Christopher Henderson, Ph.D.

VP, Neuromuscular and Movement Disorders Research and Early Development Biogen

Christopher Henderson, Ph.D.

VP, Neuromuscular and Movement Disorders Research and Early Development Biogen

Biography

Following training at the University of Cambridge (UK) and spending much of his career in France, Chris Henderson moved in 2005 to Columbia University in New York, where he co-founded the Center for Motor Neuron Biology and Disease, an initiative in translational neuroscience that created a continuum from research on motor neurons through to clinical research on the motor neuron diseases ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). He was also director of the Columbia Stem Cell Initiative, a group of 120 laboratories across the university using stem cells to better understand or treat human disease. While still at Columbia, he became (and remains) chief advisor of Target ALS, a privately funded foundation that has stimulated industry investment in ALS research by supporting cutting-edge translational research and nationwide core facilities. This, and his experience with co-founding the biotech Trophos, motivated him to become more actively engaged in drug development. In October 2014, Henderson moved to Biogen (Cambridge, MA) to lead the neuroscience research program. Now, as Vice President of Research and Early Development in Neuromuscular & Movement Disorders, he works with a team of clinicians and scientists to take programs on ALS, SMA, other neuromuscular disease, Parkinson’s disease, MSA and ataxias from early research to clinical proof of concept.

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.

All sessions by Christopher Henderson, Ph.D.