The ALS space looked promising in 2022 after Relyvrio’s approval and a green light for Oalsody in 2023. Then progress stalled a bit in 2024 as a result of Relyvrio being scheduled to be pulled off the market due to its failed Phase III clinical trial. Also, Denali Therapeutics and Sanofi did not meet primary endpoints; nor did Seelos Therapeutics.
Never Ever Give Up
As reported in BioSpace, thanks in part to the persistence and dedication of Dr. Merit Cudkowicz of Massachutts General Hospital and its neurology staff, the slowdown was temporary. In October 2023, Brainstorm Cell withdrew its application for NurOwn, its cell therapy. Then an agreement was reached between the FDA and BrainStorm on designing the trial for NurOwn. Continuing the upcycle, Clene Nanomedicine plans to a launch Phase III clinical trial in 2024 studying CNM-Au8, its novel gold nanocrystal suspension.
Although the current ALS pipeline is somewhat depleted, there are currently over 100 candidates at various levels of development that will be investigated in the near future.
Finding the Best Target
According to Dr. Cudkowicz, the emphasis should be on biology. She believes that not focusing on biology has been the hindrance. Dr. Cudkowicz further commented that there is no full understanding of the targets. Many researchers agree with the doctor. The new focus of researchers is finding the best way to stratify patients (group them into similar clusters) in order to improve clinical results.
There are five ALS investigational therapies in the mid-stage of development. These therapies target several aspects of ALS pathology:
• DNL343 from Denali Therapeutics is an investigational ALS therapy targeting elF2B, the cellular regulator. The Denali Phase IIb/III trial is on target to complete enrollment in early 2024. DNL343 is a small molecule activator of elF2B that slows or prevents disease progression. TDP-43 aggregation and stress granule formation are found in most ALS patients.
• AbbVie and Calico Life Science are in partnership in the development of ABBV-CLS-7262. The drug targets the stress response pathway. CLS 7262 is now under evaluation in the Phase II/III Healey ALS trial that is expected to conclude by the end of this year. The six-month trial has approximately 300 participants and is listed under ClinicalTrials.gov.
• NeuroSence therapeutics’ PrimeC NeuroSense presented Phase IIb data from its PARADIGM trial at Neurology’s annual meeting of the American Academy of Neurology. PrimeC is a formulation of two drugs approved by the FDA (celecoxib and ciprofloxacin). PrimeC targets ALS by reducing neuroinflammation, regulating microRNA synthesis and impacts the accumulation of iron. Dr. Cudkowicz commented that biomarkers for breathing, function, and neurofilament are headed in a positive direction. Investigators found that participants who took the drug showed a reduction in disease progression and a positive effect on their survival and quality of life.
• Utreloxastat (PTC857) from PTC therapeutics. Oxidative stress is recognized in ALS disease progression. PTC857 prevents the reduction of glutathione which is a protective antioxidant recognized in various studies as being at low levels in ALS patients’ motor cortex. The drug is now being investigated in the CardinALS Phase II trial with data expected by the end of 2024.
• And lastly the lead program of COYA Therapeutics, Coya302, a regulatory T cell (Treg) targeted therapy being developed for ALS, Parkinson’s, and frontotemporal dementia. The drug is now in Phase II ALS trials. COYA302 is a combination therapy that has dual immunomodulatory mechanism designed to enhance Tregs’ anti-inflammatory features and suppress inflammation that is produced by macrophages and monocytes. Its composition includes CTLA-4 and low-dose interleukin-2. Reports from the trial found the therapy to be well-tolerated without any discontinuation or death.
