In the quest for better treatment, rigorous analysis of a potential drug's effectiveness and safety is essential. “Fifteen years ago, there was no treatment for ALS and not much to try. Now, research discoveries are so numerous that we have to prioritize the most promising ideas,” says Merit Cudkowicz, MD, director of the Mass General Neurological Clinical Research Institute.
“We feel a great urgency to find new therapies for ALS and that means quickly identifying drugs that should move forward and those that are ineffective,” she adds. In the last year, three drugs illustrate the unit's approach.
Ceftriaxone moves forward
In an effort to efficiently identify existing drugs that could be re-purposed for ALS, researchers tested all drugs approved by the U.S. Food and Drug Administration (FDA) in a cell-based experiment to see which might protect motor neurons. Ceftriaxone was a “hit” in this screen and subsequent testing in the laboratory and ALS mice showed that it may help clear the neurotransmitter glutamate near nerve cells, protecting them from toxic over-excitation.
Although ceftriaxone is approved by the FDA for treating acute bacterial infections, Phase I and II trials were necessary to show that the drug was safe for ALS patients and that it could enter the cerebrospinal fluid where the motor neurons function. These trials were successful.
The Phase III trial, which is enrolling up to 600 people at multiple sites in the U.S. and Canada, will determine the efficacy of ceftriaxone for ALS.
Antisense drug ISIS-SOD1Rx begins Phase 1 clinical study in familial ALS patients
The explosion in genomic information has led to the discovery of many new disease-causing proteins. A new class of drugs called antisense molecules bind to messenger RNAs (mRNAs) and inhibit the production of disease-causing proteins.
Isis Pharmaceuticals is sponsoring a Phase I study that will evaluate the safety, tolerability, and pharmacokinetics of a new investigational drug, Antisense oligo ISIS 333611. It will be administered intrathecally (using a pump and a catheter to deliver medication into the spinal fluid) to patients with rapidly progressive forms of familial amyotrophic lateral sclerosis (ALS) due to mutations in the SOD1 gene.
Lithium shows no benefit
Investigators and funding organizations joined forces to rapidly replicate an intriguing study from Italy that showed a positive effect of the drug lithium in a small group of ALS patients. Because the results were so striking, many patients were eager to begin treatment with the drug, but a larger study was needed to confirm the results.
Swati Aggarwal, MD ( former Neurology faculty member) and Dr. Cudkowicz, in partnership with the Northeast ALS and the Canadian ALS consortia, quickly launched a randomized trial that enrolled 84 people over four months. Neither the patients nor the physicians knew who was receiving lithium. Unfortunately, the blind study did not show a beneficial effect of lithium on the progression of ALS and was consequently halted.
Although we were disappointed, it is essential that patient shave good information about what works and what doesn't. We will continue to forge ahead on potential drugs using the best approaches we have. We are so grateful for those patients who are willing to volunteer for clinical studies who make this work possible,” says Dr. Cudkowicz.