‘Lucky Genetics’ and Hard Work: SMA’s Leap to 3 DMTs in 4 Years

[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 talk with scientists about how this rare disease went from zero to three major therapies in four years.]

How three disease-modifying therapies (DMTs) for spinal muscular atrophy (SMA) came to be approved in four years is a mix of “lucky genetics,” the deadly nature of SMA’s most severe form, and hard work on the part of researchers, clinicians, foundations, and pharmaceuticals.

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

In separate interviews with SMA News Today, Richard Finkel and Laurent Servais, neurologists who worked on trials of all three therapies, and Karen Chen, the SMA Foundation’s CEO, shared their thoughts on this “remarkable” leap in both treatments and treatment options. 

The genetic cause of SMA — the presence of mutations in the survival motor neuron 1 (SMN1) gene — was first identified in 1995. These mutations result at best in low levels of SMN, a protein produced throughout the body and essential for motor neuron and muscle health.

Researchers also discovered that humans, unlike other mammals, have a second gene — SMN2 — with instructions to produce SMN. However, due to a small genetic difference, SMN2 can produce only 10% to 15% of normal SMN levels. 

“There’s certainly the fortunate genetics of SMA. I don’t know of another disease where the missing gene has a duplicate,” said Chen, a PhD and neuroscientist by training.

The number of SMN2 gene copies was soon found to determine SMA severity, with higher numbers leading to milder disease forms.

‘Lucky genetics’ and infants at risk

“Lucky genetics,” in essence, pointed a way to a possible treatment — that of modifying SMN2 so that it’s better able to do what SMN1 cannot. 

The discovery of a link between this gene’s duplicates and SMA severity was “sort of a proof-of-concept natural trial that showed that targeting the SMN2 gene could have an impact on the disease,” Chen said.

Finkel, MD, a pediatric neurologist at St. Jude Children’s Research Hospital in Tennessee, and previously with Nemours Children’s Health System in Florida, agreed.

Once SMA’s causative and backup genes were identified, he said, “scientists very quickly … identified different treatment strategies.”

At least 21 years would separate the discovery of SMN1 and its deleterious role, strategy-building efforts, and the arrival of SMN2 splicing modifiers that effectively and safely treat SMA by boosting SMN protein levels —  Spinraza (nusinersen, by Biogen) in 2016 and Evrysdi (risdiplam, by Genentech, a subsidiary of Roche) on Aug. 7.

Still, Finkel thought the speed quite remarkable, especially if you “look at all that was done during those years.”

When the causative gene for Duchenne muscular dystrophy was found almost 10 years earlier — in 1986 — “we thought the cure was five years away,” Finkel said. He now knows how naive that assumption was, although hope in Duchenne is finally “picking up again.”

Hasane Ratni, PhD, a medicinal chemist and program leader for drug discovery at Roche, was equally “amazed … to see three different therapeutic modalities emerge as options for treating SMA within a short time frame.”

Laurent Servais, a neurologist at the MDUK Oxford Neuromuscular Centre. (Courtesy of Dr. Servais)

To Servais, a key factor was the morbid “chance” nature of SMA type 1. Evident in babies within weeks or months of life, if untreated, this severe subtype kills before age 2. 

By its very deadly nature, said Servais, MD, PhD, a professor of pediatric neuromuscular diseases at the MDUK Oxford Neuromuscular Centre, clinicians and pharmaceuticals had a straightforward “readout” on treatment effectiveness — and in infants. This allowed studies to “very quickly” get underway, including those in presymptomatic newborns. 

“The chance we had in SMA was to be able to include in trials very young patients, including [those] with type 1, for which the readout is early and immediate. 

“If the patients die, it doesn’t work,” he said of therapy testing. “If they survive, it does.”

Servais acknowledged his argument might sound “quite simplistic.” But, he said, “if we had such a model in Duchenne — if we had a kind of Duchenne type 1 that starts at birth or during the first three months … maybe we would have a drug approved in Duchenne today, or one or two or even more.”

Since May 2019, SMA has also had a totally different approved treatment, Zolgensma by Novartis and AveXis. This gene therapy uses a virus engineered to be harmless to deliver a working copy of the SMN1 gene into cells.

Promising safety after years of toil

Sixteen years would separate the 1995 discovery of SMN1 as the causative SMA gene and the 2011 start of the clinical trials that would lead to Spinraza.

They were years of hard work and collaboration, of the basic and translational science that makes possible the creation of a new therapy.

Once the mutated gene was identified, Finkel said, he and other doctors working with patients knew investigations into treatments would follow. And those showing promise would likely move into clinical trials. 

For those tests to succeed, supportive tools had to exist.

“We had several years where we [clinicians] were working together in these study groups,” Finkel said, establishing the disease’s natural course and other measures against which to measure effectiveness.

“The scientists were trying to explore, to learn more about the basic biology” of SMA, while pharmaceuticals pursued workable “drug development strategies,” he said. We had a “responsibility to try to develop efficient clinical trials.”

“The SMA Foundation was particularly supportive of these efforts,” Finkel added, helping to create and promote such essential tools as SMA natural history studies, biomarkers, clinical trial networks, and outcome measures. “They realized the importance of clinical trial readiness.”

Richard Finkel, a pediatric neurologist at St. Jude Children’s Research Hospital. (Courtesy of St. Jude)

A natural history study of SMA type 1, characterizing its course in the absence of treatment, began in 2005, years before trials were even on the horizon. 

Finkel said he was fortunate to lead this study, which “turned out to be quite useful as a benchmark for these different clinical trials.”

The foundation’s “little toolbox,” as Chen called it, also included animal models and cell lines necessary for early, or preclinical, work. The toolbox “that the foundation really helped to fund and develop,” she said, helped make SMA a “low-hanging fruit for pharma.”

The National Institutes of Health around this time also identified SMA as a disease “worthy of special funding,” which helped to  “jumpstart a lot of the work that eventually led to the identification of [SMA therapies],” Finkel said.

These three therapies also appear to be quite exceptional — and one more point of distinction for SMA, the two neurologists said. 

While there’s much yet to be learned, because each treatment is quite new to widespread or real-world use, safety as well as efficacy results from both clinical trials and in-clinic use are “very favorable” to date, Finkel said.

“What is quite crazy in SMA,” Servais added, “is that not only do we have drugs that work, but that these drugs have very nice, very good safety profiles.”