Stress Test: Oral Drug Shows Early Promise vs. ALS

More than a month after the FDA granted its first approval for an amyotrophic lateral sclerosis (ALS) drug in five years, several promising ALS candidates are winnowing their way through clinical trials—including an oral drug that has shown the first signs of promise in an early-phase study.

Investigators from ProJenX and its clinical partners earlier this month published encouraging safety results from its hybrid Phase Ia/Ib/Ic PRO-101 trial (NCT05279755) assessing prosetin, an oral brain-penetrant MAP4K inhibitor targeting endoplasmic reticulum stress. According to the company, prosetin is the first MAP4K inhibitor to reach the clinic.

During a platform presentation at the recent 21st Annual Meeting of the Northeast ALS Consortium, as well as in an abstract published in Muscle & Nerve, the researchers reported no moderate or severe adverse events, and identified no abnormalities or general trends in any safety assessments in patients given four dose levels of prosetin, from 0.03 to 0.24 mg/kg. Plasma levels of prosetin increased in a predictable manner. The plasma half-life of prosetin was approximately 5 days and was consistent across doses.

PRO-101 is a randomized, double-blind, placebo-controlled trial designed to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of prosetin. The trial includes a study of single ascending doses (Phase Ia) and multiple ascending doses (Phase Ib) in up to 72 healthy volunteers—as well as multiple doses in up to 16 people living with ALS (Phase Ic).

The first patient was announced as being dosed with prosetin on March 1. PRO-101 is ongoing and continues to recruit patients. Should the Phase I trial prove successful, ProJenX plans to advance into a Phase II/III potential registrational trial in 2023. The landscape for drugs designed to treat ALS, also known as Lou Gehrig’s disease, has long been littered with candidates that have either failed or struggled to surmount clinical or regulatory hurdles. Last week, BrainStorm Cell Therapeutics acknowledged that the FDA issued a refusal to file letter regarding the company’s Biologics License Application (BLA) for its ALS candidate NurOwn.

​However, the ALS drug landscape has been revived in recent years with the $115 million in donations generated through the 2014 Ice Bucket Challenge events held nationwide. According to the ALS Association, Ice Bucket money is funding 40 potential treatments in development, as well as 130 research projects in 12 different countries.

Funding from the Ice Bucket Challenge has been credited with the development of Amylyx’s Relyvrio™ (sodium phenylbutyrate and taurursodiol), which won FDA approval in September after an unusual review process based on data from a single 137-patient clinical study, the Phase II CENTAUR trial (NCT03127514), and an unusual two hearings held by the FDA’s Pe­riph­er­al and Cen­tral Ner­vous Sys­tem Drugs Ad­vi­so­ry Com­mit­tee. The first hearing yielded a 6-4 vote that effectively recommended against agency approval of Relyvrio by asserting that CENTAUR and an open label extension did not establish the conclusion that the drug was effective in the treatment of patients with ALS.

At the urging of ALS patient groups, however, the advisory committee met a second time in September, where based on new analyses submitted by Amylyx, the panel concluded 7-2 that the available evidence of effectiveness was sufficient to support approval of the combination drug, then called AMX0035. Prosetin is the product of a collaboration launched more than two decades ago, when the nonprofit Project ALS funded the research of Hynek Wichterle, PhD, co-director of Columbia University’s Motor Neuron Center and a professor of pathology and cell biology (among other disciplines) at Columbia who, at the time, was a postdoc in the lab of the late Thomas M. Jessell, studying basic neurodevelopment.

Project ALS has funded the research of Wichterle and ProJenX’s other scientific co-founder, Brent R. Stockwell, PhD, Professor of Biological Sciences and Chemistry at Columbia, focused on improving models of ALS. Their work has included developing the first patient-derived, induced pluripotent stem cell models of ALS, as well as screening potential drugs and optimizing those ALS treatments to account for the swallowing difficulties and other challenges of patients. The researchers identified MAP4K as a critical regulator of motor neuron loss mediated by ER stress, a common feature across all forms of ALS and other neurodegenerative diseases.

A key factor in those diseases is the accumulation of misfolded proteins, which are supposed to be cleared by the ER. When it tries to address the misfolded proteins, resulting in stress, the ER becomes a major pathway of cell death in stress neurons. Stockwell’s lab synthesized more than 60 analogs of the research team’s initial compound until it arrived at prosetin, a compound that crosses the blood-brain barrier, having a brain-to-blood ratio in living organisms of at least 3:1.

In preclinical studies, prosetin demonstrated potent neuroprotection in an ER stress model of ALS motor neurons, as well as significant delays in weight loss and loss of grip strength—two key indicators of disease onset and progression—in the SOD1G93A mouse model of ALS. Another critical point of differentiation is prosetin’s potential for treating anyone diagnosed with ALS, since ER stress is a common feature across all of these subtypes of the disorder, in both familial and sporadic forms of ALS.

Prosetin was the first investigational drug developed through the collaboration between researchers at the Project ALS Therapeutics Core—a drug discovery and development program led by investigators at Columbia’s Center for Motor Neuron Biology and Disease and its Eleanor and Lou Gehrig ALS Center—and researchers from Columbia’s Departments of Pathology & Cell Biology, Biological Sciences, and Chemistry. Researchers at the Motor Neuron Center observed that mice dosed with prosetin had significant delays in weight loss and loss of grip strength, two key indicators of disease onset and progression. When Fleming and the researchers filed their Investigational New Drug application for prosetin with the FDA, they concluded they needed to raise significant capital to fund R&D for their ALS candidate.

Fleming and scientific co-founders Wichterle and Stockwell established ProJenX, along with Medical Excellence Capital (MEC), which led a $5.1 million seed financing for the startup. MEC is an early-stage life science venture firm that completed a $145 million inaugural fund in August. Proceeds from the seed financing are intended to fund early clinical development of prosetin, expand the company’s leadership team, and advance additional preclinical programs in its pipeline. That pipeline includes additional development of prosetin for Parkinson’s disease, glioblastoma, and Alzheimer’s disease—as well as a second candidate with an undisclosed target and mechanism designed to treat ALS.

ProJenX licensed prosetin from Columbia then launched the Phase I program to study the drug. Abel joined the company in May. Abel and Fleming are ProJenX’s two full-time employees, though the company earlier this month had advertised for an experienced project manager. The company is working on a Series A financing, targeting a $40-million raise—to complete the Phase II/III potential registration trial in ALS, advance prosetin’s second program in Parkinson’s to enrollment in a Phase II trial, and carry out further research on prosetin’s potential in  glioblastoma and Alzheimer’s.

As for plans for ProJenX to go public, Abel said: “As a venture capital-funded biotech company, you always think about that as a potential path that we would want to or need to go down. The markets have been challenging and very choppy the last several months. So, we’re glad that we’re not thinking about that right now. We’re focused on raising a private round.”

​However, Abel added, “as we continue to build the company and build the pipeline, I think that’s always a path that we will be thinking about and be prepared to go down.” https://www.genengnews.com/neurological-disorders/als/stress-test-projenxs-oral-drug-shows-early-promise-vs-als/