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Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
Clinical Challenges in Migraine:The Role of Emerging Therapiesin New Treatment Paradigms
Supported by an educational grant from Teva Pharmaceuticals
Merle L. Diamond, MDDirector Diamond Headache ClinicChicago, Illinois
Migraine Treatment Prevention
Faculty Disclosure
Dr. Merle Diamond has received honoraria related to speakers’ bureau activities from Allergan, Inc., Avanir Pharmaceuticals, Inc., Depomed, Inc., PERNIX Therapeutics, and Teva Pharmaceutical Industries Ltd.
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
Key Facts in Preventive Treatment53% of migraineurs meet disability and
frequency criteria for prevention 53% of migraineurs meet disability and
frequency criteria for prevention
< 5% of migraineurs are on preventive therapy
< 5% of migraineurs are on preventive therapy
• Dissatisfied with current treatment, and• Largely refractory or intolerant • Dissatisfied with current treatment, and• Largely refractory or intolerant
Patients are:
Main Goalsof Migraine
Preventive Therapy
Restore function Restore function
Prevent progression to chronic migrainePrevent progression to chronic migraine
↓ Headache frequency, severity and intensity ↓ Headache frequency, severity and intensity
Lipton RB et al. Headache. 2001; Lipton RB et al. Neurology. 2002
Addressing the Unmet Need in Preventive Treatment
80%
40%
13%
More than 40% of patients receiving therapy still experience at least one migraine‐related issue, including headache‐related disability, treatment dissatisfaction, and/or excessive opioid use.2
Up to 13% of patients with migraine receiving acute and/or preventive therapy still have at least 1 emergency department visit a year.3
1Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine‐preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478‐488; 2Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache.2013;53(8):1300‐1311; 3Bonafede M, Cappell K, Kim G, Sapra S, Shah N, Desai P. Healthcare utilization and annual direct costs in patients with migraine in a commercial claims database. J Manag Care Spec Pharm. 2015;21(10‐a):S48‐S49.
Approximately 80% of patients discontinue oral preventive therapy after 1 year of treatment.1
EpisodicMigraine
Chronic DailyHeadache
Time
Migraine Transformation
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
*Highlighted boxes in left column only indicate FDA approved medicationsa Classification based on original guideline and new evidence not found for this report; b For short‐term prophylaxis of menstrually related migraine
Level A: Medications with established efficacy (≥ Class I trials)
Level B: Medications are probably effective (1Class I or 2 Class II studies)
Level C: Medications are possibly effective (1 Class II study)
Level U: Inadequate or conflicting data to support or refute medication use
Other: Medications that are established as possibly or probably ineffective
• There are barriers to consultation which in turn prevent accurate diagnosis and therapy
• Current migraine preventives− Are not that effective
− Have to be given at least daily
− Have many AEs
− Result in low adherence and persistence rates
• The 50% responder rates are 50% or less• We are in need of effective preventive therapies, given less frequently with fewer adverse events
Stewart J. Tepper, MDProfessor of NeurologyGeisel School of Medicine at Dartmouth
From Bench to Practice: Expert Perspectives on Emerging Strategies and Novel Agents for Migraine Prevention
The Science of Migraine
Faculty Disclosure Dr. Stewart Tepper has received honoraria as a consultant from Acorda, Alder BioPharmaceuticals Inc., Allergan, Inc., Amgen Inc., ATI, AvanirPharmaceuticals, Inc., BioVision Inc., electroCore, LLC, Eli Lilly and Company, eNeura Inc., Kimberly‐Clark, PERNIX Therapeutics, Pfizer Inc., TEVA Pharmaceutical LTD, and Zosano Pharma Corporation; and honoraria related to formal advisory activities from Alder, Allergan, Amgen, ATI, Avanir, Dr. Reddy’s Laboratories Ltd., Kimberly‐Clark, Scion NeuroStim, TEVA, and Pfizer Inc. Dr. Tepper has also received royalties or licensing fees from Springer and the University of Mississippi Press. He has disclosed a financial relationship with the American Headache Society, Dartmouth‐Hitchcock Medical Center, and has stock optionswith ATI.
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
CGRP and Migraine Connection• CGRP immunoreactive nerves innervate human cerebral arteries
• CGRP is a potent vasodilator of human cerebral arteries
• CGRP is released into the jugular venous system during migraine
• CGRP infusion evokes migraine
• Serum CGRP levels are elevated in migraine
• CGRP receptor antagonist small molecule gepantseffectively terminate migraine attacks
• Anti‐CGRP and anti‐CGRP receptor monoclonal antibodies prevent Episodic Migraine (EM) and Chronic Migraine (CM)
Edvinsson TINS 1985, Neurosci Lett 1985, PNAS 1986, JCBFM 1987, Ann Neurol 1987.; Lassen et al. Cephalalgia. 2002;22:54–61.; Goadsby et al. Brain. 1994;117:427‐434.; Olesen et al. N Engl J Med. 2004;350:1104‐1110.; Ho TW et al. Neurology. 2008;70:1304‐1312.; Voss et al. Cephalalgia. 2016;36:887‐898.
Migraine without aura (60%)
CGRP Infusion Triggers Migraine
Lassen et al. Cephalalgia. 2002;22:54–61. Slide courtesy of Messoud Ashina MD, PhD, DMSc
The Small Molecule CGRP Receptor Antagonists: Gepants
Acute Treatment of Episodic Migraine• Olecepant IV worked and comparable to triptan proof of concept, fully published
• BI 44370 TA effective oral vs placebo in Phase 2, fully published
• Telcagepant showed promise and efficacy comparable to triptans, but development stopped due to liver toxicity, Phase 3 studies fully published
• Rimegepant (BMS‐927711) effective vs placebo in Phase 2 fully published; being readied for Phase 3
• Ubrogepant effective vs placebo in Phase 2 fully published; Phase 3 underway
Gepants have NEVER failed on EFFICACY
Preventive Treatment of Episodic Migraine• Telcagepant studied in two incomplete studies, with one terminated early due to hepatotoxicity and the other for evaluation of liver in MRM mini‐prevention
• Atogepant vs placebo underway in Phase 2 for migraine prevention
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
CGRP Receptor Antagonist Small Molecules: Gepants Effectively Abort Migraine Attacks
Olesen et al. NEJM 2004;350:1104‐1110.Slide courtesy of Messoud Ashina MD, PhD, DMSc
Voss A et al. Cephalalgia. 2016; 36:887-98.Slide courtesy of Messoud Ashina MD, PhD, DMSc
Ubrogepant Phase 2 Trial: 1° Endpoint 2h PF
The Development of Monoclonal Antibodies to CGRP or the CGRP receptor
• The monoclonal antibodies (MABs) are big molecules that do not cross the blood brain barrier
• MABs are eliminated by the reticuloendothelial system, so no risk for hepatotoxicity, as long as the gepant liver problem was metabolic degradation and not mechanism based
• Because they work, it means that peripheral, not central CGRP action is likely sufficient to trigger migraine or cluster headache
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
Bigal ME, et al. Brit J Clin Pharm. 2015;79:886‐895.
Small Molecules (gepants) vs Large Molecules (Monoclonal Antibodies, MABs)
Small Molecule~0.2–1 kDa
Small Molecule~0.2–1 kDa
IgG1 Monoclonal Antibody~150 kDa
IgG1 Monoclonal Antibody~150 kDa
Small Molecule~0.2–1 kDa
IgG1 Monoclonal Antibody~150 kDa
mAbs Have Minimal Access to CNS Due to Size and BBB• mAbs are largely confined to the vasculature, with variable distribution across different tissue types, depending mainly on the extent to which the mAb can cross the capillary endothelium
*Figure demonstrates distribution of a murine IgG1 mAb in wild‐type mice following intra‐peritoneal administration; results may not be not representative of all mAbs
Foltz IN, et al. Circulation. 2013;127:2222‐2230.; Silberstein S, et al. Headache. 2015;1171‐1182.; Tabrizi M, et al. AAPS J. 2010;12:33‐43.; Duan X, et al. Anal Chem. 2012; 4373‐4382.
0
2
4
6
8
10
Brain Heart Liver Spleen Kidney Lung
Adapted from Duan X, et al. Anal Chem. 2012;84:4373‐4382.
Plasm
a Concentration(%)
mAb Tissue Biodistribution*Percentage of Plasma Concentration
0.1%
3.1%
1.7%
3.3%4.5%
2.1%
ErenumabGalcanezumab FremanezumabEptinezumab
All Positive in Phase 2, and All That Have
Reported Are Positive in Phase 3
All 4 have demonstrated
clinical meaningful responder rates
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
• All 4 positive for prevention of Episodic Migraine (EM) and Chronic Migraine (CM) in Phase 2
• All 4 positive for prevention of EM in Phase 3• 3 of 4 have already reported or published positive findings for CM prevention in Phase 3
• All 4 have quick onset, separating from placebo in <1 week; Phase 2 fremanezumabstudy showed significance over placebo within 1 week even in the more refractory, more typical CM patients
• Almost all secondary endpoints are also positive, with reduction of acute medication days, high responder rates, and improved impact, disability, and or QOL measures
• Immunogenicity appears to be very low <3%. Less than 1% neutralizing antibodies; no impact on safety or efficacy at this point
Phase 1 Phase 2 Phase 3
≥ 50% Responder Rates From Reduction of Migraine Days, Episodic Migraine (EM), Phase 2
Dodick DW, et al. Lancet Neurol. 2014;13:885‐892.; Oakes TM, et al. AHS 58th Annual Scientific Meeting. 2016;56(S1):68.; Sun H, et al. Lancet Neurol. 2016;15:382‐390.; Bigal ME, et al. Lancet Neurol. 2015;14:1081‐1090.; Dodick DW, et al. Lancet Neurol. 2014;13:1100‐1107.
0
10
20
30
40
50
60
70
80
90
Galcanezumab150 q2w
Galcanezumab120
Erenumab Fremanezumab225
Fremanezumab675
Eptinezumab
Active
Placebo% of patients
≥ 75% Responder Rates for Prevention of EM, Phase 2
0
10
20
30
40
50
60
70
Galcanezumab150 q2w
Galcanezumab120
Fremanezumab225
Fremanezumab675
Eptimezumab
Active
Placebo
% of patients
Jackson JL, et al. PLoS One. 2015;10(7):e0130733.; Dodick DW, et al. Lancet Neurol. 2014;13:885‐892.; Oakes TM, et al. AHS 58th Annual Scientific Meeting. 2016;56(S1):68.; Bigal ME, et al. Lancet Neurol. 2015;14:1081‐1090.; Dodick DW, et al. Lancet Neurol. 2014;13:1100‐1107
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms
Safety Analysis Set. Abbreviations: AE, adverse event; IP, investigational product; SAE, serious adverse event. n = number of subjects with ≥ 1 occurrence of an AE. No SAE or AE leading to IP discontinuation was experienced by > 1 subject. a Includes AEs reported by ≥ 2% of all erenumab subjects.
• No neutralizing anti‐erenumab antibodies in any dose group
• Frequency of SAEs was low and comparable across groups (placebo 2.5%, 70 mg 3.2%, 140 mg 1.1%)
Placebo(n = 282)
Erenumab 70 mg(n = 190)
Erenumab 140 mg(n = 188)
Number of subjects reporting AEs, n (%) 110 (39.0) 83 (43.7) 88 (46.8)
Number of subjects with AEs leading to IP discontinuation, n (%)
Galcanezumab Phase 3 EVOLVE‐2 EM Prevention Adverse Events
• Most common treatment‐emergent AEs (≥2% of galcanezumab‐treated patients): injection site pain, nasopharyngitis, injection site reaction, upper respiratory tract infection, dizziness, influenza, injection site erythema, injection site pruritus, fatigue, and diarrhea.
Note: red text indicates a statistically significant higher rate of incidence compared with placebo
Anti‐CGRP and anti‐CGRP receptor monoclonal antibodies
prevent episodic migraine and chronic migraine CGRP receptor
antagonist small molecule gepantseffectively abort migraine attacks
The MABs appear safe, tolerable, and effective so far in Phase 2 and Phase 3
trials
CGRP
The Impact of a Changing Paradigm in Treatment
• Migraine affects almost 730 million people worldwide
− Those with the chronic form suffer 15 or more headache days per month
• The total economic burden of migraine in the US including direct medical costs and indirect costs such as lost work days is estimated at a minimum of $17 billion annually
• The new anti‐CGRP mAbs are the first drugs specifically designed to prevent a crippling headache before it begins
• Anti‐CGRP mAbs act more quickly than existing migraine preventive treatments; a separation between treatment and placebo groups occurs with all four in less than one week
Thank you!
Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms