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Lykos Confident That Working With FDA Will Merit MDMA-AT Approval 

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Lykos Confident That Working With FDA Will Merit MDMA-AT Approval 

Lykos Therapeutics says it is reaching out to the FDA to address outstanding questions about its New Drug Application for MDMA-assisted psychotherapy raised during a June 4 meeting of the Psychopharmacologic Drugs Advisory Committee. The company says that the discussions during the meeting will inform the ongoing development of an effective Risk Evaluation and Mitigation Strategy (REMS) drug safety program that the FDA requires for medications with serious safety concerns. 

The advisory committee voted to oppose the approval of MDMA-assisted psychotherapy as a treatment for adults with PTSD. This guidance is expected to influence the FDA’s final decision on the Lykos New Drug Application which is expected on August 11. 

Advisors voted 9-2 that data gathered by Lykos in its clinical trials was insufficient to show that MDMA-assisted therapy is effective for PTSD. The committee also voted 10-1 that the benefits of MDMA-AT do not outweigh the risks – even when administered within the FDA’s proposed REMS. 

The advisors acknowledged that clinical trials for MDMA-assisted psychotherapy, completed by the Multidisciplinary Association for Psychedelic Studies (MAPS) Public Benefit Corporation before it became Lykos Therapeutics, showed clinically meaningful improvements. MAPS PBC reported that in its first Phase 3 study, 88% of participants with severe PTSD had a clinically significant reduction of PTSD diagnostic scores two months after their third sessions with MDMA-AT, compared to 60% of placebo participants. Both MAPS PBC and Lykos emphasize the need for an effective treatment noting that 13 million adults in the U.S. suffer from PTSD in a given year and more than 350 million people have PTSD worldwide.  

The concerns raised by the advisors during the meeting included issues with unreported adverse events related to the abuse potential of MDMA, bias in patients and therapists due to blinding strategies in clinical investigations, a report of sexual abuse during a clinical trial in Canada, lack of diversity among trial participants, and concerns about safety data including outcomes related to cardiovascular issues. In this interview with Lucid News, Lykos Therapeutics addresses questions that surfaced during the advisory hearing and reflects on their strategy going forward. 

Was Lykos expecting the Psychopharmacologic Drugs Advisory Committee to issue guidance that opposed the approval of MDMA-assisted psychotherapy as a treatment for adults with PTSD. If so, what preparations had been made to address these concerns? 

Given that both of our Phase 3 clinical trials met the primary and secondary endpoints combined with the significant unmet need in PTSD, we expected the FDA Advisory Committee to support the approval of MDMA-assisted therapy. We have sent a response to the FDA to address the outstanding questions that were raised during the PDAC meeting that we did not have the opportunity to answer. In addition, we are in ongoing discussions with the FDA about a REMS program and believe the discussions that occurred at the June 4th meeting can help inform crucial elements to be incorporated into a REMS program. We are also working with the FDA to determine the most appropriate post-marketing plans to address the outstanding questions raised, including how best to support the responsible integration of MDMA-assisted therapy into the healthcare system. 

Is there information or concerns that Lykos was prepared to address during the advisory meeting that it was not given the opportunity to voice?

Yes, there was not sufficient time provided to answer the panel’s questions. A PDAC member raised questions regarding the screening and enrollment processes utilized in our Phase 3 program implying recruitment of a biased sample. As these studies were conducted at 15 clinical sites in three countries with a mix of institutional settings and private practice settings, the recruitment practices were aligned to industry best practices. The FDA is familiar with the relevant clinical protocols used and has evaluated screening and enrollment procedures in multiple company inspections.

Panel members raised questions regarding potential bias of the Phase 3 study population due to reported pre-study exposure to MDMA. Among those with prior illicit MDMA use, their use was very limited having used on average between two and four times in the previous decade. Patients with past substance use or history of substance use disorders were not excluded from the study as this was deemed crucial for generalizability given the high reported rates of substance use and substance use disorders among the PTSD patient population. 

The data do not indicate that prior MDMA use impacted observed results; there is no meaningful difference in primary outcome measure (change in CAPS-5) or adverse events reported between the subgroup of Phase 3 participants with reported prior illicit MDMA experience and the subgroup of participants without prior illicit use.

PDAC members raised additional concerns regarding the durability of the observed treatment effects. As discussed by the FDA during their presentation, the need to understand durability to support an acute treatment was identified after the MAPP1 study had been unblinded after the database was locked. Durability of this acute treatment has been assessed in both Phase 2 and Phase 3 trials in the development program. MPLONG showed that the differences between the treatment groups observed during the parent study persisted to the long-term follow-up visit (≥6 months following the last medication session in MAPP1/MAPP2). MPLONG provides evidence of durable improvement and remission for the midomafetamine group. Phase 2 studies MP-8 and MP-12 include 12-month follow-up data that were consistent with MPLONG results.

In the follow-up period after the Phase 3 study, patients were permitted to receive additional pharmacotherapies and/or psychotherapy. A PDAC member questioned whether these additional interventions could have impacted the observed durability. This was a complex patient population with [a] high degree of comorbidity (~90% Major Depressive Disorder) and the interventions were not necessarily for PTSD. Given that a substantial proportion of patients with PTSD fail to respond to available therapy (both drug and non-drug therapies) and had PTSD for an average of 15 years, this potential confounder does not undermine the general conclusion that treatment effect appears to persist for at least six months.

In context of the clinical data, there were questions raised regarding the standardization of the psychological intervention utilized. As agreed to with the FDA, we utilized a manualized, patient-directed psychological intervention throughout its clinical program. We believe the protocol helped ensure consistency in the psychological intervention, thus allowing for valid comparison between placebo and midomafetamine groups. Independent, mental health professionals with graduate-level training reviewed a subset of video recordings for each Phase 3 participant and assessed therapist adherence using 56 criteria for preparatory, experimental, and integrative sessions. Adherence raters underwent training and calibration throughout the studies to measure fidelity to the Treatment Manual and did not have contact with the therapists they were assigned to review. In both Phase 3 studies, adherence for both groups was > 90%. 

Some PDAC members raised concerns that the inclusion of psychological intervention in the Phase 3 program confounds interpretability of results with respect to drug effect. The studies were not designed to assess the independent contribution of psychological intervention to treatment benefit. It was done within the context of the SPA. The psychological intervention is seen as a key component of the treatment and to provide therapeutic intervention and patient monitoring. Ultimately, the independent effect of midomafetamine alone was demonstrated in comparison to the placebo group, as all participants were provided comparable psychological intervention. The consistency of the psychological intervention is further supported by the lack of statistically significant variability in treatment outcomes between Phase 3 sites of care (i.e., no site effects).

What is your response to the assessment of the advisory panel that the data gathered in the clinical trials is insufficient to show that MDMA-AT is effective for PTSD?

The midomafetamine clinical development program was designed in consultation with the FDA to ensure the generalizability and interpretability of trial results. The clinical data demonstrate that midomafetamine leads to a rapid, clinically meaningful, durable improvement in patients’ PTSD symptoms. The application includes data from two Phase 3 multi-site, randomized, placebo-controlled trials for midomafetamine that met their primary endpoints: MAPP1 and MAPP2. 

We are grateful to the Agency for organizing the PDAC meeting and the panelists who provided their valuable time and perspectives. The input will be valuable to the FDA as we work through a REMS plan and potential post-marketing studies.  

Do you agree with the advisors’ assessment that the benefits of MDMA-AT do not outweigh the risks?

We do not agree. MDMA-assisted therapy offers statistically significant and clinically meaningful improvement in PTSD symptoms and functional impairment compared to placebo across two Phase 3 trials with evidence of durability over time. This is a novel combination of a limited exposure to [a] drug which catalyzes psychological intervention. The adverse events experienced were as expected for MDMA and were mostly mild and self-limited. The careful screening and monitoring of prospective patients—and the selection and rigorous training of therapists — will be essential for mitigating risks. Overall, given the efficacy and safety data, and the substantial unmet medical need for treatment of a serious and life-threatening disorder – MDMA, in combination with psychological intervention, we believe could provide a potential new option for PTSD if approved. 

Why is there such a large variance between the public confidence that Lykos and MAPS PBC expressed about the chance of FDA approval for MDMA-AT and the recommendation of the advisory committee to deny passage?

Our confidence in the potential approval of MDMA-assisted therapy comes from our belief in the regulatory process and our ongoing collaboration with the FDA. This FDA Advisory Committee meeting was unprecedented in many ways including that it is atypical for an Advisory Committee to review an application that combines a drug and psychological intervention. The panel did not have the historical perspective that the FDA has, having worked with us throughout the program over the years. We believe evaluating the psychological intervention component of MDMA-assisted therapy presented a real challenge for the committee. 

Is Lykos prepared to provide additional data to the FDA, especially regarding unreported adverse events relating to the abuse potential of MDMA? If so, what are the next steps, how long do you estimate this process will take, and what will it cost? 

All adverse events and serious adverse events that were reported to the sponsor were reported to the FDA. Sites were trained to report adverse events according to the protocol that was designed with input from FDA through the SPA, and in accordance with good clinical practice requirements. Ongoing protocols have been amended to ensure reporting of all AEs including those experienced as positive or neutral. AEs of this nature were submitted in the 120 Day Safety Update Report for the NDA and will be summarized in study reports. Should MDMA be approved, any post marketing study commitments will also require reporting of AEs related to abuse potential. The costs associated with running clinical trials can vary depending on the type of study.   

Does Lykos have a response to the FDA’s concerns about the abuse potential of MDMA and its recording of that data? How will Lykos address abuse potential concerns going forward?

Lykos understands that the abuse potential of midomafetamine is an area of concern, however, the abuse potential profile of MDMA is well-characterized by the available literature and data, including through extensive prior NIH-funded research conducted in humans and animals. Importantly, illicit MDMA use is known to be primarily episodic and rarely results in substance use disorders. While use of illicit MDMA cannot be completely prevented, approval of a controlled product would provide the opportunity to regulate and monitor the field to a greater extent than what is currently possible. 

We’re working with the FDA to develop a REMS program to evaluate and mitigate the risk of serious harm resulting from patient impairment. Per the proposed REMS, MDMA will only be dispensed in certified healthcare settings and only with evidence of safe use conditions. This includes training for the prescribers, pharmacists, and therapists and patients will be counseled to support safe use. Patients will be monitored DURING and AFTER the session and will be required to be enrolled into the Midomafetamine Drug Registry.

How did Lykos calculate the potential risk to the passage of the New Drug Application by its decision not to follow the FDA guidance, including using placebos such as low dose MDMA and niacin?

The dosing of the drug and the therapy component was informed by prior information and Phase 2 studies. In the Phase 2 program, we evaluated different study designs including dose response and low-dose controls to help address functional unblinding. We also tested different numbers of preparatory and integration psychotherapy visits. In Phase 2, a greater mean reduction in CAPS-4 scores was observed in participants receiving 3 medication sessions compared to two with comparable safety. No further effect was observed in Phase 2 participants receiving four to six medication sessions. 

The time interval of at least 21 days between medication sessions allows for patients to process and integrate the outcomes of the prior medication session and sufficient time for 3 integration psychotherapy visits. These findings formed the basis for selection of the Phase 3 design which we developed in collaboration with FDA. 

Why didn’t Lykos gather the adverse effects data related to abuse potential as the FDA directed? Did MAPS PBC and Lykos investigators account for a possible bias against collecting data on abuse potential? 

The Company interpreted adverse events to mean untoward or unfavorable and therefore, in our Phase 3 studies, we did not capture effects deemed positive, favorable, or neutral, such as “euphoria” or “elated mood.” However, following dialogue with the Agency the MAPPUSX protocol as well as other ongoing clinical trial protocols have been updated to clarify that all positive, neutral, or favorable adverse events should be collected. 

How will Lykos address possible tension between advocacy from supporters of MDMA-AT and suggestions by advisors for more data going forward? 

As the first company to seek approval of MDMA-assisted therapy, we take this responsibility seriously and are working closely with the FDA to ensure that if approved, this potential new acute intervention will be implemented responsibly, monitored through regulatory pharmacovigilance requirements, and that it is administered to appropriate patients by clinicians who have been trained. We will also work with other advocates and advisors to garner input into how this is potentially rolled out. 

Will concerns by the advisors about the sexual misconduct reported by a MDMA-AT trial participant in 2018 change how Lykos approaches its policies on training and patient safety? 

We regret what happened with these therapists in our study, and the safety of our participants is of utmost importance. Since then, we have carefully developed and implemented policies and practices aimed to prevent, reasonably detect, investigate, report and thoroughly respond to allegations of misconduct. Lykos continues to assess practices regarding the safety of patients through a code of ethics, compliance procedures, a robust quality system, ongoing reviews of clinical trial processes, and ongoing risk assessments.

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How will Lykos build trust with the FDA and the public that adverse events are being adequately reported?

Sites were trained to report adverse events per the protocol and in accordance with Good Clinical Practice guidelines. An independent Data Monitoring Committee provided oversight for the studies. There have been public discussion[s] of some adverse events that were thought to have not been reported such as in the case of suicidality. These cases were because the patient population came in with a high baseline of suicidal ideation and therefore because they did not go over baseline, they were not deemed an adverse event. 

In light of the advisors’ concerns about BIPOC representation in past studies, what is the Lykos plan going forward to include more representative samples in future research?

Diverse staff is critical for recruitment and retention of people of color. In our Phase 3 program, we implemented measures to increase diversity in race and ethnic background at all sites. Our External Advisory Council focused on diversity, equity, and inclusion reviewed and recommended changes to therapist assessment tools, therapy training, recruitment of staff, therapists, and study subjects as well as protocol language. Trial sites were provided with an additional budget to compensate subjects for study-related costs, such as childcare and transportation which may provide additional barriers to entry. All therapists were required to attend a racial justice and microaggressions training and respond to a reflective knowledge assessment afterward. These tactics will need to be continued in any future studies.

Do you think that asking the FDA to evaluate psychotherapy protocols outside their area of expertise was an error and potentially amplified the advisors’ concerns about possible abuse by therapists engaged in MDMA-AT? 

The design of the study was done in collaboration with the FDA. The psychological intervention was the active control and allowed for us to access the potential benefit of adding MDMA to the treatment. Because this was the first drug plus therapy, it was likely complex for the panel. However, we believe that the FDA was comfortable with the design. The case of sexual abuse in our Phase 2 study did provide concern for the panel. If FDA-approved, prescription MDMA-assisted therapy will be launched with careful consideration of its potential benefits and risks, in accordance with established medical guidelines, protocols and quality standards.

Does Lykos anticipate that the FDA will approve the application for MDMA-AT on August 11 and what measures is it taking to persuade the agency to contradict the recommendation of the advisors? 

We have provided a letter addressing the questions from the panel that we did not have the opportunity to address during the meeting. We continue to answer any other questions that the FDA may have. We are working closely with the FDA on the potential REMS program and any post-marketing studies we may need to conduct. We are confident that the benefit-risk profile of MDMA-assisted therapy combined with the significant unmet needs, should support approval of MDMA-assisted therapy to be introduced with the appropriate risk mitigation strategies in place. 

In a story published by The New York Times on May 31, Amy Emerson is quoted as stating, “rejection of the company’s application could produce greater risks given the growing number of people taking illicit drugs or seeking MDMA therapy at underground clinics.” What responsibility does Lykos accept for potentially stimulating demand for MDMA, and what steps will the organization take to support public health related to this issue?  

As there has been a growing body of data supporting the potential use of MDMA-assisted therapy, the public has grown increasingly interested in the use of this potential new treatment for PTSD. The extensive media coverage has contributed to this as well. We believe that if this is approved, it will allow us to educate the HCPs [health care personnel] and patients about the difference between prescription MDMA, if approved, and illicit MDMA and the importance of using the treatment as studied with psychological intervention. 

Does Lykos have any response to the public comments at the advisory hearing?

There were a substantial number of people and advocates testifying to support the approval of MDMA-assisted therapy. We want to thank them for sharing their personal stories. For those who were critical, we hear you and we continue to investigate all allegations. We take them seriously and investigate them appropriately. While there have been a number of allegations, we continue to find that our studies were properly conducted with the appropriate controls in place. 

Do Lykos investors have any public comments about the advisor’s votes? 

You would have to reach out to them. 

Is Lykos anticipating management changes as a result of the advisory recommendations? 

No there are no planned management changes at this time. 

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