Nature Medicine | Spoonful of Medicine

New drug pathways under investigation for ALS

ALS-nm20111122.jpgA diagnosis of amyotrophic lateral sclerosis (ALS) is considered a life sentence. Most people with the neurodegenerative disease, which attacks the neurons responsible for motor control, only survive two or three years after their diagnosis — and 5,000 such diagnoses are made each year in the US alone. Despite the need, however, there is only a single drug on the market that targets ALS: Rilutek (riluzole), made by France’s Sanofi. But this agent only prolongs life by two or three months on average.

Recent advances provide some hope for future drug pathways that can be targeted to treat the disease. In the latest issue of Archives of Neurology, Teepu Siddique and his colleagues at the Northwestern University Feinberg School of Medicine in Chicago reported finding mutations in the gene that encodes a ubiquitin-binding protein (known as p62 or sequestosome 1) in about 3% of people with either sporadic or inherited forms of the disease. This protein assists the breakdown of other proteins, and its mutation may cause a build-up of dysfunctional proteins in neurons leading to the neurological problems associated with ALS. The research adds to previous findings, including work from the same lab that made a splash in August, implicating the protein degradation pathway in ALS (see our November 2011 news feature, ‘A raw nerve’).


It will probably take years before drugs are developed that target this pathway. But until then, there is another in the works. Dexpramipexole — under development by Knopp Biosciences of Pittsburgh, Pennsylvania and Biogen Idec of Weston, Massachusetts — helps boost mitochondrial function to protect stressed out neurons. This week, a team led by Merit Cudkowicz, a neurologist at Massachusetts General Hospital in Boston, published phase 2 trial results in Nature Medicine showing that, at the highest dose tested, dexpramipexole slowed the rate of cognitive decline by about 30% compared to placebo and by about 20% compared to the lowest dose administered.

“I think a 20% slowing of the illness is clinically significant,” Cudkowicz told Nature Medicine. “It also would suggest that mitochondria and the cell energy pathway is a good target, and it would prompt other companies and academic to develop even better drugs for that target.”

A phase 3 trial called EMPOWER, which will test the same high dose of dexpramipexole, is now fully enrolled with close to 1,000 participants, and results are expected by the end of 2012, according to Cudkowicz. A higher dose phase 3 trial, dubbed ENDEAVOR, is pending.

Image: MRI picture of an ALS brain. Provided by neuroradiologist Frank Gaillard under Creative Commons licensing.

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