Making ALS heterogeneity tractable — McGill’s Angela Genge

ALS clinical trials veteran Genge sees progress in pathway prioritization, progression modeling, endpoint execution and biomarker development

Drug development in ALS has long been hampered by heterogeneity, but Angela Genge, a neurologist at McGill University, CMO of AL-S Pharma and veteran ALS trialist, argues the field may be getting closer to making that heterogeneity tractable.

On The BioCentury Show, Genge pointed to three areas where biological understanding and clinical trial execution are improving: pathway prioritization, progression-rate prediction and endpoint standardization.

On the biology side, her optimism is not that ALS is becoming simple. Rather, she expects the complex field to converge on a small number of high-priority pathways capable of changing disease course. The implication is that ALS complexity may resolve into a few actionable bottlenecks, rather than many independent therapeutic subgroups.

SOD1 is the first clear example, validated by Qalsody tofersen from Biogen Inc. (NASDAQ) and Ionis Pharmaceuticals Inc. (NASDAQ). AL-S Pharma AG is testing whether misfolded SOD1 also marks a treatable subset of sporadic ALS.

“Maybe there are only three more,” Genge said. “Maybe there are more, but I doubt there are going to be 25 pathways we have to target to get treatments.”

A second source of heterogeneity is the wide range of disease progression rates, from less than a year to more than a decade, which makes it difficult to measure population-level changes from baseline. One important advance, said Genge, is the TRICALS model which synthesizes over a dozen variable to estimate how quickly a patient is likely to progress, helping sponsors balance trial arms. 

On endpoint execution, Genge highlighted an ongoing push for global ALSFRS rater training and for keeping the same rater with each patient to reduce scoring variability.

The biomarker toolkit is also expanding, where neurofilament is an important but not universal solution — serum NfL can vary with events unrelated to ALS, making it less broadly useful in sporadic disease than many had hoped. The next frontier is broader: microRNAs, neuronally derived exosomes, protein panels, metabolomics and AI-aided biomarker discovery. Genge said the field may be close to TDP-43 biomarkers that are mature enough to start informing ALS trials. “It may be in the next two years actually,” she said. “If we’re unlucky, it’ll take five. It’s not going take 10.”