Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.
A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.
“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.
However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.
The findings were published online Feb. 24 in the New England Journal of Medicine.
A Phase 2-3 Open-Label Study
The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.
The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.
In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.
Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.
Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
The First Oral Treatment Option
Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”
While the other two approved SMA therapies — nusinersen and onasemnogene abeparvovec — have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.
Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”
Writing in Neuroscience Insights , a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”
Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”
The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.
The study was supported by F. Hoffmann–La Roche. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.
This story originally appeared on MDedge.com, part of the Medscape Professional Network.