ALS SOD1 Trial: A ‘Watershed Moment’

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Isis Pharmaceuticals of Carlsbad, Calif., has begun a phase 1 clinical trial of its experimental compound ISIS-SOD1-Rx in people with familial (inherited) ALS caused by toxic SOD1 protein molecules.

“This is a watershed moment,” said R. Rodney Howell, a metabolic disease specialist and chairman of the MDA Board of Directors. “More than 30 people with familial ALS caused by mutations in the SOD1 gene soon will receive infusions of a SOD1 inhibitor directly into their central nervous systems.”

A so-called "antisense" compound, ISIS-SOD1-Rx is designed to block production of the toxic SOD1 (superoxide dismutase 1) protein in people who have developed ALS because of mutations in the SOD1 gene. Antisense compounds are pieces of genetic information that keep other genetic information from being processed.

SOD1 mutations account for approximately 1 percent to 3 percent of all cases of ALS (amyotrophic lateral sclerosis), and about 20 percent of all familial ALS cases.

The SOD1 form of ALS is perhaps the best-understood form of the disease and almost the only form used in animal-based ALS studies.

About the study

Investigators at Washington University in St. Louis, Massachusetts General Hospital in Boston and four additional U.S. sites will use an external pump to administer 12-hour infusions of ISIS-SOD1-Rx directly into the fluid that surrounds the brain and spinal cord. The delivery method, called "intrathecal injection," is expected to effectively target the cells that produce the toxic SOD1 protein.

The trial will assess the safety, tolerability and pharmacokinetics (the ways a drug works in the body) of the antisense compound in people with the disease. The study consists of four cohorts with eight patients each. 

Timothy Miller at Washington University in St. Louis has received MDA support to work with Isis Pharmaceuticals to develop ISIS-SOD1-Rx (formerly ISIS-333611).

Miller was part of earlier studies that showed ISIS-SOD1-Rx blocked production of SOD1 in the central nervous system and prolonged life in rats with a disease that mimics ALS.

“It is evident that certain cases of familial ALS are related to mutant forms of SOD1.  Therefore, the selective inhibition of SOD1 production could provide a way to improve the outcomes of these patients with ALS,” said Miller. 

Meaning for people with SOD1-Related ALS

This study represents the first time a drug designed to block toxic SOD1 has been administered directly into the central nervous system.

Genzyme Corp., of Cambridge, Mass., through an alliance with Isis, is poised to license the rights to further clinical development of the compound if trial results prove positive.

“ISIS-SOD1-Rx is our first antisense drug to enter clinical trials to treat a neurodegenerative disease and our first antisense drug to be administered directly to the central nervous system,” said C. Frank Bennett, senior vice president of research at Isis Pharmaceuticals.  “This study is the first step in demonstrating the applicability of antisense drugs to treat severe neurodegenerative diseases.”