Acute Treatment Benefit from Oral CGRP Receptor Antagonist and Monoclonal Antibody Combination: Poster No

Acute Treatment Benefit from Oral CGRP Receptor Antagonist and Monoclonal Antibody Combination: Poster No. P238LB Rimegepant 75 mg for Acute Treatment of Attacks During Preventive Therapy With Erenumab Kathleen Mullin, MD1; David Kudrow, MD2; Robert Croop MD3; Meghan Lovegren3; Vladimir Coric, MD3; Charles M. Conway, PhD3; Richard B. Lipton, MD4 1 New England Institute of Neurology and Headache, Stamford, CT; 2 California Medical Clinic for Headache, Santa Monica, CA; 3 Biohaven Pharmaceuticals, Inc., New Haven, CT; 4 Albert Einstein College of Medicine, Bronx, NY

Introduction Results Results cont. Results cont. • Calcitonin gene-related peptide (CGRP) is a confirmed therapeutic target in migraine Patient 1 Patient 2 • After the second 4-week period of rimegepant usage for acute treatment, she was • Small molecule CGRP receptor antagonists, also known as gepants, have started on a monthly dose of erenumab 140 mg for preventive treatment • Patient 1 is a 44 year-old White woman with a 24-year history of migraine without aura • The second patient is a 36 year-old White woman with a 19-year history of migraine demonstrated efficacy for acute and preventive treatment • Over the first 30 days of rimegepant-erenumab combination therapy, attack frequency • Prior to enrollment in the long-term safety trial of rimegepant, she reported an average without aura • Monoclonal antibodies (mAbs) to the CGRP receptor or ligand have shown efficacy for was reduced 18% to 9 MHDs of 8 monthly headache days (MHDs) with pain of moderate to severe intensity • She reported an average of 11 MHDs with pain of moderate to severe intensity preventive treatment • For these 37 attacks, no other acute migraine medications were used • Her standard of care medications are shown in Table 1 • Her treatment history involved, subcutaneous sumatriptan 6 mg, intranasal • Despite the demonstrated efficacy of mAbs, during treatment most people have • While using rimegepant alone or together with erenumab, the patient experienced no zolmitriptan, and oral tablets of rizatriptan, eletriptan, naratriptan, and almotriptan breakthrough attacks and require acute treatment Patient 1, Standard of Care Migraine Medications at Enrolment adverse events • Rimegepant 75 mg oral tablet and erenumab 70 mg and 140 mg subcutaneous Table 1. • These historical treatments were patient-rated as suboptimal for reasons that are injection have demonstrated efficacy in randomized, controlled clinical trials for acute Dose among the most common sources of dissatisfaction with acute treatment,3 specifically: Comment 1,2 Stated Use Agent and preventive treatment, respectively (mg per tablet) – Relief talking too long • The efficacy and safety of combined gepant-mAb use (ie, acute treatment with a Treatment effects not sustained for the duration of the attack • This is the first clinical report that small molecule and biologic anti-CGRP therapies Migraine only Sumatriptan 100 – can be used concomitantly to treat migraine gepant for breakthrough attacks in patients concurrently receiving a mAb for Inconsistent response from attack to attack – • The initiation of erenumab reduced MHDs from 18% to 49% in the first 4 weeks of preventive treatment) have not been previously evaluated • She also had a 6-year history of treatment with an implanted occipital nerve stimulator Acetaminophen + Acetylsalicylic acid + caffeinea 250 + 250 + 65 treatment • Her migraine treatments at enrollment are shown in Table 2 • The use of rimegepant alone or in combination with erenumab resulted in the acute Dysmenorrhea Objective Ibuprofenb 200 treatment of 111 consecutive migraine attacks with no other acute medication used Migraine Table 2. Patient 2, Standard of Care Migraine Medications at Enrolment • Describe the first clinical report that oral rimegepant, a small molecule CGRP receptor and enabled: aExcedrin®Migraine; per tablet dose is shown, adult dose is 2 tablets Agenta Dose antagonist, can be used for treatment of breakthrough migraine attacks in patients – Patient 1 to end a 22-year habit of caffeinated analgesic usage — a risk factor for bAdvil®; per tablet dose is shown, adult dose is 2 capsules Sumatriptan 100 mg concurrently taking a preventive, injectable CGRP-targeting mAb medication overuse and migraine chronification4,5 Intramuscular ketorolac tromethamine 30 mg – Patient 2 to eliminate near-daily use of 2 injectable medications — an IM • During a 30-day observation period of the clinical trial, she used sumatriptan 100 mg Intramuscular diphenhydramine 100 mg nonsteroidal anti-inflammatory drug and an IM anti-nauseant Methods to treat 10 migraine attacks of moderate to severe pain intensity Methadone 80 mg • She entered the treatment phase, received rimegepant 75 mg, and was instructed to Ondansetron 8 mg • Rimegepant 75 mg oral tablet appears to offer utility as an acute treatment for attacks • We report the cases of 2 participants in a 52-week, open-label, long-term safety study that occur during preventive treatment with CGRP-antagonist antibodies of rimegepant for the acute treatment of migraine (Study 201, NCT03266588) use it as needed, up to once daily, for the acute treatment of migraine Zonisamide 250 mg • Within 1 week, she discontinued ibuprofen for migraine Occipital nerve stimulation Continuous • Neither patient experienced an adverse event that was related to treatment during • She stopped the caffeine-containing analgesic 5 weeks after entering into treatment aOral formulation unless noted otherwise concomitant use of rimegepant and erenumab Figure 1. Study Design: Long-term Safety of Rimegepant with rimegepant 75 mg • The mechanism underlying additional benefit from an oral, acute treatment by a CGRP • After 6 months in the rimegepant study, during which she used 69 doses to treat 69 • Prior to enrollment, she stopped using methadone, a prohibited medication for the trial receptor antagonist in combination with the chronic presence of a mAb where both are attacks and averaged 9.8 MHDs (range 7-12), she was started on erenumab 70 mg • During a 30-day run-in to the rimegepant treatment period, the patient experienced 22 affecting the same molecular target is unclear, but it may involve: subcutaneous monthly as a preventive therapy (Figure 2) migraine attacks of moderate to severe intensity – Antagonism of receptors by rimegepant that are unavailable to the biologic • In the first 4 weeks of rimegepant-erenumab combination therapy: • She entered the treatment phase, received 30 tablets of rimegepant 75 mg, and was antagonist erenumab, which is ~280x larger (.53 kDa vs ~150 kDa) – Attack frequency declined 49% (from an average of 9.8 MHDs to 5 MHDs) instructed to take a single rimegepant 75 mg tablet as needed for acute treatment of – Erenumab being more susceptible to displacement than the small molecule – The patient used rimegepant 75 mg to treat 5 breakthrough migraine attacks migraine attacks of any pain intensity up to once per calendar day antagonists rimegepant, which was designed to overcome repeated waves of • In the first 4 weeks of treatment, she used 16 doses of rimegepant to treat 16 attacks CGRP release Figure 2. Patient 1, Rimegepant Alone and Combined With Erenumab • In the second 4-week treatment period, attack frequency declined (Figure 3), she used – Differential receptor kinetics of small molecules, with a stronger tendency to 11 doses of rimegepant to treat 11 attacks, and she stopped using: remain in the bound state than mAbs • Both patients described in this poster were participating in the PRN dosing group – Ondansetron 8 mg – Receptor internalization in the presence of small-molecule binding but not for 6,7 • The protocol of the long-term safety study did not allow the use of other investigational – Ketorolac 30 mg large antibody binding agents while taking rimegepant – Diphenhydramine 100 mg • Once approved by the FDA, CGRP-targeting monoclonal antibodies were allowed briefly before study enrollment closed Figure 3. Patient 2, Reduction in Attack Frequency With Rimegepant Conclusions • Both patients began subcutaneous erenumab monthly for preventive therapy and • Rimegepant 75 mg may be effective for acute treatment during concomitant used rimegepant 75 mg as-needed up to once daily for breakthrough migraine attacks erenumab administration • Rimegepant may: Subjects – Access and block receptors that remain available despite erenumab • Aged ≥18 years, with ≥1-year history of ICHD-3 beta migraine – Access sites incompletely blocked by antibodies • Two to 14 moderate or severe monthly migraine attacks • Other factors may include: • Preventive migraine medication dose stable for ≥3 months (if using) – Antibodies being more susceptible to displacement by CGRP than small • For these 74 attacks, no other acute migraine medications were used molecules Assessment and Analysis • While receiving rimegepant alone or concomitantly with erenumab, she experienced – Differential receptor kinetics no adverse events related to treatment • No statistical analyses were performed on these cases • Clinical trials are needed to follow-up these observations • Findings are based on patient self-report and investigator observation • At the end-of-study visit, she reported that she was very satisfied with rimegepant and rated it “much better” than previous treatments Rimegepant is an investigational new drug, not approved or authorized for marketing in the U.S. or any country for any indication or treatment of any disease or condition. This material is being made available through Biohaven’s Medical Affairs Department. 1. Marcus R et al. Cephalalgia. 2014;34:114-25; 2. Goadsby PJ et al. N Engl J Med. 2017;377:2123-32; 3. Lipton RB et al. Headache. 1999;39:S20-6; 4. Scher AI et al. Cephalalgia. 2010;30:321-28; 5. Scher AI et al. Neurology. 2004;63:2022-27; 6. Dubowchik GM et al. Comprehensive Medicinal Chemistry III. Oxford: Elsevier; 2017:176-224; 7. References: st Cottrell GS. Handb Exp Pharmacol. 2018. Disclosures This study was sponsored by Biohaven Pharmaceuticals. KM, DK and RBL have received honoraria and research support from Biohaven Pharmaceuticals; RBL is also a stockholder. RC, ML VC, and CMC are employed by and own stock/stock options in Biohaven Pharmaceuticals. American Headache Society 61 Annual Scientific Meeting | July 11-14, 2019 | Philadelphia, PA To download a copy of this poster, scan QR code.