Oral prosetin proves safe in early trial, paving way for Phase 2
Interim data from Phase 1 trial support continued development of ALS drug
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- Oral prosetin for ALS proved safe and well-tolerated in a Phase 1 trial.
- The drug successfully engaged its target, MAP4K, linked to motor neuron loss in ALS.
- Positive findings support advancing prosetin to a Phase 2 clinical study for ALS.
Projenx‘s prosetin was found to be safe and well tolerated at doses that engaged its therapeutic target in people with amyotrophic lateral sclerosis (ALS), supporting its continued development as a potential disease-modifying therapy.
These interim data from the fully enrolled PRO-101 Phase 1 clinical trial (NCT05279755), including its long-term open-label extension (OLE) phase, will support a Phase 2 study to test the therapy in more people with ALS.
“While PRO-101 was designed primarily to evaluate whether a safe and active dose of prosetin could be achieved in people living with ALS, longitudinal data from the OLE will guide critical decisions around upcoming study design, allowing us to select scientifically-driven eligibility criteria and study endpoints for a rigorous Phase 2 study of prosetin in ALS,” Erin Fleming, co-founder and chief operating officer of Projenx, said in a company press release.
PRO-101 interim data will be presented at the European Network to Cure ALS meeting in Madrid this month.
ALS is a progressive disease in which motor neurons, the nerve cells that control voluntary muscle movement, gradually break down and die. One key feature of the disease is the abnormal clumping of the protein TDP-43, which stresses the endoplasmic reticulum (ER), the cell’s protein-folding machinery, ultimately triggering motor neuron death.
Enzyme blocker slows disease progression
Prosetin is designed to access the brain and inhibit MAP4K, an enzyme identified as a critical driver of motor neuron loss under ER stress. By blocking MAP4K, prosetin aims to interrupt that process and slow motor neuron death and ALS progression.
In preclinical ALS models, MAP4K inhibitors reduced inflammation, promoted motor neuron survival under ER stress, and conferred broad neuroprotective effects, including significant rescue of TDP-43 clumping.
The four-part PRO-101 study is assessing the safety and tolerability of prosetin, as well as its pharmacokinetics (how a drug moves into, through, and out of the body), in up to 72 healthy volunteers and adults with ALS.
Data from the now-completed first two parts (A and B) showed that prosetin was safe and well tolerated in healthy volunteers at single or multiple ascending doses compared with a placebo.
Part C of the trial, supported by a $1 million grant from the ALS Association, evaluated the safety, tolerability, pharmacokinetics, and target engagement of prosetin in 41 patients with ALS. All of those who completed part C could join part D, the OLE phase, and all will be given prosetin for one year.
During part D, Projenx will use the ALS Digital Twin Generator, an artificial intelligence model trained on patient-level data, to generate digital twins that will serve as a placebo group to collect OLE data more quickly.
The multiple ascending dose portion of part C showed that prosetin was generally safe and well tolerated across all doses studied. No clinically significant abnormalities or trends were observed in safety assessments, and no serious adverse events have been reported to date, including during long-term evaluation in the OLE.
In blood tests, prosetin levels at the two highest dose levels (0.70 and 1.05 mg/kg/day) fell within the target therapeutic exposure range established by preclinical models.
To demonstrate target engagement, or MAP4K inhibition, researchers collected peripheral blood mononuclear cells (PBMCs), which are immune cells found in the blood, from PRO-101 participants.
Prosetin treatment correlated with a significant, exposure-related decrease in pMAP2K4, an enzyme that serves as a proxy for MAP4K inhibition. pMAP2K4 is elevated in both ALS stem cell-derived motor neurons and ALS patient PBMCs.
Projenx continues to evaluate the long-term effects of prosetin through the two-year OLE phase. It will assess levels of neurofilament light chain, a marker of nerve cell damage, along with a panel of neuroinflammatory biomarkers and the revised ALS Functional Rating Scale (ALSFRS-R) to track how ALS affects a patient’s ability to perform daily activities.
“I am encouraged by these interim findings from PRO-101,” said Jinsy Andrews, MD, director of the NYU Langone ALS Center and co-chair of the Network of Excellence for ALS consortium. “Compelling preclinical data supported evaluation of prosetin as a potential disease-modifying treatment for sporadic ALS — but in this first-ever clinical study of a brain-penetrant MAP4K inhibitor, our goal was to answer critical questions about whether prosetin could be safely administered at active dose levels in people living with ALS.”
The trial data “answers that question, supporting continued evaluation of prosetin for ALS,” Andrews said.
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