Axsome Therapeutics : AXS-12 SYMPHONY Results - Slides

topline data

March 25, 2024

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 continued commercial success of our Sunosi® and Auvelity® products and the success of our efforts to obtain any additional indication(s) with respect to solriamfetol and/or AXS-05; 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 revenues or 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; whether issues identified by FDA in the complete response letter may impact the potential approvability of the Company's NDA for AXS-07 for the acute treatment of migraine in adults with or without aura, pursuant to our special protocol assessment for the MOMENTUM clinical trial; 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 products and product candidates, if approved; the Company's anticipated capital requirements, including the amount of capital required for the continued commercialization of Sunosi and Auvelity and for the Company's commercial launch of its other product candidates, and the potential impact on 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..

This presentation contains statements regarding the Company's observations based upon the reported clinical data. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about the Company's 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.

Axsome, Auvelity, Sunosi, and MoSEIC, are trademarks or registered trademarks of Axsome Therapeutics, Inc. or its affiliates. Except as with respect to Auvelity and Sunosi for their approved indications, the development products referenced herein have not been approved by the FDA.

Today's Agenda

SYMPHONY topline dataQ+A

Mark Jacobson,

COOHerriot Tabuteau, M.D., CEO

Michael J. Thorpy,

M.D.

Dr. Thorpy & Axsome teamHerriot Tabuteau, M.D., CEO

Summary

Narcolepsy: Clinical

Perspective &

Implications of SYMPHONY Study

ResultsConcluding

Remarks

SYMPHONY Phase 3 Trial of AXS-12 in Narcolepsy Summary of Topline Results

• • AXS-12 met the primary endpoint by demonstrating a substantial and statistically significant reduction in weekly cataplexy attacks compared to placebo (p=0.018).

• • AXS-12 achieved statistically significant remission of cataplexy compared to placebo (p=0.008).

• • AXS-12 statistically significantly reduced excessive daytime sleepiness (EDS) severity compared to placebo (p=0.027, CGI-S for EDS).

• • AXS-12 statistically significantly improved concentration and memory compared to placebo (p=0.004, Cognitive Function items of FOSQ-10).

• • AXS-12 statistically significantly reduced overall severity of narcolepsy compared to placebo (p=0.007, CGI-S for narcolepsy).

• • AXS-12 statistically significantly improved overall function and quality of life compared to placebo (p=0.005, FOSQ-10 total score).

• • AXS-12 was well tolerated in the trial.

Narcolepsy: Mechanism of Disease

Norepinephrine is important to the control of muscle tone during wakefulness. Norepinephrine and dopamine play an important in sleep-wake regulation.1-3

Loss of orexin input decreases excitation of neurons that produce norepinephrine and dopamine1,2

*Type 1 narcolepsy. Cataplexy, loss of muscle tone while awake; DA, dopamine; EDS, excessive daytime sleepiness; NE, norepinephrine; NET, norepinephrine transporter; PFC, prefrontal cortex; REM, rapid eye movement.

1. Szabo ST et al. Sleep Med Rev. 2019;43:23-36. 2. Krahn LE, Zee PC, Thorpy MJ. Adv Ther. 2022;39(1):221-243. 3. Scammell TE. N Engl J Med. 2015;373(27):2654-62. 4. Stahl SM, Grady MM. J Clin Psychiatry. 2003;64 Suppl 13:13-7. 5. Burgess CR, Peever JH. Curr Biol. 2013;23(18):1719-25. 6. Wu MF et al. Neuroscience. 1999;91(4):1389-99. 7. Bruinstroop E et al. J Comp Neurol. 2012;520(9):1985-2001.

Emotional inputs activate medial prefrontal cortex

PFC NEURONS

NET

Presynaptic NE neuron

Norepinephrine reuptake

Postsynaptic neuron

Decreased norepinephrine signaling

Presynaptic DA neuron

Dopamine reuptake

Postsynaptic neuron

Decreased dopamine signaling

SPINAL AND CRANIAL MOTOR NEURONS

NET

Presynaptic NE neuron

Norepinephrine reuptake

Postsynaptic neuron

Decreased norepinephrine signaling

Decreased norepinephrine signaling may contribute to cataplexy, excessive daytime sleepiness (EDS), and cognitive impairment1,4-7Decreased dopamine signaling may contribute to EDS and cognitive impairment1,4

AXS-12: Mechanism of Action

title and content slide

AXS-12 (reboxetine) is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator*1-3

NET

Presynaptic NE neuron

Inhibited norepinephrine reuptake

Postsynaptic neuron

Increased norepinephrine Signaling2,3

Dopamine neurons

Ventral tegmental area

Presynaptic DA neuron

Cranial motor neurons

Increased norepinephrine and dopamine signaling in PFC

Inhibited dopamine reuptake via NET in the PFC

Postsynaptic neuron

Increased dopamine signaling2,3

Norepinephrine neurons

Locus coeruleus

A5, A7

Blocking norepinephrine reuptake can reduce cataplexy

AXS-12 improves norepinephrine and cortical dopamine signaling in

Spinal motor neurons

narcolepsy1-3

*In preclinical models. Cataplexy, loss of muscle tone while awake; DA, dopamine; EDS, excessive daytime sleepiness; PFC, prefrontal cortex; NE, norepinephrine; NET, norepinephrine transporter; REM, rapid eye movement.

1. O'Gorman C et al. Poster presented at: Associated Professional Sleep Societies Annual Meeting (SLEEP); August 2020. 2. Linnér L et al. J Pharmacol Exp Ther. 2001;297(2):540-546. 3. Stahl SM. Reboxetine. In: Prescriber's

Guide: Stahl's Essential Psychopharmacology. Cambridge University Press; 2020:681-686.

AXS-12 (reboxetine)

SYMPHONY Phase 3 Study Topline Data

Trial Design and Endpoints

A Phase 3 trial to assess efficacy and safety of AXS-12 as compared to placebo in the treatment of cataplexy in narcolepsy.

Study Design: Phase 3, multicenter, randomized, double-blind, placebo-controlled trial

ESS: Epworth Sleepiness Scale; NSAQ: Narcolepsy Symptom Assessment Questionnaire; QD: once daily dosing; BID: twice daily dosing

Demographics and Baseline Characteristics

Characteristic AXS-12 (n = 46)	Placebo (n = 44)
Age (years) 36 34.2
Sex (% male) 45.7% 34.1%
Time since diagnosis (years, mean) 7.9 6.3
Weekly frequency of cataplexy attacks (median) 19.3 21.6
CGI-S for EDS (mean) 5.3 5.1
ESS total score (mean) 18.3 17.3
CGI-S for narcolepsy (mean) 5.2 4.9
Use of modafinil or armodafinil (%) 32.6% 29.5%
Anxiety/depression, EQ-5D-5L scale (%) 45.5% 45.0%

EDS: Excessive Daytime Sleepiness; CGI-S: Clinical Global Impressions-Severity

Cataplexy Frequency: Primary Endpoint

Change in Weekly Cataplexy Attacks

ChangeinWeekly CataplexyAttacks

Week 1 p=0.007

1.0

Week 2 p=0.006

Week 3 p=0.031

Week 4 p=0.031

Week 5 p=0.018

RateRatio

0.5

0.65

0.49

0.53

0.53

0.49

0.0

Week 1

Week 2

Rate Ratio is calculated as the ratio of change in the AXS-12 group divided by the ratio of change in the placebo group

Week 3

Week 4

Week 5

10