1/25/2018 ARE CGRP ANTAGONISTS ANY BETTER THAN CURRENT EVIDENCE BASED TREATMENTS? Disclosures: Objectives: Headache Division

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1 ARE CGRP ANTAGONISTS ANY BETTER THAN CURRENT EVIDENCE BASED TREATMENTS? Lawrence C Newman, MD, FAHS, FAAN Clinical Professor of Neurology Disclosures: Advisory Board: Alder, Allergan, Amgen, Lilly, Supernus, Teva Honoraria: Alder, Allergan, Amgen, Lilly, Supernus, Teva Royalties: Oxford University Press 2 Objectives: Review classification of migraine preventive therapies in US Review data on commonly prescribed anti-migraine agents (Level A, B and C evidence) Review available data on the 4 injectable CGRP monoclonal antibodies 3 1

2 Desired Attributes of a Migraine Preventive Medication Effective Despite prior failure to adequately respond In setting of medication overuse Work quickly Infrequent dosing Tolerable Safe Disease modifying Available Affordable 4 Current Dogma Therapeutic trial may take 2-6 months before maximal response is evident Success is defined as: >50% reduction in attack frequency or headache days, a significant decrease in attack duration, or headache days, or A significant decrease in attack duration, or An improved response to acute medication 5 Classification of Migraine Preventive Therapies in US Modified from Silberstein et al. Neurology 2012;78: Level A: Established Efficacy (>2 class I trials) Level B: Probably Effective (1 class I or 2 class II studies) Level C: Possibly Effective (1 class II study) Divalproex sodium* Amitriptyline Lisinopril Sodium valproate Venlafaxine Candesartan Topiramate* Metoprolol Atenolol Nadolol Propranolol* Timolol* OnobotulinumtoxinA* (Chronic migraine only) * FDA approved 6 2

3 Comparisons Are Difficult if Not Impossible Few good head-to-head trials Outcome measures not consistent Reduction in mean monthly migraine days (MMD) is relatively new standard Older studies employed reduction rates ITT population not included in older studies 7 Propranolol Meta-Analysis 53 studies, 2403 patients Modal dose was 160 mg vs. placebo 44% reduction in migraine activity via daily recordings 65% reduction of migraine activity when clinical ratings of improvement and global patient reports employed AE drop out rate 5.3% Holroyd KA et al. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 1991;31: Topiramate Silberstein SD et al. Arch Neurol 2004;61: ITT population mg, 100 mg, 200 mg vs, Pbo Decrease in mean monthly migraine frequency over 6 months (primary endpoint) > 50% reduction in monthly migraine frequency (secondary endpoint) 54% 100 mg 52% 200 mg 36% 50 mg 23% Pbo 9 3

4 From: Topiramate in Migraine PreventionResults of a Large Controlled Trial Arch Neurol. 2004;61(4): doi: /archneur Figure Legend: Mean (least squares value) change from baseline in monthly migraine frequency. Missing data were computed based on the frequency of migraines observed before discontinuation. The asterisk indicates P <.001 vs placebo. Date of download: 12/17/2017 Copyright 2004 American Medical Association. All rights reserved. From: Topiramate in Migraine PreventionResults of a Large Controlled Trial Arch Neurol. 2004;61(4): doi: /archneur Figure Legend: Mean (least squares value) change from baseline in monthly migraine frequency. The asterisk indicates P <.02 vs placebo; and the dagger, P =.03 for topiramate, 50 mg/d, vs placebo. Date of download: 12/17/2017 Copyright 2004 American Medical Association. All rights reserved. Topiramate Silberstein S. Adv Stud Med 2002;2: DB,PC parallel group study 25 mg titrated weekly to 200 mg 8 week titration, 12 week maintenance 213 patients ITT Responder rate Topiramate Placebo P Value 50% 40% 34%.26 75% 20% 8% % 7% 3% 12 4

5 1/25/2018 Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double Blind, Placebo Controlled Trial Silberstein SD et al. Headache 2007;47: Topiramate May Be Effective in Setting of Medication Overuse Diener HC et al. Cephalalgia 2009;29: Post hoc analysis of 2 multicentered studies (US and EU) ITT population in USA 306 ITT population in EU 59 Statistical sig only in EU subgroup 14 Migraine Prevention With Approved Pharmacologic Preventive Treatments vs. Placebo in Adults Modified from Shamliyan TA et al. J Gen Int Med 2013;28: ACTIVE DRUG SAMPLE % WITH OUTCOME WITH ACTIVE DRUG (PLACEBO) RELATIVE RISK (95% CI) DIVALPROEX > 50% REDUCTION IN MIGRAINE FREQUENCY (23.3) 2.2 (1.1 to 4.2) TOPIRAMATE > 50% REDUCTION IN MIGRAINE FREQUENCY (25.1) 2.0 (1.5 to 2.7) (23.3) 1.7 (1.0 to 2.9) (11.0) 1.9 (1.1 to 3.1) TOPIRAMATE > 50% REDUCTION IN MIGRAINE DAYS TOPIRAMATE >75% REDUCTION IN MIGRAINE DAYS 15 5

6 Migraine Prevention With Approved Pharmacologic Preventive Treatments vs. Placebo in Adults EM Modified from Shamliyan TA et al. J Gen Int Med 2013;28: ACTIVE DRUG SAMPLE % WITH OUTCOME WITH ACTIVE DRUG (PLACEBO) RELATIVE RISK (95% CI) PROPRANOLOL > 50% REDUCTION IN MIGRAINE FREQUENCY (22.3) 2.0 (1.5 to 2.7) TIMOLOL > 50% REDUCTION IN MIGRAINE FREQUENCY (23.3) 2.1 (1.5 to 3.1) 16 Migraine Prevention With Off-Label Pharmacologic Preventive Treatments vs. Placebo in Adults EM Modified from Shamliyan TA et al. J Gen Int Med 2013;28: ACTIVE DRUG > 50% REDUCTION IN MIGRAINE FREQUENCY SAMPLE % WITH OUTCOME WITH ACTIVE DRUG (PLACEBO) RELATIVE RISK (95% CI) LISINOPRIL RCT 23.3 (0) 29.0 (1.8 to 475.4) CANDESARTAN RCT 38.3 (3.3) 11.5 ( ) GABAPENTIN (31.0) 1.5 (1.1 to 2.0) METOPROLOL (19.4) 2.0 (1.3 to 3.2) 17 Treatment Discontinuation Due to AEs Modified from Shamliyan TA et al. J Gen Int Med 2013;28: ACTIVE DRUG SAMPLE RATE (PLACEBO) RELATIVE RISK (95% CI) DIVALPROEX (7.8) 1.2 (0.5 to 2.7) TOPIRAMATE (8.5) 1.8 (1.3 to 2.2) PROPRANOLOL (5.6) 2.1 (0.6 to 7.7) AMITRIPTYLINE (5.8) 1.9 (1.0 to 3.5) GABAPENTIN (7.7) 1.9 (0.9 to 4.2) 18 6

7 OnobotulinumtoxinA Dodick D et al. Headache 2010;50: Dodick D, et al. J Headache and Pain 2013; 14 (supp 1) Pooled analysis of 1384 patients 1 Primary endpoint: mean change baseline in frequency of headache days at 24 weeks Differences seen beginning at week vs -6.6 (p<.001) 50% responder rate: reduction from baseline in frequency of headache days 47% vs. 35% (p<.001) Treatment related AEs 29% vs. 13% Injection site rx 3.2% vs. 2.0% 75% responder rate at week % vs. 16% (p<.002) 19 OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double Blind, Randomized, Placebo Controlled Phases of the PREEMPT Clinical Program Headache: The Journal of Head and Face Pain Volume 50, Issue 6, pages , 7 MAY 2010 DOI: /j x Four injectable monoclonal antibodies to CGRP or its receptor in development: Erenumab (fully human) Galcanezumab (humanized) Fremanezumab (fully humanized) Eptinezumab (humanized) Studied for EM, CM EM, CM, ech, cch EM, CM, ech, cch EM, CM Dosing Monthly SC Monthly SC Target Regulatory status November 2017 CGRP receptor CGRP peptide or ligand Submitted to US FDA for migraine prevention; Submitted to FDA CM and EM registration study fully published Monthly or Quarterly SC; IV load for CH CGRP peptide or ligand Submitted to FDA. CM study published Q3 month IV CGRP peptide or ligand Presented (+) Phase 3 EM; Continuing Phase 3 CM Slide courtesy of Stewart Tepper, MD 7

8 Phase 3 EM Prevention, Erenumab & Galcanezumab: 1 Endpoint: Monthly migraine day reduction at 6 months vs. placebo Erenumab Galcanezumab Change in monthly migraine days Improvement LS Mean Change from Baseline (SE) days days days Goadsby et al. NEJM 2017;377: Stauffer et al. Presented at AHS meeting, June Slide courtesy of Stewart Tepper MD Pivotal Registration CM Prevention Trials, Erenumab & Galcanezumab: 1 Endpoint: Monthly migraine day reduction at 3 months vs. placebo Erenumab Galcanezumab Improvement LS Mean Change from Baseline (SE) days days days Tepper et al. Lancet Neurol 2017;16: Slide Courtesy of Stewart Tepper MG Detke et al. Presented at AHS meeting, June Pivotal CM Erenumab Trial Adverse Events Placebo (n = 282) Erenumab 70 mg (n = 190) Erenumab 140 mg (n = 188) Number of subjects reporting AEs, n (%) 110 (39) 83 (44) 88 (47) Number of subjects with AEs leading to IP discontinuation, n (%) Most frequent AEs a 2 (<1) 0 (0) 2 (1) Injection site pain 3 (1) 7 (4) 7 (4) Upper respiratory tract infection 4 (1) 5 (3) 6 (3) Nausea 7 (2) 4 (2) 6 (3) Nasopharyngitis 16 (6) 6 (3) 3 (2) Constipation 1 (<1) 0 (0) 8 (4) Muscle spasms 4 (1) 1 (<1) 7 (4) Migraine 3 (1) 3 (2) 5 (3) No neutralizing anti-erenumab antibodies in any dose group Frequency of SAEs was low and comparable across groups (placebo 2%, 70 mg 3%, 140 mg 1%) 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. Tepper et al. Lancet Neurol 2017;16: Slide Courtesy of Stewart Tepper MD 8

9 Galcanezumab Phase 3 EVOLVE-2 EM Prevention Adverse Events Placebo GMB 120 mg GMB 240 mg Category N=461 N=226 N=228 n (%) n (%) n (%) Treatment-emergent AEs 287 (62.26) 147 (65.04) 163 (71.49)* Serious AEs 5 (1.08) 5 (2.21) 7 (3.07) Deaths 0 (0.00) 0 (0.00) 0 (0.00) Discontinuation due to AEs 8 (1.74) 5 (2.21) 9 (3.95) 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. Abbreviations: AE=adverse event; GMB=galcanezumab; N=patients in safety population; n=patients within each specific category. *p<.05 (vs. placebo) Skljarevski et al. Presented at AHS meeting. June 2017 Slide Courtesy of Stewart Tepper MD. Galcanezumab Phase 3 EVOLVE-2 EM Prevention Adverse Events Category Placebo N=461 n (%) GMB 120 mg N=226 n (%) GMB 240 mg N=228 n (%) Treatment-emergent AEs 287 (62.26) 147 (65.04) 163 (71.49)* Serious AEs 5 (1.08) 5 (2.21) 7 (3.07) Deaths 0 (0.00) 0 (0.00) 0 (0.00) Discontinuation due to AEs 8 (1.74) 5 (2.21) 9 (3.95) 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. Abbreviations: AE=adverse event; GMB=galcanezumab; N=patients in safety population; n=patients within each specific category. *p<.05 (vs. placebo) Skljarevski et al. Presented at AHS meeting. June Slide Courtesy of Stewart Tepper MD Eptinezumab Phase 2 CM Prevention Percent of Patients % 57% 55%* 56%* 44% Primary Endpoint 33%* 31%* 28% 27% 21% 50% Response Rate 75% Response Rate 100% Response Rate Current Standard Eptinezumab Target Response 3% Placebo (n=116) ALD403 (eptinezumab) 300mg (n=114) ALD403 (eptinezumab) 100mg (n=118) 8% 5% 4% 8% *P<0.05; P<0.005 vs placebo (one-sided, not corrected for multiplicity) Smith et al. Headache. 2017;57 (S3): 130. Presented at AHS meeting, June 2017 Slide Courtesy of Stewart Tepper MD 9

10 Eptinezumab Phase 3 EM Prevention: Reduction in mean monthly migraine days Monthly migraine days significantly reduced from baseline over weeks 1 12 Cady et al. accessed 7/2/17. Cady et al. Presented IHC Sept 2017 Slide Courtesy of Stewart Tepper MD. Fremanezumab Phase 3 EM Prevention: Primary endpoint, reduction of mean monthly migraine days P for both vs Placebo<0.001 Placebo (-2.2 days) Quarterly (-3.4 days) Monthly (-3.7 days) Silberstein SD et al. NEJM 2017;377: Slide Courtesy Stewart Tepper.. Fremanezumab Phase 3 CM Prevention: primary endpoint, headache days of at least moderate severity (monthly migraine days) P for both vs Placebo<0.001 P for both vs Placebo<0.001 (-2.5 days) Placebo (-2.5 days) Quarterly (-4.3 days) Quarterly (-4.3 days) Monthly Monthly (-4.6 days) (-4.6 days) 30 Silberstein Aycardiet al. NEJM al. 2017;377: Presented at AHS June Slide 2017 Courtesy and IHC Stewart Sept Tepper. 10

11 HALO Fremanezumab Phase 3 CM Prevention: Adverse Events Silberstein et al. NEJM 2017;377: Slide Courtesy of Stewart Tepper MD Eptinezumab Phase 3 EM Prevention Adverse Events Cady et al. Presented IHC Sept 2017 Slide Courtesy of Stewart Tepper MD So, Are CGRP MAbS Better Than Current Options? Efficacy: 50% Responder Rates Current meds ~ 45% Galcanezumab (EM) 50% Rr is 50%; 75% %% is 33% Erenumab (EM) 43% for 70 mg; 50% for 140 mg Fremenezumab (CM) 38% quarterly dosing; 41% monthly dosing All CM studies show efficacy with and w/o medication overuse Prior failures Erenumab was more efficacious in patients failing > 2 preventives vs none (OR 4.18 vs. 1.33) 1 1. Ashina et al. IHC

12 So, Are CGRP MAbS Better Than Current Options? Time to onset of effect: Current meds: 1-3 months MAbs : 1day-4 weeks Tolerability: Current meds: Variable but > placebo. Adherence in CM ranges from 26-29% at 6 months, 17-20% at 1 year. 1 MAbs: AEs similar to placebo Safety: Current meds: Must account for cardiac, renal, hepatic, respiratory comorbidities MAbs-none noted to date. Still early will need more clinical exposure No data on dosing in children, pregnancy, elderly 34 So, Are CGRP MAbS Better Than Current Options? Dosing: Current meds: QD-TID to every12 weeks MAbs: monthly to quarterly Availability: Current Meds: varies depending on plan MAbs: Too soon to tell, but would anticipate restrictions Affordability: Current meds: Wide variability MAbs: Too soon to tell 35 Take Home Messages MAbs represent the first new class of medication specifically developed for migraine prevention in > 50 years CGRP is a novel target Preliminary data is promising, but still this is not a cure nor a disease modifying therapy Long term safety data and use in special populations remain big unknowns Cost considerations, and restrictions by payers will undoubtedly have a major impact on their availability to physicians and patients 36 12

13 But Don t Just Focus On Responder Rates These agents ARE a much needed improvement in that they offer hope for the millions of our refractory patients, patients with contraindications to current therapies They appear to work for both EM and CM Quick time to efficacy will eliminate the current trial and error approach Monthly to quarterly dosing will improve adherence Excellent tolerability profile 37 CGRP MAbs Are Better Than Current Therapies 38 THANK YOU 13