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Researchers involved in developing oligonucleotide therapeutics have always been known for picking difficult problems related to difficult diseases. SOD1-ALS is a deadly neurodegenerative disease caused by a mutation in the SOD1 protein. Because the disease is due to the SOD1 mutation, it is possible to form a hypothesis that ASOs can reduce SOD1 protein expression and alleviate disease. Even within the already small population of ALS patients, SOD1 is rare. The rarity of this specific type of ALS makes it difficult to design a decisive clinical trial. This obstacle did not deter colleagues at Ionis and Biogen from developing Qalsody (tofersen) a gapmer ASO. Clinical trials showed significant reductions in a plasma biomarker, but the trials did not produce a clear clinical benefit to the relatively small number of patients involved. The FDA, however, judged that the surrogate endpoint could be reasonably expected to correlate with an eventual benefit to patients and approved the ASO. Trials to more definitively establish benefit will be ongoing, but today’s FDA approval marks an important first step towards an ASO treatment for ALS and broader application of ASOs to the CNS. I congratulate our colleagues at Ionis and Biogen for this achievement and the brave decisions behind it. I also thank the FDA for their thoughtful decision-making balancing the difficulties of definitively testing drugs for small patient populations.
