CGRP, MABs and Small Molecules David W. Dodick, M.D. Professor Department of Neurology Mayo Clinic Phoenix Arizona
Disclosure Consulting: Allergan, Amgen, Alder, eneura, Colucid, Trigemina, Eli Lilly & Company, ATI, Teva, Tonix, GBS, Dr Reddy s Laboratories, Xenon, NAS, Insys. All therapeutic drugs and biologics discussed are under investigation. None are approved for use.
From the beginning, CGRP was hypothesized to play a role in migraine Edvinsson, TINS 1985
Calcitonin Gene-related Peptide (CGRP) Neuropeptide belonging to calcitonin family (calcitonin, amylin, adrenomedulin, intermedin) In humans two forms α-cgrp (37-amino acid peptide) formed from the alternative splicing of the calcitonin/cgrp gene located on chromosome 11 β-cgrp main isoform of enteric NS (differs in 3 amino acids)
Calcitonin Gene-Related Peptide in the Trigeminovascular System Main sensory neuropeptide released by activated trigeminal neurons Physiological actions: vasodilation, mast cell degranulation, sensory transmission
CGRP within the trigeminovascular system Walker CS and Hay DL. Brit J Pharmcol 2013;170 :1293 1307
Central Distribution of CGRP Receptors thalamus AbbreviaEons: NDB, non-displaceable binding; CPu: caudate-putamen; GP, globus pallidus; LV, lateral ventricle; SN, substanea nigra; Pn, PonEne nu. rhesus brain autoradiography Baseline Receptor Visualization Studies using [ 11 C]MK-4232 Courtesy of Richard Hargreaves
Calcitonin Gene-Related Peptide in Migraine The Evidence Released during migraine attacks Persistent elevation in chronic migraine CGRP infusion triggers migraine Headache relief after sumatriptan coincides with normalization of CGRP levels CGRP blockade at key sites (TNC, PAG, thalamus) effective in preclinical models of cephalic pain Goadsby PJ, et al Ann Neurol 1988 Feb;23(2):193-6. Lassen LH, et al. Cephalalgia 2002 Feb;22(1):54-61 Juhasz G, et al. Cephalalgia 2005 Mar;25(3):179-83. Durham, P. NEJM 2004; 350(11): 1073-1075
Calcitonin Gene-Related Peptide in Migraine The Evidence Small molecule receptor antagonists neutral on vasculature Cerebral Artery CGRP potent blockade of CGGPinduced vasodilatation CGRP Receptor modulate sensory signalling within trigeminal pathways Peripheral Antagonist CGRP Receptor Antagonist Central
CGRP receptor antagonists are effective in the treatment of acute migraine (% patients pain-free at 2H) 40 30 20 10 0 44 35 35 33 31 27 27 Z E S placebo Gepant Triptan 24 23 15 10 9 10 7 2 42 32 348 333 354 70 73 69 203 85 100 133 59 113 102 Olesen et al., Ho et al., Diener et al., Marcus et al., Hewitt et al., Allergan, NEJM Lancet Cephalalgia Cephalalgia Cephalalgia Cephalalgia 2002;346:257 2008;372:2115 2011;31:573 2014;34:114 2011;31:712 2016;36:887 Olcegepant Telcagepant BI-44370 Rimegepant MK-3207 Ubrogepant Z = zolmitriptan E = electriptan S = sumatriptan
Telcagepant: Liver toxicity; possibly effective for migraine prevention Liver toxicity Ho, TW et al. Neurology 2014;83:958 966
Small Molecule vs. Monoclonal Antibodies Small Molecules Target specificity lower Clearance (Liver, kidney) Size < 1kD Oral Many enter cells and cross BBB Half-life minutes to hours Immunogenicity (No) Monoclonal Antibodies Target specificity high Clearance RES Size ~150kD Parenteral Do not enter cells or cross BBB Half-life 1-4 weeks Immunogenicity (yes) Minimal BBB transport
Phase 2 trials with CGRP Mabs: All studies met their primary endpoint Type of anbody CGRP CGRP CGRP CGRP RECEPTOR Galcanezumab Administraon SC SC IV SC 80% bioequivalent Erenumab SC Half-life 28 days 45 days 28 days ~3 weeks Episodic Study Type Single Dose POC (EM) 150 mg q 2 weeks 2 Dose POC (HFEM) 225 /675 mg q monthly Single dose POC (EM) 1000 mg quarterly 3 Dose POC (EM) 7/21/70 mg q monthly 4 Dose Phase 2 (EM) 5, 50, 120, 300 mg q monthly Chronic Study Type - 2 Dose POC 675/225 or 900 mg 4 dose POC 10-30-100-300 mg 2 dose phase 2 70-140 mg
50% Responder Rates for MABs Active vs placebo % of patients 90 80 70 60 50 40 30 20 10 0 LY 150 q2w LY 120 AMG TEV 225 TEV 675 ALD Active Placebo Gain ALD = ALD403 AMG = AMG 334 LY = LY2951742 TEV = TEV48125 Dodick et al., Lancet Neurol 2014; 13:885-892 Oakes et al., Headache; Volume 56, Issue Supplement S1 Page 68 Sun et al., Lancet Neurol 2016; 15:382-390 Bigal etal., Lancet Neurol 2015; 14:1081-1090 Dodick et al., Lancet Neurol 2014; 13:1100-1107
75% Responder Rates for MABs Active vs placebo % of patients 70 60 50 40 30 20 10 0 LY 150 q2w LY 120 TEV 225 TEV 675 ALD Active Placebo Gain ALD = ALD403 AMG = AMG334 LY = LY2951742 TEV = TEV48125, 225 or 675 mg Jackson JL, et al. PLOS ONE DOI:10.1371/journal.pone.0130733 Dodick et al., Lancet Neurol 2014; 13:885-892 Oakes et al., Headache; Volume 56, Issue Supplement S1 Bigal etal., Lancet Neurol 2015; 14:1081-1090 Dodick et al., Lancet Neurol 2014; 13:1100-1107
Rapid Onset of Efficacy (Episodic Migraine) Mean change in weekly migraine headache days from baseline (MHD) Figure 1. Baseline = normalized monthly headache days at baseline / 4. Weeks are defined around protocol injection schedules at weeks 0, 2, 4, 6, 8, and 10. Time intervals between adjacent injections are divided into 2 equal intervals (weeks) by identifying the mid-point. Skipped (missing) injection dates were imputed based on available adjacent injection dates. Weeks 11 and 12 were determined trt = treatment; blue circles = LY2951742; red crosses = placebo by extending from week 10 injection date by 7 and 14 days, respectively. p 0.05 Goadsby et al., Headache 2015 55;s3:187
Rapid Onset of Efficacy (Chronic Migraine) Effect of TEV-48125 (CM study) on headache hours at early time points Comparing baseline, post-hoc covariance analysis p < 0.05, p < 0.01, p < 0.001. Bigal et al., Neurology 2016; 87(1):41-48
Interictal Burden in Episodic Migraine 317 days per year Lampl et al. J Head and Pain (2016)
Episodic migraine: Increase in wellness on headache free days in active compared to placebo (TEV-48125) Worked/studied normally Performed household chores normally Normal speed of work or task completion To time with difficulty concentrating No time feeling very fatigued, sleepy or drained Very engaged with partner s or children s activities Very interested in doing daily activities TEV-48125 225mg (n=88) TEV-48125 675 mg (n=86) + + ++ ++ ++ + + + ++ + ++ + ++ ++ + p<0.05; ++ p<0001 Vanderpluym et al. Presented AAN 2016
Chronic migraine: Increase in wellness on headache free days in active compared to placebo (TEV-48125) Worked/studied normally Performed household chores normally Normal speed of work or task completion To time with difficulty concentrating No time feeling very fatigued, sleepy or drained Very engaged with partner s or children s activities Very interested in doing daily activities TEV-48125 225mg (n=88) TEV-48125 675 mg (n=86) - + - + + + - + + + - + - + + p<0.05; ++ p<0001 Vanderpluym et al. Presented AAN 2016
Side Effects of mabs in Phase 2 EM studies LY Dodick et al., Lancet Neurol 2014; 13:885-892 AMG Receptor Sun et al., Lancet Neurol 2016; 15:382-390 TEV Bigal et al., Lancet Neurology. 2015; 14:1081-90 ALD Dodick et al., Lancet Neurol 2014; 13:1100-1107 Placebo Active Placebo Active Placebo Active Placebo Active N 110 107 153 319 104 192 82 81 Depression - - - - 0 3 2 0 Dizziness 3 5 - - 0 3 1 4 Fatigue - - 2 3,5 1 2,5 4 4 Nausea 9 4 1 2 4 1 2 4 Paresthesia - - - - 3 1 - - Hypertension 0 5 - - 1 2 - - Weight gain - - - - - - Weight loss 0 2 Cognitive, somnolence - - - - - - - - Other Rash 0 URTI 9 5 17 - - Tremor 0 2 QT prolong 0 Dry mouth 0 4 4 Injection pain/ erythema 6 22 3 5 10 16 IV not SC
Adverse event-related drop-outs much lower with mabs compared to oral migraine prophylactics Propranolol Diener et al., Cephalalgia 2004 Valproate Freitag et al., Neurology. 2002;58(11):1652-9 Topiramate 100 mg Brandes et al., JAMA 2004;291(8):965-73 Topiramate 50-100-200 mg Silberstein et al., Arch Neur 2004;61(4):490-5 N 575 237 483 487 Drop out for AE, placebo Drop out for AE active 10% 8,7% 12% 10% 20% 8,2% 27% 23% LY 2951742 Dodick et al., Lancet Neurol 2014; 13:885-892 AMG334 Sun et al., Lancet Neurol 2016; 15:382-390 ALD403 Dodick et al., Lancet Neurol 2014; 13:1100-1107 TEV-48125 Bigal et al., Lancet Neurology. 2015; 14:1081-90 N 218 483 174 297 Drop out for AE, placebo Drop out for AE, active 0,9% (1/110) 1,3% (2/153) 0 0 0 1,9% (6/319) 0 3,1% (6/192) No drug-related serious adverse events reported thus far Jackson JL, et al. PLOS ONE 2015 DOI:10.1371/journal.pone.0130733
TEV-48125 blocks trigger-induced allodynia in MOH model BLS Periorbital BLS Hindpaw 8 15 Periorbital Withdrawal Threshold (g) 7 6 5 4 Sal + Veh Sal + TEV Suma + Veh Suma + TEV Hindpaw Withdrawal Threshold (g) 12 9 6 3 Sal + Veh Sal + TEV Suma + Veh Suma + TEV BL 1 2 3 4 5 Time (h) after stress BL 1 2 3 4 5 Time (h) after stress AOC of Periorbital Threshold 8 6 4 2 0 Sal+Veh Sal+TEV Suma+Veh Suma+TEV p<0.05 compared to D21 BL 15 AOC of Hindpawal Threshold 12 9 6 3 0 Sal+Veh Sal+TEV Suma+Veh Suma+TEV Porreca F.
CGRP Antibody Pivotal Trial Overview Migraine Cluster # of Trials 2 EM 1 CM Primary Endpoint Study Period Primary Endpoint Frequency and Administration # of Doses Being Studied EM- 6 months CM- 3 months EM/ CM- Mean change from baseline in the number of monthly migraine headache days 2 EM 1 CM (Ph2 Pivotal) EM- 6 or 3 months CM- 3 months EM- Change from baseline in mean monthly migraine days CM- Change in monthly migraine days from baseline vs month 3 1 EM 1 CM EM- 3 months CM- 3 months EM- Mean change from baseline in the monthly average number of migraine days CM-Mean change from baseline in the monthly average number of headache days Monthly SC Monthly SC Monthly SC or 3 injections quarterly SC EM- 2 doses CM- 2 doses EM- 2 doses CM- 2 doses Start Date EM/CM- Dec, 2015 EM- July, 2015 CM - Feb, 2014 Does not include stand-alone long term safety studies or long term extensions Source: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-2016AUG25 EM- 1 dose CM- 1 dose EM-Jan 2016 CM- Dec, 2015 1 EM 1 E CH 1 C CH EM- 3 months CM- 3 months EM- Response rate at month 3 Quarterly IV EM- 3 doses EM- Sept 2015 EM- Episodic Migraine CM- Chronic Migraine C CH- Chronic Cluster Headache E CH- Episodic Cluster Headache SC- Subcutaneous E CH- 3 weeks C CH- 4 weeks C CH-Mean Change from Baseline in Weekly CH Attack Frequency E CH- Mean Change from Baseline in Number of Weekly CH Attacks Monthly SC C and E CH- 1 dose E and C CH- May/ June, 2015
CGRP-knockout mice develop hypertension and renal damage (independent of BP) Important for maintaining CBF via autoregulation in chronic hypertension Neuroprotective effect in focal cerebral ischemia and vasospasm after SAH. Cardioprotective effect: decreased CGRP levels found in CAD lowers BP and protects against CHF after cardiac ischemia CGRP levels reduced in pregnant women with hypertension TIPS 2016;37:779-787
CGRP & Cardiovascular Regulation CGRP stores, bioactivity/transport and sensory nerve fibers decline with age CGRP important for ischemic preconditioning CGRP levels progressively rise during exercise in hyper and normotensive subjects CGRP levels reduced/unchanged in patients with hypertension and reduced in pulmonary hypertension Russell et al., Physiol Rev 2014;94:1099
Women with migraine at increased risk of all-cause CV morbidity and mortality Women at increased risk for microvascular coronary artery vasospasm CGRP most potently dilates distal coronary microvasculature TIPS 2016;37:779-787 Kurth et al. BMJ 2016;353:i2610 MassenVanDenBrink A, et all. TIPS 2016;37:779-787
Binding CGRP versus CGRP Receptor (Safety upsides/efficacy Downsides) Binding receptor: CGRP may exert effect through other receptors Binding peptide: Other peptides may interact through CGRP and other receptors MaassenVanDenBrink et al., Trends in Pharmacol Sci 2016; 37(9):779-788
Summary: CGRP, MABs, and Small Molecules CGRP and its receptor are validated targets for acute and preventive migraine treatment Small molecule (receptor antagonsists) development continues despite early hepatic toxicity MABs in pivotal registration trials for episodic and chronic migraine and cluster headache Medication overuse headache and posttraumatic headache are headache types worth evaluating Long-term safety data in those at cardiovascular risk will require long-term use 2013 MFMER slide-30