MAPS PBC Announces Publication of Results from Confirmatory Phase 3 “MAPP2" Trial of MDMA-Assisted Therapy for PTSD in Nature Medicine

• Study met primary and secondary endpoints confirming first Phase 3 study findings
• MAPP2 population reflects PTSD demographic with approximately half of study participants identifying as racially or ethnically diverse
• Company on track for NDA filing in 2023

SAN JOSE, Calif., Sept. 14, 2023 /PRNewswire/ -- MAPS Public Benefit Corporation (“MAPS PBC”), a clinical-stage company dedicated to changing the way mental health conditions are treated, announced that data from the company’s MAPP2 clinical trial, a multi-site Phase 3 study of MDMA-assisted therapy for post–traumatic stress disorder (“PTSD”), was published in the September issue of Nature Medicine.¹ The MAPP2 study met its primary and secondary endpoints confirming the results seen in the first Phase 3 study (MAPP1) that were also published in Nature Medicine.

“MAPP2 data confirm the findings from MAPP1 suggesting the results may be generalized to a broader population of individuals with PTSD who vary not only in the severity of their symptoms, but also in their racial and ethnic backgrounds,” said Jennifer Mitchell, Ph.D., professor of Neurology and Psychiatry & Behavioral Sciences at UCSF and associate chief of staff for research and development at the San Francisco VA Medical Center. “The peer-reviewed publication of MAPP2 confirming the results seen in the first Phase 3 study helps validate the rigor of the data that we have collected in the pivotal program.”

Participants in the MDMA-assisted therapy group experienced a significant reduction in PTSD symptoms versus participants receiving placebo with therapy as measured by a change from baseline in Clinician-Administered PTSD Scale for DSM-5 (“CAPS-5") total severity score (p < 0.001). The data also demonstrated that MDMA-assisted therapy significantly reduced clinician-rated functional impairment as measured by change from baseline in the modified Sheehan Disability Scale (“SDS”) (p = 0.0271). No serious adverse events were reported in either the MDMA group or the control group.¹

“With two positive Phase 3 studies published, we are focused on pulling all of the data together to submit the new drug application for MDMA-assisted therapy to the FDA later this year,” said Amy Emerson, chief executive officer, MAPS PBC. “Given the urgent need for novel effective treatment options for PTSD and with consistent results from two positive Phase 3 trials we are hopeful that MDMA-assisted therapy, if approved by the FDA, could be a new option for patients, providers and therapists to consider.”

In exploratory outcomes, the study showed in the MDMA-assisted therapy group, 86.5% of participants experienced a clinically meaningful improvement at 18 weeks post-baseline, defined as a > 10-point reduction in CAPS-5 total severity score versus 69% in the placebo with therapy group. In addition, results showed that 71.2% of participants who received MDMA-assisted therapy, compared to 47.6% of participants receiving placebo plus therapy, no longer met DSM-5 diagnostic criteria for PTSD at the end of the study.

Study Design
MAPP2 was a randomized, double-blind, placebo-controlled Phase 3 study assessing the efficacy and safety of MDMA-assisted therapy versus placebo with therapy in participants diagnosed with moderate or severe PTSD. The study enrolled adults (> 18 years of age) who met full DSM-5 criteria for PTSD and had a CAPS-5 total severity score of > 28 (moderate or severe) and symptom duration of > six months. The study enrolled 121 participants and of those enrolled, 104 were randomized to either a group that received a split dose separated by one and a half to two hours of 80 or 120 mg MDMA hydrochloride initially followed by 40 or 60 mg during three sessions of therapy, or a group that received placebo plus extended sessions of therapy. In total, 74/104 (71.2%) of participants were assigned female sex at birth, with a higher proportion in the placebo group (42/51, 82.4%) than the MDMA-assisted therapy group (32/53, 60.4%). Participants were ethnically and racially diverse with 33.7% (35/104) identifying their race as other than White and 26.9% (28/104) identifying their ethnicity as Hispanic/Latino. Most participants had a comorbid psychiatric disorder and had PTSD for an average duration of 16 years. The average CAPS-5 score at baseline was 39.0 and was similar between groups. Overall, 28/104 (26.9%) and 76/104 (73.1%) of participants had moderate and severe PTSD respectively. Outcomes were assessed from baseline to the primary endpoint 18-weeks post-baseline visit.

Study Results
MDMA-assisted therapy significantly reduced PTSD symptoms versus placebo with therapy as measured by a reduction in CAPS-5 total severity score from baseline to 18-weeks showing a least-squares mean (95% confidence interval [CI]) change of -23.7 (-26.94, -20.44) for MDMA-assisted therapy versus –14.8 (-18.28, -11.28) for placebo with therapy. MDMA-assisted therapy also significantly reduced clinician-rated functional impairment as measured by a reduction in modified SDS from baseline to 18-weeks resulting in a least-squares mean (95% CI) change of –3.3 (-4.03, -2.60) for MDMA-assisted therapy and –2.1 (-2.89, -1.33) for placebo with therapy. Improvements were observed across all domains including family life, social life, and work life.

Other exploratory outcomes showed that at study termination, in the MDMA-assisted therapy group versus the placebo with therapy group respectively:

• 86.5% of participants experienced a clinically meaningful improvement 18-weeks post-baseline defined by a reduction in CAPS-5 total severity score of >10, compared to 69%.
• 71.2% of participants no longer met DSM-5 criteria for PTSD compared to 47.6%.
• 46.2% met remission criteria compared to 21.4%.

Safety Findings
Safety analysis evaluated treatment emergent adverse events (“TEAEs”) in all participants who received MDMA or placebo. Common adverse events reported were similar to prior studies and consistent with the expected effects of MDMA.^2,3 The most frequently reported adverse events were muscle tightness, nausea, decreased appetite, and hyperhidrosis. These were mostly transient and were mild or moderate in severity.

In accordance with the study protocol, special attention was paid to a subset of adverse events, termed treatment emergent adverse events of special interest (“TEAESIs”), relating to cardiac function, suicide risk, and MDMA abuse, misuse, or diversion. Consistent with MAPP1, there were no new major safety issues reported and no reports of MDMA abuse or dependence, including in participants with histories of, or current, mild or moderate alcohol and substance-use disorders. Rates of cardiac TEAEs were low and they were mild. Participants in the MDMA-assisted therapy group experienced temporary dose-dependent increases in mean blood pressure and pulse during experimental sessions compared with the placebo group, consistent with MDMA’s sympathomimetic effects. ^4,5,6 These transient elevations did not require clinical intervention, including among the subset of participants with well-controlled hypertension. Consistent with PTSD, suicidal ideation was observed in both groups however, MDMA did not appear to increase this risk, and no suicidal behavior was observed.

MDMA-assisted therapy has not been approved by any regulatory agency. The safety and efficacy of MDMA-assisted therapy have not been established for the treatment of PTSD.

About MDMA
MDMA (3,4-Methylenedioxy-methamphetamine) is an entactogen – a class of psychoactive drugs that produce experiences of emotional communion, oneness, relatedness, emotional openness and are thought to have use for various medical conditions.⁷ In the 1960’s and 1970’s MDMA was used in conjunction with psychological therapy by mental health providers to enhance patients’ access, processing, and communication of difficult emotions and experiences.⁸ In 1985, the U.S. Drug Enforcement Agency (“DEA”) made MDMA a Schedule I drug under the Controlled Substances Act preventing it from being used for recreational or medical use.⁹ Since then, research has shown the unique properties of MDMA allow it to act as a powerful catalyst to support psychotherapy by helping attenuate the brain’s fear response allowing patients to access and process painful memories without being overwhelmed.¹⁰ With a growing body of evidence supporting the potential medical use of MDMA, in 2017 the U.S. Food and Drug Administration (“FDA”) granted MDMA-assisted therapy Breakthrough Therapy designation, a process designed to expedite the development and review of drugs intended to treat serious conditions and that preliminary clinical evidence indicates that it may demonstrate substantial improvement over available therapies. MAPS PBC expects to submit a new drug application including data from two Phase 3 studies (MAPP1 and MAPP2) that showed clinically significant improvements in PTSD symptoms following acute treatment with MDMA-assisted therapy to the FDA in 2023. If approved by the FDA, the DEA would reschedule MDMA making it available for prescription medical use. MDMA-assisted therapy is also being studied in other indications.

ABOUT PTSD
PTSD is a mental health condition affecting approximately 13 million Americans each year¹¹, yet currently available treatments only provide modest efficacy.¹² People with PTSD can experience debilitating symptoms that impact nearly all areas of a person’s life.¹³ They also frequently experience comorbidities including anxiety, depression, and substance use disorder.¹⁴ PTSD has an enormous economic impact resulting in an annual burden of over $200 billion.¹⁵ Currently available treatments for PTSD are inadequate to address the full spectrum of patients who need treatment and may not provide adequate relief from debilitating symptoms.¹² These limitations combined with high treatment discontinuation rates¹⁶ underscore the urgent need for novel and effective therapies.

ABOUT MAPS PUBLIC BENEFIT CORPORATION (MAPS PBC)
MAPS Public Benefit Corporation (MAPS PBC) is focused on developing and commercializing prescription psychedelics to bring better treatments to those living with mental health conditions. MAPS PBC has completed two phase 3 clinical trials evaluating investigational MDMA-assisted therapy as a potential treatment for post-traumatic stress disorder (PTSD), both of which met their pre-specified primary and secondary endpoints.^1,2 Founded in 2014, MAPS PBC is a subsidiary of the Multidisciplinary Association for Psychedelic Studies, a 501(c)(3) non-profit organization. For more information, please visit www.mapsbcorp.com and connect with us on LinkedIn and Facebook.

¹ 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.
² 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.
³ Jerome L, Feduccia AA, Wang JB, et al. Long-term follow-up outcomes of MDMA677 assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six 678 phase 2 trials. Psychopharmacology (Berl) 2020;237:2485–97.
⁴ Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Prog Neuropsychopharmacol Biol Psychiatry 201;84:221-9
⁵ Lester SJ, Baggott M, Welm S, et al. Cardiovascular Effects of 3,4-methlenedioxymethamphetamine: a double-blind, placebo-controlled trial. Ann Intern Med 2000;133:969-73.
⁶ Vizeli P, Liechti ME. Safety pharmacology of acute MDMA administration in healthy 683 subjects. J Psychopharmacol. 2017;31(5):576-88.
⁷ O’Neil, M.J., The Merck Index: An Encyclopedia of chemicals, drugs and biologicals. Merck Research Laboratories, Merck and Co. Inc, Whitehouse station, New Jersey, 2006. 319
⁸ 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.
⁹ National Institute on Drug Abuse What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov). Accessed, September 8, 2023. What is the history of MDMA? | National Institute on Drug Abuse (NIDA) (nih.gov)
¹⁰ Yazar-Klosinski B, Mithoefer MC. Potential Psychiatric Uses for MDMA. Clinical Pharmacology & Therapeutics, 2016 Nov 9. https://doi.org/10.1002/cpt.565
¹¹ VA National Center for PTSD. US Department of Veterans Affairs. Accessed February 14, 2023. https://www.ptsd.va.gov/understand/common/common_adults.asp
¹² Morina N. Remission from post-traumatic stress disorder in adults: a systematic review and meta-analysis of long term outcome studies. Clin Psychol Rev. (2014) Apr;34(3):249-55. doi: 10.1016/j.cpr.2014.03.002.
¹³ The Mayo Clinic, PTSD, Symptoms and Causes www.mayoclinic.org/diseases-conditions/post-traumatic-stress-disorder/symptoms-causes/syc-20355967c
¹⁴ Grinage B.D. Diagnosis and Management of Post-traumatic Stress Disorder. Am Fam Physician. (2003);68(12):2401-2409.
¹⁵ 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.
¹⁶ Varker T. Dropout from guideline-recommended psychological treatments for posttraumatic stress disorder: A systematic review and meta-analysis. Journal of Affective Disorders Reports (2021) Apr 2021, 100093. doi: 10.1016/j.jadr.2021.100093

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