Roche's Oral Therapy Risdiplam Significantly Improves Motor Function in SMA Patients, Meets Primary Endpoint in Phase 3 SUNFISH Trial

Today, Roche announced that its oral SMN2 gene splicing modifier, risdiplam, significantly improved motor function in patients with type 2 or type 3 spinal muscular atrophy (SMA) in the pivotal Phase 3 SUNFISH trial, meeting the primary endpoint.

The pathogenesis of spinal muscular atrophy (SMA) stems from the deficiency or dysfunction of the survival motor neuron (SMN) protein. The SMN protein is essential for the survival of motor neurons in the human body. There are two genes responsible for producing the SMN protein: SMN1 and SMN2. However, SMN1 plays a dominant role, whereas SMN2 produces only a small amount of SMN protein (approximately 10%). Consequently, when SMN1 function is impaired, patients cannot generate sufficient SMN protein, leading to rapid degeneration of motor neurons, progressive loss of muscle function, and ultimately paralysis. Patients become unable to perform vital activities such as swallowing and breathing, posing a severe threat to life. Although SMA primarily manifests during infancy, it can affect individuals across any age group, from infants to adults. Clinically, SMA is typically classified into three types: Type 1 (infantile), Type 2 (intermediate), and Type 3 (juvenile/adult-onset).

Risdiplam (RG7916) is an oral SMN2 gene splicing modifier jointly developed by Genentech, a member of the Roche Group, PTC Therapeutics, and the SMA Foundation. It modulates the splicing process of the SMN2 gene to increase the expression of SMN protein in the central nervous system (CNS) and peripheral tissues. This therapeutic strategy for spinal muscular atrophy (SMA) is highly similar to that of Spinraza, which has already been approved. The key difference lies in the fact that Spinraza utilizes antisense oligonucleotides (ASOs) to modulate RNA splicing and requires direct intrathecal injection into the cerebrospinal fluid, whereas risdiplam is a small-molecule drug that can be administered orally. Clinical trial results have demonstrated that risdiplam exhibits excellent efficacy in treating infants with Type 1 SMA. Currently, it is being evaluated in multiple clinical trials involving SMA patients ranging in age from 0 to 60 years.

▲Risdiplam increases SMN protein levels by modulating SMN2 RNA splicing (Image source: PTC Therapeutics official website)

In the SUNFISH Phase 3, double-blind, placebo-controlled clinical trial, patients with type 2 and type 3 spinal muscular atrophy (SMA) aged 2 to 25 years received risdiplam. Trial data demonstrated that after one year of treatment, patients in the treatment group achieved a statistically significant improvement from baseline in their Movement Function Measure-32 (MFM-32) scores compared to the placebo group, which constituted the primary endpoint of the study. Detailed trial results will be presented at future medical conferences.

“For patients with type 2 and type 3 SMA, the positive results from this trial represent a significant milestone,” said Dr. Levi Garraway, Chief Medical Officer and Head of Global Product Development at Roche. “SUNFISH is the largest placebo-controlled study ever conducted in patients with type 2 or type 3 SMA. We look forward to sharing these results with regulatory authorities and providing innovative treatment options for patients with SMA as soon as possible.”

References:

[1] Roche’s risdiplam meets primary endpoint in pivotal SUNFISH trial in people with type 2 or 3 spinal muscular atrophy, Retrieved November 11, 2019, from https://www.roche.com/media/releases/med-cor-2019-11-11.htm

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