Comment from Curada Public Benefit Corporation

Docket No. FDA-2026-N-4492 — Drug Repurposing for Unmet Medical Needs Public Comment of Curada Public Benefit Corporation Curada Public Benefit Corporation respectfully submits this comment and the attached evidence dossier in response to FDA’s Drug Repurposing for Unmet Medical Needs RFI. We nominate oral naltrexone hydrochloride 50-mg tablets, used on an event-driven schedule approximately 60 minutes before anticipated drinking—with FDA to determine the supported timing window—as a high-priority Scenario 1 candidate for FDA evaluation in alcohol use disorder (AUD). We ask FDA to determine whether the public record satisfies the substantial-evidence standard and, if a narrow gap remains, define an efficient Scenario 2 confirmatory pathway. The nomination is unusually tractable. Naltrexone is already approved for alcohol dependence. The proposed condition of use retains the same active ingredient, strength, immediate-release tablet, and oral route; the principal questions concern regimen, population, timing, and a reduction-of-heavy-drinking claim. FDA determined in April 2026 that ReVia (NDA 018932) was not withdrawn for reasons of safety or effectiveness. That finding does not validate targeted dosing, but it is relevant to generic reliance and potential eligibility under FD&C Act §503D (MODERN). Prong I—new scientific evidence not reflected in labeling—is the clearest basis; FDA should also assess all covered-drug predicates and whether prong III applies. The mechanism is plausible but should not be overstated. Naltrexone antagonizes opioid receptors. Administration before alcohol exposure can attenuate endogenous-opioid reinforcement and downstream reward signaling. Repeated pairing of alcohol-related cues and consumption with reduced reinforcement may weaken learned reward value, a model often called “pharmacological extinction.” FDA labeling correctly states that naltrexone’s mechanism in alcoholism is not fully understood, and plasma Tmax does not establish an exact optimal dosing interval. Multiple randomized studies directly evaluated targeted or event-driven naltrexone, including trials by Heinälä, Kranzler and colleagues, and Santos and colleagues. Findings are promising but heterogeneous across populations, instructions, counseling, and endpoints. Broader evidence establishes the molecule’s AUD activity: a Cochrane review of 50 randomized trials involving 7,793 participants found a reduced risk of heavy drinking, while later controlled-drinking reviews identify uncertainty. Human laboratory evidence also supports attenuation of alcohol reinforcement, but not the exact event-driven schedule. Europe supplies a class-and-regimen precedent: EMA authorized as-needed nalmefene, and NICE TA325 recommends it for selected patients. NICE has not endorsed targeted naltrexone. The labeling gap reflects structural market failure. The relevant method patent expired; any entity funding label development would create a benefit available to generic competitors. Duke-Margolis has described resulting reimbursement, awareness, uptake, and liability barriers. Provider and community reach supports feasibility, not effectiveness. Curada offers to support a protocol-driven literature synthesis and a prospective, auditable evidence consortium. A fit-for-purpose program could capture dose and first-drink timestamps, the FDA-qualified two-level WHO risk-drinking reduction endpoint where applicable, drinking intensity, biomarkers, safety, and prespecified comparator analyses. FDA should prioritize this nomination, initiate §503D or a literature-led labeling process if the evidence supports it, and specify the smallest remaining evidentiary step if it does not. Respectfully submitted, Mariia Markitanova Co-Founder & Director Curada Public Benefit Corporation