Understanding the integrated stress response is an important next step towards grasping the importance of target engagement biomarkers within ALS
The recently concluded AD/PD 2024 International Conference on Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) focused on innovative approaches poised to revolutionise the treatment of amyotrophic lateral sclerosis (ALS) and the use of neurochemical biomarkers in ALS drug development. As biomarkers are used for early diagnostics in clinics and as outcome parameters for novel treatment approaches in research, they are becoming key in the approval of ALS therapies, as per GlobalData.
According to GlobalData’s Drugs Database, the ALS pipeline consists of 51 candidates in various stages of development (Phase I–III) across the eight major markets, spanning the US, France, Germany, Italy, Spain, UK, Japan, and Canada.
Among these, 12 drugs are in mid-late-stage development (Phase II–III) and are poised to enter the market within the next five years. The investigational assets entail small molecules, monoclonal antibodies, antisense oligonucleoside (ASO), gene therapies, and small inferring RNAs.
At a recent symposium, focusing on therapeutic innovations in ALS, Dr. Angela Genge, director of ALS Centre of Excellence Montreal Neurological Institute and Hospital highlighted that therapies seeking approval for ALS may require support of biomarkers to differentiate in a crowded pipeline.
Momna Ali, pharma analyst, GlobalData, comments, “Alongside the exploration of novel therapies, in the last few years, considerable developments have taken place in the field of neurochemical biomarkers following Biogen’s Qalsody’s (tofersen) FDA approval in April 2023, based on neurofilament light chain (NfL) reduction, despite failing to meet primary and secondary endpoints. Regulatory bodies are increasingly keen to analyse both disease-progression biomarkers such as neurofilament light chain (NfL) and target engagement biomarkers such as TAR DNA-binding protein 43 (TDP-43).”
Understanding the integrated stress response is an important next step towards grasping the importance of target engagement biomarkers within ALS. Three investigational assets are being developed as small molecules targeting the integrated stress response through the activation of the eukaryotic translation initiation factor 2 (elF2). These assets include Bristol Myers Squibb’s elF2 in Phase I, Denali’s DNL343 in Phase II, and Calcio’s ABBV-CLS-7262 in Phase I.
Ali adds, “Other than small molecules, Ionis Pharmaceuticals and QurAlis are both investigating ASO-based therapies, in Phase III and Phase I, respectively. Ionis Pharmaceuticals’ ulfernesen reduces the production of a mutated, neurotoxin form of the Fused in Sarcoma (FUS) protein, which usually leads to ALS, while QurAlis’s programme is a splice switching ASO as opposed to gapmer ASO. The aim is to restore STATHMIN-2 (STMN2) expression in patients with ALS as STMN2 is an important protein for neural repair.”
The other three key therapies under investigation are ALS-Pharma’s monoclonal antibody AP-101 against misfolded superoxide dismutase 1 (SOD1) in Phase II, Regeneron Pharmaceuticals’ small interfering RNA (siRNA) therapy ALN-PP against SOD1 mutations and Corestemchemo’s stemcell therapy NeuoNata-R.
Ali concludes, “To address the lack of efficacious disease-modifying therapies, the treatment horizon is now abuzz with the exploration of novel approaches focused on curative therapies, and disease-progression biomarkers such as NfL and target engagement biomarkers such as TAR DNA-binding protein 43 (TDP-43). This not only offers lucrative opportunities for pharmaceutical companies but also presents a ray of hope for patients eagerly waiting for disease-modifying therapies.’’