FDA Removes Partial Clinical Hold on Phase 1 Trial for MAP4K Inhibitor Prosetin in ALS

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The phase 1 study, dubbed PRO-101, assesses the safety, tolerability, pharmacokinetics, and pharmacodynamics of prosetin in both patients with ALS and healthy volunteers.

Jinsy Andrews, MD, MSc, associate professor of neurology and director of Neuromuscular Clinical Trials, Columbia University

Jinsy Andrews, MD, MSc

According to a recent announcement, the FDA has lifted its partial clinical hold on ProJenX’s hybrid phase 1 study assessing its investigational MAP4 kinase (MAP4K) inhibitor prosetin as a potential treatment for patients with amyotrophic lateral sclerosis (ALS). Following this decision, the company will proceed with part 1c of the study assessing the agent in participants with the disease.1

Also known as PRO-101, this phase 1 trial includes 3 parts to assess prosetin, a selective, oral, brain-penetrant MAP4K inhibitor developed by ProJenX co-founders at Columbia University. Parts 1a and 1b (NCT05279755), which have been completed, consisted of a randomized, double-blind, placebo-controlled, dose-escalating study to evaluate the safety, tolerability, and pharmacokinetics of single ascending and multiple doses of prosetin in healthy volunteers.

"There is an immense unmet need for safe and effective treatment options for ALS, and prosetin is an exciting investigational therapy option in the current clinical trial landscape," Jinsy Andrews, MD, MSc, associate professor of neurology and director of Neuromuscular Clinical Trials, Columbia University, said in a statement.1 "I am encouraged by prosetin's compelling preclinical efficacy data and by its consistent safety and tolerability profile in healthy volunteers and chronic toxicology studies, and look forward to working with the ProJenX team to bring Study PRO-101 to people living with ALS in the United States."

The first healthy volunteer for PRO-101 was dosed in March 2022. Designed after consulting with the FDA, leading ALS clinicians, and ALS community advisors, PRO-101 aims to establish the safety and biomarker data necessary for rational dose selection and late-phase study design. Prosetin was also granted orphan drug designation for ALS by the FDA in 2020.

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"Recent clinical trial results in ALS have further demonstrated the urgent need for meaningful therapies that can alter the course of this devastating disease," Stan Abel, president and chief executive officer at ProJenX, said in a statement.1 "Our Columbia University and Project ALS co-founders have invested over two decades in scientific research that shows a critical role for MAP4K inhibition on ALS motor neuron survival, and we are thrilled to be advancing prosetin to people living with ALS in the coming months."

Recent work has suggested that MAPK4 regulates motor neuron degeneration in ALS. A previous study utilized a trophic factor (TF) withdrawal system to accelerate degeneration of motor neurons derived from mouse and human pluripotent stem cells. Overall, the data revealed that lowering TF levels not only increased motor neuron death, but increased levels of phosphorylated MAP4K (p-MAP4K) and downstream effectors c-Jun N terminal kinase and c-Jun.2

Published in 2019, the study also showed higher levels of p-MAP4K, JNK, and c-Jun in ALS motor neurons in TF-containing medium compared with wild-type motor neurons, suggesting that with both exogenous stress and endogenous stress, the MAPK4-JNK-c-Jun death signaling pathway is activated. When MAP4K was suppressed with independent specific siRNA or shRNAs, the levels of activated p-JNK and p-c-Jun were significantly diminished and motor neuron survival substantially increased in both mouse and human ALS motor neurons.

REFERENCES
1. ProJenX announces removal of partial clinical hold for prosetin program by FDA. ProJenX. March 28, 2024. Accessed April 3, 2024. https://www.prnewswire.com/news-releases/projenx-announces-removal-of-partial-clinical-hold-for-prosetin-program-by-fda-302101883.html
2. Watts ME, Wu C, Rubin LL. Suppression of MAP4K4 signaling ameliorate motor neuron degeneration in amyotrophic lateral sclerosis-molecular studies toward new therapeutics. J Exp Neurosci. 2019;13:117069519862798
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