Clinical Progress Update From PRO-101, a Hybrid Phase One Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Prosetin in Participants With ALS
Erin Fleming1, Kristiana Salmon1, April Ruby1, Hilde Williams1, Ingela Danielsson-Sanden1
1ProJenX
Objective:
Study PRO-101 is a hybrid Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of prosetin in participants with ALS.
Background:
ProJenX is developing prosetin, a novel, orally available, CNS-penetrant, highly potent, MAP4K inhibitor, for ALS. In preclinical models of ALS, prosetin strongly protects motor neurons against proteotoxic stress and other well-established drivers of disease pathology. PRO-101 is the first-in-human study of prosetin in healthy volunteers and participants with ALS.
Parts A and B of PRO-101 evaluated the safety, tolerability, and PK of single and multiple ascending doses of prosetin in 48 healthy volunteers. No serious adverse events or abnormalities in any safety assessments were identified, and plasma levels of prosetin increased in a predictable manner.
Design/Methods:
PRO-101, Part C is a double-blind, placebo-controlled, dose escalation study in which approximately 32 people with ALS receive prosetin, or matching placebo, at a 6:2 ratio over 14 days. All participants who complete Part C can choose to continue into Part D of the study, a 2-year open-label extension with additional data collection. In addition to safety and PK, exploratory endpoints measuring target engagement and impact on ALS disease progression are being evaluated.
Results:
Baseline characteristics from PRO-101 represent a heterogeneous ALS population, consistent with the study’s broad eligibility criteria. Interim data supports a favorable safety and tolerability profile of prosetin, and consistent plasma PK behavior. Analyses of exploratory endpoints, including target engagement, neurofilament light chain, neuroinflammatory cytokines, ALSFRS-R, SVC, and ALSAQ-5, are ongoing.
Conclusions:
A growing body of evidence links MAP4K inhibition to neuronal survival in ALS, making it an attractive target for therapeutic intervention. Available data from PRO-101 demonstrates a favorable safety profile for prosetin in ALS participants and supports further evaluation of this potential first-in-class MAP4K inhibitor in people living with ALS.
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