A Prospective Feasibility Study Investigating PhEnoconversion of CYP3A4, CYP2C19 and CYP2D6 Genotype in Paediatric and Adolescent and Young Adult patientS With an acUte diagnosiS of Hodgkin or Non-Hodgkin Lymphoma.

PEGASUS aims to test acceptability and feasibility of studying phenoconversion (the change in metabolism phenotype) using probe medications in a paediatric oncology patient population. The study will be conducted in patients (6-25 years of age) with Hodgkin lymphoma or non-Hodgkin lymphoma as exemplar cohort, but with the understanding that cancer-directed and supportive care medicines of the CYP3A4, CYP2C19, and CYP2D6 metabolic pathways are commonly utilised for the treatment of many paediatric, adolescent, young adult, and adult cancers.
The study involves administration of the probe medication at timepoints which align with pre-determined hospital visits for the treatment of lymphoma and subsequent blood draws to measure the metabolism of the probe medications.
The acceptability and feasibility of this study will inform future studies in phenoconversion within the paediatric cancer population to direct more personalised precision medicine.

Start Date01 Mar 2025

Sponsor / Collaborator

Murdoch Childrens Research Institute

NCT06632990 / Not yet recruitingPhase 1

An Open-label, Randomized, Three-arm Study Evaluating the Potential of BMS-984923 to Alter the Systemic Exposure of Three Orally Administered Probe Substrates in Healthy Adult Participants

The goal of this study is to learn if the investigational drug, BMS-984923 will impact the exposure and clearance of other medications when given together. Most drugs are broken down and cleared in the body via cytochrome P450 enzymes in the liver. The metabolism and clearance of certain drugs can be affected by other drugs when dosed together. To evaluate the impact of BMS-984923 on the clearance of other medications, we will investigate three known pathways which may be impacted by BMS-984923.
In this study participants will take one dose of the three known medications, midazolam, caffeine and dextromethorphan together. These drugs are known to be cleared by different cytochrome P450 enzymes. Blood will be collected to evaluate the exposure and clearance of these medications and their primary metabolites. Study participants will then be administered BMS-984923 for 18-days. On the 18th Day of BMS-984923 dosing, participants will again be co-administering midazolam, caffeine and dextromethorphan. Blood will be collected again, and the concentration of each drug will be measured. We will learn in this study if BMS-984923 changes the exposure and metabolism of the known drugs. These results will inform how BMS-984923 can be administered to patients who take multiple medications.

Start Date01 Nov 2024

Sponsor / Collaborator

Allyx Therapeutics, Inc.Startup

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100 Clinical Results associated with σ1 receptor x NMDA receptor

100 Translational Medicine associated with σ1 receptor x NMDA receptor

0 Patents (Medical) associated with σ1 receptor x NMDA receptor

Literatures (Medical) associated with σ1 receptor x NMDA receptor

08 Jul 2024·Psychopharmacology bulletin

The Black Book of Psychotropic Dosing and Monitoring.

Review

Author: DeBattista, Charles ; Schatzberg, Alan F

Introduction Since the last edition of the Black Book, several innovative agents have been approved or are poised to be approved in the coming year. These include novel antidepressants, the first muscarine agonist for the treatment of schizophrenia, the first psychedelic which may be approved for the treatment of PTSD (Post Traumatic Stress Disorder), and the first disease modifying drug for the treatment of Alzheimer's disease. Three new antidepressants have come to the market in the past 18 months. The first of those, Auvelity, the combination of bupropion and dextromethorphan, takes advantage of a pharmacokinetic and pharmacodynamic synergism between the two drugs.⁸⁵ Dextromethorphan has several pharmacodynamic properties including actions on the NMDA receptor and the Sigma 1 receptor, adding to the indirect norepinephrine agonist properties of bupropion. How Dextromethorphan is rapidly metabolized via the CYP2D6 isoenzyme to dextrophan that may have mu opioid agonist properties. The combination with bupropion, a CYP2D6 inhibitor, inhibits the metabolism of dextromethorphan allowing for more consistent therapeutic levels. The combination of dextromethorphan 45 mg twice per day and bupropion SR 105 mg twice daily appears to be more effective than an equivalent dose of bupropion alone both in speeding up antidepressant response and achieving remission. However, it's not clear at this time how the combination would compare with a more typical dose of bupropion of 300-450 milligrams a day range. The phase III program for Auvelity, showed that the drug was well tolerated with the most common side effects being dizziness, headache, and dry mouth.⁸⁶ Another novel antidepressant agent approved in 2023 is zuranolone (Zurzuvae). Zuranolone is an oral analog of IV brexanalone, and like brexanolone, was approved for the treatment of post-partum depression.⁸³ The advantages of zuranolone over brexanalone are many. While brexanolone is a 60-hour intravenous infusion that must be administered in a health care facility, zuranolone is a once/day oral medication that is usually taken at home. Like brexanolone, and unlike most antidepressants, zuranolone has a short course of treatment, lasting just 14 days. Zuranolone's, as does brexanolone, is thought to act primarily as allosteric modulator of the GABA-a receptors. Despite only 14 days of treatment, zuranolone produced in depression in post-partum patients a clinically and significantly meaningful improvement at day 15 and continued to day 45 or 1 month past the end of treatment. Zuranolone is a schedule IV drug. The most common side effect in clinical trials was somnolence with 36% of participants reporting this side effect vs only 6% of those on placebo.⁸⁴ Other common side effects included dizziness, diarrhea and fatigue. While the FDA declined to approve zuranolone as monotherapy or as an adjunctive treatment to standard antidepressants in major depression itself, there are positive studies in non-post-partum major depression albeit with smaller effect sizes and less consistent duration of activity. It is likely that zuranolone will continue to be studied in other depressive syndromes such as depression with anxious distress. The third "new" antidepressant approved late 2023 was gepirone (Exxua). Gepirone is not exactly a new or novel antidepressant and originally sought approval in the US about 20 years ago.⁸⁸ There had been two positive studies of gepirone during the original NDA application but also a number of failed, negative, or non-informative studies as well. Thus, the FDA declined to originally approve the drug. However, failed and negative trials are common with antidepressants and after much internal debate, the FDA ultimately agreed to approve the drug based on the positive trials and a relatively favorable side effect profile. Gepirone, like buspirone, is a partial agonist of the 5HT1a receptor and a 5HT2 antagonist. As such, gepirone does not tend to be associated with sexual side effects, weight gain, or sedation. The most common side effects are dizziness, nausea, and insomnia which tend to improve in many patients over time. Second generation antipsychotics (SGAs) continue to be the only class of agents [other than esketamine (Spravato)] approved in adjunctive treatment of resistant major depression. In addition to olanzapine (combined with fluoxetine; Symbyax), aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti), cariprazine (Vraylar) became the latest SGA to be approved in 2022.⁹⁰ Adjunctive cariprazine at 1.5 mg daily was significantly more effective than adjunctive placebo in patients with MDD who had failed to achieve an adequate response with an antidepressant alone after 6 weeks of treatment. Interestingly, a 3 mg dose of cariprazine was less consistently effective.⁹¹ The major advantage of cariprazine over some of the other approved adjunctive SGA's is easy dosing, with the starting 1.5 mg dose being the optimal therapeutic dose for most people, and a lower metabolic side effect burden with most subjects having limited or no weight gain in short term trials. The most common side effect were akathisia/restlessness, fatigue, and nausea. Lumateperone (Caplyta) is also has positive phase III data in the adjunctive treatment of major depression and is expective file for approval in late 2024. Another recent major development in psychopharmacology is the reemergence of psychedelics in the treatment of psychiatric disorders. The first of these is MDMA (phenethylamine 3,4-methylenedioxymethamphetamine) assisted psychotherapy for the treatment of PTSD. A New Drug Application (NDA) was accepted by the FDA for MDMA in the treatment of PTSD in late 2023.⁸⁷ Because the drug is being fast tracked as a "breakthrough" treatment by the FDA, it was expected to see approval in the summer of 2024. The phase II and III data for MDMA assisted psychotherapy in the treatment of PTSD have been quite consistent and impressive. However, independent reviews have pointed to significant deficiencies in these studies including the bias introduced because of functional unblinding; virtually all patients in psychedelic studies can guess whether they got the active drug or placebo. The functional unblinding, the lack of standardization of adjunctive psychotherapy as well as the abuse potential of MDMA, may delay an FDA approval. The typical regimen in these trials included 3 preparatory psychotherapy sessions followed by once/month dosing sessions (lasting about 8 hours) and using doses of 120-160 mg in a split dose. There were typically 3 monthly dosing sessions, each followed by 3 integrative psychotherapy sessions to help subjects process and understand their experiences during the dosing sessions. In the most recent phase 3 trials, over 70% of subjects no longer met criteria for PTDS compared to 46% of those treated with psychotherapy and placebo alone.⁸⁹ The only approved medications for treating PTSD are two SSRIs, paroxetine and sertraline. These drugs effect only some dimensions of PTSD with only 20-30% achieving a remission level response with these drugs. Thus, MDMA assisted psychotherapy appears to achieve much higher levels of remission and response than has been true for the SSRIs. Since MDMA is not taken continuously, side effects from MDMA tend to be short lived. Side effects have included muscle tightness, nausea, diminished appetite, excessive sweating, feeling cold and dizziness among others. Since MDMA is currently a schedule I drug, it is likely that a rigorous Risk Evaluation Mitigation (REMs) program will be put in place and a limited number of centers and clinicians will be designated to perform MDMA assisted psychotherapy for PTSD. In addition to MDMA, psilocybin-assisted psychotherapy is in phase 3 trials for treating resistant depression but unlikely to be available before late 2025 at the earliest. An argument can be made that there has not been a truly novel antipsychotic since the introduction of clozapine in the US in 1990. All first-generation antipsychotics have been dopamine 2 antagonists and second-generation drugs have involved some ratio of 5HT2 antagonism to D2 blockade. In 2023, the FDA accepted the application of xenomaline/tropsium (KarXT) which may become the first muscarinic M1M4 agonist approved for the treatment of schizophrenia.^82,83 Tropsium is added as a muscarine antagonist to block the peripheral cholinergic effects of a muscarine agonist. Xenomaline/tropsium appears to be effective in treating both positive and negative symptoms of schizophrenia. In a phase 3 study of 407 patients with schizophrenia, xenomaline/tropsium at doses of xenomaline/50 mg/tropsium 20 mg twice daily up to 125 mg/30 mg twice daily was significantly more effective than placebo in treating both and negative symptoms over 5 weeks of treatment. As would be expected, the side effect profile of xenomaline/tropsium is very different that all currently available antipsychotics. There is no risk of EPS as it is not a dopamine antagonist, and xenomaline/tropsium is not associated with significant metabolic effects. The side effects are cholinergic in nature and include constipation, dry mouth, and nausea. A decision is expected in September of 2024. The year 2023 also saw the approval of the first disease modifying drug in the treatment of Alzheimer's disease, lecanemab (Lequembi). While acetylcholinesterase inhibitors and memantine have been available for decades, these drugs modestly improve cognition in Alzheimer's disease patients and do not alter the progressive course of the illness. Lecanemab is an IV monoclonal antibody that targets the removal of beta-amyloid in the brain as well proto-fibrils that are also known to be toxic to neuronal tissue. When given early in the course of the illness, patients treated with Lecanemab showed 27% less decline on some measures of cognition and function than did patients treated with a placebo over 18 months (about 1 and a half years). It is not known whether treatment for longer than 18 months would show lesser or greater decline over time. However, there are simulation studies that suggest that Lecanemab may modestly reduce the number of patients who progress to severe Alzheimer's disease and require institutional care. The standard dose is 10 mg/kg given via IV over one hour every 2 weeks for 18 months. Lecanemab is typically administered in an infusion center so that side effects can be monitored. The most serious side effects of Lecanemab are amyloid related imaging abnormalities (ARIA) that are associated with brain edema and microhemorrhages. ARIA can occur in up to 15% of patients. More common side effects are headache and nausea. While it remains to be seen how useful these new agents will be in clinical practice, they do represent an approach to treating neuropsychiatric disorders that are a notable departure from the pharmacotherapy of the past half century. It seems likely that some patients who have not been able to respond to or tolerate traditional pharmacotherapy will find hope in these new medications.

01 Jun 2022·British Journal of Clinical PharmacologyQ2 · MEDICINE

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers

Q2 · MEDICINE

Article

Author: Sun, Lei ; Lin, Richard ; de Kam, Marieke L. ; von Moltke, Lisa L. ; van Gerven, Joop M. A. ; Siebenga, Pieter S. ; Leigh‐Pemberton, Richard A. ; Zuiker, Rob G. J. A. ; Rezendes, David ; Dijkstra, Francis M. ; Manthis, Joan D.

AimsALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for μ receptor, α1A‐adrenoceptor, α1B‐adrenoceptor, NMDA receptor and sigma non‐opioid intracellular receptor 1. This first‐in‐human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets.MethodsIn 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco‐EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12‐hour post‐dose period using mixed‐effects model for repeated measure (MMRM) with baseline as covariate.ResultsALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30–60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P‐value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed.ConclusionIn line with ALKS 7119’s in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.

14 Nov 2017·Current NeuropharmacologyQ2 · MEDICINE

Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids

Q2 · MEDICINE

Review

Author: Radzik, Tomasz ; Boczek, Tomasz ; Zylinska, Ludmila ; Rebas, Elzbieta

BACKGROUNDNeurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.METHODSShort-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research.RESULTSThe physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident.CONCLUSIONNeurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases.

News (Medical) associated with σ1 receptor x NMDA receptor

28 May 2024

·www.globenewswire.com

Axsome Therapeutics Presents Data from Multiple Programs at the 2024 American Society of Clinical Psychopharmacology Annual (ASCP) Meeting

NEW YORK, May 28, 2024 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders, today announced that data from its industry-leading portfolio of novel products for CNS disorders will be presented at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting, being held May 28-31, 2024, in Miami Beach, Florida. The presentations include new data from post-hoc analyses of Auvelity® showing improvements in anhedonic symptoms that strongly correlate with improvements in daily function in patients with major depressive disorder (MDD) and data on the clinical profile of AXS-05 in treatment of Alzheimer’s disease agitation. Details for the presentation are as follows: Major Depressive Disorder Title: Effects of AXS-05 (Dextromethorphan-Bupropion) in Improving Anhedonia and Interest-Activity Symptoms of MDD and the Associated Improvements in Functional ImpairmentPresentation Date and Time: Wednesday, May 29, 11:15 a.m. – 1 p.m.Lead Author: Roger McIntyre, MD, Professor of Psychiatry and Pharmacology at the University of TorontoPoster Number: W17Location: Salon 4 Title: Real-World AXS-05 Patient Characteristics in Major Depressive DisorderPresentation Date and Time: Wednesday, May 29, 11:15 a.m. – 1 p.m.Lead Author: Andrew Muzyk, MD, Associate Professor of the Practice of Medical Education at Duke UniversityPoster Number: W40Location: Salon 4 Alzheimer’s Disease Agitation Title: Clinical Profile of AXS-05 (Dextromethorphan-Bupropion) in Treating Alzheimer’s Disease Agitation (ADA): Results From The Phase 2/3 Development ProgramPresentation Date and Time: Wednesday, May 29, 11:15 a.m. – 1 p.m.Lead Author: Jeffrey Cummings, MD, ScD, Vice Chair of Research, UNLV Department of Brain HealthPoster Number: W47Location: Salon 4 Cognition Title: Solriamfetol Improves Cognitive Performance in Preclinical Models of Sleep Apnea and in a Randomized Placebo-controlled Study of Sleep Apnea Participants (SHARP)Presentation Date and Time: Thursday, May 30, 12:30 p.m. – 2:15 p.m.Lead Author: David Gozal, MD, MBA, Marie M. and Harry L. Smith Endowed Chair and the Chairman of the Department of Child Health at the University of Missouri Poster Number: T38Location: Salon 4 About AUVELITY®AUVELITY is a novel, oral, NMDA receptor antagonist with multimodal activity approved for the treatment of MDD in adults. AUVELITY is a proprietary extended-release oral tablet containing dextromethorphan HBr (45 mg) and bupropion HCl (105 mg). The dextromethorphan component of AUVELITY is an antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. These actions are thought to modulate glutamatergic neurotransmission. The bupropion component of AUVELITY is an aminoketone and CYP2D6 inhibitor which serves to increase and prolong the blood levels of dextromethorphan. The exact mechanism of action of Auvelity in the treatment of depression is unclear. AUVELITY received Breakthrough Therapy designation from the FDA for the treatment of MDD. INDICATION AND IMPORTANT SAFETY INFORMATION WHAT IS AUVELITY (aw-VEHL-ah-tee)? It is a prescription oral medicine used to treat adults with major depressive disorder (MDD). It is not known if Auvelity is safe and effective for use in children. Auvelity is not approved for uses other than the treatment of MDD. The ingredients in Auvelity, bupropion and dextromethorphan, are the same ingredients found in some other medicines approved for other uses. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT AUVELITY? Auvelity and other antidepressant medicines may increase suicidal thoughts and actions in some children, adolescents, and young adults, especially within the first few months of treatment or when the dose is changed. Auvelity is not for use in children. You should pay close attention to any new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. This is very important when starting or changing the dose of an antidepressant medicine. Call your healthcare provider (HCP) or get emergency help right away if you or your loved one have any of the following symptoms, especially if they are new, worse, or worry you: suicidal thoughts or actionsnew or worsening depression or anxietyagitation or restlessnesstrouble sleeping (insomnia)acting aggressive, being angry violentan extreme increase in activity and talking (mania)panic attacksnew or worsening irritabilityacting on dangerous impulsesother unusual changes in behavior or mood Do not take Auvelity if you: have or had a seizure disorder.have or had an eating disorder like anorexia or bulimia.have recently and suddenly stopped drinking alcohol or use medicines called benzodiazepines, barbiturates, or anti-seizure medicines, and you have recently suddenly stopped taking them.are taking a monoamine oxidase inhibitor (MAOI), have stopped taking an MAOI in the last 14 days, or are being treated with the antibiotic linezolid or intravenous methylene blue. Ask your HCP or pharmacist if you are unsure whether you take an MAOI. Do not start taking an MAOI until you have stopped taking Auvelity for at least 14 days.are allergic to dextromethorphan, bupropion, or any other ingredients in Auvelity. Auvelity may cause serious side effects. Ask your HCP how to recognize the serious side effects below and what to do if you think you have one: Seizures. There is a risk of seizures during treatment with Auvelity. The risk is higher if you take higher doses of Auvelity, have certain medical problems, or take Auvelity with certain other medicines. Do not take Auvelity with other medicines unless your healthcare provider tells you to. If you have a seizure during treatment with Auvelity, stop taking Auvelity and call your HCP right away. Do not take Auvelity again if you have a seizure. Increases in blood pressure (hypertension). Some people may get high blood pressure during treatment with Auvelity. Your HCP should check your blood pressure before you start taking and during treatment with Auvelity. Manic episodes. Manic episodes may happen in people with bipolar disorder who take Auvelity. Symptoms may include: greatly increased energyracing thoughtsunusually grand ideastalking more or faster than usualsevere trouble sleepingreckless behaviorexcessive happiness or irritability Unusual thoughts or behaviors. One of the ingredients in Auvelity (bupropion) can cause unusual thoughts or behaviors, including delusions (believing you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your HCP. Eye problems (angle-closure glaucoma). Auvelity may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your HCP if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Dizziness. Auvelity may cause dizziness which may increase your risk for falls. Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take Auvelity with certain other medicines. Call your HCP or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms: agitationhallucinationsconfusioncomafast heartbeatblood pressure changesdizzinesssweatingflushinghigh body temperature (hyperthermia)shaking (tremors), stiff muscles, or muscle twitchingloss of coordinationseizuresnausea, vomiting, diarrhea COMMON SIDE EFFECTS The most common side effects of Auvelity include dizziness, headache, diarrhea, feeling sleepy, dry mouth, sexual function problems, and excessive sweating.These are not all the possible side effects of Auvelity. Tell your doctor if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch. BEFORE USING Tell your HCP about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.It is important to tell your HCP if you are taking: other medicines containing bupropion or dextromethorphanmedicines to treat depression, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressantstheophyllinecorticosteroidsoral diabetes medicines or use insulin to control your blood sugarmedicines to control appetite (anorectic)nicotine medicines to help you stop smokingstreet (illicit) drugsbenzodiazepines, sedative-hypnotic (sleep medicines), or opiates If you are unsure if you take any of these medicines, ask your HCP. They can tell you if it is safe to take Auvelity with your other medicines.Tell your HCP if you are pregnant or plan to become pregnant. Auvelity may harm your unborn baby if you take it during pregnancy. Auvelity is not recommended during pregnancy. Your HCP will prescribe another treatment for females who plan to become pregnant.One of the ingredients in Auvelity passes into your breast milk. Do not breastfeed during treatment with Auvelity and for 5 days after the final dose. Tell your HCP about all your medical conditions, including if you: have problems with your liver or kidneys.have diabetes, heart disease, or high blood pressure.have a history of seizure, stroke, eating disorder, head injury, or have a tumor in your brain or spinal cord.have a history of alcohol or drug abuse.have a history of seizure, eating disorder, or abuse alcohol or drugs.have low blood sugar, low blood sodium levels, or a history of falls.you take certain other medicines that could interact with Auvelity.have or had a condition known as bipolar disorder, a family history of bipolar disorder, suicide, or depression.have high pressure in the eye (glaucoma). Review the list below with your HCP. Auvelity may not be right for you if: you drink a lot of alcohol.you abuse prescription or street drugs.you are pregnant or plan to become pregnant.you are breastfeeding or plan to breastfeed. HOW TO TAKE Auvelity is available by prescription only.Take Auvelity exactly as instructed by your HCP.Take Auvelity 1 time a day for 3 days, then increase your dose to 2 times a day (taken at least 8 hours apart). Do not take more than 2 Auvelity tablets in 24 hours.If you miss a dose, do not take an extra dose. Wait and take your next dose at the regular time. Do not take more than 1 dose of Auvelity at a time.Do not change your dose or stop taking Auvelity without talking to your HCP.Swallow Auvelity tablets whole. Do not crush, chew, or divide the tablets.Do not give Auvelity to other people.If you take too much Auvelity call your HCP or seek medical advice promptly. LEARN MORE For more information about Auvelity, call 866-496-2976 or visit Auvelity.com.This summary provides basic information about Auvelity but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your doctor. Be sure to talk to your doctor or other HCP about Auvelity and how to take it. Your HCP is the best person to help you decide if Auvelity is right for you. AUV CON BS 10/2022 Please see full Prescribing Information, including Boxed Warning for suicidal thoughts and behaviors, and Medication Guide. About Axsome Therapeutics, Inc. Axsome Therapeutics, Inc. is a biopharmaceutical company developing and delivering novel therapies for central nervous system (CNS) conditions that have limited treatment options. Through development of therapeutic options with novel mechanisms of action, we are transforming the approach to treating CNS conditions. At Axsome, we are committed to developing products that meaningfully improve the lives of patients and provide new therapeutic options for physicians. For more information, please visit the Company’s website at axsome.com. The Company may occasionally disseminate material, nonpublic information on the company website. 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 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/or data readouts, 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 statements regarding the timing of any NDA submission; 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, if approved, 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 geo-political conflicts or a global pandemic 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. Axsome Contacts: Investors:Mark JacobsonChief Operating OfficerAxsome Therapeutics, Inc.One World Trade Center, 22nd FloorNew York, NY 10007Tel: 212-332-3243Email: mjacobson@axsome.com www.axsome.com Media:Darren OplandDirector, Corporate CommunicationsAxsome Therapeutics, Inc.One World Trade Center, 22nd FloorNew York, NY 10007Tel: 929-837-1065Email: dopland@axsome.com www.axsome.com

Drug ApprovalBreakthrough TherapyNDA

13 Feb 2024

·www.biospace.com

Otsuka Drug Candidate Fails Phase III Alzheimer’s Agitation Study

Pictured: Doctor holding a brain scan with an elderly woman patient in the background/iStock, peakSTOCK Otsuka Pharmaceuticals on Monday announced that its investigational drug candidate AVP-786 fell short of its primary efficacy endpoint in a Phase III trial evaluating its effects as a treatment for agitation in Alzheimer’s disease. The Japanese multinational provided only sparse efficacy data in its announcement but said that at 12 weeks, AVP-786 was unable to significantly differentiate itself from placebo in terms of total score on the Cohen-Mansfield Agitation Inventory—a validated 29-item tool used to systematically assess levels of agitation. Full results and analyses of the trial were not yet available, the company said. However, Otsuka did reveal that there were four deaths in the study, only one of which occurred in an AVP-786-treated arm. The study also detected one treatment-emergent adverse event—a fall—that occurred at a frequency of over 5% in patients treated with Otsuka’s candidate. CMO John Kraus in a statement called the results of the study “disappointing,” adding that Otsuka will continue to evaluate the trial’s results “to determine the future potential of AVP-786 in the treatment of agitation associated with dementia due to Alzheimer’s disease.” The company will also submit these data for publication. Originally developed by Avanir Pharmaceuticals, AVP-786 consists of two drugs: ultra-low dose quinidine, an inhibitor of the CYP2D6 enzyme, plus deuterium-modified dextromethorphan, which is an agonist of the NMDA receptor and the sigma-1 receptor as well as an inhibitor of the SERT and NET transporters. The drug combo, particularly the deuterium alteration, makes AVP-786 less susceptible to metabolism and boosts its bioavailability. Otsuka acquired Avanir in December 2014 for $3.5 billion. Avanir had previously been testing AVP-786 in major depressive disorder (MDD) but Otsuka is now only assessing the candidate in agitation in Alzheimer’s disease. Otsuka has an FDA-approved asset for this indication: Rexulti (brexpiprazole), which is an atypical antipsychotic agent approved in May 2023 for the treatment of agitation in Alzheimer’s disease. Rexulti, which Otsuka developed in collaboration with Lundbeck, is also approved as an adjunctive therapy for MDD and as a monotherapy for schizophrenia. Prior to the FDA’s approval, the pharma partners in June 2022 touted strong Phase III data for Rexulti, showing a significant reduction in agitation in treated patients. These findings paved the way for a favorable vote by the FDA’s Pharmacologic Drugs Advisory Committee and its Peripheral and Central Nervous System Drugs Advisory Committee in April 2023, recommending the approval of Rexulti in this indication. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Clinical ResultPhase 3Drug ApprovalAcquisition

04 Jan 2024

·www.globenewswire.com

Axsome Therapeutics Provides Preliminary Fourth Quarter and Full Year 2023 Net Revenue and 2024 Anticipated Milestones

Preliminary total 4Q and full year 2023 net product revenue of $71 million and $204 million, respectively Auvelity preliminary 4Q and full year 2023 net product sales of $49 million and $130 million, respectively Sunosi preliminary 4Q and full year 2023 net product revenue of $22 million and $74 million, respectively 2024 anticipated regulatory milestones include NDA submission for AXS-14 in fibromyalgia and NDA resubmission for AXS-07 in migraine 2024 anticipated clinical trial readouts include topline results of the SYMPHONY trial in narcolepsy, ADVANCE-2 trial in Alzheimer’s disease agitation, and the FOCUS Phase 3 trial in ADHD 2024 anticipated trial initiations include Phase 3 trials of solriamfetol in major depressive disorder, binge eating disorder, and shift work disorder NEW YORK, Jan. 04, 2024 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders, today announced preliminary net product revenue for the fourth quarter and full year ended December 31, 2023. “Axsome completed its first full year as a commercial company in 2023 and, during that time, our medicines reached approximately 100,000 unique patients. Prescriptions for Auvelity and Sunosi totaled more than 236,000 and 139,000, respectively for the full year,” said Herriot Tabuteau, MD, Chief Executive Officer of Axsome. “Looking ahead, 2024 promises to be a busy year for us with an increased field force effort that will support continued strong commercial execution with Auvelity and Sunosi. We also anticipate multiple important clinical and regulatory milestones from our industry leading neuroscience portfolio in 2024. These include topline results from Phase 3 trials in narcolepsy, Alzheimer’s disease agitation, and ADHD, NDA resubmission and submission for migraine and fibromyalgia, respectively, and initiation of Phase 3 trials in major depressive disorder, binge eating disorder, and excessive sleepiness associated with shift work disorder. Collectively, Axsome has the potential to address conditions that impact the lives of more than 150 million patients in the U.S. We are committed to developing and delivering innovative treatments with novel mechanisms of action to address unmet medical needs in serious conditions that affect brain health.” Preliminary Fourth Quarter and Full Year 2023 Net Product Revenue (Unaudited) Based on preliminary unaudited financial information, Axsome expects total product revenue to be approximately $71 million and $204 million for the fourth quarter and full year of 2023, respectively. Auvelity® net product sales are expected to be approximately $49 million and $130 million for the fourth quarter and full year of 2023, respectively.Sunosi® net product revenue is expected to be $22 million and $74 million for the fourth quarter and full year of 2023, respectively. Net product revenue excludes $66 million in license revenue recognized by Axsome in the first quarter of 2023. The foregoing information reflects the Company's estimate with respect to net product revenue for Auvelity and Sunosi based on currently available unaudited information. This announcement is not a comprehensive statement of Axsome’s financial results and is subject to completion of Axsome’s financial closing procedures. Axsome’s final financial results will be issued upon completion of its closing procedures and may vary from these preliminary estimates. 2024 Development Pipeline Anticipated Milestones Axsome is advancing an industry-leading neuroscience portfolio encompassing five innovative late-stage product candidates for 10 serious conditions, which affect more than 150 million people in the U.S. alone. 2024 anticipated milestones for key pipeline programs are summarized below. Regulatory Milestones: AXS-07 for migraine, NDA resubmission (1H 2024)AXS-14 for fibromyalgia, NDA submission (1Q 2024) Clinical Trial Topline Results: Phase 3 SYMPHONY trial of AXS-12 in narcolepsy (1Q 2024)Phase 3 ADVANCE-2 trial of AXS-05 for Alzheimer’s disease agitation (1H 2024)Phase 3 FOCUS trial of solriamfetol in attention deficit hyperactivity disorder (ADHD) in adults (2H 2024) Clinical Trial Initiations: Phase 3 trial of solriamfetol in major depressive disorder (MDD) (1Q 2024)Phase 3 trial of solriamfetol for binge eating disorder (BED) (1Q 2024)Phase 3 trial of solriamfetol in shift work disorder (SWD) (1Q 2024)Pivotal Phase 2/3 trial of AXS-05 for smoking cessation (2024) About AUVELITY® AUVELITY is a novel, oral, NMDA receptor antagonist with multimodal activity approved for the treatment of MDD in adults. AUVELITY is a proprietary extended-release oral tablet containing dextromethorphan HBr (45 mg) and bupropion HCl (105 mg). The dextromethorphan component of AUVELITY is an antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. These actions are thought to modulate glutamatergic neurotransmission. The bupropion component of AUVELITY is an aminoketone and CYP2D6 inhibitor which serves to increase and prolong the blood levels of dextromethorphan. The exact mechanism of action of Auvelity in the treatment of depression is unclear. AUVELITY received Breakthrough Therapy designation from the FDA for the treatment of MDD. INDICATION AND IMPORTANT SAFETY INFORMATION WHAT IS AUVELITY (aw-VEHL-ah-tee)? It is a prescription oral medicine used to treat adults with major depressive disorder (MDD). It is not known if Auvelity is safe and effective for use in children.Auvelity is not approved for uses other than the treatment of MDD. The ingredients in Auvelity, bupropion and dextromethorphan, are the same ingredients found in some other medicines approved for other uses. WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT AUVELITY? Auvelity and other antidepressant medicines may increase suicidal thoughts and actions in some children, adolescents, and young adults, especially within the first few months of treatment or when the dose is changed. Auvelity is not for use in children.You should pay close attention to any new or sudden changes in mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions. This is very important when starting or changing the dose of an antidepressant medicine. Call your healthcare provider (HCP) or get emergency help right away if you or your loved one have any of the following symptoms, especially if they are new, worse, or worry you: suicidal thoughts or actionsnew or worsening depression or anxietyagitation or restlessnesstrouble sleeping (insomnia)acting aggressive, being angry violentan extreme increase in activity and talking (mania)panic attacksnew or worsening irritabilityacting on dangerous impulsesother unusual changes in behavior or mood Do not take Auvelity if you: have or had a seizure disorder.have or had an eating disorder like anorexia or bulimia.have recently and suddenly stopped drinking alcohol or use medicines called benzodiazepines, barbiturates, or anti-seizure medicines, and you have recently suddenly stopped taking them.are taking a monoamine oxidase inhibitor (MAOI), have stopped taking an MAOI in the last 14 days, or are being treated with the antibiotic linezolid or intravenous methylene blue. Ask your HCP or pharmacist if you are unsure whether you take an MAOI. Do not start taking an MAOI until you have stopped taking Auvelity for at least 14 days.are allergic to dextromethorphan, bupropion, or any other ingredients in Auvelity. Auvelity may cause serious side effects. Ask your HCP how to recognize the serious side effects below and what to do if you think you have one: Seizures. There is a risk of seizures during treatment with Auvelity. The risk is higher if you take higher doses of Auvelity, have certain medical problems, or take Auvelity with certain other medicines. Do not take Auvelity with other medicines unless your healthcare provider tells you to.If you have a seizure during treatment with Auvelity, stop taking Auvelity and call your HCP right away. Do not take Auvelity again if you have a seizure.Increases in blood pressure (hypertension). Some people may get high blood pressure during treatment with Auvelity. Your HCP should check your blood pressure before you start taking and during treatment with Auvelity. Manic episodes. Manic episodes may happen in people with bipolar disorder who take Auvelity. Symptoms may include: greatly increased energyracing thoughtsunusually grand ideastalking more or faster than usualsevere trouble sleepingreckless behaviorexcessive happiness or irritability Unusual thoughts or behaviors. One of the ingredients in Auvelity (bupropion) can cause unusual thoughts or behaviors, including delusions (believing you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your HCP. Eye problems (angle-closure glaucoma). Auvelity may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your HCP if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Dizziness. Auvelity may cause dizziness which may increase your risk for falls. Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take Auvelity with certain other medicines. Call your HCP or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms: agitationhallucinationsconfusioncomafast heartbeatblood pressure changesdizzinesssweatingflushinghigh body temperature (hyperthermia)shaking (tremors), stiff muscles, or muscle twitchingloss of coordinationseizuresnausea, vomiting, diarrhea COMMON SIDE EFFECTS The most common side effects of Auvelity include dizziness, headache, diarrhea, feeling sleepy, dry mouth, sexual function problems, and excessive sweating.These are not all the possible side effects of Auvelity. Tell your doctor if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch. BEFORE USING Tell your HCP about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.It is important to tell your HCP if you are taking: other medicines containing bupropion or dextromethorphanmedicines to treat depression, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressantstheophyllinecorticosteroidsoral diabetes medicines or use insulin to control your blood sugarmedicines to control appetite (anorectic)nicotine medicines to help you stop smokingstreet (illicit) drugsbenzodiazepines, sedative-hypnotic (sleep medicines), or opiates If you are unsure if you take any of these medicines, ask your HCP. They can tell you if it is safe to take Auvelity with your other medicines.Tell your HCP if you are pregnant or plan to become pregnant. Auvelity may harm your unborn baby if you take it during pregnancy. Auvelity is not recommended during pregnancy. Your HCP will prescribe another treatment for females who plan to become pregnant.One of the ingredients in Auvelity passes into your breast milk. Do not breastfeed during treatment with Auvelity and for 5 days after the final dose. Tell your HCP about all your medical conditions, including if you: have problems with your liver or kidneys.have diabetes, heart disease, or high blood pressure.have a history of seizure, stroke, eating disorder, head injury, or have a tumor in your brain or spinal cord.have a history of alcohol or drug abuse.have a history of seizure, eating disorder, or abuse alcohol or drugs.have low blood sugar, low blood sodium levels, or a history of falls.you take certain other medicines that could interact with Auvelity.have or had a condition known as bipolar disorder, a family history of bipolar disorder, suicide, or depression.have high pressure in the eye (glaucoma). Review the list below with your HCP. Auvelity may not be right for you if: you drink a lot of alcohol.you abuse prescription or street drugs.you are pregnant or plan to become pregnant.you are breastfeeding or plan to breastfeed. HOW TO TAKE Auvelity is available by prescription only.Take Auvelity exactly as instructed by your HCP.Take Auvelity 1 time a day for 3 days, then increase your dose to 2 times a day (taken at least 8 hours apart). Do not take more than 2 Auvelity tablets in 24 hours.If you miss a dose, do not take an extra dose. Wait and take your next dose at the regular time. Do not take more than 1 dose of Auvelity at a time.Do not change your dose or stop taking Auvelity without talking to your HCP.Swallow Auvelity tablets whole. Do not crush, chew, or divide the tablets.Do not give Auvelity to other people.If you take too much Auvelity call your HCP or seek medical advice promptly. LEARN MORE For more information about Auvelity, call 866-496-2976 or visit Auvelity.com. This summary provides basic information about Auvelity but does not include all information known about this medicine. Read the information that comes with your prescription each time your prescription is filled. This information does not take the place of talking with your doctor. Be sure to talk to your doctor or other HCP about Auvelity and how to take it. Your HCP is the best person to help you decide if Auvelity is right for you. AUV CON BS 10/2022 Please see full Prescribing Information, including Boxed Warning for suicidal thoughts and behaviors, and Medication Guide. About Sunosi® (solriamfetol) Sunosi is a dual-acting dopamine and norepinephrine reuptake inhibitor indicated to improve wakefulness in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA). Sunosi does not treat the underlying cause of OSA and Sunosi does not take the place of any device prescribed for OSA, such as a continuous positive airway pressure (CPAP) machine. It is important that you continue to use these treatments as prescribed by your healthcare provider. Sunosi received U.S. Food and Drug Administration approval on March 20, 2019 to improve wakefulness in adult patients with EDS associated with narcolepsy or OSA and was designated a Schedule IV medicine by the U.S. Drug Enforcement Agency on June 17, 2019. SK Biopharmaceuticals Co., Ltd., the discoverer of the compound, maintains rights in 12 Asian markets, including Korea, China and Japan. Sunosi has orphan drug designation for narcolepsy in the United States. Sunosi is protected by a robust patent estate with expiries out to 2042. More information about Sunosi, including Full Prescribing Information and Medication Guide, is available here. Important Safety Information Before taking SUNOSI, tell your doctor about all of your medical conditions, including if you: have heart problems, high blood pressure, kidney problems, diabetes, or high cholesterol.have had a heart attack or a stroke.have a history of mental health problems (including psychosis and bipolar disorders), or of drug or alcohol abuse or addiction.are pregnant or planning to become pregnant. It is not known if SUNOSI will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if SUNOSI passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take SUNOSI. Do not take SUNOSI if you are taking, or have stopped taking within the past 14 days, a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI). What are the possible side effects of SUNOSI? SUNOSI may cause serious side effects, including: Increased blood pressure and heart rate. SUNOSI can cause blood pressure and heart rate increases that can increase the risk of heart attack, stroke, heart failure, and death. Your doctor should check your blood pressure before, and during, treatment with SUNOSI. Your doctor may decrease your dose or tell you to stop taking SUNOSI if you develop high blood pressure that does not go away during treatment with SUNOSI.Mental (psychiatric) symptoms including anxiety, problems sleeping (insomnia), irritability, and agitation. Tell your doctor if you develop any of these symptoms. Your doctor may change your dose or tell you to stop taking SUNOSI if you develop side effects during treatment with SUNOSI. The most common side effects of SUNOSI include: headachedecreased appetiteproblems sleepingnauseaanxiety These are not all the possible side effects of SUNOSI. Call your doctor for advice about side effects. SUNOSI (solriamfetol) is available in 75 mg and 150 mg tablets and is a federally controlled substance (CIV) because it contains solriamfetol that can be a target for people who abuse prescription medicines or street drugs. Keep SUNOSI in a safe place to protect it from theft. Never give or sell your SUNOSI to anyone else because it may cause death or harm them and it is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines, or street drugs. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see here for full Prescribing Information. SUN CON ISI 05/2022 About Axsome Therapeutics, Inc. Axsome Therapeutics, Inc. is a biopharmaceutical company developing and delivering novel therapies for central nervous system (CNS) conditions that have limited treatment options. Through development of therapeutic options with novel mechanisms of action, we are transforming the approach to treating CNS conditions. At Axsome, we are committed to developing products that meaningfully improve the lives of patients and provide new therapeutic options for physicians. For more information, please visit the Company’s website at axsome.com. The Company may occasionally disseminate material, nonpublic information on the company website. 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 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/or data readouts, 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 statements regarding the timing of any NDA submission; 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, if approved, and the potential impact on the Company’s anticipated cash runway; differences between the Company’s 2023 preliminary financial information disclosed herein as compared to the Company’s final 2023 audited financial statements; delays with respect to the Company’s 2024 anticipated milestones; unforeseen circumstances or other disruptions to normal business operations arising from or related to geo-political conflicts or a global pandemic 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. Axsome Contacts: Investors:Mark JacobsonChief Operating OfficerAxsome Therapeutics, Inc.One World Trade Center, 22nd FloorNew York, NY 10007Tel: 212-332-3243Email: mjacobson@axsome.com www.axsome.com Media: Darren OplandDirector, Corporate CommunicationsAxsome Therapeutics, Inc.One World Trade Center, 22nd FloorNew York, NY 10007Tel: 929-837-1065Email: dopland@axsome.com www.axsome.com

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