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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": "02/13/2026",
      "approver_title": null,
      "file_name": "CRL_NDA220707_20260213.pdf",
      "letter_year": "2026",
      "approval_status": "Unapproved",
      "approver_name": "Center for Drug Evaluation and Research",
      "approver_center": [],
      "company_rep": "Steve Caffé, MD",
      "company_address": "321 Arsenal Street, Suite 101\nWatertown, MA 02472",
      "company_name": "Disc Medicine, Inc.",
      "text": "PN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nNDA 220707\nCOMPLETE RESPONSE\n\nDisc Medicine, Inc.\n\nAttention: Steve Caffé, MD\nChief Regulatory Officer\n\n321 Arsenal Street, Suite 101\nWatertown, MA 02472\n\nDear Dr. Caffé:\n\nPlease refer to your new drug application (NDA)\n\nor bitopertin oral tablets.\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\nCLINICAL/BIOSTATISTICS\n\nou submitted NDA 220707 for bitopertin for\n\n, Proposing the primary biomarker\nendpoint of percen’ ole blood metal-free protoporphyrin IX (PPIX) as a\nsurrogate endpoint that is reasonably likely to predict clinical benefit.\n\nIn support of approval, you submitted the results of Study DISC-1459-201 (Trial 201)\nand Study DISC-1459-202 (Trial 202). Trial 201 was a randomized, double-blind,\nplacebo-controlled trial in subjects 18 years of age and older with EPP. The trial\nincluded a 28-day screening period and a randomized 120-day treatment period. The\ntrial enrolled | subjects, including |@ randomized to bitopertin 20 mg, @ randomized\nto bitopertin 60 mg, and | randomized to placebo. The trial was conducted at 9 sites in\nthe United States. Trial was a randomized, open-label trial of bitopertin 60 mg vs.\n20 mg in subjects 12 years of age and older with EPP or XLP. The trial included a 28-\nday screening period and a randomized 168-day treatment period. The trial was\nconducted at 2 sites in Australia. The trial enrolled @, subjects, including @, randomized\nto bitopertin 20 mg and @ randomized to bitopertin 60 mg. The primary biomarker\nendpoint was the percent change in whole blood metal-free PPIX levels from baseline to\nend of the treatment period (Day 121 in Trial 201 and Day 169 in Trial 202). You\npropose an ongoing trial, DISC-1459-301, as your confirmatory trial.\n\nReference ID: 5745792\n\nNDA 220707\nPage 2\n\nThe approvability of an NDA under the provisions of me, , relies\n\non, in part, two factors: first, whether there is evidence of an effect on the proposed\nsurrogate endpoint; and second, whether the proposed surrogate endpoint, including\nhe magnitude of change, is reasonably likely to predict a clinical benefit.\n\nWith respect to the first factor, we agree that Trial 201, one adequate and well\ncontrolled trial, demonstrated an effect on its primary endpoint. In Trial 201, bitopertin\n60 mg was superior to placebo for the primary biomarker endpoint of percent change\nrom baseline to Day 121 of whole blood metal-free PPIX in adult patients with EPP\n(p<0.001). Confirmatory evidence was provided from a second, randomized, open-label\nrial, Trial 202, in which bitopertin 60 mg was superior to bitopertin 20 mg for the primary\nbiomarker endpoint of percent change from baseline to Day 169 of whole blood metal-\nree PPIX in adult and adolescent patients with EPP or XLP (p=0.018).\n\nHowever, there are uncertainties with respect to the second factor. The percent change\nin PPIX was relatively modest (about 40% reduction from baseline to Day 121 for the\nhigher 60 mg dose) and whether that magnitude of change in whole blood metal-free\nPPIX is reasonably likely to predict clinical benefit is unknown. This uncertainty is further\nexacerbated by the results from Trials 201 and 202 which did not show evidence of\nassociation between percent change in whole blood metal-free PPIX and sunlight-\nexposure based endpoints, as measured in the trials, despite the strong mechanistic\nand biological plausibility supporting the use of the PPIX biomarker in\n\nThis lack of correlation between the changes in PPIX and clinical outcomes measured\nleaves significant uncertainty that bitopertin will have the effect it purports or is\nrepresented to have under the conditions of use prescribed, recommended, or\nsuggested in its proposed labeling.\n\nFor this application to be approved, you will need to provide evidence from an adequate\nand well-controlled trial(s) demonstrating the efficacy of bitopertin for me\n\nbased on clinical endpoint(s). The Division is willing to meet with you to\ndiscuss options, such as completing your ongoing trial and, if the trial is successful,\nsubmitting the results to support a traditional approval.\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\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: 5745792\n\nNDA 220707\nPage 3\n\nCARTON AND CONTAINER LABELING\n\nWe reserve comment on the proposed labeling until the application is otherwise\nadequate.\n\nPROPRIETARY NAME\n\nPlease refer to our correspondence dated, Oe) , which addresses the\nproposed proprietary name, {9}. This name was found conditionally acceptable\npending approval of the application in the current review cycle. Please resubmit the\nproposed proprietary name when you respond to all of the application deficiencies that\nhave been identified in this letter.\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\n(1) Describe in detail any significant changes or findings in the safety profile.\n(2) When assembling the sections describing discontinuations due to adverse\n\nevents, serious adverse events, and common adverse events, incorporate new\nsafety data as follows:\n\ne Present new safety data from the studies/clinical trials for the proposed\nindication using the same format as in the original submission.\n\ne Present tabulations of the new safety data combined with the original\napplication data.\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\nthe frequencies of adverse events occurring in Clinical trials.\n\n(3) 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\n(4) Provide case report forms and narrative summaries for each subject who died\nduring a Clinical trial or who did not complete a trial because of an adverse event.\nIn addition, provide narrative summaries for serious adverse events.\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5745792\n\nNDA 220707\nPage 4\n\n(5) 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\n(6) Provide updated exposure information for the clinical studies/trials (e.g., number\nof subjects, person time).\n\n(7) Provide a summary of worldwide experience on the safety of this drug. Include\nan updated estimate of use for drug marketed in other countries.\n\n(8) 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 under\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: 5745792\n\nNDA 220707\n\nPage 5\nIf you have any questions, email\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: 5745792\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\n02/13/2026 12:35:22 PM\n\nReference ID: 5745792\n",
      "application_number": [
        "NDA 220707"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}