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  "meta": {
    "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.",
    "terms": "https://open.fda.gov/terms/",
    "license": "https://open.fda.gov/license/",
    "last_updated": "2026-08-13",
    "results": {
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  "results": [
    {
      "letter_date": "08/08/2024",
      "approver_title": null,
      "file_name": "CRL_NDA215455_20240808.pdf",
      "letter_year": "2024",
      "approval_status": "Unapproved",
      "approver_name": "Center for Drug Evaluation and Research",
      "approver_center": [],
      "company_rep": "Berra Yazar-Klosinski, PhD",
      "company_address": "Chief Scientific Officer\n3141 Stevens Creek Blvd #40547",
      "company_name": "Lykos Therapeutics",
      "text": "i Lk YN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nNDA 215455\nCOMPLETE RESPONSE\n\nLykos Therapeutics\n\nAttention: Berra Yazar-Klosinski, PhD\nChief Scientific Officer\n\n3141 Stevens Creek Blvd #40547\nSan Jose, CA 95117\n\nDear Dr. Yazar-Klosinski:\n\nPlease refer to your new drug application oe\n\nor midomafetamine capsules.\n\nWe also acknowledge receipt of your amendment dated oe , Which was not\nreviewed for this action. You may incorporate applicable sections of the amendment by\nspecific reference as part of your response to the deficiencies cited in this letter.\n\nWe have completed our review of this application, as amended, and have determined\nthat we cannot approve this application in its present form. We have described our\nreasons for this action below and, where possible, our recommendations to address\nthese issues.\n\nCOMPLETE RESPONSE ISSUES\n\nWe have concluded that your application does not provide substantial evidence of\neffectiveness or establish the safety of your product to support the approval of\nmidomafetamine for the treatment of posttraumatic stress disorder (PTSD). We have\nidentified several issues with the application that preclude its approval.\n\n1. You did not collect important information on events that the participant, therapist, or\nstudy physician considered “positive” or “favorable.” This information is necessary\nfor FDA to assess signals of abuse potential and patient impairment in the clinical\ntrials in order to adequately describe the drug effects in labeling and inform\nappropriate monitoring for the safe use of midomafetamine. In addition, FDA\ninspections also identified several unreported adverse events for at least two sites,\nwhich increase our concerns about the reliability of the safety data.\n\nFDA had advised in our ow , communication that “For all Phase 1, 2 and\n3 studies, AEs associated with potential abuse or overdose must be documented,”\nand we referred you to our guidance for industry, Assessment of Abuse Potential of\nDrugs (2017) for recommendations regarding how to appropriately document\n\nReference ID: 5427030\n\nNDA 215455\nPage 2\n\nadverse events associated with abuse potential even if they are considered\ndesirable (e.g., euphoria-related experiences, mood changes). During the sponsor\ninspection, FDA identified that the definition of an adverse event (AE) in the MAPP2\ntraining information and the safety manual were not consistent with the MAPP2\nprotocol. Specifically, the training (e.g., All-Site Community Meeting slide\npresentations) and the safety manual provided by the sponsor to the study sites\ndescribed an AE as “any undesirable, unfavorable, inappropriate, or untoward\nmedical occurrence in a patient while participating in a clinical trial... NOT positive or\nfavorable effects.” However, the MAPP2 protocol defined an AE as “any medical\n\noccurrence in a participan\nClinically significant physic:\n\n, including any abnormal sign (e.g., abnormal and\nal exam finding, laboratory finding, ECG result, or vital\n\nsign), symptom, or disease, temporally associated with the participant’s involvement\n\nin the research, whether o\nThe systematic training of\nconcerns over the reliabili\n\nr not considered related to participation in the research.”\nnot reporting “positive” or “favorable” effects as AEs raises\n'y of the safety data. All AEs, including “positive” effects,\n\nshould have been identified and reported. As you were specifically advised,\nregardless of whether a participant, therapist, or physician may find a drug\nexperience to be neutral, positive, or favorable, events that are relevant to the abuse\npotential of a drug or potential for impairment should have been captured and\nreported in the safety and abuse potential summary in the NDA. Because such\nevents were not captured and reported, the studies failed to adequately characterize\nthe safety of midomafetamine, its acute effects, the duration of impairment, or\nsignals of abuse potential within these studies. This information is necessary to\nappropriately label and provide recommendations for the safe use of\nmidomafetamine.\n\nOverall, based on this failure to collect important information on “positive” or\n“favorable” events, and the unreported adverse events identified by FDA at the study\nsites, there are substantial concerns about the reliability of the safety data which limit\nour ability to adequately assess the safety of midomafetamine for the treatment of\nPTSD.\n\nYou have not demonstrated that the effect observed with midomafetamine is durable\nbeyond the 18-week end-of-study assessments (8 weeks after the last dose of\nmidomafetamine) in MAPP1 and MAPP2. As PTSD is a chronic condition, any drug\nindicated for the treatment of PTSD is expected to provide a durable treatment\neffect. Given the proposed dosing regimen of midomafetamine of a limited duration\nof three treatment sessions, it is critical to understand whether the treatment benefit\nis durable beyond the Week 18 assessment to inform the appropriate use of\nmidomafetamine for labeling of the drug.\n\nThere are multiple design issues with MPLONG which render the data inadequate to\nestablish the durability of effect from MAPP1 and MAPP2. MPLONG consisted of\nonly a single visit. Additionally, there was marked variability in the timing of those\nvisits, with a wide range of 6 months to up to 2 years of follow-up. Only a portion of\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 3\n\nparticipants from MAPP1 and MAPP2 enrolled into MPLONG, and there is a\npotential for bias due to self-selection for participation in MPLONG. Importantly,\nmany participants used potentially therapeutic interventions in the interim period\nbetween completing MAPP1 or MAPP2 and the MPLONG assessment. Given these\nissues, the data from the MPLONG study do not provide evidence of a durable\ntreatment effect.\n\nOverall, the data contained in your application fails to establish how MDMA should\nbe used to treat this chronic disease, whether treatment with a single treatment cycle\nis adequate or if retreatment is necessary. Information as to how the drug should be\nmanaged over the course of a chronic disorder is essential in the directions to health\ncare providers in labeling.\n\n3. Although the MAPP1 and MAPP2 protocols allowed for enrollment of participants\nwith prior experience taking midomafetamine, approximately 40% of the enrolled\nparticipants reported prior use of midomafetamine, which is much higher than the\nbackground use of midomafetamine in the proposed indicated population with\nPTSD, and higher than what would be expected based on available data. Notably,\nFDA analyses of data from the 2022 National Survey on Drug Use and Health found\nthat, in individuals with past-year moderate or severe mental illness, the lifetime\nprevalence of MDMA use was 16.2% and 20.5%, respectively. Additionally, the\ninspections conducted as part of this review detected very high rates of failures\nduring the “prescreening” process prior to the formal screening (i.e., screening\nprocedures and informed consent). Together these two factors suggest the\npossibility of selection bias, with the enrolled population not being representative of\nthe general PTSD population. Not only does this potentially limit generalizability, it\nalso raises the possibility of expectation bias given that participants who have prior\nexperience with midomafetamine are more likely to recognize the effects of\nmidomafetamine (i.e., leading to functional unblinding) and anticipate a treatment\nbenefit. These limitations impact the interpretability of MAPP1 and MAPP2 and,\ntogether with failure of MPLONG to provide evidence of a durable treatment effect,\npreclude the ability to establish substantial evidence of effectiveness.\n\nWe believe that the most efficient path to address the clinical issues above would be\nto conduct a new clinical trial to assess the durability of effect and adequately\ncharacterize the safety of midomafetamine. The most informative design would be a\nrandomized, double-blind study which includes the initial treatment sessions\nfollowed by blinded long-term follow-up with pre-specified criteria for retreatment, if\nneeded. Your study design should incorporate elements that address the following\nidentified complete response issues:\n\na) Demonstrate durability of effect\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 4\n\nContinue to follow participants in a blinded manner after the acute treatment\nperiod\n\nIncorporate prespecified criteria for recurrence of PTSD symptoms and\npotential retreatment of participants who meet these criteria, with follow-up\nassessments collected. These criteria should take into account symptom\nratings as well as whether the participant seeks additional treatment outside\nthe study\n\nFollow up assessments scheduled at least monthly\n\nb) Minimize potential for bias\n\nExclude or minimize the number of participants with prior use of MDMA or\nother psychedelics\n\nIncorporate an assessment of participant expectancy at baseline\nAssess both participant and rater/therapist unblinding at the end of the study\n\nConsider the inclusion of a low-dose midomafetamine arm as a control\n\nc) Adequately characterize the safety of midomafetamine\n\nCapture all abuse-related adverse events, regardless of perceived emotional\nvalence. Refer to the FDA guidance for industry Assessment of Abuse\nPotential of Drugs (2017) for recommendations regarding how to\nappropriately document adverse events associated with abuse potential. You\nshould make every effort to characterize the nature, onset, and resolution of\nthese events.\n\nDevelop standardized criteria to assess participants’ readiness for discharge\nfollowing completion of the treatment session, which should include both\npsychological and physiological assessments.\n\nGiven the serious nature of the concerns raised about the reliability of the safety data,\nand also acknowledging comments made during the open public hearing of the advisory\ncommittee and in the public docket raising concerns about study conduct and the\nadequacy of collection of adverse event information, we recommend that you consider\nan independent third-party data audit of all study records and reports, including the\nrecordings of the treatment sessions, to identify unreported or under-reported adverse\nevents. As the review of any future resubmission would still consider data from MAPP1\nand MAPP2, addressing these issues could provide greater assurance of the\nrobustness of the findings from these studies. If you choose to conduct such an audit,\nwe recommend discussing the goals and design of the audit with the Agency prior to its\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 5\n\ninitiation. We also note that, although initial inspections have been completed for the\nsubmission, some inspection-related activities are still ongoing.\n\nADDITIONAL COMMENTS\n\nWe have identified data gaps in your application that are not approvability issues at this\ntime, and that could have been addressed with post-marketing requirements had your\napplication been approved. Your application did not include laboratory data (e.g., liver\nanalytes, electrolytes) from the phase 3 studies and the cardiac safety assessment was\nincomplete. We would expect these gaps to be addressed in a resubmission. Any\nsubsequent studies to assess the efficacy and safety of midomafetamine will need to\ninclude the following:\n\n1. Incorporate routine laboratory assessment at baseline and post-dose (e.g., liver\nanalytes, electrolytes)\n\n2. Assess vital signs (blood pressure and heart rate) at baseline, after each dose of\nstudy drug, and at the end of the medication session. Incorporation of these\nassessments into a dedicated cardiac pharmacodynamic study (see below) may\nalso be considered rather than embedding in the larger trial.\n\nWe also note that the in vitro hERG assessment is inadequate to support an integrated\nrisk assessment for midomafetamine. We recommend the evaluation of major\nmetabolites on hERG current. We recommend utilization of appropriate positive controls\n(see best practice considerations in the new ICH S7B Q &A, section 2.1), as previously\ncommunicated in the May 13, 2021, Type B Guidance Written Response Only minutes.\n\nFurther, we recommend a dedicated pharmacodynamic (ECG) study using continuous\nHolter monitoring that, at a minimum, covers the proposed therapeutic dose of\nmidomafetamine and preferably high clinical exposure as described in the guidance for\nindustry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic\nPotential for Non-Antiarrhythmic Drugs (October 2005). The design of the ECG study\nwill depend upon whether the study will use an active comparator, which may lead to an\nincrease in heart rate.\n\nAlthough the following are not considered approvability issues, we recommend that they\nbe addressed in your clinical trial:\n\n1. Characterize the extent to which psychotherapy in the treatment contributes to the\ntreatment benefit and if psychotherapy is necessary for a potential treatment benefit\nof midomafetamine to inform labeling.\n\na) The MAPS-based regimen may not be generalizable to all types of\npsychotherapy practices. We recommend using an evidence-based standard of\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 6\n\ncare psychotherapy in lieu of the MAPS-developed psychotherapy in any future\nstudies.\n\nb) Consider a factorial study design that includes an arm with no psychotherapy.\n\nImprove the diversity of your study population. For proposed recommendations\nregarding study diversity, refer to our recently published draft guidance for industry,\nDiversity Action Plans to Improve Enrollment of Participants from Underrepresented\nPopulations in Clinical Studies.\n\nFinally, there are other gaps in the application that, although not approvability issues,\n\ncou\n\nld be addressed with additional studies. You should consider including the following\n\ndata in a future resubmission:\n\n1.\n\nU.S.\n\nDrug-drug interaction study: We recommend that you consider assessing the\npotential for an interaction between midomafetamine and SSRI drugs to determine if\na taper of SSRIs is necessary prior to initiation of treatment midomafetamine.\n\nPK study in patients with impaired hepatic function: Midomafetamine is primarily\nmetabolized in the liver. The impaired liver function is anticipated to increase the\nsystemic exposures of midomafetamine. Therefore, we recommend that you conduct\na PK study in patients with hepatic impairment. We note that you plan to conduct a\nPK study in participants with moderate hepatic impairment as a post-marketing\nphase 4 study (MPKH).\n\nPK study in patients with renal impairment: Based on the available data,\nmidomafetamine appears to be minimally excreted through renal pathway.\nTherefore, the PK of midomafetamine is not likely to be altered in patients with mild\nto moderate renal impairment (estimated glomerular filtration rate (eGFR <60\nmL/min). However, given that uremic toxin could affect the hepatic disposition of\nmidomafetamine in patients with severe renal impairment (eGFR: <30 mL/min), the\nreview team recommends a reduced design renal impairment study for\nmidomafetamine in patients with severe renal impairment.\n\nClinical lactation study: When lactating women with PTSD use midomafetamine,\nthere is a potential for midomafetamine to get excreted into the breast milk.\nTherefore, it is important to conduct a milk-only clinical lactation study to understand\nthe extent of midomafetamine that is excreted into breast milk.\n\nPre- and post-natal development study: After reviewing the data available from your\nconducted reproductive toxicology studies and data found in the literature, we have\ndetermined that there is a gap in the characterization of the risk of midomafetamine\ntreatment during pregnancy on the development of the CNS and other developing\nsystems. We acknowledge that, at the End of Phase 2 meeting on °\n\n, the Division stated that a pre- and postnatal development (PPND) study would\n\nFood and Drug Administration\n\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 7\n\nnot be needed if the intended clinical use for midomafetamine remained acute and a\npregnancy test will be conducted before each session. However, because literature\nsuggests there may be an effect of MDMA on the developing brain, and based on\nthe lack of reliable pregnancy data in humans, we recommend that you conduct a\nPPND study to characterize the risk of in utero exposure to midofmafetamine to\nthese developing systems that have not been adequately evaluated in the other\nconducted reproductive studies (e.g., embryofetal development).\n\nPRESCRIBING INFORMATION\n\nWe reserve comment on the proposed labeling until the application is otherwise\nadequate. We encourage you to review the labeling review resources on the\nPrescription Drug Labeling Resources! and Pregnancy and Lactation Labeling Final\nRule? websites, including regulations and related guidance documents and the Selected\nRequirements for Prescribing Information (SRPI) - a checklist of important format items\nfrom labeling regulations and guidances.\n\nCARTON AND CONTAINER LABELING\n\nWe reserve comment on the proposed labeling until the application is otherwise\nadequate.\n\nMEDICATION GUIDE\n\nAdd the following bolded statement or appropriate alternative to the carton and\ncontainer labeling per 21 CFR 208.24(d): \"ATTENTION PHARMACIST: Each patient\nis required to receive the enclosed Medication Guide.\"\n\nPROPRIETARY NAME\n\nPlease refer to correspondence dated oe , which addresses the proposed\nproprietary name, |\") This name was found conditionally acceptable pending\napproval of the application in the current review cycle. Please resubmit the proposed\nproprietary name when you respond to all of the application deficiencies that have been\nidentified in this letter.\n\n1 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources\n\n2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-\nfinal-rule\n\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\n\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 8\n\nRISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS\n\nSection 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to\nrequire the submission of a risk evaluation and mitigation strategy (REMS) if FDA\ndetermines that such a strategy is necessary to ensure that the benefits of the drug\noutweigh the risks [section 505-1 (a)].\n\nWe acknowledge receipt of your proposed REMS, included in your submission dated\n\nand last amended on a which contains elements to\nassure Safe use, an implementation system and a timetable for submission of\nassessments of the REMS. In accordance with section 505-1 of the FDCA, we agree\nthat a REMS will be necessary for midomafetamine capsule, if it is approved, to ensure\nthat the benefits of the drug outweigh the risk of serious harm resulting from patient\nimpairment. The REMS, should it be approved, will create enforceable obligations. We\nwill continue discussion of your proposed REMS after your complete response to this\naction letter has been submitted.\n\nSAFETY UPDATE\n\nWhen you respond to the above deficiencies, include a safety update as described at\n21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical\nand clinical studies/trials of the drug under consideration regardless of indication,\ndosage form, or dose level.\n\n1. Describe in detail any significant changes or findings in the safety profile.\n\n2. When assembling the sections describing discontinuations due to adverse events,\nserious adverse events, and common adverse events, incorporate new safety data\nas follows:\n\ne Present new safety data from the studies/clinical trials for the proposed indication\nusing the same format as in the original submission.\n\ne Present tabulations of the new safety data combined with the original application\ndata.\n\ne Include tables that compare frequencies of adverse events in the original\napplication with the retabulated frequencies described in the bullet above.\n\ne For indications other than the proposed indication, provide separate tables for the\nfrequencies of adverse events occurring in clinical trials.\n\n3. Present a retabulation of the reasons for premature trial discontinuation by\nincorporating the drop-outs from the newly completed trials. Describe any new\ntrends or patterns identified.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\nPage 9\n\n4. Provide case report forms and narrative summaries for each subject who died during\na Clinical trial or who did not complete a trial because of an adverse event. In\naddition, provide narrative summaries for serious adverse events.\n\n5. Describe any information that suggests a substantial change in the incidence of\ncommon, but less serious, adverse events between the new data and the original\napplication data.\n\n6. Provide updated exposure information for the clinical studies/trials (e.g., number of\nsubjects, person time).\n\n7. Provide a summary of worldwide experience on the safety of this drug. Include an\nupdated estimate of use for drug marketed in other countries.\n\n8. Provide English translations of current approved foreign labeling not previously\nsubmitted.\n\nOTHER\n\nWithin one year after the date of this letter, you are required to resubmit or take other\nactions available under 21 CFR 314.110. If you do not take one of these actions, we\nmay consider your lack of response a request to withdraw the application\n\n21 CFR 314.65. You may also request an extension of time in which to resubmit the\napplication.\n\nA resubmission must fully address all the deficiencies listed in this letter and should be\nclearly marked with \"RESUBMISSION\" in large font, bolded type at the beginning of the\ncover letter of the submission. The cover letter should clearly state that you consider\nthis resubmission a complete response to the deficiencies outlined in this letter. A partial\nresponse to this letter will not be processed as a resubmission and will not start a new\nreview cycle.\n\nYou may request a meeting or teleconference with us to discuss what steps you need to\ntake before the application may be approved. If you wish to have such a meeting,\nsubmit your meeting request as described in the draft guidance for industry Formal\nMeetings Between the FDA and Sponsors or Applicants of PDUFA Products.\n\nThe product may not be legally marketed until you have been notified in writing that this\napplication is approved.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nNDA 215455\n\nPage 10\nIf you have any questions, contact\n\nSincerely,\n\n{See appended electronic signature page}\n\nCenter for Drug Evaluation and Research\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5427030\n\nSignature Page 1 of 1\n\nThis is a representation of an electronic record that was signed\nelectronically. Following this are manifestations of any and all\nelectronic signatures for this electronic record.\n\n(b) (4)\n\n08/08/2024 02:39:42 PM\n\nReference ID: 5427030\n",
      "application_number": [
        "NDA 215455"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}