• U.S. Food and Drug Administration requests additional Phase 3 study
• Issues raised in CRL echo those discussed in FDA Advisory Committee hearing
• The Company intends to pursue all available regulatory pathways to expeditiously bring a potential new treatment to the 13 million Americans who live with PTSD, a condition that has not had new treatments available for nearly 25 years^1,2 

SAN JOSE, Calif., Aug. 9, 2024 /PRNewswire/ -- Lykos Therapeutics ("Lykos"), a company dedicated to transforming mental healthcare, announced that the U.S. Food and Drug Administration ("FDA") has issued a complete response letter ("CRL") for the new drug application ("NDA") for midomafetamine capsules for the treatment of post-traumatic stress disorder ("PTSD") in adults. The FDA communicated that it had completed its review of the NDA and determined that it could not be approved based on data submitted to date. The FDA has requested that Lykos conduct an additional Phase 3 trial to further study the safety and efficacy of midomafetamine. Lykos 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 seeking regulatory approval for midomafetamine capsules.

The issues expressed in the CRL echo those raised during the FDA Advisory Committee meeting on June 4, 2024. The Company and other stakeholders have expressed concerns around the structure and conduct of the Advisory Committee meeting, including the limited number of subject matter experts on the panel and the nature of the discussion, which at times veered beyond the scientific content in the briefing documents. FDA itself has acknowledged potential problems with the Advisory Committee process and has opened a public docket seeking comments on how it can be improved.

Lykos has previously published its response to the substantive issues discussed at the Advisory Committee hearing. Among others, this included concerns that Lykos' clinical data were insufficient to demonstrate durability along with questions about expectancy bias stemming primarily from participants with prior MDMA use. Lykos believes that the data included in the NDA provide sufficient evidence of efficacy and durability in line with the relevant FDA guidance. FDA's draft guidance for industry on psychedelic drugs³ indicates that endpoint data should be collected at 12 weeks; Lykos' Phase 3 studies collected endpoint data at 18 weeks, with additional exploratory endpoints collected six months or more later. In addition, Lykos had aligned with the FDA in the Special Protocol Assessment ("SPA") in 2017 on a variety of bias minimization measures in the study design. Prior MDMA use among participants was not previously viewed as detrimental. As an example, nearly 30% of participants in Lykos' Phase 2 studies reported prior use, which was shared with FDA before establishing the inclusion and exclusion criteria in the Phase 3 trial design.

The Advisory Committee panelists also raised psychotherapy as a concern, with some recommending to further characterize the extent to which psychotherapy contributes to treatment benefit and if it is even necessary. Lykos acknowledges that midomafetamine-assisted therapy represents a novel combination of drug and therapy that raises unique research questions and will continue to engage the FDA as appropriate on these challenges. Lykos remains committed to continuing development of this integrated approach. 

"The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades," said Amy Emerson, Chief Executive Officer of Lykos Therapeutics. "While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature." 

Lykos will work diligently in the coming months to address FDA's concerns and to take advantage of agency processes to resolve scientific disagreements. Following the FDA meeting, Lykos expects to provide an update on next steps for the resubmission.

Emerson added, "Our heart breaks for the millions of military veterans, first responders, victims of sexual and domestic abuse and countless others suffering from PTSD who may now face more years without access to new treatment options. We intend to work tirelessly and use all available regulatory pathways to find a reasonable and expeditious path forward for patients who deserve access to midomafetamine-assisted therapy for PTSD."

As noted above, Lykos negotiated a SPA with the FDA in 2017. Breakthrough Therapy designation was granted that same year. On February 9, 2024, the FDA accepted the company's NDA for midomafetamine used in combination with psychological intervention for adults with PTSD and granted the application Priority Review.

"Developing the first-ever clinical trial design to assess the safety and efficacy of midomafetamine-assisted therapy with patients suffering from moderate to severe PTSD is an enormously complex undertaking," said Jennifer Mitchell, Ph.D., Professor of Neurology and Psychiatry and Behavioral Sciences at UCSF. "Over the course of many years, the researchers, with the support of our sponsor, Lykos, developed and executed Phase 3 studies that we believe demonstrated the approvability of this treatment. We did so in consultation with the FDA and with an agreed Special Protocol Assessment in place. The FDA's decision to request another Phase 3 study is a major setback for the field."

Midomafetamine capsules have not been approved by any regulatory agency. The safety and efficacy of midomafetamine have not been established for the treatment of PTSD. Investigational midomafetamine is also being studied in other indications.  

About PTSD
Prevalence and symptoms  
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 year with women and disadvantaged or marginalized groups more likely to be affected.^5,6 Military personnel also have a greater prevalence of PTSD than the general population.⁷ However, it may not be as widely known 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 These symptoms can impact nearly all aspects of a person's life, including their interpersonal relationships.⁴ PTSD can also be a chronic condition with a World Health Organization study showing that after ten years post-trauma, nearly a quarter of people had not recovered.¹⁰

Co-morbidities and economic impact 
People with PTSD frequently experience anxiety, depression, substance use disorder and suicidal ideation.^11,12 They also may have a greater incidence of medical conditions that impact their physical health, including heart disease, metabolic syndrome and asthma.^13,14,15,16 U.S. Army veterans who developed PTSD after military service have been shown to have approximately two times greater risk of mortality than U.S. Army veterans who did not develop PTSD after military service.¹⁵ In addition to the significant personal impact, PTSD has an enormous economic impact, resulting in an estimated annual cost of over $232 billion in the United States.¹³

PTSD treatment
Trauma-focused talk therapy, which concentrates on memories of the traumatic event or thoughts and feelings associated with the traumatic event is first-line treatment for PTSD, which can be used alone or in combination with medication.¹⁷ There are two SSRIs approved for the treatment of PTSD (sertraline and paroxetine).¹⁸ Studies have shown talk therapy lessens the severity of PTSD symptoms, however, improvements in functioning and quality of life have been modest.^19,20  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.^21,22 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.² 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.²³

About Midomafetamine-Assisted Therapy 
Midomafetamine (MDMA) is commonly known to mental health professionals. In the 1970s and early 1980s, MDMA was used in conjunction with talk therapy by mental health providers to help enhance patients' access, processing and communication of difficult emotions and experiences.²⁴ 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 demonstrated effects of increasing self-awareness leading to introspection and personal reflection.^25,26 

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.²⁷ Since then, research has suggested that MDMA may have potential as a catalyst to support psychotherapy by helping diminish the brain's fear response, allowing people to access and process painful memories without being overwhelmed.²⁸

Lykos, with longstanding roots in advocacy for psychedelic medicine, was the first company to pioneer 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 and submit an NDA to the FDA seeking approval for the treatment of PTSD in adults.

Lykos Therapeutics 
At Lykos Therapeutics, a public benefit corporation ("PBC") founded by the Multidisciplinary Association for Psychedelic Studies ("MAPS"), our mission is to transform mental healthcare. We're applying decades of evidence-based research to develop investigational psychedelics to catalyze therapeutic approaches for mental health conditions. We are relentlessly exploring and reimagining novel approaches to address unmet needs in the mental healthcare space, with an initial focus on PTSD. As a PBC, we are focused on delivering positive impact on our people, communities and society. To learn more visit us at www.lykospbc.com and on LinkedIn, X, Instagram and Facebook. 

¹ VA National Center for PTSD. US Department of Veterans Affairs. Accessed August 9, 2024. https://www.ptsd.va.gov/understand/common/common_adults.asp
² 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
³ Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry (Draft Guidance). https://www.fda.gov/media/169694/download
⁴ The Mayo Clinic, PTSD, symptoms and causes. Accessed February 14, 2024. www.mayoclinic.org/diseases-conditions/post-traumatic-stress-disorder/symptoms-causes/syc-20355967c
⁵ VA National Center for PTSD. US Department of Veterans Affairs. https://www.ptsd.va.gov/understand/common/common_adults.asp Accessed May 13, 2024.
⁶ Goldstein RB et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(8):1137–1148.
⁷ Lehavot K et al. Post-traumatic stress disorder by gender and veteran status. Am J Prev Med. 2018 Jan;54(1):e1-e9. doi: 10.1016/j.amepre.2017.09.008
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
⁹ Bryant RA. Post-traumatic stress disorder: a state-of-the-art review of evidence and challenges. World Psychiatry. 2019;18(3):259–269.
¹⁰ Rosellini AJ et al. Recovery from DSM-IV post-traumatic stress disorder in the WHO World Mental Health surveys. Psychol Med. 2018 Feb;48(3):437-450. doi: 10.1017/S0033291717001817
¹¹ Grinage B.D. Diagnosis and management of post-traumatic stress disorder. Am Fam Physician. (2003);68(12):2401-2409. PMID: 14705759.
¹² 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 Apr;28(3):318-25. doi: 10.1016/j.janxdis.2014.02.004
¹³ Edmondson D, von Känel R. Post-traumatic stress disorder and cardiovascular disease. Lancet Psychiatry. 2017 Apr;4(4):320-329. doi: 10.1016/S2215-0366(16)30377-7
¹⁴ Krantz DS, Shank LM, Goodie JL. Post-traumatic stress disorder (PTSD) as a systemic disorder: Pathways to cardiovascular disease. Health Psychol. 2022 Oct;41(10):651-662. doi: 10.1037/hea0001127
¹⁵ Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol. 2006 Apr;16(4):248-56. doi: 10.1016/j.annepidem.2005.03.009
¹⁶ Nichter B, Norman S, Haller M, Pietrzak RH. Physical health burden of PTSD, depression, and their comorbidity in the U.S. veteran population: Morbidity, functioning, and disability. J Psychosom Res. 2019 Sep;124:109744. doi: 10.1016/j.jpsychores.2019.109744
¹⁷ 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.
¹⁸ American Psychological Association. Clinical Practice Guidelines for the Treatment of PTSD. Medications (apa.org) Accessed May 17, 2024.
¹⁹ 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.
²⁰ Bonfils, KA et al, Functional outcomes from psychotherapy for people with posttraumatic stress disorder: A meta-analysis. J Anxiety Disorders. 2022;89:102576.
²¹ 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). https://doi.org/10.1080/20008198.2019.1709709
²² Steenkamp, M. M., Litz, B. T., Hoge, C. W., & Marmar, C. R. (2015). Psychotherapy for Military-Related PTSD. JAMA, 314(5), 489. https://doi.org/10.1001/jama.2015.8370
²³ 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
²⁴ 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
²⁵ Nichols, David E. Entactogens: How the name for a novel class of psychoactive agents originated. Frontiers in Psychiatry. 2022 Mar 25;13:863088. doi:10.3389/fpsyt.2022.863088
²⁶ Vollenweider, Franz X.,Dialogues Clin Neurosci. 2001 Dec; 3(4): 265–279.doi: 10.31887/DCNS.2001.3.4/fxvollenweider
²⁷ National Institute on Drug Abuse (NIDA) (nih.gov) What is the history of MDMA? . Accessed, January 17, 2024. What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov)
²⁸ Yazar-Klosinski B, Mithoefer MC. Potential psychiatric uses for MDMA. Clinical Pharmacology & Therapeutics.  2017 Feb;101(2):194-196. doi: 10.1002/cpt.565

View original content:https://www.prnewswire.com/news-releases/lykos-therapeutics-announces-complete-response-letter-for-midomafetamine-capsules-for-ptsd-302219182.html

SOURCE Lykos Therapeutics