Comment from Salah Ismail

DOCKET NO. FDA-2026-N-4390 RE: AI-Enabled Optimization of Early-Phase Clinical Trials Pilot Program - Request for Information Submitted by: Salah K. Ismail, BS Pharm, Founder & CSO, LatentRx Therapeutics Inc. Date: June 29, 2026 LatentRx Therapeutics Inc. is an AI-driven drug repurposing company operating a Molecular Resurrection Engine (MRE) pipeline that identifies FDA-approved, off-patent small molecules for new therapeutic indications via 505(b)(2) pathways. We propose extending the RTCT pilot to metabolic disease and offer a specific real-time efficacy signal framework. I. PROPOSED EXTENSION TO METABOLIC DISEASE TRIALS The current RTCT trials operate in oncology. LatentRx proposes the summer 2026 pilot include at minimum one metabolic disease trial, for two reasons. First, the unmet need is structural. Metabolic disease trials targeting diabetic nephropathy and metabolic aging face observation windows of 3-5 years around hard endpoints such as ESRD or mortality. Real-time surrogate endpoint transmission would compress this to 12-18 months without sacrificing regulatory rigor - a proportionally larger time savings than in oncology trials already designed around 6-12 month surrogates such as ORR or PFS. Second, the surrogate endpoint infrastructure is mature. eGFR slope and UACR reduction are FDA-validated surrogates for diabetic nephropathy. CGM-derived postprandial glucose AUC (PPG-AUC) is an analytically validated, continuously measurable efficacy signal for metabolic aging indications. Both are digital, high-frequency, EHR-integratable data streams ideal for real-time transmission - more so than tumor imaging endpoints requiring radiologist interpretation. II. REAL-TIME EFFICACY SIGNAL FRAMEWORK - ACARBOSE FOR METABOLIC AGING LatentRx is developing acarbose for a new indication: reduction of metabolic aging in non-diabetic adults with elevated postprandial glucose variability, via 505(b)(2). We propose the following real-time signal framework: Pre-specified signals (transmit to FDA within 72 hours of measurement): Safety: Serious adverse events; ALT/AST >3x ULN; eGFR decline >20% from baseline; hospitalization for GI events. Efficacy: 2-hour PPG-AUC change from baseline at Weeks 4, 8, 12, and 24 (CGM-derived, Dexcom G7); serum IGF-1 at Weeks 12 and 24; high-sensitivity CRP at Weeks 12 and 24. CGM generates continuous glucose data with no manual entry, no lab processing delay, and no inter-operator variability. PPG-AUC is calculated algorithmically and available within hours of each meal event - the most temporally sensitive efficacy surrogate in metabolic disease and a stronger RTCT candidate than batch-processed laboratory biomarkers. The mechanistic link between PPG-AUC reduction and metabolic aging outcomes is documented in the NIA Interventions Testing Program and STOP-NIDDM trial literature. LatentRx's FDA pre-IND briefing document is in preparation for Q3 2026 submission. III. QUESTIONS FOR FDA Does FDA intend to include non-oncology metabolic disease trials in the summer 2026 pilot, or will it be limited to oncology? For 505(b)(2) investigational IND trials, does the Study Conduct platform support real-time signal transmission from pre-approval trials, or only post-approval studies? Does FDA have a preferred AI versioning and model change control framework for sponsors to propose in IND applications for AI tools embedded in RTCT trials? IV. SUMMARY LatentRx requests that FDA expand the RTCT pilot to metabolic disease indications with CGM-derived PPG-AUC as a pre-specified real-time efficacy signal. We further request guidance on Study Conduct applicability to investigational 505(b)(2) IND trials and on AI versioning standards. LatentRx is prepared to participate as sponsor of the acarbose metabolic aging Phase 2a trial using Paradigm Health's Study Conduct platform as the proposed RTCT infrastructure. Respectfully submitted, Salah K. Ismail, BS Pharm Founder & CSO, LatentRx Therapeutics Inc. latentrx.com