MDA-supported testing is under way to determine whether the commonly used drug pyrimethamine, marketed under the brand name Daraprim, may reduce levels of abnormal SOD1 protein molecules that poison nerve cells in a familial (inherited) form of ALS.
A variety of mutations in the gene for the SOD1 protein account for approximately 20 percent of familial ALS cases, or about 2 percent of all cases of ALS.
Pyrimethamine is approved by the U.S. Food and Drug Administration for treatment in humans of the parasitic infections malaria and toxoplasmosis.
In a pilot trial, a number of patients with SOD1-related ALS showed reduced SOD1 blood levels while taking pyrimethamine, says Dale Lange, an MDA grantee and director of the MDA clinic at Joan and Sanford I. Weill Medical College of Cornell University in New York. Evidence from animal studies also shows that pyrimethamine reduces SOD1.
If SOD1 levels can be effectively decreased, “there should be a change in [disease] progression,” Lange says.
Researchers now are conducting a phase 1 study of pyrimethamine that incorporates what was learned in the pilot study. For example, the pilot study showed that people didn’t tolerate rapid increases in the pyrimethamine dose, so dose escalation will be slower in the new study.
The pilot study also revealed that SOD1 levels may go down more efficiently in spinal fluid than in blood. Researchers will be measuring SOD1 levels in spinal fluid as well as in blood.
Reduced SOD1 levels in spinal fluid are “a lot more meaningful than if we found the reduction occurring only in the blood,” Lange says. “That we can alter the biologic target in the spinal fluid means that the drug effect is very close to the target organs [the spinal cord and brain].”
The investigators noted that in the pilot study, which had 17 participants, the drug’s effects varied depending on the patient’s specific SOD1 gene mutation. Lange hopes the current study will enroll more than double the number of participants so this variation can be observed and insights about ALS and its treatment can be gleaned.
|Sean Scott, late president of the ALS Therapy Development Institute in Cambridge, Mass., initiated the high-throughput screening effort that identified pyrimethamine as an SOD1-lowering agent.
Lange says there were “no preclinical suspicions” that pointed to pyrimethamine as a potential therapeutic for ALS.
Rather, a 2002 high-throughput screening effort initiated by Sean Scott (the late president of the ALS Therapy Development Institute in Cambridge, Mass., who lost his life to ALS on Feb. 9, 2009) and molecular neuropharmacologist Dan Benjamin of New Jersey isolated the drug as one of a few out of hundreds of prospects that indicated a potential to lower SOD1 levels in cells in the laboratory.
The most potent candidates were then evaluated to determine which could reduce SOD1 levels in a dose-responsive fashion, with higher doses causing more SOD1 reduction. Says Lange, “That would suggest that the drug actually is responsible for the effect.”
Of the remaining candidates, Scott and Benjamin looked for drugs that already had been approved for other applications, permitting them to more easily and more quickly be tried in people.
“That whittled the original list down quite a bit,” Lange says. “There were a couple of promising candidates, but the one they chose was the most studied, with the best toxicity profile and least chance of causing side effects — pyrimethamine.”
For more information, contact Mona Shahbazi at (212) 774-2361, or email@example.com, or see the Clinical Trials section of MDA’s Web site. Participants must have documentation of an SOD1 genetic mutation.