Roche's Risdiplam Achieves Phase 3 Endpoint with Significant Improvement in Motor Function in Infants with Type 1 Spinal Muscular Atrophy

Recently, Genentech, a member of the Roche Group, announced that risdiplam, its oral SMN2 gene splicing modifier, significantly improved motor function in infant patients aged 1 to 7 months with type 1 spinal muscular atrophy (SMA), meeting the primary endpoint in Part 2 of the pivotal Phase 3 FIREFISH trial. Last November, the U.S. FDA granted risdiplam Priority Review designation.

The root cause of Spinal Muscular Atrophy (SMA) lies in the deficiency or dysfunction of a protein known as 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: the SMN1 gene and the SMN2 gene. The SMN1 gene plays a dominant role, whereas the SMN2 gene produces only a small amount of SMN protein (approximately 10%). Consequently, when the SMN1 gene malfunctions, patients are unable to generate sufficient SMN protein, leading to the rapid death of motor neurons and progressive loss of muscle function. This ultimately results in paralysis and the inability to perform vital activities such as swallowing and breathing, severely threatening the patient's 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, PTC Therapeutics, and the SMA Foundation. It modulates the mRNA splicing of the SMN2 gene, thereby increasing 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 administered orally. 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 gene mRNA splicing (Image source: PTC Therapeutics official website)

In the FIREFISH clinical trial, patients with type 1 spinal muscular atrophy (SMA) received risdiplam at varying doses. Part 1 of the trial was a dose-escalation study, while in Part 2, patients received the anticipated therapeutic dose of risdiplam. Results from Part 2 demonstrated that the FIREFISH study met its primary endpoint, as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). After 12 months of treatment, 29% of infant patients were able to sit unsupported for 5 seconds, a motor milestone achieved by none of the patients in the natural history cohort. Furthermore, according to measurements from the Hammersmith Infant Neurological Examination Section 2 (HINE-2), 18 infants (43.9%) were able to hold their heads upright, 13 (31.7%) were able to roll over to one side, and 2 (4.9%) were able to stand with support.

“These trial results confirm that risdiplam delivers clinically meaningful efficacy in the treatment of infants with advanced and refractory disease,” said Dr. Levi Garraway, Chief Medical Officer and Global Head of Product Development at Roche. “We thank the SMA community for their collaboration, particularly the 62 families from around the world who participated in Parts 1 and 2 of the FIREFISH study.”

References:

[1] Genentech’s Risdiplam Shows Significant Improvement in Survival and Motor Milestones in Infants With Type 1 Spinal Muscular Atrophy (SMA). Retrieved 2020-04-28, from https://www.gene.com/media/press-releases/14847/2020-04-27/genentechs-risdiplam-shows-significant-i

Original Title: Roche’s Oral Therapy Significantly Improves Motor Function in Infants with SMA, Achieving Phase 3 Endpoint Again

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