Valproic Acid Combo Therapy Fails to Improve Survival of SMA Type I Infants, Clinical Trial Shows

Valproic acid (VPA) combined with L-carnitine — previously suggested as a potential therapy for infants with spinal muscular atrophy (SMA) — does not improve the survival of SMA type I patients, according to the results of the CARNIVAL clinical trial.

The study, “Clinical Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy Type I,” appeared in the journal Muscle & Nerve.

Previous studies suggested that VPA, a histone deacetylase (HDAC) inhibitor, is a potential therapeutic candidate for SMA.

In the CARNIVAL Type I trial, researchers led by Boston’s Massachusetts General Hospital set out to investigate the safety and therapeutic potential of VPA, combined with L-carnitine, in infants with SMA. They added L-carnitine — a compound involved in cellular energy production — to the therapy since “individuals with SMA have demonstrated increased vulnerability to carnitine depletion in the setting of VPA treatment,” authors wrote.

The Phase 2 study (NCT00661453) enrolled 37 infants with SMA type I aged two weeks to 12 months from seven clinics in the United States and Canada, and one in Germany. Cure SMA and Cure SMA Canada funded the study for the North American sites, while Bild “Ein Herz für Kinder” funded the German site.

Patients completed two screening visits within a two-week period to establish disease parameters at baseline. The babies then received two daily doses of L-carnitine and VPA. Researchers measured treatment effects at three and six months and compared them to an untreated, matched disease group of 57 type I infants. They chose controls retrospectively from a larger cohort of 151 SMA type I infants enrolled in the  University of Utah’s Project Cure SMA database.

The study’s primary endpoint was to determine the treatment’s safety and adverse effects. Secondary endpoints included survival, time to death or ventilator dependence, defined as more than 16 hours of ventilator support per day.

Researchers detected 245 adverse effects, mostly related to respiratory problems, in 95 percent of patients. These resulted in 14 deaths, authors wrote, showing that “treatment with L-carnitine and VPA in symptomatic infants with SMA type I had no significant impact on either survival or the combined endpoint of time to death and/or ventilator dependence >16 hours when compared to a natural history, untreated, matched disease cohort.”

Overall, the CARNIVAL Type I trial proves no survival benefit for infants with SMA type I treated with L-carnitine/VPA.

“Pre-symptomatic diagnosis, ideally in the newborn period, or enrollment soon after the initial diagnosis is preferable to maximize therapeutic benefit for promising new therapies and minimize adverse outcomes,” the study concluded.