CGRP, MONOCLONAL ANTIBODIES AND SMALL MOLECULES (-GEPANTS)

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1 CGRP, MONOCLONAL ANTIBODIES AND SMALL MOLECULES (-GEPANTS) Hans-Christoph Diener Senior Professor of Clinical Neurosciences University Duisburg-Essen Germany

2 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

3 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

What is Calcitonin Gene-Related Peptide (CGRP)?

It is a potent vasodilator and also functions as a messenger in nerve cells.

4 What is Calcitonin Gene-Related Peptide (CGRP)? CGRP is a 37-amino acid neuropeptide derived from the gene encoding calcitonin. It is a potent vasodilator and also functions as a messenger in nerve cells. CGRP exists in two forms in humans α-cgrp is the predominant form Found in the peripheral and central nervous systems. Formed from alternative splicing of the calcitonin/cgrp gene on chromosome 11. β-cgrp is found in the enteric nervous system. This differs in 3 amino acids. Amara SG et al. Nature 1982;298:240

5 Where does CGRP bind? CGRP binds to CGRP receptors, which are found throughout the body. The CGRP receptor is a heterotrimer comprised of: Calcitonin-like receptor (CLR), a seven transmembrane Gs protein coupled structure, and Receptor activity-modifying protein 1 (RAMP1). When CLR is localized with RAMP2 or RAMP2, the receptor is activated by adrenomedullin. Karsan N, Goadsby PJ. Curr Neurol Neurosci Rep : 25.

6 Where are CGRP and CGRP receptors in the trigeminal ganglion? Immunofluorescence studies in rats, primates and humans have identified the pattern of localization of CGRP and CGRP receptors in the trigeminal ganglion. CGRP is expressed in small/medium-sized neurons CGRP receptors are expressed in large- sized neurons and satellite glial cells. Satellite glial cells are thought to play an important role in inflammation and pain. Binding studies using functional CGRP receptor antagonist antibodies has shown CGRP receptor localization consistent with a role for CGRP receptors in trigeminal sensitization and migraine pathology Courtesy of Lars Edvinsson

7 CGRP is a potent vasodilator of cerebral arteries CGRP was previously established as a potent dilator of blood vessels in peripheral vascular beds. In this in vitro study, CGRP was also significantly more potent than substance P as a vasodilator of cerebral vessels. McCulloch J et al. Proc Natl Acad Sci U S A 1986;83:

Trigeminal ganglion stimulation increases CGRP in the cranial circulation Electrical stimulation of the trigeminal ganglion increased levels of substance P-like and

8 Trigeminal ganglion stimulation increases CGRP in the cranial circulation Electrical stimulation of the trigeminal ganglion increased levels of substance P-like and CGRP-like immunoreactivity. These findings suggested a putative role of these peptides in the pathophysiology of migraine. Goadsby PJ et al. Ann Neurol 1988;23:193-6.

CGRP levels are increased in migraine sufferers During migraine attacks (with or without aura) CGRP levels increase in the extracerebral circulation (external

9 CGRP levels are increased in migraine sufferers During migraine attacks (with or without aura) CGRP levels increase in the extracerebral circulation (external jugular blood) Only CGRP levels are elevated; there is no change in other peptides thought to be involved in pain transmission Goadsby PJ et al. Ann Neurol 1990;28:183-7.

10 A new era in migraine treatment A new principle in the treatment of migraine A positive trial Titel

11 Telcagepant: Liver toxicity; possibly effective for migraine prevention Liver toxicity Ho, TW et al. Neurology 2014;83:

12 NCT NCT NCT Ongoing acute ubrogepant trials 2013 MFMER slide-12

13 CGRP plays a pivotal role in migraine Note: CGRP antagonists refers to small molecule antagonists Russell FA et al. Physiol Rev 2014;94:1099.

14 Conclusion: CGRP is a potent vasodilator in the peripheral and central nervous systems. α-cgrp is the predominant form. CGRP binds to CGRP receptors, found throughout the body and brain. CGRP receptor localization is consistent with a role in trigeminal sensitization and migraine pathology. Experimental and clinical studies support a pivotal role for CGRP and its receptor in migraine. Safety of CGRP-antagonists not yet established Importantly, agents that target CGRP or its receptor do not need to cross the blood brain barrier or act centrally for efficacy. Titel 14

15 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

16 What are monoclonal antibodies? Monoclonal antibodies are produced from a single hybridoma cell line and are therefore identical to the parent cell Human or fully human monoclonal antibodies (mabs) have been developed to reduce immunogenicity Silberstein S et al., Headache 2015;55:1171.

17 Nomenclature for therapeutic monoclonal antibodies Silberstein S et al., Headache 2015;55:1171.

18 Therapeutic monoclonal antibodies versus small molecule therapies Monoclonal antibodies Larger (~150kD); mainly extracellular Target-specific Parenteral administration Longer dosing interval (half-life: days to weeks) Small molecule therapies Smaller (<1 kd); able to enter cells and cross bloodbrain barrier Less specific Oral administration possible Shorter dosing interval (half-life: hours) Not eliminated via hepatic, renal or biliary routes Lower risk of drug-drug interactions Elimination via hepatic, renal and/or biliary routes Drug-drug interactions possible Silberstein S et al., Headache 2015;55:1171.

Benefits of therapeutic monoclonal antibodies No toxic metabolites (broken down to constituent amino acids) Restricted distribution Pharmacokinetics are ideally

19 Benefits of therapeutic monoclonal antibodies No toxic metabolites (broken down to constituent amino acids) Restricted distribution Pharmacokinetics are ideally suited for chronic disease prevention (half-life >14 days) No off-target toxicity and overall tolerability is usually good (although dependent on mechanism of action)

20 Conclusion: Monoclonal antibodies are large molecules which most probably do not cross the blood-brain barrier Humanized antibodies have a low probability to produce neutralizing antibodies Monoclonal antibodies have a long half-life MOBs are administered in a subcutaneous or intravenous way Adherence is achieved Titel 20

21 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

22 CGRP therapeutic monoclonal antibodies for primary headache Erenumab AMG 334 Eptinezumab (ALD403) Galcanezumab LY Fremanezumab TEV Target CGRP receptor CGRP CGRP CGRP Migraine types studied Episodic Chronic Episodic Chronic Episodic Chronic Cluster headache Episodic Chronic Route of administration SC (monthly) IV (quarterly) SC (2-weekly or monthly) SC (monthly) Half-life (days) Current development phase Phase 3 (both) Titel Phase 3 (Episodic Migraine) Phase 2 (Chronic Migraine) Phase 3 Phase 3

23 P. Goadsby Slide 23

24 Conclusion: Erenumab, Eptinezumab, Fremanezumab and Galcanezumab are superior to placebo in the preventive therapy of episodic (or frequent episodic) migraine This is true for most endpoints and QoL measurements At present direct no comparisons with established preventive medications Titel 24

25 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

26 P. Goadsby Titel 26

27 P. Goadsby Titel 27

28 Conclusion: Erenumab, Eptinezumab, Fremanezumab and Galcanezumab are superior to placebo in the preventive therapy of episodic and chronic migraine This is true for most endpoints and QoL measurements At present direct no comparisons with established preventive medications in chronic migraine (topiramate, onabotulinumtoxina) Titel 28

29 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

30 Therapeutic gain in migraine (highest dose) 50% responder rate Eptinezumab Erenumab Galcanzumab Fremezumab Episodic migraine Chronic migraine MFMER slide-30

31 Conclusion: There are no major differences in efficacy between the 4 MOBs in the prevention of episodic and chronic migraine Titel 31

32 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

33 Safety Profile Was Similar to Placebo and Consistent With Earlier Eptinezumab Studies ALD mg N=224 ALD mg N=223 ALD mg N=219 Placebo N=222 Subjects with any TEAE, n (%) 119 (53) 132 (59) 114 (52) 124 (56) Subjects with any serious TEAE a, n (%) Subjects with any TEAE leading to study drug withdrawal, n (%) Most frequent TEAEs b Nasopharyngitis Sinusitis Upper respiratory tract infection 2 (<1) 4 (2) 4 (2) 6 (3) 4 (1.8) 4 (1.8) 9 (4.1) 5 (2.3) 14 (6.3) 10 (4.5) 23 (10.3) 16 (7.2) 5 (2.2) 20 (9.0) 15 (6.8) 7 (3.2) 23 (10.5) TEAE, treatment-emergent adverse event. a All serious TEAEs judged unrelated to study drug. b 5% in any treatment group. Saper J et. al. Poster presented at: 18th Congress of the International Headache Society (IHC); September 7-10, 2017; Vancouver, ALD403-CLIN (5.0) 14 (6.3) 15 (6.8) Alder Confidential 33

34 AMG334 in dose-finding phase II EM trial Very high retention, confirming good tolerability 3,7 96,3 Finished core study Discontinued 70 mg 60% 40% 20% 0% Placebo-like safety 54% 54% AE Placebo 7 mg 21 mg 70 mg EM: Episodic Migraine Sun H et al. Lancet Neurol Apr;15(4):382-90

REGAIN Treatment-Emergent Adverse Events Occurring with 2% Frequency with Galcanezumab Total Event Placebo N= 558 n (%) GMB 120 mg N=273 n (%) GMB 240 mg N=282 n (%) GMB Total N=555 n (%) Subjects

35 REGAIN Treatment-Emergent Adverse Events Occurring with 2% Frequency with Galcanezumab Total Event Placebo N= 558 n (%) GMB 120 mg N=273 n (%) GMB 240 mg N=282 n (%) GMB Total N=555 n (%) Subjects with 1 TEAE 279 (50.00) 159 (58.24)* 160 (56.74) 319 (57.48)* Injection site pain 24 (4.30) 17 (6.23) 20 (7.09) 37 (6.67) Nasopharyngitis 26 (4.66) 17 (6.23) 9 (3.19) 26 (4.68) Injection site reaction 10 (1.79) 8 (2.93) 15 (5.32)** 23 (4.14)* Upper respiratory tract infection 13 (2.33) 9 (3.30) 9 (3.19) 18 (3.24) Injection site erythema 5 (0.90) 4 (1.47) 13 (4.61)*** 17 (3.06)** Nausea 23 (4.12) 9 (3.30) 8 (2.84) 17 (3.06) Dizziness 20 (3.58) 6 (2.20) 8 (2.84) 14 (2.52) Fatigue 10 (1.79) 6 (2.20) 6 (2.13) 12 (2.16) Sinusitis 5 (0.90) 4 (1.47) 8 (2.84)* 12 (2.16) Abbreviations: GMB=galcanezumab; N=number of subjects in safety population; n=number of subjects within each specific category; TEAE=treatment-emergent adverse event. *p<.05 (vs. placebo) **p<.01 (vs. placebo) ***p<.001 (vs. placebo) p<.05 (vs. GMB 120 mg) 2017 Eli Lilly and Company

36 Episodic Migraine Chronic Migraine Fremanezumab: SAEs and AE leading discontinuation Placebo 240 Quarterly dose 265 Monthly dose 270 All fremanezumab 535 Patients with at least 1 SAE 6 (2) 3 (<1) 5 (1) 8 (1) Placebo Quarterly dose Monthly dose All fremanezumab Patients with at least 1 AE leading to study discontinuation 8 (2) 5 (1) 7 (2) 12 (2) Placebo 171 Quarterly dose 193 Monthly dose 192 All fremanezumab 385 Patients with at least 1 SAE 7 (2) 3 (1) 3 (1) 6 (1) Placebo Quarterly dose Monthly dose All fremanezumab Patients with at least 1 AE leading to study discontinuation 5 (2) 5 (2) 5 (2) 10 (2)

37 Pregnancy Acute ischemic stroke Acute coronary syndrome Disruption of the bloodbrain barrier Wound healing Integrity of the mucosa of the GI tract

38 Conclusion: MOBs against CGRP or the CGRP receptor have a good tolerability profile The long term safety has not yet been established Safety in special situations has to be evaluated in prospective registries Titel 38

39 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

40 Episodic migraine study- Primary endpoint change from baseline on Migraine Days Placebo TEV mg/placebo/placebo TEV /225/225 mg 0.0 LS Mean (+/- SE) Change from Baseline Visit: Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3 TEV /225/225 mg < < < < < TEV mg/placebo/placebo < < <

Percent of patients with migraine FEM Secondary Endpoint: Preventive Benefit Achieved on the First Day Post-Infusion 35,0 30,0 ~30% of patients experienced migraine on any given day during baseline

41 Percent of patients with migraine FEM Secondary Endpoint: Preventive Benefit Achieved on the First Day Post-Infusion 35,0 30,0 ~30% of patients experienced migraine on any given day during baseline (28-day) period 25,0 20,0 15,0 10,0 53.6% 23,7 20,1 [VALUE]* 16,0 [VALUE]** 14,5 21,2 21,0 20,1 16,9 17,0 17,2 16,8 17,3 15,9 Placebo N= mg N= mg N=222 Baseline Day 1 Week 1 Week 2 Week 3 Week 4 On Day 1 post-infusion, the risk of having a migraine was reduced by >50% vs baseline *Unadjusted P= **Unadjusted P= a Benefit observed within the first infusion period. Cady et. al.. Poster presented at: 18th Congress of the International Headache Society (IHC); September 7-10, 2017; Vancouver, Canada ; ALD403-CLIN-006, ALD403-CLIN-006 Alder Confidential 41

42 Conclusion: Speed of onset of efficacy is fast This allows an early decision about treatment continuation Titel 42

43 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

44 Conclusion: At present no data in patients with chronic migraine and MOH Titel 44

45 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

46 Conclusion: The challenge will NOT be approval Reimbursement will be a challenge Initially most probably restricted to migraine patients with frequent or chronic migraine who Failed available treatment Could not tolerate available treatment Had contraindications for available treatment Titel 46

47 CGRP, Monoclonal Antibodies and Small Molecules (-gepants) Role of CGRP in migraine Monoclonal antibodies (MAB) Results from phase II Results from phase III Are all MABs the same Tolerability Safety Speed of onset Patients with MOH Which patients?

48 Final Conclusions Humanized monoclonal antibodies against CGRP or CGRP receptor are a major step forward in the prevention of migraine Excellent tolerability profile Unknown safety No comparisons with established therapy yet Reimbursement will be a major challenge Titel 48

49 Titel Thank you for your attention

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

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