Lykos Therapeutics: NDA 215455

We also acknowledge receipt of your amendment dated oe , Which was not reviewed for this action.

We have concluded that your application does not provide substantial evidence of effectiveness or establish the safety of your product to support the approval of midomafetamine for the treatment of posttraumatic stress disorder (PTSD).

We have identified several issues with the application that preclude its approval.

This information is necessary for FDA to assess signals of abuse potential and patient impairment in the clinical trials in order to adequately describe the drug effects in labeling and inform appropriate monitoring for the safe use of midomafetamine.

In addition, FDA inspections also identified several unreported adverse events for at least two sites, which increase our concerns about the reliability of the safety data.

During the sponsor inspection, FDA identified that the definition of an adverse event (AE) in the MAPP2 training information and the safety manual were not consistent with the MAPP2 protocol.

Specifically, the training (e.g., All-Site Community Meeting slide presentations) and the safety manual provided by the sponsor to the study sites described an AE as "any undesirable, unfavorable, inappropriate, or untoward medical occurrence in a patient while participating in a clinical trial...

Given the proposed dosing regimen of midomafetamine of a limited duration of three treatment sessions, it is critical to understand whether the treatment benefit is durable beyond the Week 18 assessment to inform the appropriate use of midomafetamine for labeling of the drug.

Information as to how the drug should be managed over the course of a chronic disorder is essential in the directions to health care providers in labeling.

FDA analyses of data from the 2022 National Survey on Drug Use and Health found that, in individuals with past-year moderate or severe mental illness, the lifetime prevalence of MDMA use was 16.2% and 20.5%, respectively.

These limitations impact the interpretability of MAPP1 and MAPP2 and, together with failure of MPLONG to provide evidence of a durable treatment effect, preclude the ability to establish substantial evidence of effectiveness.

The most informative design would be a randomized, double-blind study which includes the initial treatment sessions followed by blinded long-term follow-up with pre-specified criteria for retreatment, if needed.

Your study design should incorporate elements that address the following identified complete response issues:

Incorporate prespecified criteria for recurrence of PTSD symptoms and potential retreatment of participants who meet these criteria, with follow-up assessments collected.

Potential of Drugs (2017) for recommendations regarding how to appropriately document adverse events associated with abuse potential.

We have identified data gaps in your application that are not approvability issues at this time, and that could have been addressed with post-marketing requirements had your application been approved.

1. Characterize the extent to which psychotherapy in the treatment contributes to the treatment benefit and if psychotherapy is necessary for a potential treatment benefit of midomafetamine to inform labeling.

Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1 (a)].

In accordance with section 505-1 of the FDCA, we agree that a REMS will be necessary for midomafetamine capsule, if it is approved, to ensure that the benefits of the drug outweigh the risk of serious harm resulting from patient impairment.

The REMS, should it be approved, will create enforceable obligations.