8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(D)

of the Securities Exchange Act of 1934

April 6, 2020

Date of report (Date of earliest event reported)

Axsome Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

Delaware	001‑37635	45‑4241907
(State or other jurisdiction of incorporation)	(Commission File Number)	(IRS Employer Identification No.)

200 Broadway, 3rd Floor
New York, New York
(Address of principal executive offices) 10038
(Zip Code)

Registrant’s telephone number, including area code (212) 332‑3241

(Former name or former address, if changed since last report)

Securities registered pursuant to Section 12(b) of the Act:

Title of each class:	Trading Symbol(s)	Name of each exchange on which registered:
Common Stock, Par Value $0.0001 Per Share	AXSM	The Nasdaq Global Market

Check the appropriate box below if the Form 8‑K is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425).

☐Soliciting material pursuant to Rule 14a‑12 under the Exchange Act (17 CFR 240.14a‑12).

☐Pre-commencement communications pursuant to Rule 14d‑2(b) under the Exchange Act (17 CFR 240.14d‑2(b)).

☐Pre-commencement communications pursuant to Rule 13e‑4(c) under the Exchange Act (17 CFR 240.13e‑4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b‑2 of the Securities Exchange Act of 1934 (§240.12b‑2 of this chapter).

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒

Item 8.01. Other Events.

On April 6, 2020, Axsome Therapeutics, Inc. (the “Company”) issued a press release announcing that AXS‑07 met the co‑primary endpoints in the Company’s INTERCEPT Phase 3 trial in the early treatment of migraine. The Company will host a conference call at 8:00 a.m. ET on April 6, 2020 to discuss the results of the INTERCEPT trial.

The full text of the press release is filed as Exhibit 99.1 hereto and is incorporated herein by reference. A copy of the presentation that the Company will use in connection with the conference call is filed as Exhibit 99.2 hereto and is incorporated herein by reference.

Item 9.01.Financial Statements and Exhibits.

(d)Exhibits.

Exhibit No.	Description
99.1	Press Release dated April 6, 2020.
99.2	INTERCEPT Presentation.

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SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

	Axsome Therapeutics, Inc.
Dated: April 6, 2020	By:	/s/ Herriot Tabuteau, M.D.
	Name:		Herriot Tabuteau, M.D.
	Title:		President and Chief Executive Officer

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EX-99.1

Exhibit 99.1

Axsome Therapeutics Announces AXS-07  Achieves Both Co-Primary Endpoints  and Prevents Migraine Pain Progression in the INTERCEPT Phase 3  Trial in the Early Treatment of Migraine

Achieved freedom from migraine pain in 33% of AXS-07 patients versus 16% for placebo at 2 hours  (co-primary endpoint, p=0.002)

Prevented progression of migraine pain beyond mild intensity in 74% of AXS-07 patients versus 47% for placebo from 2 to 24 hours (p<0.001)

Return to normal functioning achieved in 74% of AXS-07 patients versus 47% for placebo at 24 hours (p<0.001)

Significantly reduced rescue medication use, with 15% of AXS-07 patients using rescue versus 42% of placebo over 24 hours (p<0.001)

Achieved freedom from most bothersome symptom in 44% of AXS-07 patients versus 27% for placebo at 2 hours (co-primary endpoint, p=0.003)

Rapidly relieved migraine symptoms with numerical superiority starting 30 minutes after dosing

NDA submission of AXS-07 in the acute treatment of migraine on track for 4Q 2020

Company to host conference call today at 8:00 AM ET

NEW YORK, April 6,  2020 (Globe Newswire) – Axsome Therapeutics, Inc. (NASDAQ: AXSM), a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, today announced that AXS-07 substantially and significantly eliminated migraine pain, and substantially and significantly prevented progression of migraine pain intensity in the INTERCEPT Phase 3 trial of AXS-07 in the early treatment of migraine. In the trial, AXS-07 met the co-primary endpoints of freedom from migraine pain and freedom from most bothersome symptoms as compared to placebo. AXS-07 is Axsome’s novel, oral, multi-mechanistic investigational medicine for the acute treatment of migraine.  INTERCEPT was a randomized, double-blind, placebo-controlled trial in which a total of 302 patients were randomized in a 1:1 ratio to treat a single migraine attack with a single dose of AXS-07 (20 mg MoSEIC™ meloxicam/10 mg rizatriptan), or placebo, at the earliest sign of migraine pain, while the pain intensity was mild.

AXS-07 met both of the two co-primary endpoints  by demonstrating a statistically significantly greater percentage of patients as compared to placebo achieving pain freedom (32.6% versus 16.3%, p=0.002) and freedom from most bothersome symptom (43.9%  versus 26.7%, p=0.003), 2 hours after dosing. AXS-07 durably relieved migraine pain with a statistically significantly greater percentage of patients as compared to placebo achieving sustained pain freedom from 2 to 24 hours after dosing (22.7% versus 12.6%, p=0.030), and from 2 to 48 hours after dosing (20.5% versus 9.6%, p=0.013). AXS-07 rapidly eliminated migraine symptoms, with numerical separation from placebo as early as 30 minutes for migraine pain freedom and most bothersome symptom freedom, achieving statistical significance for migraine pain at 90 minutes (p=0.003) and at every timepoint thereafter.

A single dose of AXS-07 significantly prevented progression of migraine pain beyond mild intensity while significantly reducing the use of rescue medication. Freedom from pain progression from 2 to 24 hours after dosing was achieved by 73.5% of AXS-07 patients versus 47.4% of placebo patients (p<0.001). The effect on pain progression translated to a significant reduction in the use of rescue medication, with only 15.3% of AXS-07 patients requiring rescue medication through 24 hours after dosing, versus 42.2% of placebo patients (p<0.001).

AXS-07 substantially and significantly reduced functional disability, and demonstrated overall disease improvement. AXS-07 treatment resulted in 73.5% of patients able to perform normal activities at 24 hours compared to 47.4% of placebo patients (p<0.001).  On the Patient Global Impression of Change (PGI-C) scale, 52.4% of AXS-07 patients were very much or much improved compared to 27.7% of placebo patients (p<0.001).

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“The INTERCEPT study demonstrated high rates of freedom from migraine pain with AXS-07 treatment, and utilized an innovative design to evaluate migraine pain progression. It is remarkable that early treatment with AXS-07 prevented migraine pain progression in the vast majority of patients and enabled a similarly high percentage of patients to return to normal functioning,” said Dr. Stewart Tepper, Professor of Neurology at the Geisel School of Medicine at Dartmouth. “The multiple mechanisms of AXS-07 address the many disordered physiological processes implicated in migraine attacks. These results, coupled with previous clinical data showing superiority of AXS-07 over an active comparator, provide clinical evidence that this synergistic, multi-mechanistic approach and the rapid absorption of AXS-07 may translate to important benefits for a wide range of patients. As clinicians continue to seek options for their patients with improved efficacy over currently available therapies, AXS-07 may offer an important new treatment for this disabling condition.”

AXS-07 was generally safe and well tolerated in the trial.  The most commonly reported adverse events with AXS-07 were somnolence, dizziness, and paresthesia, all of which occurred at a rate of less than five percent.  There were no serious adverse events in the trial.

“We are very pleased with the strong results of the Phase 3 INTERCEPT trial, which confirm the superior and durable efficacy of AXS-07. The prevention of migraine pain progression, and the substantial increase in the rate of pain freedom demonstrated with early treatment with AXS-07, expand and enhance its differentiated profile for the acute treatment of migraine,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “With INTERCEPT and the previously completed MOMENTUM Phase 3 trial in patients with a history of inadequate response to prior acute treatments, AXS-07 has now been evaluated in two positive well-controlled trials. These trials demonstrate the efficacy of AXS-07 against potent active and placebo comparators, across a spectrum of migraine attack settings, regardless of the timing of migraine treatment, disease severity, or baseline pain intensity. INTERCEPT strengthens our planned NDA for AXS-07 in the acute treatment of migraine, which remains on track to be submitted to the FDA in the fourth quarter.”

AXS-07 has been evaluated in the completed MOMENTUM Phase 3 trial for which positive results were previously announced. The MOMENTUM trial enrolled only patients with a history of inadequate response to prior acute treatments, with patients waiting to treat their attacks only when the migraine pain had reached moderate or severe intensity. This is in contrast to the INTERCEPT trial, which enrolled all comers and in which patients were instructed to administer AXS-07 at the earliest sign of migraine pain while the pain was mild, before progressing to moderate or severe intensity.

“Migraine is one of the most disabling disorders, incapacitating sufferers and seriously damaging home life, social activity and the ability to work. Published surveys have underscored that patients remain dissatisfied with the efficacy of currently available therapies,” said Cedric O’Gorman, MD, Senior Vice President of Clinical Development and Medical Affairs of Axsome. “The results of the INTERCEPT trial demonstrate for the first time that AXS-07 can halt migraine pain progression before reaching moderate or severe intensity. These data grow the body of clinical evidence in support of the potential of AXS-07 to be a multi-mechanistic treatment for migraine with efficacy that is superior to the current standard of care, and which can rapidly, robustly, and durably alleviate symptoms, and return patients to their normal daily activities.”

AXS-07 is a novel, oral, rapidly absorbed, multi-mechanistic investigational medicine for the acute treatment of migraine, consisting of MoSEIC™ meloxicam and rizatriptan. AXS-07 is thought to act by inhibiting CGRP release, reversing CGRP-mediated vasodilation, and inhibiting neuro-inflammation, pain signal transmission, and central sensitization. Axsome’s MoSEIC™ technology significantly increases the speed of absorption of the meloxicam component after oral administration while maintaining a long plasma half-life. AXS-07 is covered by more than 30 issued U.S. and international patents providing protection out to 2036, and Axsome maintains worldwide rights.

Detailed study results, including additional secondary endpoints, will be submitted for presentation at upcoming medical meetings and for publication.

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Summary of Topline Results of the INTERCEPT Trial

Patient Population

     Patients were instructed to administer AXS-07 at the earliest sign of migraine pain, while the pain was mild, before progressing to moderate or severe intensity.

     Enrolled all comers.

Co-Primary Endpoints, Onset, and Durability

     AXS-07 demonstrated statistically significant improvement as compared to placebo on both of the co-primary endpoints of pain freedom (32.6% versus 16.3%, p=0.002), and freedom from most bothersome symptom (43.9% versus 26.7%, p=0.003), 2 hours after dosing.

     AXS-07 was numerically superior to placebo as early as 30 minutes for migraine pain freedom and most bothersome symptom freedom, achieving statistical significance for migraine pain freedom at 90 minutes (p=0.003) and at every time thereafter.

     Sustained pain freedom from 2 to 24 hours after dosing was experienced by 22.7% of patients treated with AXS-07, compared to 12.6% with placebo (p=0.030).

     Sustained pain freedom from 2 to 48 hours after dosing was experienced by 20.5% of patients treated with AXS-07, compared to 9.6% with placebo (p=0.013).

Prevention of Migraine Pain Progression, and Rescue Medication Use

     AXS-07 prevented progression of migraine pain intensity beyond mild in 73.5% of patients versus 47.4% of placebo patients from 2 to 24 hours (p<0.001).

     Rescue medication was used by 15.3% of AXS-07 patients, compared to 42.2% of placebo over 24 hours (p<0.001).

Functional and Global Improvement

     The ability to perform normal activities was achieved by 73.5% of AXS-07 patients compared to 47.4% of placebo patients at 24 hours (p<0.001).

     On the Patient Global Impression of Change (PGI-C) scale, 52.4% of AXS-07 patients were very much or much improved compared to 27.7% of placebo patients (p<0.001).

Safety and Tolerability

     AXS-07 was generally safe and well tolerated in the trial.

     The most commonly reported adverse events with AXS-07 were somnolence, dizziness, and paresthesia, all of which occurred at a rate of less than five percent.

     There were no serious adverse events in the trial.

Conference Call Information

Axsome will host a conference call and webcast with slides today at 8:00 AM Eastern to discuss the topline results of the INTERCEPT trial of AXS-07 in the early treatment of migraine. To participate in the live conference call, please dial (844) 698-4029 (toll-free domestic) or (647) 253-8660 (international), and use the passcode 5960729. The live webcast can be accessed on the “Webcasts & Presentations” page of the “Investors” section of the Company’s website at axsome.com. A replay of the webcast will be available for approximately 30 days following the live event.

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About the INTERCEPT Trial

INTERCEPT (Initiating Early Control of Migraine Pain and Associated Symptoms) is a Phase 3, randomized, double-blind, multicenter, placebo-controlled trial evaluating the early treatment of migraine with AXS-07. A total of 302 patients were randomized in a 1:1 ratio to treatment with AXS-07 or placebo. Patients were instructed to administer AXS-07 at the earliest sign of migraine pain, while the pain was mild. The two co-primary endpoints of the trial are the proportion of patients who are free from headache pain two hours after dosing, and the proportion of patients who no longer suffer from their most bothersome migraine-associated symptom (nausea, photophobia, or phonophobia) two hours after dosing.

About Migraine

Over 37 million Americans suffer from migraine according to the Centers for Disease Control, and it is the leading cause of disability among neurological disorders in the United States according to the American Migraine Foundation. Migraine is characterized by recurrent attacks of pulsating, often severe and disabling head pain associated with nausea, and sensitivity to light and or sound. It is estimated that migraine accounts for $78 billion in direct (e.g. doctor visits, medications) and indirect (e.g. missed work, lost productivity) costs each year in the United States [1]. Published surveys of migraine sufferers indicate that more than 70% are not fully satisfied with their current treatment, that nearly 80% would try a new therapy, and that they desire treatments that work faster, more consistently, and result in less symptom recurrence [2,3].

About AXS-07

AXS-07 is a novel, oral, investigational medicine with distinct dual mechanisms of action under development for the acute treatment of migraine. AXS-07 consists of MoSEIC™ meloxicam and rizatriptan. Meloxicam is a new molecular entity for migraine enabled by Axsome’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in rapid absorption of meloxicam while maintaining a long plasma half-life. Meloxicam is a COX-2 preferential non-steroidal anti-inflammatory drug and rizatriptan is a 5-HT_1B/1D agonist. AXS-07 is designed to provide rapid, enhanced and consistent relief of migraine, with reduced symptom recurrence. AXS-07 is not approved by the FDA.

About Axsome Therapeutics, Inc.

Axsome Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders for which there are limited treatment options. Axsome’s core CNS product candidate portfolio includes five clinical-stage candidates, AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14. AXS-05 is being developed for major depressive disorder (MDD), treatment resistant depression (TRD), Alzheimer’s disease (AD) agitation, and for smoking cessation treatment. AXS-07 is being developed for the acute treatment of migraine. AXS-12 is being developed for the treatment of narcolepsy. AXS-14 is being developed for the treatment of fibromyalgia. AXS-05, AXS-07, AXS-09, AXS-12, and AXS-14 are investigational drug products not approved by the FDA. For more information, please visit the Company’s website at axsome.com. The Company may occasionally disseminate material, nonpublic information on the company website.

References

1.      Gooch CL, Pracht E, Borenstein AR. The burden of neurological disease in the United States: A summary report and call to action. Ann Neurol. 2017 Apr; 81(4):479-484.

2.      Smelt AF, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJ, De Gucht V, Ferrari MD, Assendelft WJ. What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study. PLoS One. 2014 Jun 16;9(6):e98933.

3.      Lipton RB, Stewart WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(suppl 2):S20-S26.

Forward Looking Statements

Certain matters discussed in this press release are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify

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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, pace of enrollment and completion of the trials (including our ability to fully fund our disclosed clinical trials, which assumes no material changes to our currently projected expenses), futility analyses and receipt of interim results, which are not necessarily indicative of the final results of our ongoing clinical trials, and the number or type of studies or nature of results necessary to support the filing of a new drug application (“NDA”) for any of our current product candidates; our ability to fund additional clinical trials to continue the advancement of our product candidates; the timing of and our ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates (including, but not limited to, FDA’s agreement with the Company’s plan to discontinue the bupropion treatment arm of the ADVANCE-1 study in accordance with the independent data monitoring committee’s recommendations); the potential for the MOMENTUM clinical trial to provide a basis for approval of AXS-07 for the acute treatment of migraine in adults with or without aura, pursuant to our special protocol assessment; the potential for the ASCEND clinical trial, combined with the GEMINI clinical trial results, to provide a basis for approval of AXS-05 for the treatment of major depressive disorder and accelerate its development timeline and commercial path to patients; 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 and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s product candidates, if approved; the Company’s anticipated capital requirements, including the Company’s anticipated cash runway; unforeseen circumstances or other disruptions to normal business operations arising from or related to COVID-19; and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstance. The data disclosed in this press release are considered topline data and subject to further statistical review and the final results may vary.

Axsome Contact:

Mark Jacobson
Chief Operating Officer
Axsome Therapeutics, Inc.
200 Broadway, 3rd Floor
New York, NY 10038
Tel: 212-332-3243
Email: mjacobson@axsome.com

www.axsome.com

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EX-99.2

Exhibit 99.2

NASDAQ: AXSM INTERCEPT Phase 3 Trial of AXS-07 Topline Results Conference Call in Migraine April 6, 2020 © Axsome Therapeutics, Inc.

Overview AXS-07 in Migraine Acute Treatment INTERCEPT Phase 3 Trial Topline Results Clinical Development & Medical Affairs Dave Marek, Chief Commercial Officer © Axsome Therapeutics, Inc. 2 Introduction Mark Jacobson, Chief Operating Officer Overview and Summary Herriot Tabuteau, MD, Chief Executive Officer INTERCEPT Trial Design & Results Cedric O’Gorman, MD, Senior Vice President, Q&A Presenters, Nick Pizzie, Chief Financial Officer and Concluding Remarks Herriot Tabuteau, MD, Chief Executive Officer

FLS Forward-Looking Statements & Safe Harbor Certain information contained in this presentation may include “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that 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, pace of enrollment and completion of the trials (including our ability to fully fund our disclosed clinical trials, which assumes no material changes to our currently projected expenses), futility analyses and receipt of interim results, which are not necessarily indicative of the final results of our ongoing clinical trials and the number or type of studies or nature of results necessary to support the filing of a new drug application for any of our current product candidates; our ability to fund additional clinical trials to continue the advancement of our product candidates; the timing of and our ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates (including, but not limited to, FDA’s agreement with the Company’s plan to discontinue the bupropion treatment arm of the ADVANCE-1 study in accordance with the independent data monitoring committee’s recommendations); the Company’s ability to obtain additional capital necessary to fund its operations; the Company’s ability to generate revenues in the future; the potential for the MOMENTUM clinical trial to provide a basis for approval of AXS-07 for the acute treatment of migraine in adults with or without aura, pursuant to our special protocol assessment; the potential for the ASCEND clinical trial, combined with the GEMINI clinical trial results, to provide a basis for approval of AXS-05 for the treatment of major depressive disorder and accelerate its development timeline and commercial path to patients; 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 and collaborations; the enforceability of the Company’s license agreements; the acceptance by the market of the Company’s product candidates, if approved; the Company’s anticipated capital requirements, including the Company’s anticipated cash runway; unforeseen circumstances or other disruptions to normal business operations arising from or related to COVID-19; 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. The data disclosed in this presentation are considered topline data and subject to further statistical review and the final results may vary. © Axsome Therapeutics, Inc. 3

Overview and Summary Herriot Tabuteau, MD CHIEF EXECUTIVE OFFICER AXSOME THERAPEUTICS, INC. © Axsome Therapeutics, Inc. 4

INTERCEPT AXS-07 INTERCEPT Phase 3 Trial: Summary of Topline Results • AXS-07 is a novel, oral, multi-mechanistic investigational medicine for the acute treatment of migraine • The INTERCEPT trial randomized patients to treat a single migraine attack with a single dose of AXS-07 or placebo, at the earliest sign of migraine pain, while the pain was mild • AXS-07 met the two co-primary endpoints, demonstrating robust rates of migraine pain freedom and and most bothersome symptom freedom at 2 hours compared to placebo • AXS-07 significantly prevented progression of migraine pain beyond mild in the majority of patients from 2 to 24 hours • Treatment with AXS-07 enabled return to normal functioning for the majority of patients at 24 hours • AXS-07 significantly reduced rescue medication use • With the INTERCEPT and MOMENTUM Phase 3 trials, the efficacy of AXS-07 has been demonstrated in two positive trials, across a spectrum of migraine attack settings • The positive INTERCEPT trial results strengthen the planned NDA filing for AXS-07 in the acute treatment of migraine, which remains on track for 4Q 2020 © Axsome Therapeutics, Inc. 5

INTERCEPT Migraine: Disabling Disease in Need of New Treatments • 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 • Migraine treatment guidelines encourage rapid early treatment of migraines to limit reoccurance5 There is an urgent need for new treatments that provide improved 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;390:1211-1259 4Antonaci et al. J Headache Pain. 2011;12:115–125. 5 Silberstein. Neurology. 2000 Sep 26;55(6):754-62. © Axsome Therapeutics, Inc. 6

AXS-07 AXS-07 (MoSEIC™ Meloxicam/Rizatriptan) Multi-Mechanistic Treatment for Migraine  Inhibition of CGRP release  Reversal of CGRP-mediated vasodilation CGRP Mediated Rizatriptan  Cyclooxygenase inhibition  PGE2 synthesis inhibition MoSEIC™ meloxicam Neuroinflammation  Decrease passage of pain signals to trigeminal nucleus caudalis Pain Signal Transmission Rizatriptan MoSEIC™ meloxicam Central Sensitization  Reversal of central sensitization Mechanisms of AXS-07 address multiple disordered physiological processes observed during migraine attacks © Axsome Therapeutics, Inc. 7 Migraine Process AXS-07 Mechanism / ActionComponent

INTERCEPT Phase 3 Trial Design & Results Cedric O’Gorman MD, MBA SENIOR VICE PRESIDENT, CLINICAL DEVELOPMENT AND MEDICAL AFFAIRS AXSOME THERAPEUTICS, INC. © Axsome Therapeutics, Inc. 8

INTERCEPT INTERCEPT Phase 3 Trial: Design Summary INTERCEPT: INiTiating EaRly Control of MigrainE Pain & Associated SympToms Phase 3 trial of AXS-07 for the acute treatment of migraine Single dose Taken at earliest onset of migraine pain Screening n=152 1:1 randomization n=150 Co-Primary Endpoints: • Pain Freedom at 2 hours • Freedom from MBS at 2 hours Secondary Endpoints include: • Sustained pain freedom • Freedom from migraine pain progression • Change in functional disability • Use of rescue medication Abbreviations: MBS, most bothersome migraine-associated symptom. © Axsome Therapeutics, Inc. 9 Placebo AXS-07 (MoSEIC meloxicam 20 mg / rizatriptan 10 mg)

INTERCEPT INTERCEPT Phase 3 Trial: Key Entry Criteria Inclusion Criteria • Male or female, 18 to 65 years of age, inclusive • Established diagnosis (at least 1 year) of migraine with or without aura as defined by the ICHD-3 criteria • An average 2 to 8 migraines per month Exclusion Criteria • Cluster headaches, tension headaches, or other types of migraines • Chronic daily headache (≥15 non-migraine headache days per month) • History of significant cardiovascular disease • Uncontrolled hypertension Abbreviations: ICHD-3 = International Classification of Headache Disorder, 3rd Edition; mTOQ-4 = Migraine Treatment Optimization Questionnaire. © Axsome Therapeutics, Inc. 10

INTERCEPT INTERCEPT Baseline Demographics Characteristics: AXS-07 (20 mg MoSEIC Mlx / 10 mg Riz) Placebo n=140 n=143 Age, years 41.7 (11.58) 41.4 (11.11) Female gender, n (%) 119 (85.0%) 122 (85.3%) Race, n (%) White Black or African American Asian Other or Multiple 118 (84.3%) 18 (12.9%) 1 (0.7%) 3 (2.1%) 116 (81.1%) 17 (11.9%) 7 (4.9%) 3 (2.1%) BMI (mg/kg2) 28.7 (5.68) 28.4 (5.76) Baseline pain intensity, mild 100% 100% Data are mean (SD) unless otherwise stated. Abbreviations: BMI = Body Mass Index; Mlx = meloxicam; Riz = rizatriptan © Axsome Therapeutics, Inc. 11

INTERCEPT Co-Primary Endpoints: Pain Freedom and MBS Freedom at 2 Hours P=0.002 P=0.003 50% 35% 30% 40% 25% 30% 20% S-07 acebo 15% 20% 10% 10% 5% 0% 0% Resolution of MBS at Hour 2 Pain Freedom at Hour 2 Difference P-Value Co-Primary Endpoints AXS-07 - Placebo 16.3% 0.002 Pain Freedom 2 Hours after Dose Resolution of Most Bothersome Symptom 2 Hours after Dose 17.3% 0.003 Most Bothersome Symptom = nausea, photophobia, or phonophobia © Axsome Therapeutics, Inc. 12 Percent of Patients 32.6% 16.3% 43.9% 26.7% AX Pl

INTERCEPT Rapid and Durable Freedom from Time Migraine Pain: Migraine Pain Freedom over 80% .001 70% 60% 50% 40% 30% 20% 10% 0% 0 2 4 6 8 101214 Hour 16 18 20 22 24 • • Numerical separation from placebo as early as 30 minutes after dosing 64% and 69% of AXS-07 patients pain free at 12 and 24 hours, versus 42% and 47% of placebo, respectively. © Axsome Therapeutics, Inc. 13 Percent of Patients Achieving Pain Freedom P<0 P<0.001P<0.001 P<0.001 P<0.001 AXS-07Placebo

INTERCEPT Rapid and Durable Freedom from Migraine Pain: Sustained Pain Freedom 24-Hour Sustained Pain Freedom 48-Hour Sustained Pain Freedom P=0.030 25% 25% 20% 20% 15% 15% AXS-07 Placebo 10% 10% 5% 5% 0% 0% Sustained Pain Freedom (Hour 2-48) Sustained Pain Freedom (Hour 2-24) © Axsome Therapeutics, Inc. 14 Percent of Patients P=0.013 20.5% 9.6% 22.7% 12.6%

INTERCEPT Rapid Freedom from Most Bothersome Symptom: Most Bothersome Symptom Freedom over Time P<0.001 60% 50% 40% AXS-07 Placebo 30% 20% 10% 0% 30 minutes Hour 1 Hour 2 Hour 4 • • Numerical separation from placebo as early as 30 minutes after dosing Most bothersome symptoms: nausea, photophobia, or phonophobia © Axsome Therapeutics, Inc. 15 Percent of Patients Achieving Most Bothersome Symptom Freedom 56% P=0.003 44% 34% 22% 27% 6%4% 15%

INTERCEPT Prevention of Worsening Migraine Pain: Freedom from Pain Progression 2-24 Hours P<0.001 80% 70% 60% 50% S-07 acebo 40% 30% 20% 10% 0% 2-24 Hour Freedom from Pain Progression • A single dose of AXS-07 significantly prevented migraine pain progression beyond mild © Axsome Therapeutics, Inc. 16 Percentage of Patients Free from Migraine Pain Progression 73.5% 47.4% AX Pl

INTERCEPT Prevention of Worsening Migraine Pain: Rescue Medication Use Over Time 50% P<0.001 40% 36% 30% 20% 10% 0% Hour 2 Hour 4 Hour 12 Hour 16 Hour 24 AXS-07 Placebo © Axsome Therapeutics, Inc. 17 Percent of Patients Using Rescue Medications P<0.001 P<0.00142% 39% 15% P<0.001 24% 14% 9% 13% 4%5%

INTERCEPT Return to Normal Functioning: Functional Disability at Hour 24 P<0.001 80% 70% 60% 50% AXS-07 Placebo 40% 30% 20% 10% 0% No Functional Disability at Hour 24 © Axsome Therapeutics, Inc. 18 Percentage of Patients 73.5% 47.4%

INTERCEPT Global Improvement in Migraine Symptoms: Patient Global Impression of Change at Hour 2 P<0.001 60% 50% 40% AXS-07 Placebo 30% 20% 10% 0% "Very Much Improved" or "Much Improved" © Axsome Therapeutics, Inc. 19 Percentage of Patients 52.4% 27.7%

INTERCEPT Safety of AXS-07: Adverse Events Occurring in ≥2% of Subjects AXS-07 (N = 140) Placebo (N = 143) Any Treatment-Emergent AE Somnolence Dizziness Paraesthesia 25 (17.9%) 6 (4.3%) 4 (2.9%) 3 (2.1%) 11 (7.7%) 3 (2.1%) 2 (1.4%) 0 Data presented as number of subjects (% of subjects) • There were no SAEs in the trial © Axsome Therapeutics, Inc. 20

INTERCEPT INTERCEPT Phase 3 Trial Results: Summary • Treatment with AXS-07 resulted in rapid, sustained, and statistically significant efficacy as compared to placebo • Early treatment with AXS-07 resulted in significant prevention of migraine pain progression • Efficacy benefits of AXS-07 translated into significantly less use of rescue medication and return to normal functioning in the vast majority of AXS-07 treated patients • AXS-07 was generally safe and well tolerated in this study © Axsome Therapeutics, Inc. 21

Q&A © Axsome Therapeutics, Inc. 22

Concluding Remarks Herriot Tabuteau, MD CHIEF EXECUTIVE OFFICER AXSOME THERAPEUTICS, INC. © Axsome Therapeutics, Inc. 23

AXS-05 AXS-07: Clinical Development in Migraine Indication Acute treatment of migraine Acute treatment of migraine Acute treatment of migraine History of inadequate response to prior treatments Participation in MOMENTUM or INTERCEPT Patient population All comers Migraine pain severity and treatment timing Moderate or severe migraine pain Earliest onset of migraine pain, while pain is mild Treat all attacks, as needed Phase Pivotal Phase 3 Supportive Phase 3 Open-label Phase 3 Efficacy of AXS-07 vs. Riz vs. MoSEICTM Mlx vs. PBO Efficacy of AXS-07 vs. PBO Long-term safety of AXS-07 Objectives Abbreviations: OL = Open-label; PBO = placebo; Riz = rizatriptan; Mlx = meloxicam • NDA filing of AXS-07 for the acute treatment of migraine, based on positive results from MOMENTUM study, on track for 4Q 2020 © Axsome Therapeutics, Inc. 24 StatusCompletedCompletedOngoing Patients Dosed1526283751 Clinical Program MOMENTUMINTERCEPTAXS-07 / OL

Overview Our CNS Candidates and Pipeline • Five differentiated clinical-stage CNS assets targeting significant and growing markets • Patent protection to 2034-2036, worldwide rights for most product candidates ease: Fast Track Designation Abbreviations: BUP = Bupropion; CNS = Central Nervous System; DM = Dextromethorphan; Mx = Meloxicam; Riz = Rizatriptan; S-BUP = Esbupropion. © Axsome Therapeutics, Inc. 25 Product Candidate Phase 1 Phase 2 Phase 3 NDA AXS-05 (DM + BUP) Major Depressive Disorder: B Treatment Resistant Depress Agitation in Alzheimer’s Dis Smoking Cessation reakthrough Therapy Designati ion: Fast Track Designation on AXS-07 (MoSEIC™ Mx + Riz) Migraine AXS-12 (Reboxetine) Narcolepsy: U.S. Orphan Des ignation AXS-14 (Esreboxetine) Fibromyalgia AXS-09 (DM + S-BUP) CNS Disorders

Corporate Our Clinical and Regulatory Milestones ● NDA submission (4Q) Abbreviations: AD = Alzheimer’s Disease; BUP = Bupropion; DM = Dextromethorphan; MDD = Major Depressive Disorder; Mx = Meloxicam; Riz = Rizatriptan; TRD = Treatment Resistant Depression. ✓ Accomplished milestone. ● Upcoming milestone. 26 © Axsome Therapeutics, Inc. CONFIDENTIAL & PROPRIETARY Product Candidate Indication 2020 AXS-05 (DM + BUP) MDD ● NDA submission (4Q) TRD ✓ STRIDE-1 topline results • Phase 3 trial start (Q3 2020) AD Agitation ● ADVANCE-1 Phase 2/3 topline results (early 2Q) Smoking Cessation ● FDA meeting (2020) AXS-07 (MoSEIC™ Mx + Riz) Migraine  INTERCEPT Phase 3 topline results AXS-12 (Reboxetine) Narcolepsy ● Phase 3 trial start (2020) AXS-14 (Esreboxetine) Fibromyalgia ● FDA feedback (2020)

For more information, please contact Mark Jacobson Chief Operating Officer 212-332-3243 mjacobson@Axsome.com axsome.com