Optimizing Care of Spinal Muscular Atrophy in an Advancing Treatment Era

NeurologyLiveAugust 2019
Volume 2
Issue 4

In this Peer Exchange, experts discussed current SMA therapies, what they have learned, and what the future holds for treatment of this devastating disease.

Nancy L. Kuntz, MD

Nancy L. Kuntz, MD

In the closing days of 2016, the FDA approved nusinersen (Spinraza; Biogen) for the treatment of spinal muscular atrophy (SMA). It was the first drug approval for the debilitating neuromus- cular condition after decades of research by clinicians and investigators for a better understanding of how to help patients with SMA, many of whom face a tragically shortened life span.

Since then, development of therapies that act on the SMN gene has exploded. With several treatments in the pipeline and an improved understanding of options for patients with SMA, clinicians are now in a better position to make a difference.

To discuss how the treatment landscape has shifted and provide some insight into future developments, Nancy L. Kuntz, MD, a pediatric neurologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, joined NeurologyLiveTM to lead a panel of expert clinicians in a discussion of these agents.

Improving Care and Screening

Kuntz began by highlighting how clinicians can optimize care in the evolving SMA treatment model, noting several questions that remain unanswered, including whether gene therapies will be used in combination with one another or in tandem with other supportive treatments. Kuntz also mentioned the need to improve newborn screening and the perspective that current treatments and therapies provide in promoting it.

Claudia Chiriboga, MD, MPH, professor of neurology and pediatrics at Columbia University Medical Center in New York, New York, shared her insight.

“All the studies that have been discussed show that even if it’s later-onset SMA or infant SMA, early treatment is important, and there’s a differential response to early treatment, with [anti-sense oligonucleotide] treatment showing the best response and possibly normal development,” Chiriboga said. “It’ll be very exciting to see on an equal playing field these presymptomatic studies that are ongoing [and]... comparing the small molecule risdiplam with AVXS-101, in the SPR1NT study as well as the NURTURE study, to see whether there’s any benefit or advantage to one over the other.”

The biggest differentiator, Chiriboga noted, is whether the therapy in question is a central nervous system (CNS)—restricted treatment, such as nusinersen, rather than a more widely disseminated treatment. She explained that in her approach to the symptomatic child or infant, a treatment such as Zolgensma (previously AVXS-101; AveXis) has been very effective in those younger than 5 months.

“The response would come to flat once they got past a certain age, which may reflect a critical number of neurons that you need. If you’re more advanced, there’s not enough gene to produce it,” Chiriboga said. She added that currently with CNS restriction, if clinicians start therapy early enough, it might make a difference. The jury is still out, however, on whether presymptomatic chil- dren with SMA will need the combination therapy.

“When they’re symptomatic, it’s a different story because you want to maximize SMN, and then combination therapy with a gene transfer and an SMN to a slicing modulator—either risdiplam or an antisense oligonucleotide—may make sense, if we’re permitted to do so,” Chiriboga said. “The studies in the pipeline now that are using ancillary drugs that are not SMN specific but that enhance muscle are another option to use in combination with an SMN-modifying therapy. It will be exciting to see how much benefit is given.”

Basil Darras, MD, director of the Neuromuscular Center and the Spinal Muscular Atrophy Program at Boston’s Children’s Hospital in Massachusetts, noted that in addition to preventing the disease, clinicians need to understand that they may be able to diminish the

cost of treatment.

“It’s not just [about] having a child who has more normal development but also having a child who does not have to be admitted to the hospital multiple times and sometimes into the intensive care unit, which we all know can be quite expensive.”

“We [also] tend to forget the value of the preconception carrier screening, which aims at diminishing the number of babies who are born with SMA,” Darras continued. “One in 50 people in the general population [is a carrier] of this mutation, which means it’s quite common, and it will help enormously, and it prevents the disease if prospective parents are screened for carrier status around the world.”

Elizabeth Kichula, MD, PhD, a clinical assistant professor of neurology at Penn Medicine and a pediatric neurologist at Children’s Hospital of Philadelphia in Pennsylvania, mentioned that even with the inclusion of SMA screening in the American College of Obstetricians and Gynecologists recommendations update in 2017, limits to carrier screening still exist.

“It’s important to remember that that’s screening and not testing, but I think sometimes not everyone is aware of that,” Kichula said. “Primarily, it tests for the deletion and not for sequence variance, which would miss about 5% of patients.”

Additionally, she pointed out that in certain cases, a higher percentage of individuals will have 2 copies of the SMN1 gene on 1 chromosome—particularly in black patients. The sensitivity of carrier testing in these patients is only between 70% and 80% compared with well over

90% in white patients.

“Really trying to think about those limitations and the interpre- tation of this, I think, is also important. And newborn screening could help fill in some of those holes, although it will still miss some of them,” Kichula said.

"It's not just (about) having a child who has more normal development, but also having a child who does not have to be admitted to the hospital multiple times... which we all know can be quite expensive," said Basil Darras, MD.

Zolgensma Gene Therapy

Data for Zolgensma, which the FDA approved in May 2019,1 have demonstrated rapid motor function gains and milestone achievements with intrathecal delivery in the phase 1 STRONG trial, prolonged event-free survival in addition to motor function increases and milestone achievement in the phase 3 STR1VE trial, and age-appropriate motor milestone accomplishments in the SPR1NT trial.2

AveXis’ gene transfer strategy includes the commonly used adeno-associated virus 9. Kichula was involved in the trials and shared her experience with the novel treatment.

“It is a virus that doesn’t integrate its DNA into the human genome, so we shouldn’t run into issues that arose in clinical trials from decades ago, where there was an increased cancer risk with certain gene therapies,” Kichula said. “Rather, the viral caps just sit there in the cell but can continually express SMN. The choice of the virus is a really important thing when you’re talking about gene therapies because every virus has particular cells that it likes to infect.”

She also shared some of the clinical findings with Zolgensma. The initial phase 1 study included 15 patients, of whom the first 3 received a lower dose to evaluate basic safety, whereas the other 12 received a higher dose.

“A lot of the outcomes that they looked at had significant overlap with things that you’ve already heard about,” Kichula said. “The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND] test scores had significant improvement and really improved quite rapidly over the first several months following infusion. In addition, none of the patients required any full-time ventilatory support. None of the patients died during the trial--all things that in the untreated SMA type 1 population we would have anticipated to see during that [time period].”

In addition, continuous and drastic improvements were observed in feeding, bulbar involvement, speech, and the ability to walk independently.

“It’s important for me to backtrack a little bit and note that in these phase 1 patients, they are giving the medication intravenously, so the virus completely crossed the blood—brain barrier,” Kichula said. “We don’t run into those issues that we get with nusinersen, so it is a onetime intravenous injection. Then the virus has to just sit there and will continue to express the protein.”

Risdiplam: An Oral Agent

Kuntz then inquired about the idea of promoting the development or production of SMN2 and the SMN protein, particularly outside the available genetic approaches. Chiriboga, who was involved in the clinical development of risdiplam, discussed the advantages and findings regarding the agent thus far.

“It’s an oral medication given once a day that works in a very similar fashion as nusinersen does, in that it increases alternative slicing of the SMN2 gene so that more SMN is produced,” Chiriboga said. “A difference, other than that it’s administered orally, is that it also penetrates systemically. It goes uniformly into the CNS with a 1-to-1 penetration, at least in many species, including monkeys, so that blood levels are thought to reflect concentrations in the brain.”

The treatment was shown to be successful in the recently announced results of the FIREFISH and SUNFISH studies. In FIREFISH, investiga- tors determined the proper dose and are now assessing it in a pivotal open-label trial. In the dose-finding portion, even though the pediatric participants were older than those included in the ENDEAR study or with Zolgensma, they showed notable improvements.3,4

“A significant proportion of them improved at least 3 points on their CHOP INTEND; if they didn’t have swallowing difficulties, they didn’t develop swallowing difficulties; and they didn’t reach the end point,” Chiriboga said. “Similar to the ENDEAR study, in which the outcome with survival included an end point of survival or permanent ventilation—defined as 16 hours on a ventilator or a tracheostomy—if they didn’t have these issues, they did not develop them, which was very striking given that they were a bit older.”

Chiriboga added that given the success that risdiplam demonstrated in trials, Hoffmann-La Roche now plans to submit the agent for FDA approval.

Nusinersen: The First Approval

To close the discussion, Kuntz brought up the translational research that has led to new treatments in SMA, brought on in part by the approval of nusinersen. “This is truly a new generation,” she noted, asking Darras to detail what the field learned from the development of this treatment.

“The SMN2 gene is a major phenotypic modifier but also has become the target of pharmaceutical research, and the effort is that they’re trying to increase projection of full-length SMN protein from the SMN2,” Darras said. Nusinersen is designed to improve the splicing of the SMN2 gene.

“It binds to a particular site in intron 7 next to exon 7, and by doing so, it does displace a particular protein that binds to the same site, which is a splicing repressor. And by inhibiting this particular repressor protein binding, it increases the splicing of the inclusion of exon 7 to the splicing events,” Darras said. “This, in turn, can up the production to 90% of the full-length protein—though this oligonucle- otide does not cross by the brain barrier, so it must be given by intrathecal injection.”

Ultimately, after nusinersen showed a number of successes in the ENDEAR study in SMA type 1, Biogen submitted an application to the FDA, including the results of the open-label studies dating back to 2012. That led to the approval of nusinersen as the first treatment for all types of SMA, regardless of age.

“Although the approval was based primarily on type 1 results, [the FDA] decided to approve it for all types of SMA. And we started treating all types of patients, from very severe to less severe, from babies with severe forms to the sitters or walkers,” Darras said. “We learned that the theoretical idea that you can correct the splicing of the SMN2 can work in humans, but it’s not actually a cure for SMA; it’s only a treatment with different types of responses from mild improvement to significant improvement or only to stabilization of function.”

Kuntz concluded by pointing out that by comparing outcomes and change over time in various treatment groups, it appeared “very clearly” that patients with the same number of copies of SMN who were treated earlier did better, which prompted “a lot of the impetus for early identification and newborn screening.”


1. AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA) [news release]. Basel, Switzerland: Novartis; May 24, 2019. https://www.novartis.com/news/media-releases/avexis-receives-fda-approv- al-zolgensma-first-and-only-gene-therapy-pediatric-patients-spinal-muscular-atrophy-sma. Accessed June 15, 2019.

2. AveXis presented robust data at AAN demonstrating efficacy of Zolgensma in broad spectrum of spinal muscular atrophy (SMA) patients [news release]. Basel, Switzerland: AveXis; May 5, 2019. novartis.com/news/media-releases/avexis-presented-robust-data-aan-demonstrating-efficacy-zol- gensma-broad-spectrum-spinal-muscular-atrophy-sma-patients. Accessed July 9, 2019.

3. PTC Therapeutics announces risdiplam (RG7916) is well tolerated at all dose levels with no drug-re- lated safety findings [news release]. Dallas, TX: Cure SMA; June 19, 2018. www.curesma.org/news/ ptc-therapeutics-update-june2018.html. Accessed February 19, 2019.

4. Baranello G, Servais L, Day J, et al. FIREFISH part 1: early clinical results following a significant increase of SMN protein in SMA type 1 babies treated with RG7916. Presented at: 23rd Annual Congress of the World Muscle Society; October 2-6, 2018; Mendoza, Argentina. Poster 258. wms2018.com/wp-content/uploads/2018/full-congress-%20issue-final_28_9.pdf.

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