ALS Clinical Trial Landscape: Investigational Therapies Targeting Sporadic ALS

The drug development pipeline for amyotrophic lateral sclerosis (搜索)搜索该疾病 (ALS (搜索)搜索该疾病) 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 (搜索)搜索该疾病 patients is the presence of TDP-43查看药品详情 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查看公司主页 is testing an antisense oligonucleotide (ASO) called BIIB-105查看药品详情, delivered via intrathecal injection. This ASO targets the Ataxin-2 (ATXN2) protein, with the goal of reducing TDP-43查看药品详情 aggregation. The "ALSpire" study (NCT04494256查看临床试验) is a dose-escalating study investigating the safety and tolerability of BIIB-105 in approximately 108 ALS (搜索)搜索该疾病 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查看药品详情 and DNL343查看药品详情, both oral small molecule drugs. These regimens aim to slow ALS (搜索)搜索该疾病 progression by targeting the harmful buildup of TDP-43查看药品详情 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 (搜索)搜索该公司, ABBV-CLS-7262查看药品详情 (NCT05740813查看临床试验) 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查看药品详情 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查看公司主页, DNL343查看药品详情 (NCT05842941查看临床试验) 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 (搜索)搜索该词条' investigational drug, QRL-201查看药品详情, is in Phase 1 clinical trials in Canada (NCT05633459查看临床试验). QRL-201 uses ASO technology delivered via intrathecal injection and aims to restore STATHMIN-2 (STMN2 (搜索)搜索该靶点) expression in people with ALS (搜索)搜索该疾病. 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查看药品详情, an investigational drug called a Sigma-1 Receptor (S1R) agonist, is being tested in the Healey Platform trial (NCT04615923查看临床试验). S1R is a protein highly expressed in the brain and spinal cord, regulating various processes often impaired in people with ALS (搜索)搜索该疾病. Earlier this year, Prilenia (搜索)搜索该词条 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 (搜索)搜索该公司's CNM-Au8查看药品详情 (aka gold nanocrystals) is being tested as Regimen C in the Healey Platform Trial (NCT04414345查看临床试验). 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 (搜索)搜索该疾病.

Targeting Upper Motor Neurons

Akava Therapeutics’ AKV9

Akava Therapeutics (搜索)搜索该词条 received FDA clearance to proceed with first-in-human testing of AKV9查看药品详情, 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 (搜索)搜索该疾病 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查看公司主页 is developing therapies using regulatory T cells (Tregs). In a proof-of-concept (POC) study with its therapy called COYA-302查看药品详情, 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查看药品详情 is an oral pill and a tyrosine kinase inhibitor in late-stage development for ALS (搜索)搜索该疾病. Two of masitinib's cellular targets are mast cells and microglia, both of which play a key role in inflammation. AB Science (搜索)搜索该词条 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查看药品详情 (aka Debamestrocel) is one of the most eagerly anticipated in the ALS (搜索)搜索该疾病 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 (搜索)搜索该疾病 have estimated completion dates extending into 2025 and 2026, it is likely that NurOwn查看药品详情 will be the only sporadic ALS therapy that will be submitted for FDA approval for a few years.