#AANAM – Risdiplam Shows Promise for Treating SMA Types 2 and 3, Clinical Data Shows

Risdiplam continues to show promise as a therapy for individuals with spinal muscular atrophy (SMA) types 2 and 3, results from an ongoing Phase 2/3 trial show.

Results from the study, “Update from SUNFISH Part 1: Safety, Tolerability and PK/PD from the Dose-Finding Study, Including Exploratory Efficacy Data in Patients with Type 2 or 3 Spinal Muscular Atrophy (SMA) Treated with Risdiplam (RG7916),” were presented by researcher Laurent Servais during the 2019 American Academy of Neurology (AAN) Annual Meeting, being held in Philadelphia.

SMA is caused by mutations in the SMN1 gene that lower the levels of the SMN protein in specialized cells controlling muscle contraction, called motor neurons. SMN2 can also generate the SMN protein, but normally in a shorter and unstable version.

Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral therapy designed to boost the ability of the SMN2 gene to produce a full-length and functional SMN protein in motor neurons.

Specifically, this investigational treatment is a splicing modifier, which means it can change the way pre-messenger RNA molecules — those generated from DNA in protein production — are edited to generate full-length mature RNA from SMN2.

A powder, risdiplam can be made into a liquid, making it potentially easier to administer orally to babies. If patients have trouble swallowing, it can also be given through a gastric tube directly into the stomach.

The multicenter, placebo-controlled SUNFISH trial (NCT02908685) is testing risdiplam in patients ages 2 to 25, with type 2 or 3 SMA. Part 1, with 51 participants of diverse functional levels, assesses the safety, tolerability and pharmacological profile of different doses of risdiplam. In turn, the pivotal second part analyzes the safety and efficacy of the dose selected in the study’s first part, now given to 180 patients.

At the beginning of the study, the patients’ functional status ranged from individuals who were unable to sit, to those capable of walking. Scoliosis ranged from none to severe.

Part 1 study results showed treatment with risdiplam led to a sustained and over two-fold increase in median SMN protein blood levels after one year, compared with pretreatment levels.

Researchers used the Motor Function Measure-32 (MFM32) scale — suitable for detecting motor function changes in a broad range of patients — to assess motor function from weak type 2 to strong type 3 SMA.

Patients receiving risdiplam showed improvements in motor function compared with the natural history of the disease, independent of age at study enrollment, and disease severity. However, the speaker noted that the earlier the treatment, the bigger the improvements.

Among the 43 patients who completed the MFM32 scale at all visits up to one year, 58% saw an improvement of at least three points compared with assessments done at the beginning of the study.

“Gaining 3 points in the MFM scale is ‘very rare,’” Servais said.

Three-point gains were seen in 71% of patients ages 2 to 11, and in 42% of those ages 12 to 25.

“[T]he cohort of all [this] data [is] really becoming quite exciting — to potentially get an oral treatment agent to patients. We hope to submit data to health authorities in the second half of this year,” Susan Begelman, MD, vice president, Neurology, Nonmalignant Hematology, Influenza, U.S. Medical Affairs at Genentech, told SMA News Today.

While risdiplam is being developed as a stand-alone therapy, “the potential for combination therapies is on everyone’s mind — healthcare providers certainly, certainly ours. But that would have to be studied,” Begelman added.

“Things are moving at a fast clip. If you really put that in context of the greater whole in SMA, you back a few years, there was nothing for a disease that was so devastating. To see such tremendous advances in a short amount of time is really a thrill to be able to do that for patients. I’m really happy for the community,” she said.

Risdiplam has been well-tolerated at all doses, and there have been no drug-related safety findings leading to withdrawal in any patient. Adverse events were mostly mild, including fever, cough, vomiting, and respiratory infections, but all were resolved and reflected the underlying disease. The most common serious adverse event, in two patients, was pneumonia.

The trial also included a very extensive ophthalmological examination, to exclude possible retinal toxicity based on preclinical data. None of the patients showed any signs of worsening at that level.

Part 1 of SUNFISH has helped determine the dose for the second part of the study, which is currently ongoing, with results expected by the end of this year.