ProJenX reported positive interim Phase 1b results for prosetin, an oral MAP4K inhibitor in ALS, showing safety, target exposure, and biomarker activity, with longer-term data to guide Phase 2 development.
Written By: Fariha Sameen, PharmD
Reviewed By: Pharmacally Editorial Team
ProJenX reported positive interim data from PRO-101, a Phase 1b study (NCT05279755) of prosetin in amyotrophic lateral sclerosis (ALS), showing favorable safety, achievement of target therapeutic exposure at higher dose levels, and statistically significant target engagement. The findings support continued development of the oral MAP4K inhibitor as a potential disease-modifying treatment for ALS.
The PRO-101 multiple ascending dose (MAD) study enrolled 41 participants across five dose cohorts ranging from 0.16 to 1.05 mg/kg/day. Investigators evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamic activity. Enrollment is complete, and participants continue into a two-year open-label extension (OLE) assessing longer-term outcomes.
Targeting MAP4K in ALS
Prosetin is a potent, selective, central nervous system (CNS)-penetrant inhibitor of mitogen-activated protein kinase kinase kinase kinase (MAP4K), a signaling pathway implicated in motor neuron degeneration. Research from ProJenX and academic collaborators has linked MAP4K activity to proteotoxic stress and TDP-43 pathology, two key drivers of ALS progression.
ALS remains a rapidly progressive neurodegenerative disease with limited treatment options and a substantial unmet medical need. Therapies capable of slowing neuronal loss and disease progression remain a major focus of ALS drug development, positioning MAP4K inhibition as a promising therapeutic strategy.
Evidence of Safety and Biological Activity
Interim analyses showed that prosetin was well tolerated across all dose levels studied. Investigators reported no treatment-related serious adverse events and no clinically meaningful safety signals, including among participants receiving longer-term treatment in the OLE phase.
Pharmacokinetic analyses confirmed that the two highest dose levels, 0.70 mg/kg/day and 1.05 mg/kg/day, achieved the target therapeutic exposure range predicted by preclinical PK/PD modeling.
Prosetin also demonstrated biological activity, producing a statistically significant, exposure-dependent reduction in phosphorylated MAP2K4 (pMAP2K4) levels in peripheral blood mononuclear cells. pMAP2K4 is considered a biomarker of MAP4K pathway activity and has been shown to be elevated in ALS patient cells compared with healthy controls. The finding provides early clinical evidence that prosetin is engaging its intended target in people with ALS.
Clinical Implications
Dr. Jinsy Andrews, Director of the NYU Langone ALS Center and ALS Clinical Trials at NYU Langone, said the study addressed a critical early question for the program: whether a brain-penetrant MAP4K inhibitor could be safely administered at therapeutically active dose levels in people living with ALS.
According to Andrews, the findings support continued clinical evaluation of prosetin as a potential disease-modifying therapy and represent an important step in translating encouraging preclinical data into human studies.
Next Steps in Development
The ongoing OLE will generate longer-term safety, pharmacokinetic, biomarker, and functional outcome data, including assessments of neurofilament light chain (NfL), inflammatory biomarkers, and ALS Functional Rating Scale-Revised (ALSFRS-R) scores.
These results are expected to inform dose selection, eligibility criteria, and endpoint strategies for a planned Phase 2 trial.
ProJenX will present the interim PRO-101 findings at the European Network to Cure ALS (ENCALS) 2026 meeting in Madrid, including a poster presentation and an update during the TRICALS satellite session.
Together, the data establish proof of target engagement and support further clinical evaluation of MAP4K inhibition, positioning prosetin for advancement into Phase 2 testing as a potential new treatment approach for ALS.
What This Means for Patients
ALS is a progressive neurological disease that destroys motor neurons, leading to muscle weakness, loss of mobility, impaired speech and swallowing, and ultimately respiratory failure. Despite recent advances, treatment options remain limited and most patients continue to experience steady decline.
The Phase 1b results indicate that prosetin can be administered safely at biologically active dose levels and effectively engage a disease-related target linked to motor neuron degeneration. While the study was not designed to measure clinical benefit, these findings establish proof-of-mechanism and support further development. Ongoing long-term studies and future Phase 2 trials will determine whether MAP4K inhibition can slow progression or improve outcomes for people living with ALS.
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About the Writer
Fariha Sameen, PharmD (LinkedIn), is a clinical pharmacy professional with hands-on experience in patient counselling, medication review, therapeutic monitoring, and clinical documentation across multiple departments. She has experience identifying and assessing drug-related problems and supporting medication safety practices. Her interests include pharmacovigilance, ADR reporting, clinical research, and medical writing focused on clear, evidence-based communication.