SERT x 5-HT2A receptor

On Friday , two days ahead of schedule, the FDA handed Lykos Therapeautics a complete response letter for the drugmaker's midomafetamine capsules for PTSD. In the letter, the agency communicated that the NDA could not be approved based on the data submitted and requested that Lykos conduct an additional phase 3 trial to further study the safety and efficacy of midomafetamine. The issues expressed in the CRL echo those raised during the FDA AdComm meeting back in June , where the Psychopharmacologic Drugs Advisory Committee voted against treatment's approval on the grounds of both efficacy (2-9 against) and risk benefit (1-10 against). There have been concerned expressed about the AdComm meeting, however, including the limited number of subject matter experts on the panel and the nature of the discussion, which, according to Lykos, went beyond the scientific content in the briefing documents. Lykos has previously published a response to the issues discussed at the hearing, including concerns that Lykos' clinical data were insufficient to demonstrate durability along with questions about expectancy bias stemming primarily from participants with prior MDMA use. If it had been approved, the treatment — which involves MDMA capsules used in combination with psychological intervention — would have be the first psychedelic-assisted therapy approved for PTSD and the first new treatment for PTSD in more than two decades. Lykos says it plans to request a meeting with the FDA to ask for reconsideration of the decision and to further discuss the agency's recommendations for a resubmission.

Novel compounds protected under Enveric’s intellectual property portfolio provide potential licensing opportunities and non-dilutive revenue streams. CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Enveric Biosciences (NASDAQ: ENVB) (“Enveric” or the “Company”), a biotechnology company dedicated to the development of novel neuroplastogenic small-molecule therapeutics for the treatment of depression, anxiety, and addiction disorders, today announced the discovery of multiple, promising novel compounds sourced using the company’s Psybrary™ platform and proprietary computational chemistry and artificial intelligence (AI) drug-discovery system (PsyAI™). The novel compounds span seven distinct molecule classes totaling at least 57 unique product opportunities, all of which are protected by Enveric’s expansive intellectual property portfolio and represent potential out-licensing opportunities and non-dilutive revenue streams for the Company. Together, the novel and distinct molecule classes broaden and deepen Enveric’s library of assets targeting difficult-to-address mental health disorders, adding to its lead candidate EB-003, a first-in-class neuroplastogen designed to eliminate hallucinations, and EB-002, formerly EB-373, a next generation synthetic prodrug of the active metabolite, psilocin. “Our ability to identify EB-003 and EB-002 as our lead drug candidates was the result of an extensive process in which our research team analyzed more than one thousand compounds spanning numerous classes of molecules, utilizing our proprietary PsyAI and Psybrary platforms,” said Joseph Tucker, Ph.D., Director and CEO of Enveric. “As a result, Enveric now possesses what we believe to be one of the most diverse portfolios of potential drug molecules for the treatment of key, underserved mental health and neurological disorders. Our dedicated approach to protecting our discoveries should enable us to generate significant near- and long-term value for our shareholders via potential partnering and/or licensing agreements.” The novel compounds span seven diverse molecule classes and subclasses, including: Novel Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRI) Also known as triple reuptake inhibitors (TRIs), SNDRIs are an emerging class of medications designed to treat severe depression and anxiety disorders. Enveric SNDRI compounds show strong binding to serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT). Enveric SNDRI compounds also demonstrate distinct additional serotonin receptor binding profiles that bear similarities to those of the antidepressant Nefazodone and the anxiolytic Buspirone. Non-selective Serotonin Reuptake Inhibitor (NSRI) Enveric NSRI compounds show strong binding to SERT, as well as to the 5-HT1A receptor, known to be a therapeutically valuable target. Certain of Enveric’s NSRIs demonstrate additional binding to various serotonin and dopamine family receptors, with binding profiles similar to the antidepressant Vortioxetine and the atypical antipsychotic Aripiprazole. Novel MDMA Derivatives (EMD) Series Twenty novel MDMA derivatives are separated into three subgroups: Strong 5-HT2A receptor binding, Weak 5-HT2A binding, and No 5-HT2A receptor binding. Current literature indicates agonism of the 5-HT2A receptor is linked to hallucination in humans and also to the induction of neuroplasticity. Each subgroup of Enveric’s novel MDMA derivatives demonstrates unique and expanded receptor binding activity targeting adrenergic and/or dopaminergic receptors as well as epinephrine/norepinephrine family receptors. Some of the resulting receptor binding profiles are similar to the anxiolytic Buspirone, the antiepileptic Fenfluramine, the ADHD drug Guanfacine, and the atypical antipsychotic Aripiprazole. Bifunctional Psilocin Prodrugs (BPP) BPPs are readily absorbed, detectable in plasma, and converted to therapeutically relevant levels of plasma psilocin, with demonstrated lower Head Twitch Response (HTR) relative to psilocybin in mice; HTR is reported in the literature to be a predictive indicator for hallucination in humans. Each BPP parent prodrug demonstrates its own unique binding pro serotonin 5-HT1A receptor, 5-HT1B receptor and SERT, with similarities to anxiolytics Buspirone, antidepressant/anxiolytic Flesinoxan, and the antidepressant Paroxetine. Novel Psilocin Prodrug (NPP) Series NPPs are designed to be metabolized to release therapeutic levels of systemic psilocin at varying rates, providing treatment regimen optionality. Included in this series are four compounds that can be converted upon direct intravenous injection to psilocin: potentially bypassing the need for first-pass metabolism, making them amenable to non-oral forms of administration (e.g. intranasal, sublingual, buccal). Melatonin-Receptor Agonist (MRA) Series Melatonin, a natural indolamine, is essential for regulating circadian rhythm in mammals and is often used in to treat a variety of sleep disorders. Enveric MRA compounds demonstrate strong binding to the MT1 Melatonin receptor with some being highly selective for MT1 while others demonstrate expanded target binding profiles similar to the antidepressants Agomelatine, Vortioxetine, Imipramine, and Trazodone. Neuroplastogenic Antidepressant (NAD-01) Designed to induce neuroplasticity and promote long-term therapeutic benefit in patients suffering from severe depressive mood disorders. Demonstrates neuroplastogenic activity comparable to known 5-HT2A receptor agonist N,N-Dimethyltryptamine (DMT). Demonstrates weak 5-HT2A receptor binding affinity and activation. Produces lower Head Twitch Response relative to psilocin and DMT, while promoting recovery of sucrose preference (SP) in stressed mice - an accepted model for evaluation of antidepressant activity. For more information about Enveric’s novel preclinical compounds spanning multiple, distinct classes of molecules, please visit: . About Enveric Biosciences Enveric Biosciences (NASDAQ: ENVB) is a biotechnology company dedicated to the development of novel neuroplastogenic small-molecule therapeutics for the treatment of depression, anxiety, and addiction disorders. Leveraging its unique discovery and development platform, Psybrary™, Enveric has created a robust intellectual property portfolio of New Chemical Entities for specific mental health indications. Enveric’s lead program, EB-003, is a first-in-class approach to the treatment of difficult-to-address mental health disorders designed to promote neuroplasticity without inducing hallucinations in the patient. Enveric is also developing EB-002, formerly EB-373, a next generation synthetic prodrug of the active metabolite, psilocin, being studied as a treatment of psychiatric disorders. Enveric is headquartered in Naples, FL with offices in Cambridge, MA and Calgary, AB Canada. For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements and forward-looking information within the meaning of applicable securities laws. These statements relate to future events or future performance. All statements other than statements of historical fact may be forward-looking statements or information. Generally, forward-looking statements and information may be identified by the use of forward-looking terminology such as “plans,” “expects” or “does not expect,” “proposed,” “is expected,” “budgets,” “scheduled,” “estimates,” “forecasts,” “intends,” “anticipates” or “does not anticipate,” or “believes,” or variations of such words and phrases, or by the use of words or phrases which state that certain actions, events or results may, could, should, would, or might occur or be achieved. Forward-looking statements may include historical statements and statements regarding beliefs, plans, expectations, or intentions regarding the future and are based on the beliefs of management as well as assumptions made by and information currently available to management. Actual results could differ materially from those contemplated by the forward-looking statements as a result of certain factors, including, but not limited to, the ability of Enveric to: carry out successful clinical programs in Australia; achieve the value creation contemplated by technical developments; avoid delays in planned clinical trials; establish that potential products are efficacious or safe in preclinical or clinical trials; establish or maintain collaborations for the development of therapeutic candidates; obtain appropriate or necessary governmental approvals to market potential products; obtain future funding for product development and working capital on commercially reasonable terms; scale-up manufacture of product candidates; respond to changes in the size and nature of competitors; hire and retain key executives and scientists; secure and enforce legal rights related to Enveric’s products, including patent protection; identify and pursue alternative routes to capture value from its research and development pipeline assets; continue as a going concern; and manage its future growth effectively. A discussion of these and other factors, including risks and uncertainties with respect to Enveric, is set forth in Enveric’s filings with the Securities and Exchange Commission, including Enveric’s Annual Report on Form 10-K and its Quarterly Reports on Form 10-Q. Enveric disclaims any intention or obligation to revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

PDUFA date is August 11, 2024 If approved, this would be the first MDMA-assisted therapy and psychedelic-assisted therapy SAN JOSE, Calif., Feb. 9, 2024 /PRNewswire/ -- Lykos Therapeutics (formerly MAPS Public Benefit Corporation) ("Lykos"), a company dedicated to transforming mental healthcare, announced that the U.S. Food and Drug Administration ("FDA") has accepted its new drug application ("NDA") for midomafetamine capsules ("MDMA") used in combination with psychological intervention, which includes psychotherapy (talk therapy) and other supportive services provided by a qualified healthcare provider for individuals with post-traumatic stress disorder ("PTSD"). The FDA has granted the application priority review and has assigned a Prescription Drug User Fee Act ("PDUFA") target action date of August 11, 2024. If approved, this would be the first MDMA-assisted therapy and psychedelic-assisted therapy. "Securing priority review for our investigational MDMA-assisted therapy is a significant accomplishment and underscores the urgent unmet need for new innovation in the treatment of PTSD," said Amy Emerson, chief executive officer of Lykos Therapeutics. "We remain focused on working with the FDA through the review process and preparing for a controlled launch with an emphasis on quality should this potential treatment be approved." The NDA submission included results from numerous studies including two randomized, double-blind, placebo-controlled Phase 3 studies (MAPP1 and MAPP2) evaluating the efficacy and safety of MDMA used in combination with psychological intervention versus placebo with therapy in participants diagnosed with severe or moderate to severe PTSD, respectively. Both MAPP1 and MAPP2 studies met their primary and secondary endpoints and were published in Nature Medicine. 1, 2 The primary endpoint for both studies was to assess changes in PTSD symptom severity as measured by the change from baseline in Clinician-Administered PTSD Scale for DSM-5 ("CAPS-5"). The key secondary endpoint of both studies was to assess improvement in functional impairment associated with PTSD as measured by the change from baseline in the Sheehan Disability Scale ("SDS"). No serious adverse events were reported in the MDMA group in either study. The FDA grants priority review for drugs that, if approved, would represent significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.3 MDMA-assisted therapy has not been approved by any regulatory agency. The safety and efficacy of MDMA-assisted therapy has not been established for the treatment of PTSD. Investigational MDMA-assisted therapy is also being studied in other indications. About PTSD PTSD is a serious mental health condition that can develop when a person experiences or witnesses a traumatic event. 4 PTSD affects approximately 13 million Americans each year5 with women and disadvantaged or marginalized groups more likely to be affected. 6 Military personnel also have a greater prevalence of PTSD than the general population7 however, it may not be as widely known that that the largest cause of PTSD is non-combat-related trauma (e.g., sexual violence, unexpected death of a loved one, life-threatening traumatic event or interpersonal violence). 8 PTSD results in debilitating symptoms including nightmares and intrusive thoughts related to the trauma, mental and/or physical distress in response to trauma-related stimuli, avoidant behaviors, negative thoughts and feelings, and hyperarousal. 9, 10 These symptoms can impact nearly all aspects of a person's life.[11] People with PTSD frequently also experience anxiety, depression, substance use disorder and suicidal ideation. 12,13 They also may have a greater incidence of medical conditions that impact their physical health, including heart disease, metabolic syndrome and asthma. 14, 15, 16, 17 In addition to the significant personal impact, PTSD has an enormous economic impact resulting in an annual cost of over $232 billion in the United States.18 PTSD Treatment Trauma-focused talk therapy, which concentrates on memories of the traumatic event or thoughts and feelings associated with the traumatic event 19 is first-line treatment for PTSD , which can be used alone or in combination with medication. There are two SSRIs approved for the treatment of PTSD (sertraline and paroxetine). 20 Studies have shown talk therapy lessens the severity of PTSD symptoms, however improvements in functioning and quality of life have been modest. 21,22 Trauma-focused talk therapy is associated with a high risk of dropout and lingering symptoms which occur in as many as two-thirds of people who complete treatment. 23, 24 Current treatments for PTSD are "reasonably efficacious" (Bryant, 2019, p.265), however many people don't respond to treatment or stop treatment early, underscoring the urgent need for new evidence-based therapies and approaches to address this important public health issue. 25 While there have been advancements in the management of PTSD, there have been no new drug treatments approved by the FDA in over twenty years.26 About MDMA-Assisted Therapy MDMA (3,4-methylenedioxymethamphetamine) is not new to mental health professionals. MDMA is an entactogen— a class of psychoactive compounds that are differentiated from classic psychedelics (i.e., psilocybin, mescaline and LSD) and are defined based on their mechanism and known effects of increasing self-awareness leading to introspection and personal reflection.27,,28 In the 1970's and early 1980's MDMA was used in conjunction with talk therapy by mental health providers to enhance patients' access, processing, and communication of difficult emotions and experiences.29 In 1985, the U.S. Drug Enforcement Administration ("DEA") made MDMA a Schedule I drug under the Controlled Substances Act preventing it from being used for recreational or medical use. 30 Since then, research has shown the unique properties of MDMA allow it to act as a powerful catalyst to support psychotherapy by helping diminish the brain's fear response allowing people to access and process painful memories without being overwhelmed. 31 However, additional clinical trials would be needed to secure regulatory review and potential approval. Lykos, with longstanding roots in advocacy for psychedelic medicine, pioneered the first randomized, double-blind, placebo controlled clinical trials evaluating the efficacy and safety of MDMA-assisted therapy as an investigational modality using midomafetamine (MDMA) in combination with psychological intervention to treat PTSD. With a growing body of evidence supporting the potential medical use of MDMA, in 2017 the FDA granted the company's investigational MDMA-assisted therapy Breakthrough Therapy designation, a process designed to expedite the development and review of drugs intended to treat serious conditions for which preliminary scientific evidence indicates that it may demonstrate a substantial improvement over available therapies. If approved by the FDA, the U.S. Drug Enforcement Administration ("DEA") would be required to reschedule MDMA making it available for prescription medical use. Lykos Therapeutics (Formerly MAPS PBC) At Lykos, formerly MAPS PBC, our mission is to transform mental healthcare. We aspire to challenge the status quo through the development of novel therapies and therapeutic approaches to treat mental health conditions. With 30+ years of experience researching psychedelic-assisted therapies, we remain committed to the rigorous pursuit of evidence-based development of novel approaches. Founded in 2014 by the non-profit MAPS, Lykos is a for-profit public benefit corporation ("PBC") established to further the development of investigational psychedelic-assisted therapies. As a PBC, we consider the impact of our decisions on society just as we think about financial implications. Everything we do is viewed through a public benefit lens. To learn more visit us at and on LinkedIn, X, Instagram and Facebook. 1 Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 609 2021;27:1025–33 2 Mitchell JM, Ot'alora MG et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023 Sept 14 doi: 10.1038/s41591-023-02565-4. Online ahead of print. 3 FDA Priority Review. Available at: . Accessed January 2024. 4 The Mayo Clinic, PTSD, Symptoms and Causes . Accessed January 2024. 5 VA National Center for PTSD. US Department of Veterans Affairs. Accessed February 14, 2023. 6 Goldstein RB et al. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(8):1137–1148. 7 Lehavot K, et al. Am J Prev Med. 2018;54(1):e1-e9. 8 Kessler RC, Rose S, Koenen KC, et al. How well can post-traumatic stress disorder be predicted from pre-trauma risk factors? An exploratory study in the WHO World Mental Health Surveys. World Psychiatry. 2014 Oct;13(3):265-74. doi: 10.1002/wps.20150. PMID: 25273300; PMCID: PMC4219068. 9 Davis LL. The economic burden of posttraumatic stress disorder in the United States from a societal perspective. J Clin Psychiatry. (2022) Apr 25;83(3):21m14116. doi: 10.4088/JCP.21m14116. 10 Bryant RA. Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry. 2019;18(3):259–269. 11 The Mayo Clinic, PTSD, Symptoms and Causes 12 Grinage B.D. Diagnosis and Management of Post-traumatic Stress Disorder. Am Fam Physician. (2003);68(12):2401-2409. 13 Rojas SM et al. Understanding PTSD comorbidity and suicidal behavior: associations among histories of alcohol dependence, major depressive disorder, and suicidal ideation and attempts. J Anxiety Disord. 2014;28(3):318–325. 14 Edmondson D, von Känel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017;4(4):320–329. 15 Krantz DS et al. Post-traumatic stress disorder (PTSD) as a systemic disorder: Pathways to cardiovascular disease. Health Psychol. 2022;41(10):651–662. 16 Boscarino, JA. Posttraumatic Stress Disorder and Mortality Among U.S. Army Veterans 30 Years After Military Service. Ann Epidemiol. 2006;16(4):248–256. 17 Nichter B et al. Physical health burden of PTSD, depression, and their comorbidity in the U.S. veteran population: Morbidity, functioning, and disability. J Psychosom Res 2019;124:109744. 18 Davis LL. The economic burden of posttraumatic stress disorder in the United States from a societal perspective. J Clin Psychiatry. (2022) Apr 25;83(3):21m14116. doi: 10.4088/JCP.21m14116. 19 Watkins LE, Sprang KR, Rothbaum BO. Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions. Front Behav Neurosci. 2018 Nov 2;12:258. doi: 10.3389/fnbeh.2018.00258. PMID: 30450043; PMCID: PMC6224348. 20 American Psychological Association. Clinical Practice Guidelines for the Treatment of PTSD. Medications (apa.org) Accessed February 5, 2024. 21 Cusack K, et al. Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis. Clin Psychol Rev. 2016;43:128-141. 22 Bonfils, KA et al, Functional outcomes from psychotherapy for people with posttraumatic stress disorder: A meta-analysis. J Anxiety Disorders. 2022;89:102576. 23 Lewis, C., Roberts, N. P., Gibson, S., & Bisson, J. I. (2020). Dropout from psychological therapies for post-traumatic stress disorder (PTSD) in adults: systematic review and meta-analysis. European Journal of Psychotraumatology, 11(1). 24 Steenkamp, M. M., Litz, B. T., Hoge, C. W., & Marmar, C. R. (2015). Psychotherapy for Military-Related PTSD. JAMA, 314(5), 489. 25 Bryant RA. Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry. 2019;18(3):259–269. 26 Stein MB, Rothbaum BO. 175 Years of Progress in PTSD Therapeutics: Learning From the Past. Am J Psychiatry. 2018 Jun 1;175(6):508-516. doi: 10.1176/appi.ajp.2017.17080955. PMID: 29869547. 27 Nichols, David E.Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated. Frontiers in Psychiatry. Vol 13, 2022. DOI= 10.3389/fpsyt.2022.863088. 28 Vollenweider, Franz X., Brain mechanisms of hallucinogens and entactogens. Dialogues Clin Neurosci. 2001 Dec; 3(4): 265–279.doi: 10.31887/DCNS.2001.3.4/fxvollenweider 29 Wagner MT, Mithoefer MC, Mithoefer AT, MacAulay RK, Jerome L, Yazar-Klosinski B, Doblin R. Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol. 2017 Aug;31(8):967-974. doi: 10.1177/0269881117711712. Epub 2017 Jun 21. PMID: 28635375; PMCID: PMC5544120. 30 National Institute on Drug Abuse What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov). Accessed, January 17, 2024. What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov) 31 Yazar-Klosinski B, Mithoefer MC. Potential Psychiatric Uses for MDMA. Clinical Pharmacology & Therapeutics, 2016 Nov 9. SOURCE Lykos Therapeutics