Building a science-based pipeline of disease-modifying therapies for ALS
Despite the existence of two FDA-approved drugs, there are still no potent disease-modifying therapies for ALS. At Biogen, where Neuromuscular Disease is a priority area, our first programs focus on the monogenic familial forms of ALS and use antisense oligonucleotides (ASOs) to reduce the levels of the disease-triggering RNAs, in partnership with Ionis Pharmaceuticals. Gain-of-function mutations in superoxide dismutase 1 (SOD1) are responsible for 2% of all ALS cases. We developed SOD1 ASOs that potently reduce SOD1 mRNA and protein and extend survival by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of CMAP in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels (pNFH), a promising biomarker for ALS, are prevented by SOD1 ASO therapy (McCampbell et al., J. Clin. Invest. 2018; 128: 3558-3567).
On the basis of these and other preclinical data, the SOD1 ASO BIIB067 moved into clinical trials. We recently reported that interim analysis of the MAD portion of the Phase 1 study showed lowering of SOD1 protein levels in CSF vs. placebo (n=12 placebo, n=10 BIIB067; p = 0.002), and a trend toward slowing of clinical decline, improved respiratory function, and improved muscle strength (n=12 placebo, n=10 BIIB067). These exciting data nevertheless reflected small cohorts, so Biogen moved immediately to a pivotal study with longer treatment and larger cohorts. Initial readout is expected in 2021.
To deepen our approach to genetic ALS, in parallel we are recruiting patients for the Phase 1 trial of BIIB078, an ASO that targets those C9ORF72 transcripts that contain expanded hexanucleotide repeats. And to address the significant challenge of sporadic ALS, where no single causal gene can be identified, we are basing our approach on emerging biology that implicates targets in multiple models of ALS, rather than being specific to a single gene mutation. The first of these is BIIB100, a small-molecule inhibitor of XPO1 (exportin 1), which will test the hypothesis, for which there is strong preclinical data, that perturbations in nucleocytoplasmic transport contribute to disease onset and progression.
With thanks to the many internal and external collaborators who made these studies possible.