CGRP, MABs and Small Molecules. David W. Dodick, M.D. Professor Department of Neurology Mayo Clinic Phoenix Arizona
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1 CGRP, MABs and Small Molecules David W. Dodick, M.D. Professor Department of Neurology Mayo Clinic Phoenix Arizona
2 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.
3 From the beginning, CGRP was hypothesized to play a role in migraine Edvinsson, TINS 1985
4 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)
5 Calcitonin Gene-Related Peptide in the Trigeminovascular System Main sensory neuropeptide released by activated trigeminal neurons Physiological actions: vasodilation, mast cell degranulation, sensory transmission
6 CGRP within the trigeminovascular system Walker CS and Hay DL. Brit J Pharmcol 2013;170 :
7 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
8 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): Lassen LH, et al. Cephalalgia 2002 Feb;22(1):54-61 Juhasz G, et al. Cephalalgia 2005 Mar;25(3): Durham, P. NEJM 2004; 350(11):
9 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
10 CGRP receptor antagonists are effective in the treatment of acute migraine (% patients pain-free at 2H) Z E S placebo Gepant Triptan Olesen et al., Ho et al., Diener et al., Marcus et al., Hewitt et al., Allergan, NEJM Lancet Cephalalgia Cephalalgia Cephalalgia Cephalalgia 2002;346: ;372: ;31: ;34: ;31: ;36:887 Olcegepant Telcagepant BI Rimegepant MK-3207 Ubrogepant Z = zolmitriptan E = electriptan S = sumatriptan
11 Telcagepant: Liver toxicity; possibly effective for migraine prevention Liver toxicity Ho, TW et al. Neurology 2014;83:
12 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
13 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 mg 2 dose phase mg
14 50% Responder Rates for MABs Active vs placebo % of patients LY 150 q2w LY 120 AMG TEV 225 TEV 675 ALD Active Placebo Gain ALD = ALD403 AMG = AMG 334 LY = LY TEV = TEV48125 Dodick et al., Lancet Neurol 2014; 13: Oakes et al., Headache; Volume 56, Issue Supplement S1 Page 68 Sun et al., Lancet Neurol 2016; 15: Bigal etal., Lancet Neurol 2015; 14: Dodick et al., Lancet Neurol 2014; 13:
15 75% Responder Rates for MABs Active vs placebo % of patients LY 150 q2w LY 120 TEV 225 TEV 675 ALD Active Placebo Gain ALD = ALD403 AMG = AMG334 LY = LY TEV = TEV48125, 225 or 675 mg Jackson JL, et al. PLOS ONE DOI: /journal.pone Dodick et al., Lancet Neurol 2014; 13: Oakes et al., Headache; Volume 56, Issue Supplement S1 Bigal etal., Lancet Neurol 2015; 14: Dodick et al., Lancet Neurol 2014; 13:
16 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 = LY ; red crosses = placebo by extending from week 10 injection date by 7 and 14 days, respectively. p 0.05 Goadsby et al., Headache ;s3:187
17 Rapid Onset of Efficacy (Chronic Migraine) Effect of TEV (CM study) on headache hours at early time points Comparing baseline, post-hoc covariance analysis p < 0.05, p < 0.01, p < Bigal et al., Neurology 2016; 87(1):41-48
18 Interictal Burden in Episodic Migraine 317 days per year Lampl et al. J Head and Pain (2016)
19 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 mg (n=88) TEV mg (n=86) p<0.05; ++ p<0001 Vanderpluym et al. Presented AAN 2016
20 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 mg (n=88) TEV mg (n=86) p<0.05; ++ p<0001 Vanderpluym et al. Presented AAN 2016
21 Side Effects of mabs in Phase 2 EM studies LY Dodick et al., Lancet Neurol 2014; 13: AMG Receptor Sun et al., Lancet Neurol 2016; 15: TEV Bigal et al., Lancet Neurology. 2015; 14: ALD Dodick et al., Lancet Neurol 2014; 13: Placebo Active Placebo Active Placebo Active Placebo Active N Depression Dizziness Fatigue ,5 1 2,5 4 4 Nausea Paresthesia Hypertension Weight gain Weight loss 0 2 Cognitive, somnolence Other Rash 0 URTI Tremor 0 2 QT prolong 0 Dry mouth Injection pain/ erythema IV not SC
22 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): Topiramate 100 mg Brandes et al., JAMA 2004;291(8): Topiramate mg Silberstein et al., Arch Neur 2004;61(4):490-5 N Drop out for AE, placebo Drop out for AE active 10% 8,7% 12% 10% 20% 8,2% 27% 23% LY Dodick et al., Lancet Neurol 2014; 13: AMG334 Sun et al., Lancet Neurol 2016; 15: ALD403 Dodick et al., Lancet Neurol 2014; 13: TEV Bigal et al., Lancet Neurology. 2015; 14: N Drop out for AE, placebo Drop out for AE, active 0,9% (1/110) 1,3% (2/153) ,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: /journal.pone
23
24 TEV blocks trigger-induced allodynia in MOH model BLS Periorbital BLS Hindpaw 8 15 Periorbital Withdrawal Threshold (g) Sal + Veh Sal + TEV Suma + Veh Suma + TEV Hindpaw Withdrawal Threshold (g) Sal + Veh Sal + TEV Suma + Veh Suma + TEV BL Time (h) after stress BL Time (h) after stress AOC of Periorbital Threshold Sal+Veh Sal+TEV Suma+Veh Suma+TEV p<0.05 compared to D21 BL 15 AOC of Hindpawal Threshold Sal+Veh Sal+TEV Suma+Veh Suma+TEV Porreca F.
25 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) AUG25 EM- 1 dose CM- 1 dose EM-Jan 2016 CM- Dec, 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
26 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:
27 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
28 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: Kurth et al. BMJ 2016;353:i2610 MassenVanDenBrink A, et all. TIPS 2016;37:
29 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):
30 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
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