As the Phase III amyotrophic lateral sclerosis pipeline thins out, the ALS community is placing its hopes on earlier-stage trials sponsored by Denali Therapeutics, PTC Therapeutics and more.
After a years-long drought, progress in the amyotrophic lateral sclerosis (ALS) space began to accelerate with the 2022 approval of Amylyx’s Relyvrio and Biogen and Ionis’ Qalsody in 2023. But now, that progress appears to have stalled. Earlier this month, Amylyx announced it would pull Relyvrio from the market after a failed Phase III trial, and closely watched trials from Seelos Therapeutics and Sanofi and Denali Therapeutics recently missed their primary endpoints.
“We went from having lots of trials to all of a sudden, there’s not that many right now, or they’re small or early,” Merit Cudkowicz, chair of the neurology department at Massachusetts General Hospital and a leading ALS researcher, told BioSpace.
Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, agreed, saying that the high-profile pipeline “looks a bit thinner.”
After withdrawing its Biologics License Application for cell therapy NurOwn in October 2023, BrainStorm Cell Therapeutics has reached an agreement with the FDA on the design of a Phase IIIb trial. Meanwhile, Clene anticipates launching a Phase III trial this year for its investigational gold nanocrystal suspension CNM-Au8.
But while the later-stage ALS pipeline may be depleted, there are still more than 100 investigational candidates in various stages of clinical development. Ultimately, Cudkowicz said, “we need more focus on the biology. That’s what’s hindering us. It’s not understanding what the best targets are.”
There is a big push now, she said, to discover more biomarkers for a greater understanding of how to stratify patients to get the best clinical results. Here, BioSpace takes a closer look at five mid-stage therapies targeting various aspects of ALS pathology.
Denali Therapeutics’ DNL343
Fortunately for Denali—and ALS patients—the South San Francisco, Calif.–based company has another arrow in its quiver of investigational therapies. Denali is currently recruiting for a Phase IIb/III trial of DNL343, a small molecule activator of the eukaryotic initiation factor 2B (eIF2B). In January, Denali listed completing enrollment of this trial as a key milestone for 2024.
DNL343 was designed to inhibit the cellular integrated stress response and prevent or slow disease progression by interfering with stress granule formation and TDP-43 aggregation, which is present in nearly all ALS patients, according to a recent press release.
In April 2023, Denali reported data from a Phase Ib trial showing that DNL343 was “generally well-tolerated at doses that demonstrate robust inhibition of biomarkers associated with the integrated stress response.”
Calico Life Sciences’ ABBV-CLS-7262
Like DNL343, Calico Life Sciences’ drug—being developed in partnership with AbbVie—is an eIF2B activator that targets the integrated stress response pathway. ABBV-CLS-7262 is the fruit of a deal struck in 2014 between AbbVie and Google-backed Calico to develop novel treatments for age-related diseases.
ABBV-CLS-7262 is currently being evaluated in the Healey ALS Platform Trial, on which Cudkowicz is the lead investigator. The Phase II/III double-blind trial, which includes an estimated 300 patients, will last six months and is followed by a treatment extension period. Enrollment is now complete, Cudkowicz said, and the trial is expected to wrap up in October of this year, according to ClinicalTrials.gov.
NeuroSense Therapeutics’ PrimeC
Earlier this month at the American Academy of Neurology’s annual meeting, NeuroSense Therapeutics presented data from the Phase IIb PARADIGM trial of PrimeC, a novel formulation of two FDA-approved drugs, ciprofloxacin and celecoxib. PrimeC aims to treat ALS by regulating microRNA synthesis, reducing neuroinflammation and influencing iron accumulation.
Cudkowicz, who gave the presentation and is one of the trial’s lead investigators, said the results are “trending in the right direction” in terms of function, breathing and neurofilament biomarker levels.
In December 2023, NeuroSense announced topline results from the six-month, double-blind trial, showing that PrimeC met the study’s primary safety and tolerability endpoints and also achieved secondary clinical efficacy endpoints. Patients treated with the investigational drug saw a “meaningful slowing of disease progression” on the ALS Functional Rating Scale-Revised, with the data favoring PrimeC by 29% compared to placebo. In February, the company reported further data showing that the drug had a clinically meaningful effect on quality of life and complication-free survival.
PTC Therapeutics’ Utreloxastat
In December 2022, PTC Therapeutics reported Phase I trial results for its ALS candidate, utreloxastat (PTC857), showing that the drug “was safe, well tolerated and displayed promising pharmacological properties in healthy people,” according to ALS News Today.
A small molecule, PTC857 inhibits 15-lipoxygenase to reduce oxidative stress—a widely recognized factor in ALS disease progression—and aims to prevent the depletion of glutathione, a protective antioxidant that studies suggest may be reduced in the motor cortex of ALS patients.
PTC857 is currently being assessed in the Phase II CardinALS trial, with topline data expected in the fourth quarter of 2024.
Coya Therapeutics’ COYA 302
Coya Therapeutics’ lead program, COYA 302, is a regulatory T cells (Treg)-targeted therapy in development for ALS, frontotemporal dementia, Parkinson’s disease and Alzheimer’s disease. It is currently in Phase II trials for ALS.
COYA 302 is a biologic combination therapy with a dual immunomodulatory mechanism of action intended to enhance the anti-inflammatory function of Tregs and suppress the inflammation produced by activated monocytes and macrophages. It is composed of low-dose interleukin-2 and CTLA-4 Ig.
In February 2023, Houston-based Coya announced results from a proof-of-concept study in which a small cohort of ALS patients were given the dual-mechanism immunotherapy for 48 weeks. The study evaluated safety and tolerability, Treg function, serum biomarkers of oxidative stress and inflammation and clinical functioning as measured by the ALSFRS-R scale. Coya reported that the therapy was well-tolerated, with the most common adverse event being mild injection-site reactions. There were no discontinuations or deaths.
Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.
