FDA Extends Review Period for Roche's SMA Drug Risdiplam Following Submission of Additional Clinical Data

Compiled by Keke

Genentech, a member of the Roche Group, announced on April 7 that the U.S. FDA had extended the approval date for the New Drug Application (NDA) of risdiplam for the treatment of spinal muscular atrophy (SMA), pushing the PDUFA date back by three months to August 24, 2020. The delay was due to Genentech’s recent submission of supplemental data for risdiplam, including data from the pivotal Part 2 of the SUNFISH study, which was conducted in close collaboration with the FDA.

In November 2019, the U.S. FDA granted priority review for Risdiplam and decided to issue a final decision by May 24 of this year. In February, following discussions with the FDA, Genentech resubmitted supplementary data to support the use of Risdiplam in a broader population of patients with spinal muscular atrophy (SMA). This included 12-month efficacy and safety data from Part 2 of the SUNFISH study, which is the only placebo-controlled study to date conducted in patients aged 2 to 25 years with Type 2 or Type 3 SMA. The results demonstrated that Risdiplam significantly outperformed placebo in improving motor function scores. The FDA stated that additional time was required for review due to the substantial volume of the submitted supplementary data.

Since the approval of Spinraza in 2016, no new therapies for spinal muscular atrophy (SMA) have been approved. Biogen’s antisense oligonucleotide drug Spinraza and Novartis’s gene therapy Zolgensma are both indicated for patients with type 1 SMA, while Risdiplam will challenge these two drugs as well as the population of SMA patients who currently have no treatment options.

Dr. Levi Garraway, Chief Medical Officer and Head of Global Product Development at Genentech, stated, “The company is working closely with the FDA to support the review of Risdiplam. Our goal is to make this therapy available to infants, children, and adults with SMA as soon as possible.”

Currently, Genentech has submitted marketing applications for Risdiplam to the health regulatory authorities in six other countries/regions worldwide. In December 2018, the European Medicines Agency (EMA) granted Risdiplam priority medicine status; therefore, the company is also expected to submit its marketing authorization application for the drug to the EMA by mid-2020.

Spinal Muscular Atrophy (SMA) is a hereditary, progressive neuromuscular disease that can lead to devastating muscle atrophy and disease-related complications. It is the most common genetic cause of infant mortality and one of the most prevalent rare diseases, affecting approximately 1 in every 11,000 live births. Patients with Type 1 SMA typically do not survive beyond the age of two, whereas those with milder forms, Type 2 and Type 3, may have longer survival times. However, even the milder forms of the disease are associated with mobility impairment, respiratory infections, and mortality.

Spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to a deficiency of SMN protein. Researchers have identified SMN protein in humans, and growing evidence indicates that SMA is a multisystem disorder; the loss of SMN protein may affect numerous tissues and cells, thereby potentially impairing bodily functions.

As part of the collaboration with the SMA Foundation and PTC Therapeutics, Genentech led the clinical development of risdiplam, an investigational, orally administered liquid formulation SMN2 splicing modifier for spinal muscular atrophy (SMA), designed to durably increase and maintain SMN protein levels throughout the central nervous system and peripheral tissues. Its potential to enable the SMN2 gene to produce more functional SMN protein in vivo is currently being evaluated.

Genentech has designed an extensive clinical trial program for risdiplam in the treatment of spinal muscular atrophy (SMA), enrolling patients ranging from newborns to 60 years of age, including those who had previously received other SMA-targeted therapies. Risdiplam is currently being evaluated in four multicenter trials involving patients with SMA:

SUNFISH (NCT02908685): A two-part, double-blind, placebo-controlled pivotal study in patients with type 2 or type 3 spinal muscular atrophy (SMA) aged 2–25 years. Part 1 determined the dose for the confirmatory study in Part 2. During the 12-month treatment period of Part 2, motor function was assessed using the total score of the Motor Function Measure-32 (MFM-32), evaluating abilities such as head and limb movement, sitting, standing, and walking, as well as upper limb strength and flexibility. The MFM-32 is a validated scale for assessing fine and gross motor function in patients with neurological disorders, including SMA. The study met its primary endpoint.

FIREFISH (NCT02913482): An open-label, pivotal clinical trial comprising two parts for infants with type 1 spinal muscular atrophy (SMA). Part 1 was a dose-escalation study involving 21 infants, with the primary objective of evaluating the safety of risdiplam in this population and determining the dose for Part 2. Part 2 was a single-arm study treating 41 infants with type 1 SMA for 24 months, followed by an open-label extension period. Enrollment was completed in November 2018. The primary objectives were to assess the efficacy of risdiplam and to evaluate the proportion of infants able to sit without support (defined as sitting for 5 seconds without support) after 12 months of treatment, as assessed by tools such as the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and the Hammersmith Infant Neurological Examination (HINE) motor scale.

JEWELFISH (NCT03032172): An open-label, exploratory trial for SMA patients aged 6 months to 60 years who had previously received SMA-targeted therapy or olesoxime; enrollment has been completed.

RAINBOWFISH (NCT03779334): An open-label, single-arm, multicenter study evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants with genetically diagnosed spinal muscular atrophy (SMA) who are presymptomatic, from birth to six weeks of age (initial dose). The study is currently recruiting participants.

Reference Source:

1、FDA sets back review date for Roche’s SMA drug by 3 months

2、FDA delays decision on Roche spinal muscular atrophy drug