axs-07 and the acute treatment of migraine

NASDAQ: AXSM

AXS-07 and the Acute Treatment of Migraine

R&D Day Conference Call

November 25, 2019

© Axsome Therapeutics, Inc.

Certain information contained in this presentation may include “forward-looking statements” within the meaning of the Private

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convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s

statements regarding trends and potential future results are examples of such forward-looking statements. The forward-

looking statements include risks and uncertainties, including, but not limited to, the success, timing and cost of our ongoing

clinical trials and anticipated clinical trials for our current product candidates, including statements regarding the timing of

initiation and completion of the trials, interim analyses and receipt of interim results; the timing of and our ability to obtain and

maintain U.S. Food and Drug Administration or other regulatory authority approval of, or other action with respect to, our

product candidates; the Company’s ability to obtain additional capital necessary to fund its operations; the Company’s ability

to generate revenues in the future; the Company’s ability to successfully defend its intellectual property or obtain the

necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research

and development programs; the enforceability of the Company’s license agreements; the acceptance by the market of the

Company’s product candidates, if approved; and other factors, including general economic conditions and regulatory

developments, not within the Company’s control. These factors could cause actual results and developments to be materially

different from those expressed in or implied by such statements. Forward-looking statements are not guarantees of future

performance, and actual results may differ materially from those projected. The forward-looking statements are made only as

of the date of this presentation and the Company undertakes no obligation to publicly update such forward-looking statements

to reflect subsequent events or circumstance.

This presentation also contains estimates and other statistical data made by independent parties and by us relating to market

size and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not

to give undue weight to such estimates. Neither we nor any other person makes any representation as to the accuracy or

completeness of such data or undertakes any obligation to update such data after the date of this presentation. In addition,

these projections, assumptions and estimates are necessarily subject to a high degree of uncertainty and risk.

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Forward-Looking Statements & Safe Harbor


FLS

3

AXS-07 andUnmet Needs in the Acute Treatment of Migraine


Overview

Topic Discussant

Introductions Mark JacobsonSENIOR VICE PRESIDENT, OPERATIONS

Welcome Herriot Tabuteau, MDCHIEF EXECUTIVE OFFICER

Migraine: Multiple Mechanisms of Disease, Treatment Targets and the Potential for AXS-07

Stewart J. Tepper, MDPROFESSOR OF NEUROLOGY,GEISEL SCHOOL OF MEDICINEAT DARTMOUTH UNIVERSITY

Inadequate Response to Acute Migraine TreatmentRichard B. Lipton, MDPROFESSOR OF NEUROLOGYPAST PRESIDENT OF THE AMERICAN HEADACHE SOCIETY

Update on the Clinical Development of AXS-07Cedric O’Gorman, MDSENIOR VICE PRESIDENT,CLINICAL DEVELOPMENT & MEDICAL AFFAIRS

MINDSET Physician Survey Informs Market Opportunity Dave MarekCHIEF COMMERCIAL OFFICER

Panel Discussion and General Q&A Presenters

Welcome

4© Axsome Therapeutics, Inc.

Herriot Tabuteau, MD

CHIEF EXECUTIVE OFFICERAXSOME THERAPEUTICS, INC.

Migraine: Multiple Mechanisms of Disease, Treatment Targetsand the Potential for AXS-07


Stewart J. Tepper, MD

PROFESSOR OF NEUROLOGYGEISEL SCHOOL OF MEDICINE AT DARTMOUTH

• The World Health Organization classifies severe migraine attacks as among the most

disabling illnesses, comparable to dementia, quadriplegia and active psychosis1,2

• Debilitating pain, and the often constant fear of the next migraine attack, damage family

life, social life and employment3

• Depression and anxiety are twice as common in people with migraine than in healthy

individuals4

• Widespread misperception of the seriousness of migraine contributes to its under-

recognition and under-treatment3

• More than 70% of patients are not fully satisfied with their current treatment5

6

Migraine:Disabling Disease in Need of New Treatments


AXS-07

There is an urgent need for new treatments that provideimproved efficacy for this serious neurological disease

1Menken et al. Arch Neurol. 2000;57:418-420.2Shapiro and Goadsby. Cephalalgia. 2007;27:991-4.3Global Burden of Disease Study. Lancet. 2017;390:1211-12594Antonaci et al. J Headache Pain. 2011;12:115–125. 5Lipton and Stewart. Headache. 1999;39(suppl 2):S20-S26.

• Emerging therapies are expected to increase treatment options for migraine sufferers:

– Anti-CGRP antibodies for prevention

– AXS-07 for acute treatment

– Oral anti-CGRPs (gepants) and lasmiditan for acute treatment

• Anti-CGRP antibodies for prevention:

– May increase the addressable market for acute treatments by increasing disease

awareness, and leading patients to seek therapy

– Most appropriate for chronic migraine (about 10% of patients)

– Reduction of about 2 migraine days per month compared to placebo

7

Migraine:Emerging Treatment Landscape


AXS-07

100% of migraine patients, including those on preventive therapy, need acute treatment


AXS-07

• AXS-07 is a novel, oral, investigational medicine consisting of MoSEIC™

meloxicam and rizatriptan under development for the acute treatment of migraine

• Meloxicam is a COX-2 preferential non-steroidal anti-inflammatory drug

• Rizatriptan is a 5-HT1B/1D agonist

• AXS-07 is designed to provide rapid absorption, enhanced and consistent relief

of migraine, and reduced symptom recurrence

AXS-07 (MoSEIC™ Meloxicam/Rizatriptan) Multi-Mechanistic Treatment for Migraine

AXS-07

Migraine Process Mechanism / Action Component

CGRP Mediated✓ Inhibition of CGRP release

✓Reversal of CGRP-mediated vasodilationRizatriptan

Neuroinflammation✓Cyclooxygenase inhibition

✓PGE2 synthesis inhibition

MoSEIC™

meloxicam

Pain Signal Transmission✓Decrease passage of pain signals

to trigeminal nucleus caudalis Rizatriptan

Central Sensitization ✓Reversal of central sensitizationMoSEIC™

meloxicam

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AXS-07 (MoSEIC™ Meloxicam/Rizatriptan) Multi-Mechanistic Treatment for Migraine


AXS-07

Mechanisms of AXS-07 address multiple disorderedphysiological processes observed during migraine attacks

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AXS-07 (MoSEIC™ Meloxicam/Rizatriptan) Pharmacokinetic Profile – Phase 1 Results


AXS-07

• Therapeutic AXS-07 MoSEIC™ meloxicam concentrations reached in 17 minutes

• Maximum concentrations of AXS-07 rizatriptan reached in 38 minutes

• MoSEIC™ meloxicam terminal half-life of 18.2 hours

O’Gorman C et al. Presented at the 19th Congress of the International Headache Society, 5-8 September 2019, Dublin, Ireland.

Mean Meloxicam Concentrations Mean Rizatriptan Concentrations

AXS-07 (20 mg meloxicam/10 mg rizatriptan)

Mobic® (15 mg meloxicam)

AXS-07 (20 mg meloxicam/10 mg rizatriptan)

Maxalt® (10 mg rizatriptan)

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Temporal Alignment: AXS-07 PK versus CGRP and PGE2 Increases


AXS-07

Sarchielli et al. Cephalalgia. 2000;20:907-18.

Abbreviations: CGRP, Calcitonin gene-related peptide; PGE2, Prostaglandin E2.

Time (hrs)

Me

an

Mo

SE

IC™

me

loxic

am

co

nce

ntra

tion

(ng

/mL

)M

ea

n r

iza

trip

tan c

on

ce

ntr

atio

n (

pg

/mL

)

CGRP PGE2

CGRP (mean peak 76.7 pmol/L)

Peaks at 1 hr; decreases over 6 hrs

PGE2 (mean peak 6.38-6.62 pmol/L)

Peaks at 2 hrs; maintained through 6 hrs

• Migraine is a highly disabling neurological disease, characterized by debilitating pain, that

damages family life, social life and employment

• There is an urgent need for new treatments that provide improved efficacy for this serious

neurological disease

• Physiological changes during a migraine attack include CGRP-mediated vasodilation, and

neuroinflammation leading to initiation and maintenance of pain; and central sensitization

(allodynia) contributing to difficult-to-treat pain

• The mechanisms of AXS-07 address the multiple disordered physiological processes

observed during migraine attacks

• AXS-07 is rapidly absorbed resulting in a PK profile which aligns temporally with the

increases in CGRP and inflammatory markers observed during migraine attacks

• The multiple mechanisms of action of AXS-07 combined with a favorable PK profile may

result in improved efficacy in the acute treatment of migraine

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Migraine: Summary


AXS-07

Inadequate Response toAcute Migraine Treatment


Richard B. Lipton, MD

PROFESSOR OF NEUROLOGYPAST PRESIDENT OF THE AMERICAN HEADACHE SOCIETY

• New acute treatments for migraine must address unmet needs

• Unmet needs for efficacy can be measured using the Migraine Treatment Optimization

Questionnaire (mTOQ)

• Unmet needs are consequential

• Combining a fast-acting NSAID and a fast-acting triptan is a rational approach for

addressing unmet efficacy needs

• The MOMENTUM study enrolls patients with a history of inadequate response to their

prior acute treatments, assessed using the mTOQ-4

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Overview


AXS-07

• The mTOQ-4 is a patient-reported

outcome (PRO) developed to:

– Identify patients with an inadequate

treatment response

– Identify patients who require a change

of their current acute treatment

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Determining Success with Acute Treatments: Migraine

Treatment Optimization Questionnaire (mTOQ-4)


AXS-07

Lipton et al. Neurology. 2015;84:688-95.

• The mTOQ-4 is a patient-reported

outcome (PRO) developed to:

– Identify patients with an inadequate

treatment response

– Identify patients who require a change

of their current acute treatment

17

Determining Success with Acute Treatments: Migraine

Treatment Optimization Questionnaire (mTOQ-4)


AXS-07

Lipton et al. Neurology. 2015;84:688-95.

IMPACTAfter taking your medication, do you feel in control enough to feel no disruption to daily activities?

GLOBAL ASSESSMENTAfter taking your medication, are you pain free within 2 hours of most attacks?

EMOTIONAL RESPONSEAre you comfortable enough with your medication to be able to plan daily activities?

CONSISTENCY OF RESPONSEDoes one dose of medication relieve your headache and keep it away for at least 24 hours?

American Migraine Prevalence and Prevention Study (AMPP)

• 8,233 respondents with episodic migraine

• 56.0% reported Inadequate 2-hour Pain Freedom response to usual acute treatment

• 53.7% reported Inadequate 24-hour Pain Relief

• Of those who achieved Adequate 2-hour Pain Freedom, 25.7% reported

Inadequate 24-hour Sustained Pain Relief or recurrence

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Inadequate Response to Acute Migraine Treatments

AMPP Study


AXS-07

Lipton RB et al. Headache. 2016 Nov;56(10):1635-1648.

56.0%53.7%

44.0%

0%

10%

20%

30%

40%

50%

60%

Inadequate 2 hour Pain Freedom Inadequate 24 hour Pain Relief Adequate 2 hour Pain Freedom

Pro

po

rtio

n o

f p

atie

nts

25.7%

had Inadequate

Sustained Pain

Relief

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Inadequate Response to Acute Treatment is Consequential


AXS-07

Progression from Episodic to Chronic Migraine by Acute Treatment Efficacy Category

6.8%

4.4%

2.7%

1.9%

0%

1%

2%

3%

4%

5%

6%

7%

8%

Very poor Poor Moderate Maximum

% P

rog

res

sin

g f

rom

EM

to

CM

8

7

6

5

4

3

2

1

0

Abbreviations: OR: Odds Ratio; CI: Confidence Index; EM: Episodic Migraine; CM: Chronic Migraine.1American Migraine Prevalence and Prevention (AMPP) Study. Lipton et al. Neurology. 2015;84:688-95.

OR = 2.55; 95% Cl 1.42–4.61

OR = 1.69; 95% Cl 1.02–2.81

OR = 1.26; 95% Cl 0.81–1.97

Degree of Treatment Optimization

Total N of group 369 1,007 2,657 1,648

Inadequate initial treatment of episodic migraine can lead to chronic migraine

Strongest predictors of Inadequate Response, based on 2-hour pain freedom,

ranked in order of strength of association:

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Strongest Predictors of Inadequate Response AMPP Study


AXS-07

Greater Pain Intensity

Presence of Cutaneous Allodynia

Meeting criteria for Depression

Higher body mass index

Higher average monthly headache day frequency

Lipton RB et al. Headache. 2016 Nov;56(10):1635-1648.

21

Allodynia and Inadequate ResponseAMPP Study


AXS-07

Inadequate 24-hour Pain Response by Drug Class and Allodynia Status

Allodynia was associated with inadequate outcomesfor all medication groups (n=5,236)1

1American Migraine Prevalence and Prevention (AMPP) Study. Lipton et al. Headache. 2017;57:1026-1040.

40.7

64.268.3

57.9

29.5

50.053.4

43.7

0

10

20

30

40

50

60

70

Triptans NSAIDs Opioids Barbituates

Allodynia No Allodynia

Pe

rce

nta

ge

P<0.001

P<0.001 P<0.001

P<0.001

• MOMENTUM is enrolling only patients with a history of inadequate response to their prior

acute treatments, assessed using the mTOQ-4:

– Targets patient population at greatest clinical need

– To date majority of patients screened also exhibit cutaneous allodynia

– Enriches for population of patients with difficult-to-treat migraine

• The multiple mechanisms of AXS-07 may address the two strongest predictors of inadequate

treatment response:

– Higher pain intensity: AXS-07’s multiple mechanisms may synergize to enhance pain relief

– Cutaneous allodynia: The MoSEIC™ meloxicam component of AXS-07 may reverse

central sensitization which manifests clinically as allodynia

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Implications for AXS-07 MOMENTUM Phase 3 TrialEvaluating Patients with Inadequate Response


AXS-07

• MOMENTUM incorporates active comparator rizatriptan:

– Rizatriptan is considered one of the most effective and fastest acting acute migraine

therapies

– Comparative efficacy data with AXS-07 vs. rizatriptan will be generated

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Implications for AXS-07 MOMENTUM Phase 3 TrialEvaluating Patients with Inadequate Response


AXS-07

• New acute treatments for migraine must address unmet needs, and unmet needs for

efficacy can be measured using the mTOQ-4

• Ineffective acute treatment results in medication overuse, chronification of migraine and

poor long-term outcomes

• More than half of migraine patients report inadequate response to their usual acute

migraine treatment

• AXS-07, by combining a fast-acting NSAID and a fast-acting triptan, may address the two

strongest predictors of inadequate treatment response, which are greater pain intensity and

the presence of cutaneous allodynia

• By enrolling only patients with a history of inadequate response, the MOMENTUM study is

targeting the population where AXS-07 may have the greatest clinical utility

• Inclusion of the active comparator rizatriptan in the MOMENTUM study will generate

important comparative data

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Summary


AXS-07

Update on theClinical Developmentof AXS-07


Cedric O’Gorman MD, MBA

SENIOR VICE PRESIDENT,CLINICAL DEVELOPMENT & MEDICAL AFFAIRSAXSOME THERAPEUTICS, INC.

Patient Population

• Adult subjects with established diagnosis of migraine with or without aura

• History of inadequate response as assessed by the mTOQ-4

Co-Primary Endpoints (AXS-07 vs placebo)

• Pain Freedom at 2 hours

• Freedom from MBS at 2 hours

Key Secondary Endpoint (AXS-07 vs rizatriptan and MoSEIC™ meloxicam)

• Superiority of AXS-07 to individual components (component contribution) based on

sustained pain freedom 2-24 hours after dosing

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MOMENTUM Study of AXS-07For the Acute Treatment of Migraine


AXS-07

MOMENTUM: Maximizing OutcoMEs iN Treating acUte MigrainePhase 3 study of AXS-07 for the acute treatment of migraine in adults

with history of inadequate response to prior treatment

2:2:2:1

randomization

Single dose, following a qualifying migraineScreening

Rizatriptan

AXS-07

MoSEIC™ meloxicam

Placebo

✓ Study being conducted

pursuant to FDA Special

Protocol Assessment (SPA)

✓ MOMENTUM study is fully

enrolled

✓ On track to report topline

results: Q4’19

n=875

Abbreviations: MBS, most bothersome migraine-associated symptom; mTOQ-4, Migraine Treatment Optimization Questionnaire.

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INTERCEPT Study of AXS-07For the Acute Treatment of Migraine


AXS-07

INTERCEPT: INiTiating EaRly Control of MigrainE Pain & Associated SympToms

Phase 3 trial of AXS-07 for the acute treatment of migraine

1:1

randomization

Single dose, immediately following migraine pain onsetScreening

Placebo

AXS-07n=300

Patient Population

• Adult subjects with an established diagnosis of migraine with or without aura

• Will initiate treatment at the first sign of migraine pain onset

Co-Primary Endpoints (AXS-07 vs placebo)

• Pain Freedom at 2 hours

• Freedom from MBS at 2 hours

Abbreviations: MBS, most bothersome migraine-associated symptom.

✓ On track to report

topline results: Q1’20

MINDSET Physician Survey Informs Market Opportunity


Dave Marek

CHIEF COMMERCIAL OFFICERAXSOME THERAPEUTICS, INC.

42%Neurologists,HA Specialists

35%Neurologists,

Other

24%Primary Care Physicians

Primary Survey Objectives

• Understand physicians’ views of the unmet

needs in the acute treatment of migraine

• Understand physicians’ receptivity to the

potential AXS-07 product profile

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Migraine Treatment Needs and Physician Receptivity (MINDSET) Survey


AXS-07

Physicians Surveyed (N=106)1

Treat >50,000 migraine patients annually

1Defined as personally treating at least 100 patients with migraine at least once per year.

The MINDSET Survey was commissioned by Axsome Therapeutics and conducted by MEDACorp® in October 2019

42%

34%

21%

3% 1%

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The Survey Highlighted Physicians’ Concerns for Patients with Difficult-to-Treat Migraine Attacks


AXS-07

Half of patients with difficult-to-treat migraines have a history of inadequate response to prior acute migraine treatments

Three-quarters of physicians are significantly-to-moderately concerned about patients progressing to chronic migraine if they have a suboptimal response to one or more acute therapies

31%of patients have difficult-to-treatmigraine attacks

Source: MINDSET Survey conducted by MEDACorp® with Neurologists and Primary Care Physicians in October 2019; n=106.

50

39

24 2320 19

0

25

50

1

History of inadequateresponse to migrainetreatment(s)

Pain intensity (severe)

Inability to toleratecurrent treatment(s)

Migraine associatedwith allodynia

Menstrual-associatedmigraine

Morning migraine ormigraine upon awakening

Significantly concerned

Moderately concerned

Somewhat concerned

Slightly concerned

Not at all concerned

Pe

rcen

tage o

f D

ifficult-t

o-T

reat

Pa

tie

nts

(%

)

Characteristics of Difficult-to-TreatMigraine Patients

Percentage of Physicians Concerned about Progression to Chronic Migraine

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The Survey Strongly Confirmed the Greatest Unmet Need in Migraine Remains Efficacy


AXS-07

Patients switch acute treatments predominantly due to efficacy

Physicians believe, overwhelmingly, efficacy is the most significant unmet need in the acute treatment of migraine


62

26

108

0

25

50

75

1

Efficacy

Tolerability

Mode of administration

Safety

Efficacy

Tolerability

Mode of administration

Safety

Pe

rcen

tage o

f P

atie

nts

(%

)

Reasons for Switching

Most Significant Unmet Need in Migraine

85%

7% 3%

1%

16%

40%

35%

7%

1% 2%

18%

38%

31%

8%

4%

2%

32

Physician Receptivity to AXS-07Potential Product Profile


AXS-07

87%

Prescribe AXS-07

over currently available treatmentsPrescribe AXS-07

over drugs in development1

91%

Physicians’ likelihood to prescribe AXS-07 if it is shown to be superior to rizatriptan on 2-24hr sustained pain freedom in a difficult-to-treat population

with a history of inadequate response to prior acute migraine treatments:

1Including oral CGRPs.


Significantly greater

Moderately greater

Slightly greater

Same

Slightly less

Significantly less

Percentage of Physicians

33

Physician Receptivity to AXS-07Informs Product Positioning


AXS-07

Physicians’ likelihood to prescribe AXS-07 if shown to be superior to the current standard of care on 2-24 hour sustained pain freedom in a difficult-to-treat

population, with a similar safety profile, and no additional access/payer barriers

*Including oral CGRPs.


Percent of patients to whom physicians would prescribe AXS-07

Initial target patient population

22

35

41

49

0

25

50

Category 1 Category 2 Category 3 Category 4

Pe

rcen

tage o

f P

atie

nts

(%

)

Treatment naive

1 priorfailure

2 priorfailures

3 or more prior failures

• Migraine-treating physicians have a significant percentage of their patients who have

difficult-to-treat migraine

• Physicians are highly concerned about difficult-to-treat migraine patients advancing to

chronic migraine

• Improved efficacy remains the greatest unmet need in the acute treatment of migraine

• If AXS-07 achieves superiority vs. rizatriptan in the MOMENTUM trial, approximately

9 out of 10 physicians would prescribe it more often than current standard-of-care and

more than other emerging therapies without demonstrating similar superiority

• AXS-07 target population expected to be patients with prior suboptimal response to

acute therapy

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MINDSET Survey: Summary


AXS-07

35

Q&A


Closing Remarks


Herriot Tabuteau, MD

CHIEF EXECUTIVE OFFICERAXSOME THERAPEUTICS, INC.

axsome.com

axs-07 and the acute treatment of migraine

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