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.
“Data generated thus far in PRO-101 supports further evaluation of prosetin as a potential treatment for ALS,” the researchers concluded. “Our hybrid Phase I approach, which includes people living with ALS, may allow for more efficient and disease-relevant clinical development for potential ALS therapies.”
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.
A changed landscape for ALS drugs
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.
“Any new step forward or a significant step forward in this area is welcome, not only for the field of research, but clearly from a person living with ALS; they now have another treatment option,” ProJenX president and CEO Stan E. Abel told GEN Edge.
“As we’ve seen from Amylyx, they will consider one-study approvability in this setting,” Abel continued. “If it’s a well-designed, adequately powered single trial that reports out a clear, positive benefit, they will consider one-study approvability. Because of that, the time to potential approval is truncated versus a normal timeline where you could be looking at five, six, seven, eight years. We could have this trial done in 2025 and submit prosetin for approval sometime by the end of 2025.”
Relyvrio is one of only six drugs approved for treating ALS and its symptoms that have won FDA authorization. The other five are:
- Radicava® (edaravone), a Mitsubishi Tanabe Pharma drug approved in 2017 as the first new ALS-specific treatment in 22 years, with oral form Radicava ORS® approved in May.
- Rilutek®(riluzole), a glutamate release inhibitor shown to prolong life approximately three months. Developed by Rhône-Poulenc Rorer (acquired by Aventis, since merged into Sanofi) and approved in 1995, the drug is now available as a generic.
- Tiglutik®, a thickened liquid form of riluzole developed by ITF Pharma and approved in 2018 for both oral and PEG tube use.
- Exservan™, an oral film formulation of riluzole developed by Mitsubishi Tanabe Pharma and approved in 2019.
- Nuedexta® (dextromethorphan HBr and quinidine sulfate), developed by Avanir Pharmaceuticals to treat pseudobulbar affect (PBA) in patients with ALS and other underlying neurologic conditions, approved in 2010.
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 was launched in 1998 by sisters Jenifer, Meredith and Valerie Estess after Jenifer—a theatre and film director who co-founded Naked Angels theater company in New York—was diagnosed with ALS five years later, at age 35.
“There were really no laboratory models available. There was one mouse model. There were no in vitro models, so Project ALS in 2000 funded Dr. Wichterle in a blue-sky experiment to see if he could make a motor neuron from an embryonic stem cell,” Erin Fleming, ProJenX’s Co-Founder and Vice President, Research and Development, recalled to GEN Edge. She joined ProJenX last year after three years as director of research operations for Project ALS.
“In a very elegant way, he [Wichterle] succeeded in making the first in vitro models of ALS, the first stem cell-derived models of motor neurons,” Fleming added.
Since then, 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.
“When this amazing team from Columbia found a family of compounds that showed really profound activity in these models, and demonstrated really dramatic motor neuron protection they expanded the collaboration to work with Stockwell,” Abel said. “They synthesized compounds and optimized those compounds, for not only their activity in protecting motor neurons, but also in terms of drug properties that would be important for ALS.”
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.
“In ALS, our team found that if you treat these patient-derived motor neurons with ER stressors, they get really sick,” Fleming said. “We started to screen for compounds that would rescue these patient-derived motor neurons from ER stress. We were agnostic to mechanism throughout this entire process. We really, from the very beginning, wanted to understand: What’s happening in a motor neuron that has ALS? And how do you rescue what’s happening in a motor neuron that has ALS? We wanted to see what could rescue 100% of these motor neurons in a dish.”
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.
“As we made these 60 analogs through the optimization process, we found that all of the compounds that could rescue motor neurons inhibited MAP4 kinase,” Fleming recalled. “Motor neurons with ALS get sick when stressed. So we could stress these cells in a dish and then screen for drugs that would protect them and rescue motor neurons. And prosetin, our lead compound or lead candidate in the clinic, rescued 100% of motor neurons in a dish.”
Abel said prosetin differed from many other ALS drugs, which were initially designed for other indications, tried in ALS, and failed.
“All along the way, it was synthesized and created in advance with ALS patient biology being foremost of importance,” Abel said. “ALS patient cells, when they are treated in a dish with prosetin, you see profound motor neuron protection and survival. And that’s a key differentiation, I think, from most other drugs that have been taken into the clinic.”
Another key point of differentiation, Fleming said, was 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.
“A big issue with many other compounds is that they get shuttled out of the brain,” Fleming said. “You need to develop a compound that gets into the brain, and then has the right properties like lipophilicity to stay in the brain and be able to engage with its target.”
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.
“I knew the folks at Medical Excellence Capital, because we’d worked together on other companies over the years, and they introduced me to Erin and the team and ProJenX,” Abel recalled. “I was really moved by how much they had accomplished, and how that passion drove that effort over a 20-year period to come up with a compound that we think is really promising. It looks very, very encouraging, for potentially addressing ALS in a very meaningful way. So, it was an easy decision for me to want to join the company.”
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.”