Bupropion Hydrochloride/Dextromethorphan

NEW YORK, April 01, 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, announced the initiation of the ENGAGE Phase 3 trial of solriamfetol, an investigational treatment for binge eating disorder (BED) in adults. ENGAGE (Elucidating TAAR-1, Dopamine, and Norepinephrine in Binge Eating Disorder Using Solriamfetol) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of solriamfetol for the treatment of BED in adults. Approximately 450 patients will be randomized in a 1:1:1 ratio to receive solriamfetol (150 or 300 mg) or placebo for 12 weeks. The primary endpoint will be the change in binge eating episodes. The first patient was screened in the ENGAGE trial in March 2024. About Binge Eating Disorder Binge eating disorder (BED) is a serious, chronic biologically based disorder characterized by recurrent episodes of eating excessive amounts of food within a discrete period of time while also feeling a lack of control over the eating, distress about the bingeing, and without weight-compensatory behaviors seen in bulimia nervosa, such as purging.1 BED is the most common eating disorder, affecting an estimated 2.8% of U.S. adults, or about 7 million, and it is 1.75 times more common in women.2 About Solriamfetol Solriamfetol is a dopamine and norepinephrine reuptake inhibitor and trace amine-associated receptor 1 (TAAR1) agonist. Solriamfetol is not approved by the FDA for the treatment of binge eating disorder. 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 References: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.J. I. Hudson, E. Hiripi, H. G. Pope, and R. C. Kessler, “The Prevalence and Correlates of Eating Disorders in the National Comorbidity Survey Replication,” Biol. Psychiatry, vol. 61, no. 3, pp. 348–358, Feb. 2007, doi: 10.1016/j.biopsych.2006.03.040.

Pictured: Fractured time and melting clock/Taylor Tieden for BioSpace While the past few decades have seen a focus on treating Alzheimer's disease at the source, which is widely considered to be the build-up of amyloid fibrils and tau tangles, many companies are also chasing the first approval of a drug to treat the related psychosis. Anti-amyloid drugs like Eisai and Biogen’s Leqembi and Eli Lilly’s donanemab represent a leap forward, but many experts say success rates are modest, and Aduhelm, Biogen and Eisai’s first anti-amyloid treatment, was discontinued in January. Against this backdrop, companies are increasingly focusing on symptomatic treatments, said Graig Suvannavejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Using a financial model, Suvannavejh estimated that 35% of Alzheimer’s patients have psychosis. Even discounting patients who may not be diagnosed or have access to treatments, this translates to roughly 1 million patients in the U.S. alone, making for a large market opportunity, he told BioSpace. Unconventional Targets According to ClinicalTrials.gov, there are more than 600 active trials studying interventional treatments for Alzheimer’s disease, but fewer than 30 that focus on Alzheimer’s-related psychosis. Given the lack of options, Alzheimer’s patients who experience psychosis may be prescribed off-label antipsychotics approved for schizophrenia, said Christoph Correll, a professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Most antipsychotics target the receptors of dopamine and serotonin, neurotransmitters that are common to many processes in the body. Because of this overlap between molecular pathways in the brain and the rest of the body, the drugs can cause side effects like excessive sleepiness, swallowing difficulties and uncontrolled movements. These effects make compliance an issue for Alzheimer’s patients in particular, who are likely on other medications and may be unwilling to tolerate additional side effects, Correll said. Christiana Bardon, a co-managing partner at MPM BioImpact, told BioSpace that the side effects associated with all antipsychotics are a significant complaint. “Patients who need the antipsychotics discontinue the drugs because of the intolerable side effects,” she said, and the dearth of tolerable treatments for Alzheimer’s patients with psychosis is “a huge unmet medical need.” This is particularly true as the prevalence of the condition increases. “We're having more and more patients develop not just agitation but also psychosis,” Bardon said. With this in mind, many companies are working to make better schizophrenia medicines, and some are repurposing these candidates for Alzheimer's-related psychosis. Karuna Therapeutics is developing KarXT for both schizophrenia and Alzheimer’s-related psychosis. KarXT combines xanomeline, which activates muscarinic receptors, and trospium, which prevents xanomeline from affecting muscarinic receptors outside the brain. This combination helps to prevent side effects like nausea, vomiting and diarrhea, according to the company. Having shown positive clinical trial results in schizophrenia, KarXT is now being tested in Phase III trials for Alzheimer’s-related psychosis. Andrew Miller, Karuna’s founder and president of research and development, told BioSpace the company has seen a “broad spectrum of benefits,” in Alzheimer’s patients, including a lessening of hallucinations and delusions and a reduction in aggression and vocal outbursts. Cerevel Therapeutics’ emraclidine also targets the muscarinic pathway. The candidate selectively binds only one type of muscarinic receptor and, like KarXT, affects the balance of neurotransmitters in the brain. Emraclidine is currently in Phase II trials for schizophrenia and is also in development for Alzheimer’s-related psychosis. A third candidate with an unconventional target is Axsome’s AXS-05, a combination of two drugs: dextromethorphan, which blocks NMDA receptors, and bupropion, which increases the bioavailability of dextromethorphan. Originally conceived as an antidepressant, AXS-05 is now in Phase III trials for Alzheimer’s-related agitation. Agitation usually comes across as physical restlessness or aggression, whereas psychosis involves hallucinations and delusion. The two can often overlap in Alzheimer’s patients but cannot be treated alike, Bardon said. “Agitation is the broader subset that we have to address, and then as the disease progresses, psychotic features may emerge as well,” she explained. Clinical Development Considerations A key sticking point when developing drugs for Alzheimer’s-related psychosis is a lack of biological information. “We don’t really know what the underlying biological mechanism of psychosis and Alzheimer’s is,” Correll said. Unlike in Alzheimer’s disease, there are no clear or unique molecular targets for the related psychosis, according to a 2022 article published in Nature Reviews Neurology. Some studies suggest that genes like APOEε4 and SUMF1 may be involved, but these links have not been substantiated. A lack of good animal models compounds this difficulty, hindering basic research, Bardon said. These uncertainties mean that drug-makers have no concrete targets to aim for. Even when repurposing known antipsychotics, companies must cater to older patients, who have different metabolic rates, require more tightly controlled doses and often have lower tolerability, Bardon explained. It is paramount to ensure safe side effect pro especially because older patients are more likely to also be on other medications, she said. Suvannavejh added that it is also imperative in developing these therapies to recruit a patient population that is as homogeneous as possible, whether by age or the severity of their Alzheimer’s disease or psychosis. When it comes to evaluating the endpoints of a trial, placebo effects are a major concern, Suvannavejh said. This is especially true for neuropsychiatric conditions, as patients may be more suggestible than in other disease areas. Companies must ensure that raters, who track patient responses and behaviors, are trained well and follow the same protocols across sites, Suvannavejh said. Finally, when using existing or new antipsychotics to treat Alzheimer’s-related psychosis, physicians must look closely at the trial data. Correll prioritizes safety and efficacy and then looks at the effect size, which he said is an indicator of the study’s strength. He is also keen to explore new mechanisms that can sidestep the rather overused dopamine and serotonin pathways. A drug with a novel mechanism may be worth testing even if it comes with some side effects, Correll said, as it would allow physicians to tackle the issue from new angles. Correll noted three key aspects of clinical trials in this space: testing drugs first on a small scale, selecting sites and patient populations to reflect the actual medical need and performing thorough follow-ups. These precautions inevitably translate to reliable and sound results, allowing physicians and regulatory bodies to make informed decisions, he said. Precedent Needed The increase in drug development in this space is emblematic of a renewed interest in neuroscience overall, Suvannavejh said. Small companies can focus exclusively on specific problems yet pivot when needed. This combination of focus and flexibility allows them to pursue neglected questions, he noted, paving the way for larger companies to take the solutions forward. Frontrunners Karuna and Cerevel have each been acquired by pharma giants, with Bristol-Myers Squibb paying $14 billion for Karuna and AbbVie putting up $8.7 billion for Cerevel in December 2023. Despite the increased activity, regulatory guidelines are still being established in this space. Although the FDA is working closely with companies, Miller said there is room for improvement. “I think having more clarity and understanding when you work with [regulators] is really important,” he said. Miller looks forward to seeing the first drug approval for Alzheimer’s-related psychosis. “It would establish a clear clinical trial and endpoint precedent,” he said. “I think it would also, importantly, be an example of success.” Sruthi S. Balakrishnan is a freelance academic editor, science writer and fact-checker based in Santa Barbara, California. She can be reached at sruthisb@sciscriber.com.