Muscle and Combo Therapies Likely Next Focus for SMA, Experts Say

[Editor’s Note: This is part of a series of articles into the discovery and development of Evrysdi, SMA’s newly approved disease-modifying therapy and its first oral and at-home one, as well as the scope of SMA issues and treatments. Here, we look at what’s ahead for SMA, including the possibility of combining both approved treatments and those showing promise in testing.]

Treatment combinations, including future muscle-targeted therapies, are part of what likely lies ahead for spinal muscular atrophy (SMA), according to experts in the SMA community.

In separate interviews with SMA News Today, Richard Finkel and Laurent Servais, neurologists who worked on trials of all approved SMA therapies, as well as Karen Chen, the SMA Foundation’s CEO, discussed what’s on the horizon for SMA.

Three disease-modifying therapies are now approved in the U.S. for SMA patients: Spinraza (nusinersen, by Biogen), Zolgensma (by Novartis and AveXis), and Evrysdi (risdiplam, by Genentech, a subsidiary of Roche).

Spinraza is open to all SMA types without restrictions, while Evrysdi was approved for patients 2 months and older. Zolgensma is for children up to 2 years old in the U.S. and Japan, and children with almost all types weighing up to 21 kilograms (about 46 pounds) in Europe. 

Karen Chen, CEO of the SMA Foundation. (Photo courtesy of the Foundation)

“We are fortunate that there are three different treatments, each with its pros and cons,” said Chen, PhD, a neuroscientist who has served as the foundation’s CEO since 2007.

Despite their differences, each targets the disease’s underlying cause: a deficiency in the SMN protein. SMN is found in virtually every cell in the body, but motor neurons appear to be highly SMN-dependent, dying without it.

The loss of these nerve cells, which control voluntary muscle movement, results in the progressive muscle weakness and atrophy that characterizes SMA.

While the gene therapy Zolgensma delivers a healthy copy of the SMN1 gene to cells, both Spinraza and Evrysdi treat the disease by targeting SMN2, a gene that can partly compensate for the loss of SMN1-derived SMN protein.

A single administration of Zolgensma is expected to promote a sustained production of SMN in cells that do not divide into new cells (like motor neurons), and as such are less likely to lose the newly introduced gene.

But this therapy can only be given once due to the body’s natural production of antibodies against the viral vector used to deliver the gene. For this reason, Spinraza or Evrysdi may be “natural combinations” with Zolgensma for SMA patients, Chen said.

In a February interview, Sharon Hesterlee, PhD, an executive vice president and chief research officer for the Muscular Dystrophy Association, voiced a similar opinion.

“Drugs like Spinraza and risdiplam act differently than gene replacement,” Hesterlee said, “and as these and other approaches that work further downstream get approved, I think combining them is the next logical step.”

It certainly interests researchers. 

“We’re very interested in seeing if the SMN-targeted [therapies], in combination, will provide added benefits,” said Finkel, MD, a pediatric neurologist at St. Jude Children’s Research Hospital in Tennessee.

Indeed, this is among the goals of an ongoing clinical study of risdiplam, called JEWELFISH (NCT03032172), which includes people previously treated with Zolgensma or Spinraza.

While using Spinraza with Evrysdi makes little sense, as both target SMN2, patients may want to switch from one to the other, or use either of these treatments before or after the gene therapy. It’s necessary to establish safety. 

Patients and parents “will probably be looking at combinations of these SMN-upregulating therapies, or even in combination with other types … like muscle-directed [therapies] that have nothing to do with SMN,” Chen said.

Servais, MD, PhD, a professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Centre, supports the latter strategy. He is not “sure at all” that combining different SMN-based therapies “would be very successful and cost-effective.”

In a recent consensus statement, a panel of European neuromuscular experts agreed. Different SMN-targeted therapies are not likely to bring added benefit “due to [their] common downstream pathway and mode of action,” unless their distribution throughout a person’s system is substantially different.

“I think now we should change the target,” Servais, who was a member of that panel, said.

Treatments that act specifically on muscle — including those intending to prevent the production of myostatin, a molecule that suppresses muscle growth — may well be “the next big area” in SMA, Chen said. Such therapies may be quite important for older patients with milder forms of SMA, as they can “increase function through targeting the muscle.”

Richard Finkel, a pediatric neurologist, has worked on trials of all SMA targeted therapies. (Photo courtesy of St. Jude)

One such potential treatment, known as SRK-015 (by Scholar Rock), is currently being evaluated in type 2 and 3 patients in a Phase 2 clinical trial called TOPAZ (NCT03921528).

Finkel is also quite eager to see TOPAZ’s results, and whether this type of treatment provides added benefits to those targeting SMN. He also expects more SMA therapies aimed at supporting muscle, and more types of these therapies, to come along.

As for the SMA Foundation, its CEO said her group’s near-term focus is on muscle-targeted therapies fairly well along in clinical trials, while longer term goals favor regenerative medicine now in preclinical testing.

“Academic investigators, at places like Harvard and Stanford, are really working on a way to transplant stem cells or regenerate neurons … so there might be a possibility for the regeneration of lost motor neurons,” which does not happen naturally.

“We’re kind of exploring that, but it’s still very early days,” Chen said. “I’m hopeful. I’m a positively hopeful person — I see a silver lining.”