The drug development pipeline for amyotrophic lateral sclerosis (ALS) is currently robust, with numerous promising therapies under investigation. These trials focus on both sporadic and genetic forms of ALS, addressing various pathological mechanisms. Several interventional drug trials are actively enrolling participants with sporadic ALS, while others are in completed Phase 2 or future Phase 1/2 stages.
Targeting TDP-43 Pathology
One common feature among most ALS patients is the presence of TDP-43 aggregates in motor neurons. Approximately 97% of people with ALS have TDP-43 aggregates, making it an important therapeutic target. Several clinical trials are focusing on reducing or clearing these aggregates.
Biogen's BIIB-105
Biogen is testing an antisense oligonucleotide (ASO) called BIIB-105, delivered via intrathecal injection. This ASO targets the Ataxin-2 (ATXN2) protein, with the goal of reducing TDP-43 aggregation. The "ALSpire" study (NCT04494256) is a dose-escalating study investigating the safety and tolerability of BIIB-105 in approximately 108 ALS patients. The anticipated completion date is July 15, 2026. Preclinical studies have shown that ASOs targeting ATXN2 protein levels caused significant improvement in both survival and walking in animal models.
Healey Trial Regimens
The Healey Platform Trial is currently enrolling two regimens, ABBV-CLS-7262 and DNL343, both oral small molecule drugs. These regimens aim to slow ALS progression by targeting the harmful buildup of TDP-43 via the integrated stress response. The trial includes a crossover design, with all participants receiving the treatment during an Open Label Extension after the 24-week double-blinded trial. Both regimens are collecting biomarker data from blood, urine, and cerebral spinal fluid (CSF).
ABBV-CLS-7262
Developed by Calico Life Sciences in collaboration with AbbVie, ABBV-CLS-7262 (NCT05740813) aims to activate eIF2B, a key regulator of the integrated stress response (ISR). Activating elF2B may help motor neurons survive harmful stress conditions by restoring normal protein levels, reducing stress proteins, and dissolving stress granules that may lead to TDP-43 aggregates. The trial's primary endpoint is change in disease progression as measured by the ALSFRS-R score. The estimated completion date is April 2025.
DNL343
Developed by Denali Therapeutics, DNL343 (NCT05842941) is also being tested in the Healey Platform Trial. The trial's primary endpoint is change in disease progression as measured by the ALSFRS-R score. Preliminary Phase 1 data showed that once-daily dosing of DNL343 was generally safe and well-tolerated, with extensive target distribution throughout the cerebrospinal fluid and robust inhibition of biomarkers associated with the integrated stress response (ISR). The estimated completion date is May 2025.
QurAlis' QRL-201
QurAlis' investigational drug, QRL-201, is in Phase 1 clinical trials in Canada (NCT05633459). QRL-201 uses ASO technology delivered via intrathecal injection and aims to restore STATHMIN-2 (STMN2) expression in people with ALS. STMN2 expression is significantly decreased in nearly all ALS patients and is an important protein for neural repair and axonal stability. The anticipated completion date of the Phase 1 trial is May 2025.
Targeting Sigma-1 Receptor
Prilenia's Pridopidine
Pridopidine, an investigational drug called a Sigma-1 Receptor (S1R) agonist, is being tested in the Healey Platform trial (NCT04615923). S1R is a protein highly expressed in the brain and spinal cord, regulating various processes often impaired in people with ALS. Earlier this year, Prilenia released topline results from its Phase 2 study of Pridopidine, showing some consistent, positive trends in motor function, speech & bulbar function, and in disease-related biomarker neurofilament light (NfL). The ALS community is eagerly awaiting the results and release of the data from the longer Open Label Extension.
Targeting Energy Metabolism
Clene's CNM-Au8
Clene's CNM-Au8 (aka gold nanocrystals) is being tested as Regimen C in the Healey Platform Trial (NCT04414345). The Phase 2/3 Healey trial of CNM-Au8 is completed. The mechanism of action for CNM-Au8 is targeting energy metabolism, promoting neuronal health by increasing NAD, ATP, and protein homeostasis, while decreasing oxidative stress. Clene plans to meet with the FDA in the third quarter of 2023 to identify next steps in the development pathway for CNM-Au8 for ALS.
Targeting Upper Motor Neurons
Akava Therapeutics’ AKV9
Akava Therapeutics received FDA clearance to proceed with first-in-human testing of AKV9, a drug targeting diseased upper motor neurons (UMNs). AKV9 is a protein aggregation inhibitor that is the first compound targeting the health of UMNs that degenerate and die in ALS and primary lateral sclerosis (PLS). Akava reported that it had filed its Investigational New Drug application with the FDA in May of 2023 and it was granted on July 3rd. First the company will start a Phase 1a study in healthy volunteers, perhaps before the end of 2023. Then, if the Phase 1a safety study shows no toxicity in people without ALS, it can then start a Phase 1b/2a trial in which the drug could be given to people with ALS hopefully in 2024.
Targeting Regulatory T Cells
Coya’s Treg Therapies
COYA Therapeutics is developing therapies using regulatory T cells (Tregs). In a proof-of-concept (POC) study with its therapy called COYA-302, the team used subcutaneous injection of interleukin-2 in a combination T-reg therapy that can be scalable for manufacturing and large studies. Although it was only a small open label study with four people, the POC early study of COYA 302 showed promising results. COYA plans to present and/or publish its biomarker data in the second half of 2023 concurrently with preparing for a meeting with the FDA in the fall of 2023. If the FDA gives the okay, COYA hopes to start a large, double-blind placebo controlled Phase 2 trial in 2024.
Targeting Inflammation
AB Science’s Masitinib
Masitinib is an oral pill and a tyrosine kinase inhibitor in late-stage development for ALS. Two of masitinib's cellular targets are mast cells and microglia, both of which play a key role in inflammation. AB Science has submitted its application for Conditional Approval to both the Canadian and EU regulatory authorities (the equivalent to the FDA). There is, however, an ongoing phase 3 study that can be used as the confirmatory trial for the EU application as well as a trial to support an application for approval in the US.
FDA Decision on NurOwn
The FDA's decision about NurOwn (aka Debamestrocel) is one of the most eagerly anticipated in the ALS community. NurOwn is a mesenchymal stem cell therapy treated with neurotrophic factors. On September 27th, the FDA will hold an Advisory Committee meeting (AdCom) to discuss the BLA. December 8th is the deadline (PDUFA date) for the FDA’s biologics division (CBER) to make its decision about NurOwn’s approval.
Given that currently enrolled trials for sporadic ALS have estimated completion dates extending into 2025 and 2026, it is likely that NurOwn will be the only sporadic ALS therapy that will be submitted for FDA approval for a few years.
