SMA Debate: Might Systemic Treatment Be Best?

[Editor’s Note:  This is part of a series of articles about the discovery and development of Evrysdi — the newly approved disease-modifying therapy for spinal muscular atrophy and the first oral, at-home one — as well as the scope of SMA issues and treatments. Here, we talk with scientists about the importance of restoring healthy SMN protein levels bodywide.] 

With increasing evidence showing spinal muscular atrophy (SMA) is “a whole body disease,” experts wonder if Evrysdi (risdiplam) — by reaching both central nervous system and peripheral tissues — might offer benefits not possible for SMA’s other targeted treatments. 

“This is something that is still being broadly discussed in the community,” Laurent Servais, MD, PhD, a pediatric neurologist with the MDUK Oxford Neuromuscular Centre, said in an interview. “Some people are convinced that it’s very important for all patients to have broad distribution. … But for me, it’s purely speculative.”

All agree there is still a lot to learn, and the start of Evrysdi’s wider use — the newly approved therapy is the only one designed to have a bodywide, or systemic, effect — should help them better understand the importance of targeting peripheral tissues in SMA.

In a series of separate interviews with SMA News Today, researcher-clinicians and experts with the SMA Foundation, Roche, and PTC Therapeutics discussed SMA’s bodywide nature and the potential advantages of a systemic treatment.

SMA is caused by a deficiency in SMN (survival motor neuron), produced by virtually every cell in the body and involved in several cellular processes regulating protein balance.

Motor neurons, the specialized nerve cells of the central nervous system (CNS, brain and spinal cord) that control voluntary muscle movement, appear to be highly sensitive to SMN deficiency, dying without it. Their loss results in the progressive muscle weakness and atrophy that marks SMA.

Stuart Peltz, CEO of PTC Therapeutics. (Photo courtesy of PTC)

Over the past few years, an increasing number of studies have shown that other tissues and organs also are affected by the disease, particularly its more severe forms.

“There’s an array of effects, it’s just that the most pronounced effects [are in the CNS] … but other cells in other tissue types still need it,” said Stuart Peltz, PhD, co-founder and CEO of PTC, which collaborated with Roche in the development of Evrysdi.

“It’s almost incontrovertible that SMN protein levels are important and important in all tissue types,” he added.

Among the areas reported to be affected are skeletal muscle, bones, and the liver, heart, and pancreas; the neuromuscular junction (the point where a motor nerve cell contacts and communicates with a muscle cell); and the  vascular and immune systems. 

In addition, non-neurological problems have been reported in babies and children who later show SMA’s hallmark symptoms, indicating that tissues other than the CNS are affected, and possibly at early disease stages.

Nikolai Naryshkin, PhD, PTC’s vice president of biology and head of its SMA program, said “very strong arguments based on the literature,” and published studies both in patients and animal models, support the “multi-systemic nature of SMA.”

“It’s becoming increasingly clear that SMA is a whole-body disease,” said Karen Chen, MD, a neuroscientist and the SMA Foundation’s CEO. She noted that muscle, for example, might be affected “not just downstream of the inputs from the spinal cord and the motor neurons, but there might be an SMN intrinsic deficit in muscle.”

Nevertheless, it’s still “hard to separate” what results from damage within the CNS from that outside of it, Paulo Fontoura, MD, PhD, global head of neuroscience and rare disease clinical development for Roche, said in an April interview.

“We measure motor function as an outcome, and motor function is dependent on all of them … intact neurons, intact neuromuscular junction, and intact muscles,” Fontoura said.

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

Biogen’s Spinraza (nusinersen) and Evrysdi are approved for all SMA types and most ages, while Novartis’ gene therapy Zolgensma is advised for children up to age 2 in the U.S. and Japan, and those with most types who weigh up to 21 kilograms (about 46 pounds) in Europe.

Each of these therapies work to boost the production of SMN, but only Evrysdi, an oral therapy taken daily as a flavored liquid, is designed to target every cell in the body. As a small molecule, it can reach peripheral tissues through the bloodstream, and those of the CNS by crossing the blood-brain barrier.

This barrier is a specialized membrane that prevents larger molecules and potentially harmful microorganisms like bacteria, which circulate in the blood, from reaching the brain. 

This ability to cross the blood-brain barrier is a major difference between Evrysdi and Spinraza, and the reason why Spinraza is given by injection directly into the fluid that bathes the CNS. Spinraza’s effectiveness as a once-every-four-months treatment is established, but its targeted nature is thought to limit its effects in peripheral tissues.

Zolgensma, a one-time therapy, uses a harmless virus that can cross the blood-brain barrier to deliver a working copy of SMN1, the mutated gene in SMA, to cells. While it is administered to the bloodstream, Zolgensma is expected to promote a sustained production of SMN throughout life only in cells that do not renew or divide into new cells, which are less likely to lose the newly introduced gene.

Most cells can renew and be replaced, but most neurons cannot. “Once you’re born with them — as the dogma is — that’s what you have,” Chen said. As such, Zolgensma is considered to mainly target nerve cells, including motor neurons. 

While none of these therapies will “restore the lost motor neurons,” she added, targeting tissues “where you do have regeneration and renewal,” such as the muscle, could have a great impact on the lives of SMA patients.

Naryshkin thought the differing clinical trial results for all three approved therapies made it “quite clear” that “systemically bio-distributed pharmacological agents have a benefit,” even in patients with more advanced disease.

Peltz agreed, saying “we know that muscle growth, muscle effects, interaction with the muscle–nerve … are mitigated by the SMN protein, and the cells are fundamentally different as a consequence of that [its absence].”

Other researchers concede this might be true — only time will tell.

Richard Finkel, a pediatric neurologist, has worked on trials of all SMA-targeted therapies. (Photo courtesy of St. Jude Children’s Research Hospital)

Richard Finkel, MD, a pediatric neurologist at St. Jude Children’s Research Hospital who specializes in neuromuscular diseases, acknowledged that Spinraza and Zolgensma, while working well, “don’t target muscle the way that risdiplam does,” which can potentially “provide [an] added benefit.”

“I think we need to learn more about this,” Finkel added.

Servais, a professor of pediatric neuromuscular diseases at the Oxford center, agrees on that point. 

“I appreciate that there is a broad distribution,” Servais said. “It can be an advantage, especially in early [more severe] forms. For later forms, in people who have survived so far with little SMN expression outside the central nervous system, it is not a major issue” in the clinic. 

“I’m not saying it will never happen,” he said of systemic distribution’s possible importance. “I’m just saying that we don’t have a strong rationale today to say we are surely going to see that.”

Rather, from what he sees in those he treats, peripheral involvement is “in the very last position” in a ranking of problems to address.

“Of course my patients, as many others, have bone issues. But they don’t have more or less bone issues than patients with congenital myopathy who do not move,” he said. “It’s definitely not the main issue, definitely not the main unmet need.” 

Ultimately, it’s clear that only more study might determine the extent to which SMN is required by tissues other than motor neurons, and clarify the importance of rising SMN levels in peripheral tissues. Long-term data on Evrysdi, as it comes into use, should help, Fontoura said.

“We still have a lot to learn,” Finkel said, adding that he is “very comfortable” with Evrysdi “given the amounts of safety information and the effectiveness” seen in trials to date. 

“But the learning doesn’t stop there,” Finkel said. “I think there’s a lot more we still have to learn about all three of these drugs going forward.”