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Clinical Challenges in Migraine:The Role of Emerging Therapies in New Treatment Paradigms

©MediCom Worldwide, Inc. 1

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.



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



Migraine Preventive TreatmentConsider When:

• Headache frequency greater than 6 per month

• Headache related disability occurs too often regardless of headache frequency

Special circumstances exist:Profound disabilityProlonged migraine auraHistory of migraine related stroke

• Acute medications are:− Ineffective or not tolerated May augment efficacy

− Likely to be overused

− Contraindicated

Preventive Therapy for Migraine: Caveats

• Advise patient re: latency & side effects

• Start low, go slow, but strive for a therapeutic dose

• Treat for an adequate duration; set realistic goals

• Evaluate response with calendars

• Prescribe concomitant acute therapy, but avoid interfering or overused medication

Silberstein S. Preventive Migraine Treatment; Continuum (Minneap Minn) 2015 Aug; 21(4 Headache): 973–989.

Preventive Medication Reduces Costs18‐month Comparison study; Acute/Preventive Therapies

Silberstein S. Preventive Migraine Treatment; Continuum (Minneap Minn) 2015 Aug; 21(4 Headache): 973–989.

.

Office visits

51%

ED visits

82%

Medication Costs $138 Month/Patient

48%

MRI scans

88%

CT scans

75%



Migraine Prevention Mechanisms

Modulate sympathetic

or serotonergic tone

Stabilize More Reactive

Nervous System

Effect on sodium

and/or calcium

ion channels

Block

neurogenic

inflammation

Inhibit

sensitization

Inhibit cortical

spreading

depression

Enhance

antinociception

Inhibit migraine

generation

(?cortex, PAG)

Raise Threshold to Migraine Activation

Drugs that are useful in the prophylaxis of migraine suppress cortical spreading

depression

Ayata, et al. Ann Neurol. 2006;59:652‐661

All Approved Drugs Similarly Prevent Migraine

Approved Drug

• Topiramate (9 RCTs)

• Divalproex (3 RCTs)

• Timolol (3 RCTs)

• Propranolol (4 RCTs)

• Topiramate and antidepressants more adverse events

• No significant differences between labelled drugs

• ACE inhibitors and BB most tolerable and effective

• Long term (>3 month data lacking)

Shamlyian T. J Gen Int Med. April 2013.

215 publications of RCTs provided mostly low‐strength evidence because of the risk of bias and imprecision

Off Label Drug

• Metoprolol (4 RCTs)

• Atenolol (1 RCT)

• Nadolol (1 RCT)

• Captopril (1RCT)

• Lisinopril (1RCT)

• Candesartan (1RCT)



Migraine Comorbidity and Coexisting ConditionsTherapeutic Opportunities and Limitations

If uncontrolled, ergot & triptanb‐blockers, Ca++ channel antagonistsHypertension

TCA, SSRI, SNRIValproate, topiramateBipolar disorder

β‐blockers, ergotsCa++ channel antagonistsRaynaud’s phenomenon

TCA, SSRI, SNRITopiramate, valproate, gabapentinEpilepsy

TCA, valproate, gabapentinTopiramate, SNRIObesity

Ergot, triptanAspirinStroke

TCASleep disturbance

TCA, SNRI, β‐blockersAnxiety

β‐blockersTricyclic antidepressants (TCA), selective serotoninreuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI)

Depression

Avoid or CautionConsiderDisorder (+ migraine)

Nonpharmacologic Therapies Tested in Clinical Trials

*Demonstrated efficacy in clinical trials

Adapted from US Headache Consortium Headache Guidelines. www.aan.neurology.org. 2000

Cognitive / behavioral therapy (CBT)*

Electromyographic biofeedback therapy*

Thermal biofeedback training*

Hypnotherapy

Relaxation training*

Behavioral Treatments

TMS

GON stimulation

Physical therapyCervical manipulation

Occlusaladjustment

Transcutaneous electrical nerve stimulation (TENS)

Acupuncture

Physical Treatments

AHS Guidelines: Migraine Preventive Therapies

*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

Antiepileptic drugsAntidepressants/SSRI/SSNRI/TCA

ACE inhibitorsLisinopril

Carbonic anhydrase inhibitor

Established as not effective

Divalproex sodium* AmitriptylineAngiotensin receptor blockers

Acetazolamide Antiepileptic drugs

Sodium valproate Venlafaxine Candesartan Antithrombotics Lamotrigine

Topiramate* ‐Blockers ‐Agonists Acenocoumarol Probably not effective

‐Blockers Atenolola Clonidinea Coumadin Clomipraminea

Metoprolol Nadolola Guanfacinea Picotamide Possibly not effective

Propranolol* Triptans (MRMb) Antiepileptic drugsAntidepressants SSRI/SSNRI

Acebutolola

Timolola* Naratriptanb Carbamazepinea Fluvoxaminea Clonazepama

Triptans (MRMb) Zolmitriptanb ‐Blockers Fluoxetine Nabumetonea

Frovatriptanb Nebivolol Antiepileptic drugs Oxcarbazepine

Pindolola Gabapentin Telmisartan

Antihistamines TCAs

Cyproheptadine Protriptylinea

‐Blockers

Bisoprolola



Classification of Migraine Preventive Therapies (available in the US) of Herbal Preparations, Minerals, Vitamins, NSAIDs, and Others

Level A: medications with established efficacy (at least Class I trials)

Level B: medications are probably effective (one Class I or at least two Class II studies)

Level C: medications are possibly effective (one 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

Herbal preparations, vitamins, minerals, and other

NSAIDs NSAIDs NSAIDs Probably not effective

Petasites Fenoprofena

Flurbiprofena

Aspirin Leukotriene receptor antagonist

Ibuprofena

Mefenamic acida

Indomethacina

Montelukast

Ketoprofena

Herbal preparations vitamins, minerals, and other

Herbal preparations vitamins, minerals, and other

Naproxena

CoQ10 Omega‐3

Naproxen sodiuma

Estrogen Other

Herbal preparations, vitamins, minerals, and other

Antihistamine Hyperbaric oxygen

Magnesium Cyproheptadine

MIG‐99 (feverfew)

Riboflavin

Histamines

Histamine SC

Onabotulinum Toxin AOnly FDA Approved Agent for Chronic Migraine

• Variable studies with migraine and tension‐type headaches with variable doses and sites, techniques

• Botulinum toxins not interchangeable

Injection Sites for PREEMPT Study

Muscle Injected Standard Dose Optional Sites

Procerus 5 U (one site) n/a

Corrugator 5 U each side (10 U) n/a

Frontalis 10 U each side (20 U) n/a

Temporalis 10 U each side (20 U) Up to 2 sites (10 U)

Cervical Paraspinals 10 U each side (20 U) n/a

Occipitalis 15 U each side (30 U) Up to 2 sites (10 U)

Trapezius 15 U each side (30 U) Up to 4 sites (20 U)

Total 155 U Up to 40 U

How Onabotulinum Toxin A Might Work

X

• Inhibits release of Ach at NMJ, inhibiting striated muscle contractions− Pain relief often occurs before muscle paralysis

• Blocks peripheral sensitization− Blocks release of glutamate and SP from nociceptive neurons− C‐fos expression prevented upon peripheral exposure



Side Effects Affect Patient Choices

Older patients reject

for tremor

Kowacs P et al. Headache 2009;49:1022‐1027

Better acceptance is >10 symptomatic medications/month (especially for loss of energy and

somnolence)

Most rejected: weight gain, memory loss,

depression

Weight loss better accepted with higher BMI

BMI>

Considerbehavioraltechniques

Lifestylemodifications

Nonpharmacologic StrategiesSleep

Exercise

Diet

Stressmanagement

Stop smoking

What Do We Need for Optimal Migraine Prevention?

• Can be given infrequently

• Has a high rate of adherence and persistence

• Has few AEs

• Is easy to administer

• Has proven efficacy to decrease headache days

• Works when other preventive therapies do not

• Is cost effective

We need preventive medication that:



Summary

• 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.



From CMEP, AHS Program

Migraine Pathophysiology

Dura

Cutaneousallodynia

Throbbingpain

Muscle tenderness

Activated central neuron(thalamus)

Sensitized peripheral neuron

(trigeminal ganglion)

Meningealblood vessel

Sensitizedcentral neuron

(trigeminal cervical complex)

Pain perception

Activation of the Trigeminovascular System in Migraine

Meningeal Events• Inflammation• Peripheral sensitization

Vasodilationof cerebral vessels

Brainstem Events• Pain signal to CNS• Central sensitization• Allodynia

Adapted with permission from Durham PL. NEngl J Med. 2004;350:1073–1075.

Migraine Pathogenesis

Calcitonin Gene‐Related Peptide (CGRP)• Neuropeptide belonging to calcitonin family

• Calcitonin

• Amylin

• Adrenomedullin

• Intermedin

• In humans two forms • α‐CGRP: 37‐amino acid peptide

• β‐CGRP: main isoform of enteric NS; differs in 3 amino acids

CLR=calcitonin receptor‐like receptor; RAMP=receptor activity modifying protein; RCP=receptor component protein

adenylyl

cyclase

Gs

RCP

CGRP

RAMP1

CLR

cAMP



Cortex

CGRP Receptors Occur at All Sites Involved in Migraine Pathogenesis

Benarroch EE. Neurology. 2011;77(3):281‐287.

Brain SD, et al. Nature. 1985;313(5997):54‐56.; Edvinsson L, et al. Brain Res Brain Res Rev. 2005;48(3):438‐456.; McCulloch J, et al. Proc Natl Acad Sci USA. 1986;83(15):5731‐5735.; Moskowitz MA. Neurol Clin. 1990;8(4):801‐815.Slide courtesy of Marcelo Bigal, MD, PhD

CGRP: Vasodilation and Neurogenic Inflammation

CGRP First Identified as a PotentialMediator of Trigeminal Inflammation

Afridi SK, et al. Brain. 2005;128:932‐939.

Bahra A, et al. Lancet. 2001;357:1016‐1017.

Weiller C, et al. Nat Med. 1995;1:658‐660.

PET

fMRI

Adapted from CMEP, AHS Program

Activation of Brainstem During Migraine Attacks; CGRP Binds Here



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



Olcegepant IV

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



Small Molecules Monoclonal Antibodies

Target specificity lower Target specificity high

Clearance (liver, kidney) Clearance RES

Size < 1kD Size ~150kD

Oral Parenteral

Many enter cells and cross BBB

Do not enter cells or cross BBB

Half‐life minutes to hours Half‐life 3‐6 weeks

Immunogenicity (No) Immunogenicity (yes)

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


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



• 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



Erenumab

ErenumabSubmitted to the FDA for the indication of prevention of migraine in May 2017

Erenumab Galcanezumab Fremanezumab Eptinezumab

Studied for EM, CM EM, CM, eCH, cCH EM, CM, eCH, cCHEM, CM

Dosing Monthly SC Monthly SCMonthly or Q3 month SC; IV load for CH

Q3 month IV

Target CGRP receptor CGRP peptide or ligand CGRP peptide or ligand CGRP peptide or ligand

Regulatory status 7/2017

Submitted to FDA for migraine prevention; CM registration study

fully published

Presented (+) Phase 3 EM & CM

Presented (+) Phase 3 CM;

Announced (+) Phase 3 EM

Announced (+) Phase 3 EM;

Continuing Phase 3 CM

Galcanezumab



Galcanezumab




Q3 month IV




fully published






Phase 3 EM Prevention, Erenumab & Galcanezumab:1° Endpoint: Migraine Day Reduction at 3 Mos vs. Placebo

‐2.81 days

‐4.73 days‐4.57 days

.

Goadsby et al. Headache. 57(S3): 128‐129.; Stauffer et al. Presented at AHS meeting, June 2017.

Phase 3 CM Prevention, Erenumab & Galcanezumab:1° Endpoint: Migraine Day Reduction at 3 Mos vs. Placebo

*p<0.001a

‐2.67

‐5.03

‐5.10

‐3.56

‐6.21

‐6.45

‐4.18 days

‐6.63 days

‐6.64 days

PBO

70 mg

140 mg

‐7.5

‐6.5

‐5.5

‐4.5

‐3.5

‐2.5

‐1.5

‐0.5

Baseline Week 4

*

*

**

* *

Week 8 Week 12

LS

Mea

n C

han

ge

fro

m B

asel

ine

(SE

)

Imp

rove

men

t

‐2.74 days

‐4.83 days‐4.62 days

Tepper et al. Lancet Neurol 2017;16:425–434.; Detke et al. AHS meeting June 2017.



Phase 3 CM Erenumab Adverse Events

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 (%)

2 (0.7) 0 (0.0) 2 (1.1)

Most frequent AEsa

Injection site pain 3 (1.1) 7 (3.7) 7 (3.7)

Upper respiratory tract infection 4 (1.4) 5 (2.6) 6 (3.2)

Nausea 7 (2.5) 4 (2.1) 6 (3.2)

Nasopharyngitis 16 (5.7) 6 (3.2) 3 (1.6)

Constipation 1 (0.4) 0 (0.0) 8 (4.3)

Muscle spasms 4 (1.4) 1 (0.5) 7 (3.7)

Migraine 3 (1.1) 3 (1.6) 5 (2.7)

Tepper et al. Lancet Neurol 2017;16:425–434.

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

50

CategoryPlaceboN=461n (%)

GMB 120 mgN=226n (%)

GMB 240 mgN=228n (%)

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)

Abbreviations: AE=adverse event; GMB=galcanezumab; N=patients in safety population; n=patients within each specificcategory.

*p<.05 (vs. placebo)

Skljarevski et al. AHS meeting. June 2017.

Fremanezumab



Fremanezumab




Q3 month IV




fully published






HALO Phase 3 – Prevention of Episodic Migraine

• Primary Endpoints: Decreased Migraine Days, 3rd month;

• Relief experienced within 1 week and continued to experience reduction in migraine for up to 3 months compared to placebo

• Monthly SC Dosing

− Placebo: (‐2.2 days)

− Fremanezumab: (‐3.7 days), p<0.0001

− # of days with disability decreased by 64.7%

• 2° endpoint‐ Decreased acute medication days:

− Decreased by 39.0%, p < 0.0001

• Quarterly SC dosing reported highly significant results for decrease in migraine days:

− Fremanezumab ‐3.4 days or 37.0%,

• P < 0.0001

Trial Met All Primary and Secondary Endpoints Across Both Monthly and Quarterly Dose Regimens

Teva Press Release June 2017. http://www.tevapharm.com/news, accessed July 2, 2017.

Phase 3 Data: CM Prevention – HALO StudyPrimary endpoint: change from baseline in headache days of least moderate severity

Change from baseline: headache days of at least moderate severity during first 4 weeks

Aycardi et al. Presented at AHS meeting June 2017.



HALO CM Fremanezumab Phase 3 Prevention of CM: Adverse Events

Aycardi et al. Presented at AHS meeting June 2017.

Eptinezumab

EptinezumabErenumab Galcanezumab Fremanezumab Eptinezumab

Studied for EM, CM EM, CM, eCH, cCH EM, CM, eCH, cCH EM, CM


Q3 month IV

Target CGRP receptorCGRP peptide or

ligandCGRP peptide or

ligandCGRP peptide or

ligand



fully published








41%

21%

3%

57%†

33%*

8%

55%*

31%*

5%

56%*

28%

4%

44%

27%

8%

0

10

20

30

40

50

60

50% Response Rate 75% Response Rate 100% Response Rate

Percent of Patients

Placebo (n=116)

ALD403 (eptinezumab) 300mg(n=114)ALD403 (eptinezumab) 100mg(n=118)ALD403 (eptinezumab) 30mg(n=117)ALD403 (eptinezumab) 10mg(n=123)

Current Standard Eptinezumab Target Response

Primary Endpoint

Eptinezumab Phase 2 Prevention of CM

*P<0.05; †P<0.005 vs placebo (one‐sided, not corrected for multiplicity)

Smith et al. Headache. 57 (S3): 130.

Cady et al. www.alderbio.com, accessed 7/2/17.

Monthly migraine days were significantly reduced from baseline over weeks 1 – 12

Eptinezumab Phase 3 Prevention of EM, Met

Primary and Key Secondary Endpoints

Eptinezumab Phase 3 EM Prevention Adverse Events

Cady et al. www.alderbio.com, accessed July 2, 2017.



CGRP receptors present at crucial locations in

migraine pathophysiology

CGRP infusion evokes migraine

Serum CGRP levels are elevated in migraine

CGRPs in 2017

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

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