Antisense drug ISIS-SOD1Rx to treat amyotrophic lateral sclerosis (Lou Gehrig’s disease) goes on human studies: Isis

ISIS-SOD1Rx, an experimental therapy for patients with an inherited, aggressive form of Lou Gehrig’s disease also known as familial amyotrophic lateral sclerosis (ALS), is currently undergoing phase 1 human studies, announced Isis Pharmaceuticals, the developer of the drug.

Approximately 20 percent of all familial ALS cases are caused by a mutant form of superoxide dismutase, or SOD1.

ISIS-SOD1Rx is an antisense drug designed to inhibit the production of SOD1.

In preclinical studies, Isis, in collaboration with Timothy Miller, Don Cleveland (University of California, San Diego), and Richard Smith (Center for Neurological Study) were able to lower production of SOD1 with ISIS-SOD1Rx in neurons and surrounding cells and prolong life in rats that showed many symptoms of ALS.

In December 2007, US FDA granted ISIS-SOD1Rx Orphan Drug designation for the treatment of ALS.
Because antisense drugs do not cross the blood-brain barrier, a small pump administers the drug directly into the central nervous system infusing the drug into the cerebral spinal fluid.

This kind of direct administration of the drug into the central nervous system is called intrathecal infusion.

As part of Isis’ alliance with Genzyme, Genzyme has a right of first negotiation to license ISIS-SOD1Rx from Isis.

The ALS Association and the Muscular Dystrophy Association are providing funding for the development of ISIS-SOD1Rx.

“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,” stated Timothy Miller, M.D., Ph.D., assistant professor of Neurology at Washington University School of Medicine and Director of the Christopher Wells Hobler Laboratory for ALS Research at the Hope Center for Neurological Disorders in a press release.

ISIS-SOD1Rx is Isis’ first antisense drug to enter clinical trials to treat a neurodegenerative disease.

ISIS-SOD1Rx is also the first antisense drug to be administered directly into the central nervous system.

The phase 1 study of ISIS-SOD1Rx is a placebo-controlled, dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile of ISIS-SOD1Rx in patients with familial ALS that is caused by mutations within the SOD1 gene.

The study consists of four cohorts with eight patients each. In this study, ISIS-SOD1Rx will be administered intrathecally using an external pump to deliver the drug directly into the spinal fluid during a single, 12-hour infusion.

The study will be conducted in multiple centers within the United States.

Isis has successfully commercialized the world’s first antisense drug and has 22 drugs in development.

Isis’ drug development programs are focused on treating cardiovascular, metabolic and severe neurodegenerative diseases and cancer.

Isis’ partners are developing antisense drugs invented by Isis to treat a wide variety of diseases.

Isis and Alnylam Pharmaceuticals are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development and commercialization of microRNA therapeutics.

What is amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig’s disease, is a rapidly progressive fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles.

In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away, and twitch.

Eventually the ability of the brain to start and control voluntary movement is lost.

Individuals with ALS lose their strength and the ability to move their arms, legs, and body. When muscles in the diaphragm and chest wall fail, individuals lose the ability to breathe without ventilatory support.

ALS does not affect a person’s ability to see, smell, taste, hear, or recognize touch, and it does not usually impair a person’s thinking or other cognitive abilities.

No cure has yet been found for ALS. However, the FDA has approved the first drug treatment for the disease—riluzole.  Riluzole is believed to reduce damage to motor neurons and prolongs survival by several months, mainly in those with difficulty swallowing.