ISIS-SOD1-Rx: So Far, So Good

Early results of a phase 1 clinical trial of ISIS-SOD1-Rx, an antisense oligonucleotide drug for SOD1-related amyotrophic lateral sclerosis (ALS), show the drug appears to be safe and well tolerated at the lowest dosage level, based on a group of six patients who received 12-hour infusions of it into their spinal fluid.

ISIS-SOD1-Rx is being developed by Isis Pharmaceuticals of Carlsbad, Calif., with MDA support. Investigators plan to test the safety and tolerability of the drug at three higher dosage levels during phase 1.

Although directed at an inherited form of ALS caused by a mutated SOD1 gene, the trial also may reveal more about the feasibility of using antisense oligonucleotides (sometimes called AONs) against other forms of ALS.

At the lowest dosage level, researchers detected ISIS-SOD1-Rx in the spinal fluid after the infusions, a desired goal. There were no indications of clinical benefit, but none are expected in this phase 1 trial.

The most commonly reported adverse event was headache related to the drug delivery method, a procedure known as intrathecal delivery.

Timothy Miller from Washington University in St. Louis, who has been involved with the development of ISIS-SOD1-Rx, reported these interim results for the trial during the 63rd annual meeting of the American Academy of Neurology (AAN), held in Honolulu April 9-16.

About ISIS-SOD1-Rx

ISIS-SOD1-Rx is an antisense molecule directed against the genetic instructions (RNA) for the SOD1 protein. (Antisense compounds are pieces of genetic information that keep other genetic information from being processed.)

Mutations in the SOD1 gene result in the production of abnormal, toxic SOD1 protein, and are the cause of about 1 percent to 2 percent of all ALS cases.

ISIS-SOD1-Rx is designed to block production of both normal and abnormal SOD1 protein. Laboratory studies have indicated that a lack of normal SOD1 protein is not nearly as problematic as having toxic SOD1 protein, so the expectation is that a drug that reduces both kinds of SOD1 would provide benefit.

About the ISIS-SOD1-Rx trial

The trial for which preliminary findings were reported will involve 32 people with ALS who have a mutation in the SOD1 gene.

The principal investigators for this trial are Miller, a neurologist and neurophysiologist at Washington University School of Medicine in St. Louis, who has direct MDA support for this project; and neurologist Merit Cudkowicz, who directs the MDA/ALS Center at Massachusetts General Hospital in Boston and has MDA research support for ALS studies.

There are four groups in the trial, each slated to receive a higher dose of ISIS-SOD1-Rx than the previous group. Within each dose group, six patients are randomly assigned to receive ISIS-SOD1-Rx and two to receive a placebo (saline solution).

The infusions are done into the fluid around the spinal cord via a catheter placed through the skin at the level of the lower back.

Each trial participant receives one 12-hour infusion. Standard safety measures, ALS functional testing and respiratory functional testing are being conducted prior to and after the infusions.

Trial is recruiting participants

The phase 1 trial has now moved up to the second dosage group.

About Clinical Trials

A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur. MDA has no ability to influence who is chosen to participate in a clinical trial. To learn more, see Understanding Clinical Trials and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to

Recruitment of trial participants is ongoing at five study centers in the United States, and travel funds are available. Participants must have familial ALS due to a SOD1 mutation.

For details and contact information about the trial, see:

Or, contact Patrica Andres at the Northeast ALS Consortium (NEALS) Coordinating Center in Boston, at (617) 724-8995 or

Meaning for people with ALS

"So far, so good" is the take-home message from the first group of people with ALS who have received ISIS-SOD1-Rx.

If the drug is safe and reaches the desired level in the spinal fluid during the phase 1 trial, then the next phase of testing will involve seeing whether it can be given at a high-enough dosage and for a long enough time to significantly reduce SOD1 protein levels, and whether such reduction will slow, stop or even perhaps reverse the disease course in SOD1-related ALS.

The trial has the greatest implication for people with the SOD1 form of ALS. However, if ISIS-SOD1-Rx is safe and effective, it's likely antisense strategies can be used to reduce synthesis of other proteins that behave abnormally in ALS.

For more about antisense in general and ISIS-SOD1-Rx development in particular, see:

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