Dr. Michael Lopez is a co-investigator of a clinical trial involving a new drug for spinal muscular atrophy.
A new drug is in late-stage clinical trials at Children’s of Alabama for spinal muscular atrophy (SMA), a rare genetic disease marked by progressive muscle deterioration and atrophy. The drug, apitegromab, has a different mechanism of action than other SMA treatments and is being studied in patients already taking others.
Apitegromab is a human monoclonal antibody that targets the myostatin pathway, which affects muscle cell mass. “The thought is that if you can inhibit this pathway, then you could increase the muscle cell mass,” said Michael Lopez, M.D., Ph.D., co-investigator with Han Phan, M.D., at Children’s. Numerous animal studies show that inhibiting the myostatin pathway increases muscle mass, while overactivation reduces muscle mass.
Apitegromab binds to the precursor (pro/latent) myostatin, preventing its conversion into the active, mature form of the protein. This prevents the muscle cells from receiving the signals to reduce their mass. Because it works differently from the gene-based therapies already available, it’s being investigated as an adjunctive therapy, ideally providing another avenue to building muscle and reversing the weakness and atrophy SMA patients experience. “Muscle is regenerative; it can repair and renew itself,” Lopez said.
Apitegromab is the latest encouraging investigational drug in SMA treatment. In 2016, the FDA approved the first disease-modifying treatment for SMA, nusinersen, which works by increasing the amount of spinal motor neuron (SMN) protein produced by the SMN2 gene. SMA patients have nonfunctional SMN1 genes but several copies of SMN2 genes.
Since then, two other treatments, the gene therapy onasemnogene abeparvovec—which is administered just once to those less than 2 years of age—and the oral therapy, risdiplam—which also alters how effectively the SMN2 gene makes the SMN protein—have been approved.
In the latest clinical trial, called SAPPHIRE, participants must already be taking nusinersen or risdiplam. The trial will evaluate the drug in patients ages 2 to 12 who have SMA type 2 or 3 and can no longer walk. They will be randomized to receive one of two doses of apitegromab or placebo by IV infusion every 4 weeks for a year. Children’s is one of several participating centers in the U.S.
Previously, a phase 2 trial called TOPAZ showed improved motor function, even in patients who couldn’t walk. “The preliminary data was encouraging, but additional study is required,” Lopez said.
The progress that’s been made in SMA in the last few years, which Lopez called “revolutionary and game changing,” would not have been possible without the support of the families enrolling in clinical trials for the currently approved drugs, he said. “And they didn’t know if there would be a benefit, or even if they were in the investigational arm or placebo arm.” He also praised the Muscular Dystrophy Association Clinic at Children’s for the “superb care provided.”
“Every day, I’m in awe of the progress that has been made in treating this disease,” Lopez said. “We have gone from not having any treatment options at all and watching patients succumb to the disease to knowing that every patient now has a different life ahead of them—something that wasn’t imaginable when I started med school.”