulthood, particularly after menopause in female patients.[18,19] There are two major types of migraine: migraine with aura and migraine without aura.[14] Migraine with aura occurs in approximately a third of patients,[16] and includes migraine with typical aura or with brainstem aura, hemiplegic migraine, and retinal migraine.[14] Migraine can be also classified, based on the frequency of migraines or headaches, as episodic migraine (EM) or chronic migraine (CM) (see below).[14]

B.1.3.1.1. Migraine diagnosis and classification

Diagnosis

Migraine diagnosis is a clinical diagnosis and there are no confirmatory diagnostic tests available.[20] Migraine diagnosis is made in accordance with the criteria listed in Table 3,[14] and is based on a patient’s medical history and findings of a physical examination.[9] It is important to differentiate migraine from other types of primary headaches such as cluster and tension headaches, generally not dangerous, and can be diagnosed with the help of headache diaries and trigger trackers; and secondary headaches, which are caused by more serious underlying conditions and can be diagnosed with the help of invasive or advanced diagnostics such as lumbar puncture, computerised tomography (CT), and magnetic resonance imaging (MRI).[21,22] Diagnosis should also include the differentiation of migraine from trigeminal neuralgia, a much less prevalent but distinct disorder of severe facial pain.[22] The diagnosis of migraine consists of two steps: the first step is to rule out a secondary headache disorder, and the second step is to use the frequency and duration of migraines to confirm a specific primary headache syndrome.[23]

Table 3: ICHD Diagnostic Criteria for Migraine

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The diagnostic criteria for CM have evolved over time and result in variability in estimated prevalence globally. Abbreviations: CM, chronic migraine; ICHD, International Classification of Headache Disorders Reference: International Classification of Headache Disorders 3rd Edition, 2018[14]

Classification

Migraine is classified according to whether or not patients experience aura, or a preceding sensation such as flashing lights, blurred vision, weakness, numbness, or ringing in the ears.[14 ]

Migraine can be also classified, based on the frequency of migraines or headaches, as episodic migraine (EM) or chronic migraine (CM), and the focus of this submission is EM based on the rimegepant indication. The generally accepted definition of CM is ≥15 monthly headache days (MHDs), with ≥8 days showing typical migraine features, while patients with EM have headache occurring on less than 15 days a month over the last three months, which on some days is migraine.[24] Currently, CM is classified as a separate subtype, as the frequency of the headaches may make it difficult to distinguish between individual attacks or episodes.[9,14,25,26] Variability of MHDs within individuals over time makes a fixed cut-off point challenging for CM versus EM. Migraine frequency can vary over time in both directions, and the within-person variation in migraine frequency is substantial.[27-29]

B.1.3.1.2. Clinical presentation of migraine

Patients with migraine experience debilitating symptoms during migraine attacks, and they also experience the cumulative burden of repeated attacks.

Typically, migraine attacks occur in 4 phases — the prodrome, aura, headache, and postdrome — although there may be considerable overlap in the phases as an attack develops.[17]

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• The prodrome phase may last 24 to 48 hours, and patients may experience symptoms of yawning, irritability, reduced concentration, depression, neck stiffness, cravings for certain foods, and constipation.[9,17]

• The aura phase typically lasts approximately 1 hour and can include positive (e.g. jerking, paraesthesia, seeing bright shapes or objects) or negative (e.g. loss of feeling, hearing, vision) symptoms affecting the motor-, somatosensory-, auditory- and visual systems.[9] Typically, aura develops gradually, however it can be confused with a stroke or transient ischaemic attack (TIA).[9]

• During the headache phase, patients often experience unilateral, throbbing pain that lasts from four to 72 hours and is accompanied by photophobia, phonophobia, nausea, and occasionally vomiting.[9,17]

• The postdrome phase, also known as the hangover phase, occurs in about 80% of patients and can last for another 24 to 48 hours.[30,31] The symptoms are similar to those of the prodrome phase and can include fatigue, exhaustion, difficulty concentrating, or euphoria.[9,17]

B.1.3.2. Disease burden

B.1.3.2.1. Epidemiology

Migraine is one of the most frequent neurological diseases. It is thought that, mainly because of the transient nature of primary headache, the burden is generally underestimated.[32]

The National Institute for Health and Care Excellence (NICE) estimated that there are 190,000 migraine attacks experienced every day in England and six million people suffer from migraine in the UK.[5] Based on the 2003 survey conducted among the population aged 16-65 years in mainland England, the one-year prevalence of migraine with or without aura was 14.3% among the adult population.[33] One in seven adults (5.85 million) are affected and 100,000 people miss school or work as a result of this condition each day.[34]

B.1.3.2.2. Clinical burden

Migraine is a major public health issue throughout the world with a significant clinical burden that has increased over the past three decades.[35]

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Migraine chronification:

In some patients with EM, the headache frequency may increase over time until it crosses the threshold for CM which is defined as 15 monthly headache days (MHDs) per month, with ≥8 showing typical migraine features for at least three consecutive months. This process is termed migraine chronification. Every year, 2.5% to 7.6% of people with EM will develop CM.[27,29,36] Risk factors for developing CM include age and race, socioeconomic status, migraine medication overuse, ineffective acute treatments, most migraine comorbidities, stress, hormonal changes, high frequency of episodic migraine (≥10 headache days per month), and long duration of illness.[23,37-40]

Suboptimal acute treatment may increase the risk of progressing from EM to CM. Patients with very poor acute treatment efficacy have more than a three-fold increased risk of progressing from EM to CM.[41] Frequent and extended activation in nociceptive pathways (involved in pain processing) may facilitate pathophysiological changes indicative of CM.[42] This suggests that effective migraine management not only provides immediate relief to the patient, but prevents further progression of disease. In fact, relapsing pain and more frequent use of acute medications (NSAIDs or triptans) have been shown to be associated with increased risk of CM.[43,44] Inadequate management of migraines with triptans, illustrated by the high rates of discontinuation and frequent medication overuse headache (MOH), further increases the risk of chronicity. This highlights the need for novel therapies for preventing disease progression and alleviating the clinical and economic burden associated with increased monthly frequency of migraine.

Medication overuse:

Medication overuse headache (MOH) is believed to affect up to 2% of the general population, with much higher prevalence reported in chronic daily headache patients, and with 65% of cases having migraine as the underlying primary headache disorder.[45]

MOH occurs when patients with a pre-existing primary headache develop a new type of headache or a significant worsening of their pre-existing headache, in association with medication overuse.[14] As shown in Table 4, MOH is defined by the ICHD as headache occurring on 15 or more days per month developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more, or 15 or more days per month, depending on the medication) for more than three months.[14 ] The use of opioids, combination analgesics, ergots, or triptans on ≥10 days per month; and paracetamol or NSAIDs on ≥15 days per month can cause MOH.[46] The treatment of choice for MOH is to stop using the

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medication that is being overused; however, this can be challenging due to the withdrawal or detoxification process, which can take up to 10 days and require inpatient hospital withdrawal in the case of certain medications such as opioids.[47,48]

Table 4: MOH Diagnosis Criteria

ICHD-III MOH

• A. Headache occurring on ≥15 days/month in a patient with a pre-existing headache disorder

• B. Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache

• C. Not better accounted for by another ICHD-III diagnosis

Abbreviations: ICHD-III = The International Classification of Headache Disorders 3[rd] Edition; MOH = medication overuse headache References: IHS 2019[14]

Certain analgesics and front-line abortive medicines, like triptans, are associated with greater risk of MOH.[49] Overuse of triptans has been found to lead to MOH faster (1.7 years) and with lower dosages (18 single doses per month) compared with other acute medication such and analgesics (4.8 years; 114 single doses per month).[50] In the ‘Migraine in America Symptoms and Treatment (MAST) study’, patients with acute medication overuse reported significantly more MHDs (12.9±8.6 vs. 4.3±4.3, p<0.001) compared to patients without acute medication overuse.[51] In most cases, MOH resolves when overuse is discontinued.[14] MOH as a result of overuse of certain medications can increase the risk of developing CM.[52]

B.1.3.2.3. Humanistic burden

Migraine is the second highest cause of disability worldwide[53] and the most disabling of all health conditions in those younger than 50,[54] with considerable negative effects on patients’ quality of life. Migraine is an episodic but recurrent pain syndrome characterised by neurological and gastrointestinal symptoms, and is associated with impaired functioning, quality of life and psychological impairment.[55]

Among patients with migraine, those with a higher frequency in headache days and more severe depression and anxiety have increased disability when measured with the migraine disability assessment MIDAS.[56,57] In addition, patients with migraine experiencing three or more headache days per month reported severe disability which worsened to very severe levels after ten or more headache days.[58] An increased MIDAS score in patients with migraine has also been correlated with having several sensory hypersensitivities, younger age, increased MMD, and a higher Kessler Psychological Distress (K6) score.[59]

A survey conducted in a random sample of adults in England revealed that 25% of

respondents with migraine (N=574) reported high levels of pain (rated 9-10 on a 10-point Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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scale).[33] A mean pain rating of 7.5 on a 10-point scale (where 10=most intense pain) was observed in both males (n=113) and females (n=461).[33] Pain and discomfort during attacks often results in poor quality of sleep, which in turn is associated with poor health, significant functional and cognitive impairment, and psychiatric comorbidity.[60,61]

The intense pain and other symptoms associated with migraine can have a substantial negative impact on daily life in those experiencing attacks.[62] Many patients suffering from severe migraine attacks are unable to perform daily activities and can be confined to bed during an attack. Some studies have found that approximately 80% of individuals with migraine are unable to work or function normally during attacks, 69% need help with daily activities on a median of nine to 10 days over a three-month period, and most (53%) report severe impairment and/or requiring bed rest.[63,64] Patients with migraine often seek clinical care for relief, leading to frequent visits to healthcare professionals (HCPs) and EDs.[65]

Attacks can vary in duration, and can last for days if left untreated.[66] Migraine not only adversely affects patients during an attack, but also has an impact between attacks.[67] This is referred to as interictal burden; it presents as worry and concern about when the next painful attack will be, and what its impact will be on plans and activities.[67] According to a 2022 qualitative analysis from the US, Canada, and the UK, patients with migraine (n=35) relayed feelings of unreliability and inability to make plans during the interictal period and reported feeling anxious about a forthcoming migraine, requiring changes to their lifestyle, needing to decrease or stop working, and avoiding social or family activities.[68]

Evidence suggests that migraine-related disability is similar to that of other serious diseases, such as acute myocardial infarction, dementia, and moderate multiple sclerosis.[69] The burden of migraine increases with an increase in MMD. Compared to people with fewer MMD, people with more MMD experience a higher burden on health, relationships, career, and finances; increased disability, comorbidities, and health care resource utilisation; and decreased quality of life and productivity.[70-75]

In addition to the impacts of migraine itself, many patients respond insufficiently to treatments or experience intolerable adverse effects.[76-78] Almost half of patients who have concerns about the efficacy or tolerability of their treatment are moderately or severely disabled, and only 20% of those who discontinue their treatment are able to function normally and work while having headaches.[78]

Several quality of life and patient-reported outcome (PRO) measures have been utilised in the literature to evaluate the impact of disability and reduction in quality of life.[79,80] Migraine-

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specific HRQoL measures include the Migraine Disability Assessment (MIDAS) questionnaire,[77] the Migraine-Specific Quality of Life Survey (MSQ),[79] and the Migraine Functional Impact Questionnaire (MFIQ).[81] Other measures that can be used to assess migraine burden and changes due to treatment include the Headache-Attributed Lost Time (HALT) over 90 days (HALT-90) or 30 days (HALT-30).[82] These indexes were derived from MIDAS.[82]

B.1.3.2.4. Economic and societal burden

Migraine has a substantial impact on the healthcare system. In the UK, around 2.5 million primary care appointments are linked to headaches and migraines, around 100,000 of which are referred to hospital for further assessment (2018/2019).[83] The number of admissions to hospitals in England for headaches and migraines has increased by 14% over a five-year period, NHS Digital data shows an increase emergency admissions from 95,548 in 2014/15 to 108,711 emergency admissions in 2018/19.[83] In total, it is estimated that the NHS spends around £150 million per year on treating migraines and £250 million on care for headache sufferers.[83] In patients with migraine, as the number of headache days increase so does the burden of disease including healthcare utilisation.[84] Further, the NHS has reported (NHS RightCare, 2019)[85] an addressable issue of inappropriate referral to secondary care for migraine patients. Avoidable specialist neurology appointments delay access for patients with potentially serious secondary headache disorders or other neurological conditions that require investigation urgently. Introduction of new treatment options into the primary care setting can help to reduce such inappropriate referrals to secondary care, bringing benefit to patients, reducing waiting times and reducing NHS costs associated with unnecessary attendances in secondary care.

Migraine is also associated with substantial impacts on work productivity and social interactions and is a considerable burden on employers, families, patients, and society.[16,73,86-90] There are a number of instruments that assess the impact of disease on work productivity, including the generic Work Productivity and Activity Impairment (WPAI) questionnaire and the migraine-specific Migraine Work and Productivity Loss Questionnaire (MWPLQ).[91] There is a particular impact on women, as migraine is about three times more common among women than men[92 ] making improving migraine treatment a need well aligned with the new Women’s Health Strategy for England.[93]

As migraine prevalence is greatest among individuals aged 35-49 years, migraine-related disability has an enormous impact on what are typically the most productive years of life.[66,94,95] The Office for National Statistics (ONS) data indicate that headaches and

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migraines account for 4.9% of sickness absence (2020) in the UK.[96] Migraine-related absenteeism (sick days off work) and presenteeism (reduced effectiveness at work) combined is estimated to be responsible for 55–86 million equivalent workdays lost per annum at a cost of between £5.6 and £8.8 billion in lost productivity (using prevalence estimates of 15% and 23.3%).[97] NHS data indicate around £4.4 billion a year lost to three million migraine-related sick days.[83] The impact of migraine is also felt among NHS’s own staff, for example in a single month of November 2021, 2.3% of total NHS staff absences were due to migraine or headache, the migraine absence accounted for 51,179 FTE days lost.[98]

Other source of data corroborate these findings, using data from the Eurolight project (outpatient care, investigations, acute medications, hospitalisations, and prophylactics) direct costs are estimated to be between £600 million and £1 billion per annum (data applied to 15% UK prevalence and GBD 2016 UK adult migraine prevalence, respectively).[97] Direct costs are responsible for approximately 10% of the total cost burden.[97] When combined, indirect and direct costs attributed to migraine in the UK are estimated to be in the region of £6.2 to £9.7 billion per year.[97]

B.1.3.3. Clinical pathway of care

Migraine can be managed by avoiding or managing triggers (when identified), using nonpharmacological and complementary therapies such as acupuncture and cognitive behavioural therapy, or using acute or preventive pharmacological treatments.[22,99,100] Acute treatments are taken for symptomatic relief during attacks, and preventive treatments are taken regularly to prevent attacks and/or reduce the frequency and severity of attacks.[39,101] The main classes of acute treatments include analgesics and triptans.[39,102] Classes of preventive treatments include antiepileptics/anticonvulsants, antidepressants, beta-blockers, calcium channel antagonists, serotonin reuptake inhibitors, botulinum neurotoxins, and calcitonin gene-related peptide (CGRP) antagonists.[39,103] Many patients will require both acute and preventive treatments if they have frequent and severe headaches.[103]

Currently, there is no single medication recommended by NICE for both the acute and preventive treatment of migraine. Existing medications are often underutilised and/or discontinued due to lack of efficacy and tolerability as well as concerns of increased risk of MOH.[16,77,104,105] In addition, linked to these concerns, patients tend to treat too late, or at a lower dose.[16,77,104,105] Patients can become resistant or refractory to treatment, and inadequate response to treatment can result in increased disease burden, disability, and despair.[106 ]

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Current recommendations for migraine management include using acute or preventive pharmacologic treatments along with supportive measures including avoiding or managing triggers and using non-pharmacologic and complementary therapies such as acupuncture and cognitive behavioural therapy.[99]

B.1.3.3.1. Acute migraine in clinical practice

Acute migraine: Current treatments and pathway

The current treatment pathway for therapies in people with acute migraine based on NICE guidance is summarised in Figure 3. The pathway is based mainly on CG150, which includes, unless contraindicated, simple analgesics (i.e. ibuprofen, aspirin or paracetamol) or a triptan with or without paracetamol or an NSAID. Oral triptans are recommended unless vomiting restricts treatment. Anti-emetics (e.g. metoclopramide or prochlorperazine) should be considered even in the absence of vomiting.

Figure 1: Clinical pathway of care: treatment of acute migraine

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Abbreviations: AEs, adverse events; BSC, best supportive care; NSAIDs, non-steroidal anti-inflammatory drugs Notes: 1Consider an anti-emetic in addition to other acute treatment for migraine even in the absence of nausea and vomiting

2When prescribing a triptan, start with the one with the lowest acquisition cost References: NICE CG150[107]

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Acute migraine: Unmet need

Limitations of current available therapies

The unmet need in acute migraine—an indication in which there have been no new therapies approved in Europe or the UK in over 20 years—includes issues relating to efficacy, safety and tolerability, as well as medication overuse headache (MOH).

The main classes of acute treatments include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), and triptans, which may be used alone or in combination (eg, NSAID + triptan or paracetamol + triptan).[107] While triptans are commonly used for the acute treatment of migraine attacks, some patients may not have adequate symptom control due to lack of efficacy, intolerable side effects, and safety concerns for those with a history of vascular disease, multiple risk factors for vascular diseases, and during pregnancy.[108] The British Association for the Study of Headache (BASH) guidelines, recommend that after two treatment failures with an initial triptan, an alternative triptan is offered, as the first one is unlikely to be effective in subsequent attacks.[109] Limited studies have investigated whether a patient not responding to a first triptan may benefit from a second one.[110,111] Five studies[112-] 116 provide some evidence that switching from a triptan that is ineffective to a second one can result in varying levels of success. It is not clear whether there are factors that mean some patients respond poorly to all triptans.[110,111] In addition, a systematic literature review published in 2020, suggested some patients may benefit from trying a second triptan after failure of one, but there are no prospecti/ve clinical trials or observational studies supporting the use of a third triptan after two have failed.[3]

The needs of many patients with migraine are therefore not met with traditional acute treatments.[78,117] It has been estimated that 15% to 25% of patients currently using migrainespecific acute therapies may have inadequate symptom control and would benefit from access to novel treatments.[108] A two-year retrospective cohort study of newly prescribed triptan users in the UK (n=3,618), France (n=2,051), and Germany (n=954) highlights the unmet need for acute migraine treatment.[118] The study found that >55% of patients did not obtain a refill prescription for the first triptan that they were prescribed.[118] In the UK, 56% of patients did not refill their index triptan, with 5% switching to a different triptan, 2% switching to a different class of prescription medication, and 49% receiving no further migraine prescription after the index triptan, underscoring the lack of suitable options for patients who do not benefit from triptans. Side-effects are a basis for patients limiting triptan use, i.e. they may refill the prescription but not treat every attack (thus losing benefit) because of concerns about side effects. Sometimes patients will try to endure a migraine because triptan side-

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effects are disabling (brain fog). Among patients who did refill the index triptan, 15% only obtained one refill. By the end of the two-year study period, 84% of UK patients were receiving no migraine prescriptions.[118] However, in a recent retrospective analysis using the CPRD Aurum dataset, the data shown that only 4.8% of migraineurs have tried more than two different type of triptans for the acute treatment of migraine, suggesting that a third triptan after treatment failure remains relatively uncommon in clinical practice.[2]

This unmet need has been consistently demonstrated in clinical practice and trial data showing that new users of triptans have relatively low persistence and retention rates.[118-121] Also, common alternatives to triptans, such as NSAIDs, are associated with an increased risk of serious gastrointestinal safety and renal toxicity events[122-124]

Between 55.2% and 81.5% of patients who use triptans report discontinuation of treatment.[125] Common reasons for discontinuing triptans include inadequate efficacy, adverse effects, and contraindications.[104,126,127] For the more than 20 years that triptans have been recommended as first-line therapy,[128,129] there has been a largely unmet need for additional treatment options for patients with migraine who are not eligible to use triptans due to AEs, lack of response, or cardiovascular contraindications.[117,130-132]

Progressing to chronic migraine

Suboptimal acute treatment may increase the risk of progressing from episodic to CM. Patients with very poor acute treatment efficacy have more than a three-fold increased risk of progressing from episodic to CM.[41] This suggests that effective management of the acute attack not only provides immediate relief to the patient and an early return to normal activities but prevents recurrent attacks. In fact, relapsing pain and an increase in days per month of acute medication utilisation (e.g., NSAIDs or triptans) has shown to be associated with increased risk of CM.[43,44] and the risk of developing medication overuse headache. A more targeted and efficacious approach to treating the acute attack, involving selective CGRP inhibition, may have potential to prevent escalation to episodic or chronic migraine, with their associated clinical and economic burden.

Emergency migraine care

Another critical component of unmet need in acute migraine is that some patients must seek emergency care due to unresolved pain and overlap of migraine symptoms with potentially life-threatening conditions (e.g., sub-arachnoid haemorrhage or stroke), and due to

inadequacies or perceived inadequacies of treatment options in primary care. An analysis

from the Neurology Alliance, showed a marked increase (17%) in migraine-related hospital Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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admissions compared to 2012/13. In the same period population growth was just 3%.[133] The analysis reported that emergency admissions now account for 97% of all hospital inpatient admissions with an ICD-10 code indicating a primary diagnosis on admission episode of headache or migraine.[133] These data could indicate that people with migraine are increasingly relying on emergency services for medical care, rather than going through primary care, likely adding significant, avoidable costs to the NHS.

In a 2017 EU5 study, over six months, migraine patients had an increasing ED visits with increasing MHDs, (a mean of 0.28 ED visits for those with one to three MHDs, 0.38 for those with four to seven MHDs, and 0.42 for those with eight to 14 MHDs).[134] Effective and tolerable oral acute migraine treatments have potential to significantly reduce the need for emergency migraine care, which may entail measures such as subcutaneous sumatriptan or parenteral NSAIDs, with or without antiemetics.[109] An audit was conducted of all adult presentations to the emergency department of Guy’s and St Thomas’ Hospitals which were coded as “headache” over the first six months of 2018.[135] Of 78,273 attendances to the emergency department, there were 976 presentations to the emergency department with “headache” as the primary complaint.[135] “Migraine” was the most frequent of all diagnoses, accounting for 30% of all headache presentations and 25% of headache admissions.[135] With regard to investigations, 21% of patients with migraine had CT scans, while 4.4% had MRI or MRA scans, and 5% had lumbar punctures. The cost of admitting and investigating migraine was estimated as £131,250 over the six-month period.[135]

Medication overuse headache

As discussed in Section B.1.3.2.2, certain analgesics and front-line abortive medicines, like triptans, are associated with an increase in the risk of MOH.[49] Overuse of triptans has been found to precipitate MOH more rapidly and with lower dosages than other acute medications, such as analgesics.[50]

The recognised unmet need for adequate and safe treatment of migraine has resulted in the development of new drugs e.g. 5-hydroxytryptamine (5-HT1F) receptor agonists (e.g. lasmiditan), and small molecule CGRP receptor antagonists (gepants, e.g. rimegepant).[136]

Proposed positioning of rimegepant for the treatment of acute migraine

The clinical pathway of care, based on NICE advice for acute migraine, with the proposed place in therapy of rimegepant is shown in Figure 2. Rimegepant would be an option for patients with migraine (with or without aura) who have had inadequate symptom relief after taking at least two triptans or in whom triptans are contraindicated or not tolerated.

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Rimegepant targets the molecular causes of migraine by selectively binding with high affinity to the CGRP receptor, which is thought to relieve migraine by: 1) blocking neurogenic inflammation; 2) decreasing artery dilation; and 3) inhibiting pain transmission.[137 ] As discussed in Section B.2, rimegepant acts rapidly on acute migraine attacks with a welltolerated safety profile. A potential ancillary benefit of rimegepant use in the acute setting is the potential to also reduce migraine frequency over time.[138-141] Rimegepant therefore provides an additional treatment option, giving patients who have tried and failed (or are contraindicated for) the existing treatments the ability to achieve symptom relief, with potential for reduced disability, improved productivity, and enhanced quality of life.

Figure 2: Rimegepant in clinical pathway of care: treatment of acute migraine

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Abbreviations: AEs, adverse events; NSAIDs, non-steroidal anti-inflammatory drugs Notes:

1Consider an anti-emetic in addition to other acute treatment for migraine even in the absence of nausea and vomiting

2When prescribing a triptan, start with the one with the lowest acquisition cost References: NICE CG150[107]

B.1.3.3.2. Preventive treatment of migraine in clinical practice

Preventive treatment of migraine: current treatments and pathway

The goal of preventive therapy in migraine is to decrease the overall clinical characteristics of migraine including frequency, intensity and duration of attacks to improve responsiveness to acute therapy, and to reduce the migraine-related disability while avoiding occurrence of MOH. The current pathway based on NICE guidance is summarised in Figure 3.

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Figure 3: Clinical pathway of care for the preventive treatment of episodic migraine

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References: NICE CG150; NICE TA260; NICE TA659; NICE TA682; NICE TA764[4,5,107,142,143]

The current NICE guidelines recommend oral preventive treatments including the antiepileptic, topiramate, the beta-blocker, propranolol, and the antidepressant, amitriptyline, as first-, second-, and third-line preventive treatment options.[107] These may be sequenced in any order based on the patient’s preference, comorbidities and risk of AEs.[107] The decision to move to the next line of treatment is based on lack of efficacy or poor tolerability.[107] Some patients find relief from a course of acupuncture.[107] Patients should be reviewed every six months to assess a need for continuation of prophylaxis.

The BASH guidelines[109] and recent NICE guidance recommend the following injectable monoclonal antibody (mAb) calcitonin gene-related peptide (CGRP) antagonists erenumab 140 mg, galcanezumab and fremanezumab as treatments for EM and CM if at least three preventive drug treatments have failed.[4,142,143]

The BASH guidelines[109] also recommend off-label candesartan (an angiotensin II receptor blocker [ARB); however, while candesartan has been shown to be beneficial in the preventive treatment of migraine it is not licensed for this indication.[144]

For patients with CM who have a history of three or more failed treatments, botulinum toxin A is also recommended as a fourth-line treatment.[5]

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While preventive therapies for migraine aim to reduce MMD, it is rare that a patient will eliminate migraine headaches completely. The migraine attacks that occur while a patient is taking prophylactic treatments are referred to as “breakthrough” events, and patients are likely to treat these migraine attacks with acute therapies to provide symptom relief (e.g., triptans), and rescue medications in the case that those acute therapies fail (e.g., NSAIDs and opioids). While preventive migraine therapies aim to achieve a clinically meaningful reduction in MMD, the vast majority of patients will use acute medications to manage breakthrough events.[145-147]

Preventive treatment of migraine: Unmet need

Limitations of current available therapies

There are several challenges relating to the attributes of currently available preventive migraine treatments.

Traditional preventive treatments (e.g. topiramate, beta-blockers and antidepressants) have not been specifically designed for migraine, many are only moderately effective and have suboptimal outcomes with high rates of adverse effects, poor tolerability, and have interactions or contraindications.[16,148-152] These options are associated with patients frequently switching, discontinuing or delaying therapies due to a lack of efficacy or poorer tolerability and impact adherence. Some therapies may impact the effectiveness of hormonal contraceptives, e.g. topiramate.[107]

Discontinuation rates have been reported for propranolol (23%), amitriptyline (45%), and topiramate (43%). AEs were the most common reason cited for discontinuing therapy, including 17% for amitriptyline and 24% for topiramate.[148,153,154]

Adherence to migraine prophylactic therapies is low, with patients frequently switching, discontinuing or delaying taking prescription therapies due to a lack of efficacy or poor tolerability.[155] Less than half of patients on prophylactic treatments report being satisfied with their current treatment regimen, and many resort to over-the-counter medications (e.g. NSAIDs, or sumatriptan). Real-world data shows that adherence rates range from 17–20% after one year, and that persistence falls below the threshold of 80% after only six months.[119,154] Adverse events (AEs) such as taste perversion, weight loss and paraesthesia are common in oral prophylactic treatment options for migraine. A recent systematic review of 159 randomised controlled trials (RCTs) of treatments for episodic migraine reported that 2.1–16.6% of patients discontinued treatment due to adverse events after two to three months of follow-up.[156] Patients who cannot tolerate traditional oral therapies will receive no Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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benefit at all.[157] In clinical practice, clinicians consider not only the efficacy of the drug in question, but also the patient’s comorbidities, contraindications, likely compliance, and the risk of AEs as part of their decision-making.

In accordance with current guidelines,[107,109] switching between preventive treatments is common, however persistence worsens as patients cycle through various treatments.[153] The proportion of patients who experienced ≥4 MMD increased with increasing switches between preventive treatments.[158] In an Italian study of 1,100 patients with migraine, only 12% had ≥50% reduction in migraine frequency with first-line preventive treatments and 550 dropped out due to adverse effects.[159] Current preventive treatments have significant limitations in relation to efficacy, tolerability, sustainability, and specificity, resulting in dissatisfaction, nonadherence, and increased burden.[160]

Anti-CGRP mAbs have been developed to address this unmet need for effective tolerable treatments for migraine prevention. A number of these treatments are approved for EM and CM, including erenumab, fremanezumab, galcanezumab, and eptinezumab.[161-168] These anti-CGRP mAb preventive treatments have advantages over traditional migraine therapies including no need to escalate the dose slowly, a relatively rapid onset of action and treatment benefit, and efficacy in patients refractory to other preventive treatments.[16,169] However, there are several challenges to consider with anti-CGRP mAbs. The injectable mAbs have long half-lives ranging from 27 to 30 days,[165,166,168] which can require waiting several months to eliminate the drug from the body if a change to treatment is desired. This can pose a challenge for women of childbearing age, who form a large portion of the migraine population, and who may need to make treatment changes to plan or manage pregnancy. The monthly administration schedule also leads to waning of effectiveness between doses, with patients more likely to experience breakthrough migraine attacks near the end of the treatment cycle.[170] The three mAbs currently recommended by NICE can be self-injected by patients after being trained, although patients generally prefer selfadministered oral medication over injections.[165,166,168,171] Training patients on injections also adds to the burden on healthcare professionals, who have a substantial backlog and limited staffing due to the effects of the COVID-19 pandemic meaning that wait time for treatment can be lengthy.[172] However, some patients still need ongoing support for injections.[4]

In addition, other challenges associated with CGRP mAbs include the side-effect burden (e.g. constipation has been reported in up to 43% of erenumab patients in clinical practice),[173-176] high rates of discontinuation observed in real-world clinical practice,[170,177,178]

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Preventive migraine treatment preferences were explored in a discrete-choice experiment of patients having a mix of EM and CM and the results indicated that patients would value more effective and tolerable treatments and would prefer daily oral medications and monthly injections to more frequent injections (two a month).[179] In another discrete-choice experiment in 506 patients with migraine in the US and Germany,[180][180] the most apparent difference between treatments was the mode of administration which may be particularly important to patients who have not previously used injectable therapy. Patients significantly preferred oral administration to quarterly infusion (p<0.01) and quarterly (p<0.01) or monthly (p=0.02) injection.[180]

Proposed positioning of rimegepant for the preventive treatment of episodic migraine

Rimegepant is proposed for the preventive treatment of adults with episodic migraine who have four or more migraine attacks per month and have failed three conventional oral treatments. Figure 4 depicts the proposed pathway for migraine prevention and proposed positioning of rimegepant. Based on the current patient pathway, these patients would be eligible to receive one of the injectable mAbs recommended by NICE, such as erenumab, fremanezumab and galcanezumab are deemed the most appropriate comparators. For patients who have failed conventional therapy, rimegepant provides an alternative to currently available injectable therapies. A novel, oral anti-CGRP option may enable patients to receive this type of treatment more quickly and conveniently in the primary care setting rather than having to be referred to secondary care. Such patients can expect to achieve clinically meaningful reduction in MMD and improved quality of life (i.e. improved patient functioning, wellbeing, and activities of daily living) with rimegepant.[181]

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Figure 4: Rimegepant in the clinical pathway of care for the preventive treatment of episodic migraine

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References: NICE CG150; NICE TA260; NICE TA659; NICE TA682; NICE TA764[4,5,107,142,143]

B.1.4. Equality considerations

Frequent and severe migraine is classified as a disability under the 2010 Equality Act.[182] The addition of rimegepant to the treatment pathways for acute treatment and also prevention of migraine may help to address inequalities of care and reduce disability thus improving equality in migraine management. Frequent and severe migraine is classified as a disability under the 2010 Equality Act.[182]

Given that migraine is about three times more common among women than men, [92] insufficiently managed migraine can have a greater impact on women, particularly in the workplace. In addressing this gendered health impact disparity, it is important to recognise that there is no significant difference in the likelihood of women or men consulting or accessing the health system for headache and migraine. In fact, compounding the greater incidence of migraine in women is that women’s pain reports are taken less seriously and they are less likely to be offered treatment than men’s.[183] A systematic review of the evidence on gender and consultation for headache and migraine,[184] including UK data, reported that the evidence for greater consultation amongst women was weak and inconsistent, while a separate UK study found that women were no more likely than men to consult a general practitioner in the previous year and, in addition, women were no more likely than men to consult at a given level of severity for a given condition type.[185] Examples of the evidence for gender disparity in pain treatment include a prospective cohort study of Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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adults with acute pain showing that women were 13% to 25% less likely than men to receive pain treatment and that women waited longer to receive their pain treatment. Further, a study reporting two experiments published in 2021 showed gender bias in the estimation of pain, specifically that perceivers underestimated female patients’ pain is compared with male patients and that perceivers prescribed psychotherapy for female and more pain medicine for male patients.[183]

Migraine can have a major impact on absenteeism, presenteeism, and work productivity, which can lead to loss of employment or reduced opportunity for occupational advancement.[186,187] Moreover, migraine is likely to have a greater impact on hourly workers, who may have fewer opportunities to make up work hours missed due to migraine episodes, relative to salaried professional workers.[186] This issue also has a greater impact on women than men: women comprise the majority of the nearly one million UK workers on a zero-hour contract as of September 2021, with 3.6% of female and 2.5% of male workers on such contracts (564,000 women and 433,000 men).[188]

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B.2. Clinical effectiveness

Please note that given the appraisal of rimegepant in the acute migraine and episodic migraine prevention populations, this section provides the clinical evidence for the acute and prevention populations as follows:

B.2.1. Identification and selection of relevant studies

B.2.1.1. Treatment of acute migraine with rimegepant

A systematic literature review (SLR) was conducted to identify relevant randomised controlled trials (RCTs) in the acute treatment of migraine. The SLR, including search strategy, study selection, and details of selected studies, is described in detail in Appendix D: acute (Section D.1.1.A). A total of 25 publications reporting four unique studies were included in the review (Table 5 [refer also to Appendix D: acute, Section D.1.2.A]).

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Table 5. Identified clinical effectiveness evidence: acute treatment of migraine with rimegepant

Abbreviations: NA, not applicable Notes: *Conference abstracts or clinical trials record

B.2.1.2. Preventive treatment of migraine with rimegepant

A SLR was conducted to identify relevant RCTs in the preventive treatment of migraine. The

SLR, including search strategy, study selection, and details of selected studies, is described Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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in detail in Appendix D: prevention (Section D.6.1.P). A total of 442 publications reporting 22 unique studies evaluating interventions for the prevention of migraine were included in the review (refer to Appendix D: prevention [Section D.7.P] for results). Of the total included studies, a total of five publications reporting one study were identified that evaluated rimegepant for the prevention of migraine (Table 6).

Table 6. Identified clinical effectiveness evidence: prevention of migraine with rimegepant

Notes:

*Conference abstracts or clinical trials record

B.2.2. List of relevant clinical effectiveness evidence

B.2.2.1. Treatment of acute migraine with rimegepant

The clinical development program that supported rimegepant for the acute treatment of migraine comprised three Phase 3, multicentre, single-dose, placebo-controlled studies of similar design (BHV3000-301,[138] BHV3000-302,[211] BHV3000-303[139,212] ) plus an open-label long-term safety study (BHV3000-201)[140,222] (Figure 5).

The Phase 3 trials assessed the efficacy and safety of rimegepant 75 mg in the acute treatment of migraine in adults with at least a one-year history of migraine with or without aura (based on International Classification of Headache Disorders 3[rd] edition [ICHD-III] beta version diagnostic criteria), a history of two to eight migraine attacks of moderate or severe intensity per month, and fewer than 15 monthly headache days (migraine or non-migraine) over the previous three months.[138-140,211,212,222] The Phase 3, BHV3000-303 study assessed the safety and efficacy of the rimegepant oral dispersible tablet (ODT) formulation, while the two Phase 3, BHV3000-301 and BHV3000-302 studies assessed the safety and efficacy of the rimegepant 75 mg oral tablet formulation.[138-140,211,212] The ODT formulation is

bioequivalent to the oral tablet formulation.[223] This ODT formulation can be advantageous for Company evidence submission template for rimegepant for treating or preventing migraine [ID1539]

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patients who want quick relief and/or have nausea or vomiting and do not want to drink liquids or would otherwise prefer to avoid swallowing a tablet.[224-226] A pooled analysis from the Phase 3 studies provides sufficient patient numbers to assess the efficacy of rimegepant 75 mg in triptan failure patients (Section B.2.7),[190] which is the population most relevant for the proposed positioning of rimegepant for the acute treatment of migraine (Section B.1.1 and Section B.1.3.3).

The long-term, open-label, safety study, BHV3000-201, assessed the safety and tolerability of the rimegepant 75 mg oral tablet and demonstrated that rimegepant is well-tolerated for long-term use (up to 52 weeks).[140,222,227] As this study was a single arm study, it did not meet eligibility criteria for the SLR but did support the marketing authorisation application.

Other completed clinical trials of rimegepant in the treatment of acute migraine not reported in this submission include:

• CN170-003 (NCT01430442): Phase 2 study that evaluated the efficacy and safety of six different doses of rimegepant, placebo, or sumatriptan in the treatment of acute migraine.[189] The study was not included in this submission as it was a small dosefinding study in which 75 patients received rimegepant 75 mg tablets,[189] with evidence from the study superseded by the Phase 3 studies of rimegepant in the acute treatment of migraine. In this study, which was not powered to compare rimegepant to sumatriptan, sumatriptan had significantly higher response rates than placebo on primary and secondary outcomes.[189] However, the placebo response rate was relatively high; for example, over half of patients on placebo reported pain relief at two hours postdose.[189] Response rates on many endpoints were numerically similar for sumatriptan and rimegepant 75 mg, including sustained pain freedom (two to 24 hours post-dose), sustained pain freedom (2-48 hours post-dose), sustained pain relief (two to 24 hours post-dose).[189 ]

• BHV3000-310 (NCT04574362): Phase 3, double-blind, randomised, placebo controlled trial of rimegepant 75 mg for the acute treatment of migraine.[191,228] This study was conducted in 86 sites in China and Korea and completed in January 2022. Collectively, the results from Study BHV3000-310 demonstrated a favourable benefit-risk profile for rimegepant 75 mg ODT in the acute treatment of moderate or severe migraine in Asian patients. Significant efficacy of rimegepant compared to placebo was demonstrated for the co-primary endpoints of freedom from pain and freedom from MBS at two hours post-dose, as well as for all key secondary endpoints. Significant evidence of both early onsets of benefit and durability of response were seen across an array of key secondary

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endpoints. Rimegepant 75 mg ODT was safe and well tolerated in adult participants with moderate to severe migraine. The study was identified in the searches on clinical trial registries but has recently completed. It was not included in the main submission as it did not support the marketing authorisation application and was conducted in an Asian population with limited generalisability to the UK clinical practice. Results are summarised in Appendix L.[228 ]

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Figure 5: Summary of rimegepant clinical trial programme for the treatment of migraine included in the submission

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o
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Abbreviations: EOD, every other day; MBS, most bothersome symptom; MMD, monthly migraine day; ODT, orally dispersible tablet; PRN, as needed; Notes:

aTriptan treatment failure was defined as a self-reported history of triptan discontinuation due to either inadequate efficacy, intolerability or both of any class of triptan medication References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222] Study BHV3000-305: Croop 2021;[216] Data on File: Clinical Study Report BHV3000-305 (Final Week 12), 2020;[214] Data on File: Clinical Study Report BHV3000-305 (Addendum), 2020;[215]

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Table 7: Pivotal clinical effectiveness evidence for rimegepant ODT and oral tablet in the acute treatment of migraine

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Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CGRP, calcitonin gene-related peptide; EOD, every other day HRQoL, health-related quality of life, ICHD-III, International Classification of Headache Disorders-3rd edition; mAb, monoclonal antibody; MBS, most bothersome symptom; MIDAS, Migraine Disability Assessment Test; MSQoL, Migraine-Specific Quality of Life Questionnaire; ODT, orally dispersible tablet; PoM, preference of medication; PRN, pro re nata (as needed); SAE, serious adverse event; ULN, upper limit of normal

Notes:

aSupportive analyses: Durability (pain freedom, pain relief, MBS, functional disability, nausea, photophobia, and phonophobia) at 2-24, 3-24, 4-24 hours and 2-48, 3-48, and 4-48 hours; Time to rescue medication; Time to first report of absence of various symptoms (MBS, nausea, photophobia, phonophobia, and return to normal functioning; Endpoints at 3 hours post-dose (freedom from pain, freedom from MBS, freedom from photophobia, freedom from phonophobia, freedom from nausea, pain relief, functional disability scale); and, exploratory efficacy endpoints: Freedom from functional disability at 24 hours post-dose, mITT participants; Pain relief at 15 minutes post-dose, mITT participants; Pain relief at 30 minutes post-dose, mITT participants; pain relief at every timepoint post-dose, mITT participants;

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222]

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B.2.2.2. Preventive treatment of migraine with rimegepant

The clinical evidence for the preventive treatment of migraine is taken from Study BHV3000305, a pivotal, Phase 2/3, randomised, double-blind, placebo-controlled study that evaluated the efficacy of rimegepant 75 mg tablet administered EOD for up to 12-weeks (Figure 5).[214,216] Table 8 summarises the study design of the BHV3000-305 trial. Data were also available from a long-term open-label Phase 2/3 safety study (Study BHV3000-201).[140,222,230]

Table 8: Pivotal clinical effectiveness evidence for rimegepant in the preventive treatment of migraine

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• Mean change from baseline in MSQoL role function at Week 12 • Mean change from baseline in MIDAS total score at Week 12 All other reported None additional outcomes

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CGRP, calcitonin gene-related peptide; EOD, every other day; HRQoL, health-related quality of life; mAb, monoclonal antibody; MMD, monthly migraine days, MIDAS, Migraine Disability Assessment; MSQoL, Migraine-Specific Quality of Life Questionnaire; SAE, serious adverse event

References: Croop 2021;[216] Data on File: clinical study report BHV3000-305 (Final Week 12), 2020;[214] Data on File: clinical study report BHV3000-305 (Addendum), 2020;[215]

Acute treatment of migraine

The following sections report the relevant clinical evidence for the treatment of acute migraine (heading prefixed with A:)

B.2.3. A: Summary of methodology of the relevant clinical effectiveness evidence in the acute treatment of migraine

B.2.3.1. A: BHV3000-303, BHV3000-301 and BHV3000-302 (acute): study design and methodology

A summary of study design and methodology used and outcomes assessed in the studies (Study BHV3000-303, Study BHV3000-301, and Study BHV3000-302 and BHV3000-201), are provided in Table 7, Table 9 and Table 10, respectively. Additional information is available in Appendix M and the clinical study reports (CSRs).

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Table 9: Summary of study design and methodology for eligible clinical studies evaluating rimegepant in acute treatment of migraine

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Abbreviations: CV, cardiovascular; EOD, every other day; EOT, end of treatment; SoC, standard of care; US, United States; vs, versus References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222]

Table 10: Summary of outcomes for eligible clinical studies evaluating rimegepant in acute treatment of migraine

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Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; CYP3A4, Cytochrome P450 3A4; EOT, end of treatment; MBS, most bothersome symptom; ODT, orally dispersible tablet; SAE, serious adverse event; SoC, standard of care; ULN, upper limit of normal Notes

✓ Outcomes reported

aSafety and tolerability were assessed as the primary endpoint with additional liver-specific safety events assessed as secondary endpoints.

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222]

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B.2.4. A: Statistical analysis and definition of study groups in the relevant clinical effectiveness evidence in the acute treatment of migraine

A summary of trial populations and statistical analysis across the four eligible clinical studies of rimegepant for the acute treatment of migraine is provided in Table 11. The hypothesis and statistical analyses conducted for the BHV3000-301 and BHV3000-302 studies were similar to the BHV3000-303 study, although there were slight differences in the categorisation of patients as treatment failures

Table 11: BHV3000-303, BHV3000-301, BHV3000-302 and BHV3000-201 (acute): Trial populations and statistical analyses

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Abbreviations: AE, adverse event; CI, confidence interval; CRO, contract research organisation; EOT, end of treatment; ICF, informed consent form; ID, identification; IWRS, interactive web response system; MBS, most bothersome symptom; MedDRA, Medical Dictionary for Regulatory Activities; mITT, modified intent-to-treat; NA, not applicable; PT, preferred term; SAEs, serious adverse events; SoC, system organ class; SOP, standard operating procedures

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222]

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B.2.5. A: Quality assessment of the relevant clinical effectiveness evidence for treatment in the acute treatment of migraine

A summary of quality assessments across the three eligible randomised clinical studies of rimegepant for the acute treatment of migraine is provided in Table 12. Modified criteria from the CRD handbook (Box 1.5) for assessment of risk of bias in the included RCTs were used to assess study quality.[231] A summary of quality assessment of the open-label safety study for the treatment of migraine is provided in Table 12. Full quality assessments of each study can be found in Appendix D: acute (Section D.5.A).

Table 12: Overview of quality assessment of eligible randomised controlled trials that evaluated rimegepant for the acute treatment of migraine

Abbreviations: CRO, contract research organisation; IWRS, interactive web response system; MBS, most burdensome symptom; mITT, modified intent-to-treat; NA, not applicable

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] Study BHV3000-302: Lipton 2019;[211]

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B.2.6. A: Clinical effectiveness results for the relevant trials for treatment in the acute treatment of migraine

The following sections present results for the trial populations for Studies BHV3000-303, BHV3000-301, and BHV3000-302. Results supporting rimegepant’s anticipated positioning are provided in Section B.2.7.1.1.

B.2.6.1. A: Participant disposition (acute)

B.2.6.1.1. A: BHV3000-303, BHV3000-301, and BHV3000-302 (acute)

Participant disposition for each of the 3 randomised control trials is provided in Appendix D: acute (Section D.4.A).

B.2.6.1.2. A: BHV3000-201 (acute)

Participant disposition is provided in Appendix D: acute (Section D.4.A).

B.2.6.2. A: Baseline characteristics (acute)

B.2.6.2.1. A: BHV3000-303 (acute)

A total of 1,466 patients were randomised in Study BHV3000-303, with 1,375 patients experiencing a qualifying migraine event within the study period and 1,351 patients evaluable for efficacy (669 on rimegepant and 682 on placebo).[212]

Rimegepant ODT and placebo groups were well matched on demographic variables and appeared well-balanced between treatment arms in terms of age, sex, ethnicity, weight, height, or body mass index (BMI) (Table 13).[212]

Participants had a mean age of 40·2 years (SD 12·0), and most were female (85%) and white (75%).[212] Participants had a mean weight of 84·8 kg (SD 23·2) and a mean bodymass index of 30·9 kg/m² (SD 8·1).[212] The primary migraine type was migraine without aura in 70% of participants and migraine with aura in 30% of participants.[212] The mean history of moderate to severe attacks per month was 4·6 (SD 1·8), and untreated attacks lasted a mean of 29·5 hours (SD 21·6).[212] Historically, the most bothersome symptom was photophobia for 770 (57%) participants, nausea for 317 (23%), and phonophobia for 261 (19%).[212] For the treated attack, the most bothersome symptom was photophobia for 733 (54%) participants, phonophobia for 209 (15%), and nausea for 384 (28%).[212]

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B.2.6.2.2. A: BHV3000-301 (acute)

A total of 1,162 patients were randomised in the BHV3000-301 study; 1,095 patients received a dose of study drug, and therefore comprised the safety population, and 1,084 patients comprised the modified intent-to-treat (mITT) population for efficacy analyses.[138] The demographic and disease characteristics were well-balanced between the treatment groups.[138]

B.2.6.2.3. A: BHV3000-302 (acute)

A total of 1,186 patients were randomised in the BHV3000-302 study; 1,086 patients received a dose of study drug, and therefore comprised the safety population, and 1,072 patients comprised the mITT population for efficacy analyses.[211] The demographic and disease characteristics between the treatment groups were similar, (Table 13).[211]

B.2.6.2.4. A: BHV3000-201 (acute)

A total of 1,800 patients received ≥1 dose of the rimegepant 75 mg tablet in the BHV3000201 study; 1,693 comprised the follow-up population, and 1,197 completed study treatment.[140] Most participants (89.4%) were female; median age was 43 years and 3.7% were ≥65 years.[222]

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Table 13: Baseline demographics and disease characteristics across eligible clinical studies of rimegepant for the acute treatment of migraine

Abbreviations: ITT, intention-to-treat; MBS, most bothersome symptom; mITT, modified intent-to-treat; NR, not reported; SD, standard deviation Notes:

aRestricted to moderate and severe attacks; bRace categorised in Study BHV3000-302 as Black

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301[138] ClinicalTrial.gov NCT03235479;[232] Study BHV3000-302: Lipton 2019;[211] Study BHV3000-201: Data on File Clinical Study Report BHV3000-201;[140] Croop 2020b[222]

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B.2.6.3. A: Efficacy outcomes in the acute treatment of migraine

• B.2.6.3.1. A: Co-primary endpoint: Freedom from pain at two hours postdose and freedom from MBS at two hours post-dose (acute)

A: BHV3000-303 (acute)

Rimegepant 75 mg demonstrated rapid onset of pain relief and return to normal function along with sustained effects with a single dose in the acute treatment of migraine in the BHV3000-303 study.[212] Rimegepant achieved statistical significance on both co-primary endpoints of freedom from pain and freedom from MBS at two hours post-dose (Table 14).[212]

• For freedom from pain at two hours post-dose, the therapeutic gain (risk difference) for rimegepant was 10.4%; 142 (21.2%) patients in the rimegepant group achieved freedom from pain versus 74 (10.9%) in the placebo group (p<0.0001).[212 ]

• For freedom from MBS at two hours post-dose, the therapeutic gain for rimegepant was 8.3%; 235 (35.1%) patients in the rimegepant group achieved freedom from MBS versus 183 (26.8%) in the placebo group (p=0.0009).[212 ]

A: BHV3000-301 (acute)

In a modified intention-to-treat (mITT) analysis, significant efficacy was demonstrated on both of the coprimary endpoints of freedom from pain and freedom from MBS at two hours post-dose (Table 14):

• For freedom from pain at two hours post-dose, the therapeutic gain (risk difference) for rimegepant was 4.91% (104 [19.2%] rimegepant participants vs 77 [14.2%] placebo participants; p=0.0298).[138,232 ]

• For freedom from MBS at two hours post-dose, the therapeutic gain for rimegepant was 8.90% (199 [36.6%] rimegepant participants vs 150 [27.7%] placebo participants; p=0.0016).[138,232 ]

A: BHV3000-302 (acute)

In a modified intention-to-treat (mITT) analysis, significant efficacy was demonstrated on both of the coprimary endpoints of freedom from pain and freedom from MBS at two hours post-dose (Table 14).

• For freedom from pain at two hours post-dose, the therapeutic gain (risk difference) for rimegepant was 7.6% (95% CI, 3.3 to 11.9; p<0.001: 105 [19.6%] rimegepant

participants vs 64 [12.0%] placebo participants.[211 ]

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• For freedom from MBS at two hours post-dose, the therapeutic gain (risk difference) for rimegepant was 12.4% (95% CI, 6.9 to 17.9; p<0.001: 202 [37.6%] rimegepant participants vs 135 [25.2%] placebo participants.[211]

B.2.6.3.2. A: Secondary endpoints (acute)

A: BHV3000-303 (acute)

Rimegepant was superior to placebo on 19 of 21 secondary endpoints, including pain relief and ability to function normally at 60 minutes post-dose, freedom from pain and freedom from most bothersome symptom at 90 minutes post-dose, rescue medication use within 24 hours, and sustained freedom from pain and pain relief from two hours to 24 hours and two hours to 48 hours post-dose; the only exceptions were freedom from nausea and pain relapse (Table 14).[212] Because of the non-significant result on two-hours freedom from nausea and the pre-planned hierarchical gate-keeping procedure for the analysis of efficacy, statistical inferences cannot be drawn for this endpoint and the subsequent endpoint of pain relapse from two hours to 48 hours post-dose.

Participants treated with rimegepant were more likely to have relief of migraine headache pain during the observation period than participants treated with placebo.[212] The percentage of participants reporting pain relief post-dose was significantly better for rimegepant than for placebo at minutes 60 (p<0·05), 90 (p<0·001) and 120 (p<0·001).[212]

A: BHV3000-301 (acute)

Secondary efficacy endpoints were tested hierarchically. Significant results were achieved on freedom from photophobia, freedom from phonophobia, and pain relief at two hours postdose. The secondary endpoint of freedom from nausea at two hours post-dose was not significant and therefore it, and all endpoints listed afterwards in the hierarchy, were not considered significant (Table 14).[138,232] All 11 secondary endpoints had numerical differences in favour of rimegepant.[138,232]

A: BHV3000-302 (acute)

Secondary efficacy endpoints were tested hierarchically. Significant results were achieved on freedom from photophobia, freedom from phonophobia, and pain relief at two hours postdose.[211] The secondary endpoint of freedom from nausea at two hours post-dose was not significant and therefore it, and all endpoints listed afterwards in the hierarchy, were not considered significant (Table 14). All 11 secondary endpoints had numerical differences in favour of rimegepant.[211]

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B.2.6.3.3. Exploratory objectives: outcomes research (acute)

A: BHV3000-303 (acute)

Patient preference of medication at 24 hours post-dose (mITT participants) indicated *****% (**********) of rimegepant-treated participants preferred rimegepant over their previous medication, compared with % (******) of placebo-treated participants (Table 15).[212]

Median Migraine Quality of Life Questionnaire (MQoLQ) score indicated more favourable results for rimegepant than for placebo (Table 15).[212]

A: BHV3000-301 (acute)

Patient preference of medication at 24 hours post-dose (mITT participants) indicated *****% (**********) of rimegepant-treated participants preferred rimegepant over their previous medication, compared with % (****) of placebo-treated participants (Table 15).[138,232]

Median MQoLQ score indicated more favourable results for rimegepant than for placebo (Table 15).[138,232]

A: BHV3000-302 (acute)

Patient preference of medication at 24 hours post-dose (mITT participants) indicated *****% (**********) of participants who provided a response, preferred rimegepant compared with *****% (**********) in the placebo-treated participants (Table 15).[211]

Median MQoLQ score indicated more favourable results for rimegepant than for placebo (Table 15).[211]

.

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Table 14. Primary and secondary endpoint results for mITT participants in acute treatment studies BHV3000-303, BHV3000-301 and BHV3000-302

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Abbreviations: CI, confidence interval; MBS, most bothersome symptom; mITT, modified intent-to-treat; NR = not reported; NS = not significant Percentages are Cochran-Mantel-Haenszel estimates

aSecondary endpoints are listed in the hierarchical testing order for Study BHV3000-303

bData reported as no use of rescue mediation ≤24 hours post-dose in BHV3000-303 and as use of rescue medication ≤24 hours post-dose in BHV3000-301 and BHV3000-302. cData reported as no pain relapse from 2 to 48 hours post-dose in BHV3000-303 and as pain relapse from 2 to 48 hours post-dose in BHV3000-301 and BHV3000-302. References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301;[138] ClinicalTrial.gov NCT03235479;[232] Study BHV3000-302: Lipton 2019a[211]

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Table 15. Outcomes research endpoints for mITT participants in acute treatment studies BHV3000-303, BHV3000-301 and BHV3000-302

Abbreviations: CI, confidence interval; MBS, most bothersome symptom; mITT, modified intent-to-treat; MQoLQ, Migraine Quality of Life Questionnaire; NR = not reported; NS = not significant; PoM = preference of medicine

Notes:

aMigraine preference of medicine (PoM) scale: The PoM is a subject-rated, 5-point scale that measures preference of the study medication compared to the previous medications to treat migraine pain. The eDiary was used to evaluate the PoM

References: Study BHV3000-303: Croop 2019;[212] Study BHV3000-301: Data on File Clinical Study Report BHV3000-301;[138] ClinicalTrial.gov NCT03235479;[232] Study BHV3000-302: Lipton 2019a[211]

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B.2.6.3.4. A: Study BHV3000-201 (acute)

The primary objective of the BHV3000-201 study was to evaluate the long-term safety of the rimegepant 75 mg tablet formulation, with efficacy outcomes restricted to exploratory analyses.[140,222,230]

Study BHV3000-201 was a Phase 2/3, open-label long-term safety trial of rimegepant 75 mg oral tablet for the acute treatment of migraine. The study was conducted between August 30, 2017 and July 15, 2019. The total sample size of 1,800 treated in the long-term treatment (LTT) period: 1,033 (57.4%) participants in the PRN (2 to 8 moderate to severe migraine attacks per month) group, 481 (26.7%) participants in the PRN (9 to 14 moderate to severe migraine attacks per month) group, and 286 (15.9%) participants in the scheduled EOD + PRN group.[140,222,230]

The exploratory efficacy objectives of this study were to assess the effects of repeated dosing of rimegepant on migraine-related disability, MSQ, MMD, absenteeism, presenteeism, and lost time due to migraine (LTM).[222,230,233-242]

A: Reduction in MMD Frequency of Repeated Acute Treatment

A post-hoc analysis of Study BHV3000-201 evaluated the reduction in MMD observed with rimegepant PRN for the acute treatment of migraine and assessed if any benefits observed might support a hypothesis that intermittent CGRP-receptor blockade could result in reductions in MMD over time.[237] The analysis was conducted in the 1,044 participants with six or more MMD at baseline.[237] Median time to a ≥30% reduction was 12-weeks (95% CI 4 to 40 weeks) and median time to ≥50% reduction was 32 weeks (IQR 12 to NR weeks).[237] Changes were non-linear with greater reductions in the first weeks of treatment, followed by a stable rate over the remainder of the follow up period, and the change pattern was consistent across the three MMD cluster groups.[237] By Week 52, a ≥30% reduction in baseline MMD was observed in 78.6% of patients and a ≥50% reduction in baseline MMD was observed in 63.3% of patients.[237] These findings highlight that a large percentage of patients presenting with migraine frequencies of six or more per month may achieve clinically significant reductions in MMD with treatment over a reasonable period of time.[237]

A: Absenteeism, Presenteeism and Lost Productivity

Table 16 shows baseline mean (standard error) absenteeism, presenteeism, and lost productivity time and mean (95% CI) changes from baseline at Weeks 12, 24, 36, 52. Improvements vs. baseline were clinically relevant and statistically significant at all timepoints (p<0.0001).[187]

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Table 16: BHV-3000-201 - Absenteeism, Presenteeism, and Lost Productivity Time Over 52 Weeks

Abbreviations: CI, confidence interval; SE, standard error Notes: aAbsenteeism, presenteeism and lost productivity time were assessed at baseline and Weeks 12, 24, 36, and 52 using the validated Migraine Disability Assessment Instrument. Absenteeism and presenteeism were assessed from Items 1 and 2 and lost productivity time was derived from the formula, lost productivity time = absenteeism + presenteeism x 0.5 References: L’Italien 2020[187]

A: Patient Preference and Satisfaction, Clinical Global Impression of Change

An analysis of Study BHV-3000-201 investigated patient preference and satisfaction with medication, as well as clinical global impression of change (CGI-C), an observer-rated scale administered by the investigator, in 1,514 patients treated with rimegepant 75 mg PRN.[242] At Week 24 and Week 52, it was found that 78.7% and 79.8% of rimegepant patients, respectively, preferred rimegepant over their previous migraine medications, and the majority (89.4% at Week 24 and 90.5% at Week 52) reported being satisfied with rimegepant (defined as completely satisfied, very satisfied, or somewhat satisfied).[242] The investigatoradministered CGI-C scale demonstrated that 88.8% and 90.9% of patients treated with rimegepant were considered improved at Weeks 24 and 52, respectively, compared with study entry.[242]

A: Use of Analgesics and Antiemetics:

Another post-hoc analysis of Study BHV3000-201 explored the relationship between rimegepant for the acute treatment of migraine attacks and the use of over-the-counter (OTC) or prescription analgesics and antiemetics during the 30-day observation period and over time in the rimegepant long-term treatment period.[235] Of the 1,800 participants treated (PRN [n=1514], EOD+PRN [n=286]), 89.4% were female, and mean age was 43 years. The most commonly used analgesics were ibuprofen, fixed combination

acetaminophen/aspirin/caffeine, acetaminophen, and naproxen (select analgesics). The most commonly used antiemetics were ondansetron, promethazine, dimenhydrinate, meclizine, and prochlorperazine (select antiemetics).[235] During the first 12-weeks of

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rimegepant treatment, an increase in patients reporting freedom from using select analgesics and antiemetics was observed (19.9% during the observation period, 44.6% from Weeks 1 to 4, 58.3% at Weeks 5 to 8, and 61.6% from Weeks 9 to 12).[235] During Weeks 9 to 12, 56.5% of patients who had been using analgesics and antiemetics in the observation period reported a 100% reduction in use, and through Weeks 49 to 52, this proportion had increased to 61.3%.[235] These results were observed both in patients taking rimegepant PRN and those who received rimegepant on an EOD + PRN basis.[235] With long-term rimegepant treatment, the majority of patients were able to avoid using common analgesic and antiemetic medications.[235]

B.2.7. A: Subgroup analysis in the acute treatment of migraine B.2.7.1. A: BHV3000-303, BHV3000-301, and BHV3000-302 (acute)

A summary of results for co-primary efficacy outcomes by the following pre-specified subgroups in the final scope: headaches per month (<4 vs. ≥4) and cardiovascular risk contraindicating triptans (yes/no) are provided in Appendix E: acute.

A summary of results for efficacy outcomes by the following pre-specified subgroups: age (<40 vs. ≥40 years); race (White vs. Black or African American vs. other); sex (male/female); aura (yes/no); triptan non-responder (yes/no); and cardiovascular risk contraindicating triptans (yes/no) are also provided in Appendix E: acute.

Subgroup analysis in patients for whom ≥2 prior treatments with triptan have failed (acute) is provided in Section B.2.7.1.1.

B.2.7.1.1. A: Patients for whom ≥2 prior treatments with triptan have failed (acute)

A summary of the clinical effectiveness results for the primary and secondary endpoints for the subgroup of patients relevant for the decision problem, i.e. patients for whom >2 prior treatment with triptan have failed are presented in this section.

Data across the three Phase 3 trials (Study BHV3000-303, Study BHV3000-301, Study BHV3000-302) were pooled to facilitate a post-hoc analysis by triptan treatment history). The definition used for treatment failure of triptans in the post-hoc pooled analysis differed to the definition used for the individual Phase 3 studies (see Table 18for a summary of the differences). Of note, whilst both definitions used self-reported data from trial participants, the inclusion of treatment failure for reasons of intolerability as well as efficacy, and removing the requirement to have failed on all routes of administration in the post-hoc

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pooled analysis increased the clinical relevance compared with the pre-specified analyses in the individual Phase 3 studies, and provides the rationale for the use of the post-hoc pooled analysis as the basis for the efficacy outcome in the economic model.

Table 17. A summary of the differences between the definitions of failure of prior treatment with ≥2 triptans in the pre-specified analyses from individual Phase 3 studies (Study BHV3000-303, Study BHV3000-301, Study BHV3000-302) and the post-hoc pooled analysis

Of the 3,507 participants in the three trials (rimegepant n=1,749, placebo n=1,758), 2,272 (64.8%) had no history of triptan treatment failure, and 1,235 (35.2%) had a history of treatment failure with 1 or ≥2 triptans (Table 18).[190] The differences in definitions of prior triptan failure between the analyses of the single trials and the post-hoc pooled analysis mean that sample size of the pooled analysis (rimegepant n= 148; placebo n= 177) was larger than the sum of the sample sizes from the three individual Phase 3 studies (rimegepant n=78; placebo n=104).

Baseline characteristics are provided in Table 19.

Table 18: Historical use of discontinued triptans mITT participants in Study BHV3000301, Study BHV3000-302, and Study BHV3000-303

Abbreviations: mITT, modified intention to treat References: Data on File: Pooled analysis of BHV3000-301, BHV3000-302 and BHV3000-303 (final version), 2021;[190,197,198]

Treatment response to rimegepant was superior to placebo across the subgroups for the coprimary endpoints (Table 20), with pairwise comparisons demonstrating no difference in response between the subgroups (Table 21).[190,197] Data by prior triptan treatment failure are Company evidence submission template for rimegepant for treating relapsed or preventing migraine [ID1539]

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also summarised (no historical use of discontinued triptans [“no historical use of triptan failure”, where no discontinued triptan could include patients who had either never taken a triptan or had taken a first triptan but had not failed treatment], historical use of one discontinued triptan [“failed one triptan”], and historical use of two discontinued triptans [“failed ≥2 triptans”]).[190,197] These data generally show that rimegepant provides benefit to patients versus placebo across a variety of endpoints even if they have previous treatment failure on triptans (Table 20).[190,197] Overall, these data suggest that response to rimegepant is independent of response to previous triptans, and would therefore provide an efficacious treatment for patients with limited treatment options.[190,197] In addition, the proportion of patients treated with rimegepant responding with pain freedom at two hours post-dose was remarkably consistent (around 20%) across the subgroups (“no historical use of discontinued triptans”, “failed one triptan”, and “failed ≥2 triptans”).[190,197]

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Table 19: Baseline characteristics for mITT participants in acute treatment from studies BHV3000-303, BHV3000-301 and BHV3000-302 stratified by historical discontinuation of triptans

Abbreviations: CI, confidence interval; hrs, hours; MBS, most bothersome symptom; mITT, modified intent-to-treat Notes:

aModerate or severe; bNo discontinued triptan could include patients who had either never taken a triptan or had taken a first triptan but had not failed treatment References: Data on File: Pooled analysis of BHV3000-301, BHV3000-302 and BHV3000-303 (final version), 2021;[190,197,198]

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Table 20: Primary and secondary endpoint results for mITT participants in acute treatment from studies BHV3000-303, BHV3000-301 and BHV3000-302 stratified by historical discontinuation of triptans[a]

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