The former malaria therapy pyrimethamine reduces levels of an ALS-linked protein in the spinal fluid of patients whose disease stems from gene mutations, a Phase 1/2 clinical trial shows.
The protein is SOD1. The mutations connected with amyotrophic lateral sclerosis are in the SOD1 gene that controls the protein.
The study, “Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations,” was published in the journal Annals of Neurology.
Developed to treat malaria, pyrimethamine is now used to treat pneumonia and the toxoplasma gondii parasite. It works by interfering with DNA synthesis in bacteria and parasites.
A Phase 1 clinical trial showed that pyrimethamine lowers SOD1 protein levels in the white blood cells of ALS patients with SOD1 mutations.
The goal of the nine-month Phase 1/2 trial (NCT01083667) was to see whether pyrimethamine could lower levels of mutated SOD1 in the cerebrospinal fluid of ALS patients with SOD1 mutations. The study covered 32 patients at five centers.
Researchers used a number of measuring tools in their analysis. They took spinal fluid and blood samples, and evaluated patients’ strength, movement capabilities, and quality of life. They also checked for adverse effects of treatment.
Pyrimethamine led to a 13.5 percent drop in spinal-fluid SOD1 protein at week 18, and to a 10.5 percent drop at week 36.
“Our multi-center international study found that pyrimethamine reduced levels of SOD1 in the cerebrospinal fluid of patients with familial [genetically based] ALS, and the amount of lowering was related to the dose of pyrimethamine,” Dr. Dale J. Lange, the study’s principal investigator, said in a news release. “There is currently no cure for this devastating disease, but our study represents the first time a drug lowered a protein known to be relevant to disease progression.” That reduction equated to “a slowing of disease progression,” he added.
Pyrimethamine was safe, and patients tolerated it well. Side effects included headache, nausea, diarrhea, falls, upper respiratory tract infections, shortness of breath, fatigue, weight loss, and decreased appetite. The drug did not lead to a decline in patients’ quality of life of patients, researchers noted.
“Although not proven by this study, a slowing of disease progression was observed,” Lange added. “A larger study is needed, and is being planned, to determine if pyrimethamine does indeed influence the disease course in ALS patients.”