Background Breakdown of regulatory pathways designed to prevent aggregation and accumulation of disease‐associated proteins contributes to or causes Alzheimer’s Disease (AD). Under these conditions epichaperomes form and take control of pathological pathways. PU‐AD is a small‐molecule, orally bioavailable inhibitor specific to epichaperomes with little or no effect on normal cells, and has shown dramatic beneficial effects in animal models of AD. We describe the first‐in‐man trial of PU‐AD. Objectives This Phase 1, double‐blind, placebo‐controlled, single and multiple‐ascending dose study evaluated the safety and pharmacokinetics (PK) of single and multiple doses of oral PU‐AD. Methods Cohorts of 8 subjects were randomly assigned to active treatment or placebo in a 6:2 ratio. Single doses of oral PU‐AD were 10 mg, 20 mg, and 30 mg in healthy subjects ages 18‐60 years, and daily doses of 20 mg and 30 mg daily for 7 days in healthy subjects >59 years old. Safety was evaluated through observation of adverse event incidence and severity; and changes from baseline in clinical laboratory test results, vital signs, physical examinations, or electrocardiogram results. Plasma PK parameters of PU‐AD were determined, and cerebrospinal fluid (CSF) was sampled for PU‐AD concentration and for biomarkers of neurodegenerative disease in the multiple‐dose cohorts. Results PU‐AD was well‐tolerated, with an adverse event profile comparable to that of placebo. No adverse events were serious, severe, or led to withdrawal of dosing. Additionally, there were no other clinically significant safety findings to report. PK was dose‐proportional between 10 mg to 30 mg and showed minimal accumulation with repeated dosing. CSF analyses will be presented. Conclusion PU‐AD, a novel and selective epichaperome inhibitor shown to be efficacious in animal AD models, warrants further evaluation in an AD population. This first‐in‐man trial demonstrated that PU‐AD is well‐tolerated, has favorable plasma PK and CSF exposure, and is a candidate for advancement into Phase 2A trials in AD populations to evaluate target engagement and pharmacological effects.

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double-blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited).Unsolicited AEs were generally mild to moderate and not rezafungin-related.Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (C max ) was 105.0 ng/ml and the median time to C max was 144 h. The GM area under the concentration-time curve was 32,770 ng*h/ml. The median estimated terminal half-life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re-evaluation of the rezafungin s.c. formulation could be considered in the future.How to cite this article: Gu K, Ruff D, Key C, et al. A phase I randomized, double-blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects.

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Background/Introduction: Effective therapies for FGFR2-driven cholangiocarcinoma (CCA) and other advanced solid tumors remain unmet medical needs. RLY-4008 is a potent, highly selective and irreversible FGFR2 inhibitor designed to target both primary FGFR2 oncogenic alterations and clinically relevant resistance mutations. RLY-4008 is currently being studied in a Phase 1/2 clinical trial to treat patients with FGFR2-driven CCA. To guide RLY-4008 dosing in cancer patients, we report here results from a clinical study to assess the effect of food and proton pump inhibitor (PPI) esomeprazole (ESO) on the pharmacokinetics (PK) of RLY-4008 in healthy subjects (HS). Methods: This was a randomized, open-label, three-period, fed and fasted two-treatment crossover and fixed sequence, drug-drug interaction study to assess the effect of food and ESO on RLY-4008 PK. Twenty-four HS were enrolled to receive single oral doses of 50 mg RLY-4008 (fasted or fed with a high fat, high calorie meal) or RLY-4008 with ESO (fasted), with ≥7 days washout between each treatment. RLY-4008 PK was assessed up to 120 hours post dose. The effect of food and ESO was assessed using log-transformed RLY-4008 Cmax and AUC by linear mixed-effect modeling and calculating point estimates and associated 90% confidence intervals (CI) of geometric least squares mean ratios (LSGMR). Safety and tolerability were assessed through discharge/end of study. Results: Twenty-four HS were enrolled and completed the study. The median Tmax of RLY-4008 was similar when administered fasted, with food or with ESO. LSGMRs of Cmax, AUC(0-tlast) and AUC (0-inf) between RLY-4008 administered with food and fasted were 87%, 105%, and 106%, respectively, and the associated 90% CIs were 77-97%, 100-110%, and 100-110%, respectively. The LSGMRs and associated 90% CIs of AUCs were fully contained within 80% to 125%, while the lower bound of 90% confidence of Cmax LSGMR was below 80%. The 13% reduction in RLY-4008 Cmax with food was not considered clinically relevant. LSGMRs of Cmax, AUC(0-tlast) and AUC (0-inf) between RLY-4008 administered with ESO and alone were 110%, 113%, and 113%, respectively, and the associated 90% CIs were 102-119%, 109-117%, and 109-117%, respectively, and were fully contained within 80% to 125%. RLY-4008 was safe and well tolerated in HS when administered fasted, fed or with ESO. Conclusion: Food and ESO does not have a clinically relevant effect on RLY-4008 PK in HS, indicating that RLY-4008 can be dosed with or without food and can be dosed with PPIs, H2-blockers and anti-acids in cancer patients. Citation Format: Jinshan Shen, Rishikesh Sawant, Rick Blakesley, Kai Yu Jen, Fabien Ricard, Xiaoyan Li, Cassandra Key, Djuro Karanovic. A food effect and esomeprazole drug-drug interaction study of RLY-4008, a highly selective FGFR2 inhibitor, in healthy subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2795.

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