Risdiplam (formerly RG7916) is an investigative oral therapy for all types of spinal muscular atrophy (SMA), a neurodegenerative disease characterized by progressive muscle weakness and wasting (atrophy).

Risdiplam is now under priority review for possible approval by the U.S. Food and Drug Administration. An FDA decision is expected on or before May 24, 2020.

An oral small molecule, given as a liquid, risdiplam is being developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation.

How does risdiplam work?

Risdiplam works by potentially rectifying the underlying cause of SMA: a lack of the survival motor neuron (SMN) protein. This protein is essential to the health of motor neurons, the nerve cells that control muscle movement. The brain and spinal cord relay messages to the muscles via motor neurons. The correct transmission of these messages is vital for muscle health because they instruct muscles to contract and move. SMN protein deficiency breaks down nerve cells and impedes their ability to work, causing muscles to atrophy. 

Two genes — SMN1 and SMN2 — carry instructions to make SMN protein. The vast majority of functional SMN protein in the body is produced from the SMN1 gene. The protein that comes from SMN2 is usually short and unstable.

Mutations in the SMN1 gene are the main cause of SMA, while the number of SMN2 gene copies determines the disease’s severity.

Messenger RNA (mRNA) is the molecule that ultimately guides protein production inside cells. The genetic information contained in the DNA is first transcribed into mRNA, which is then translated to make a protein. There are several integral steps in the process, and problems in any of these steps can affect overall protein production. The unstable nature of the SMN protein produced from SMN2 is caused by such a problem.

A gene typically has several coding and non-coding regions, so-called exons and introns. When the gene is transcribed into mRNA, both sets of codes get imprinted on the mRNA produced the so-called pre-mRNA (one of the many molecular steps taking place before mRNA is formed from DNA).

Pre-mRNA, which is first generated from the DNA, is a less mature version of mRNA. For pre-mRNA to become mature mRNA, its genetic material is edited in a process called splicing; in splicing, the non-coding introns are removed. Splicing determines the fate of the generated protein.

Risdiplam is a splicing modifier, meaning it changes the way the pre-mRNA is spliced so that it contains all the information necessary to make functional SMN protein. In this way, risdiplam promotes the production of a full-length and functional SMN protein from the SMN2 gene. It is expected this promotion will increase working SMN protein levels inside cells, to support muscle health.

Results of an animal study, published in December 2018, found daily treatment with risdiplam for 39 weeks resulted in a significant increase in SMN protein levels body-wide —including in muscles, the brain, spinal cord, and peripheral tissues — in mice, rats, and monkeys. This study, published in the journal Pharmacology Research & Perspectivessupported the start of trials in people.

Risdiplam in clinical trials

A Phase 1 study (NCT02633709) investigating the safety and tolerability of increasing doses of risdiplam in healthy volunteers finished in August 2016. That study also evaluated risdiplam’s pharmacokinetics (its movement in the body), and its pharmacodynamics (effect on the body). Its goal was to collect data that would help to determine the optimal therapeutic dose for studies in SMA patients.

Four Phase 2 trials of risdiplam — FIREFISH, SUNFISH,  JEWELFISH, and RAINBOWFISH — are currently underway testing the treatment’s efficacy and safety in a wide range of SMA patients.

Data from FIREFISH (part one) and SUNFISH (parts one and two) supported the approval request, submitted by Roche and Genentech (a member of the Roche group), and accepted by the FDA in November 2019.

FIREFISH (NCT02913482) is evaluating the effectiveness of risdiplam in infants with SMA type 1, ages 1 to 7 months. The study is divided into two parts. The first was exploratory and assessing the safety, tolerability, and pharmacokinetics of multiple ascending doses of risdiplam, given orally once daily for four weeks. The second part is an open-label extension phase to evaluate potential improvements in muscle function. Its primary goal is the percentage of infants able to sit without support at 12 months. Secondary endpoints include the percentage of infants who experience adverse events, changes in blood biomarkers, and assessments of the number of milestones reached in the children’s development.

Genentech announced positive topline results (based on preliminary analysis) for the second part of the FIREFISH study in January 2020. According to the announcement, the results showed improvement in the number of infants who can sit without support after 12 months of treatment which was assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III). Data from the trial will be presented at an upcoming medical congress.

FIREFISH opened in December 2016 and is expected to conclude in November 2023.

The two-part SUNFISH (NCT02908685) trial is assessing the safety, tolerability, and effectiveness of risdiplam in patients, ages 2 to 25, with SMA type 2 or SMA type 3 against placebo. Both type 2 and type 3 are later onset than type 1.

Enrolled patients are divided into two groups based on their age for this second trial. The first group includes adolescents and adults ages 12 to 25, and the second includes children ages 2 to 11. In part one, 51 patients were randomly given either risdiplam or placebo for 12 weeks to determine the optimal treatment dose. In part two, patients are being treated for up to two years at the dose decided in those 12 weeks. After two years of treatment, patients are offered the opportunity to enter an open-label extension study where all will be given risdiplam.

SUNFISH’s primary endpoint for both age groups is the change in total motor function (MFM-32) after 12 months. Secondary endpoints include changes in blood biomarkers and measures of different motor functions.

Roche and PTC Therapeutics presented preliminary results from part one in July 2017. It reported a 400% increase from the study’s start (baseline measures) in full-length SMN mRNA produced from the SMN2 gene in treated patients. These findings suggest that risdiplam does promote the correct splicing of the SMN2 gene in SMA patients. Because low levels of the SMN protein are related to the loss of nerve and muscle function in SMA, the effects of risdiplam on SMN2 gene splicing support that the therapy is targeting the underlying cause of SMA.

Topline data from part two found risdiplam treatment met SUNFISH’s primary goal — that of statistically significant improvements in motor function from baseline on the Motor Function Measure 32 (MFM-32) scale — after 12 months of treatment compared to placebo. Risdiplam was well-tolerated and no treatment-related safety findings leading to study withdrawal were observed.

The third trial, called JEWELFISH (NCT03032172), is an open-label study evaluating risdiplam’s safety and tolerability in a range of SMA patients, ages 6 months to 60 years, all previously treated with another SMA-targeted therapy, including Spinraza and Zolgensma/AVXS-101. The study is enrolling people with SMA types 1, 2, and 3 at sites in the U.S., the U.K., and Europe. All are being given risdiplam once a day, at various doses, for 24 months. The study’s primary goals are safety in these pre-treated patients, measured by the percentage of adverse or serious side effects, new or worsening symptoms,  and measures of blood biomarkers like risdiplam concentrations.

JEWELFISH aims to enroll up to 180 participants and to fully finish in December 2024.

Data on all three trials were presented at the 24th International Annual Congress of the World Muscle Society, held in Copenhagen in October 2019. These preliminary results found risdiplam appears to be safe and well-tolerated at every dose tested in the three studies, without any patients withdrawing for treatment-related reasons.

A two-fold increase in SMN protein levels in the blood was noted in patients given risdiplam for four weeks. SUNFISH study data also showed clinically relevant improvement in motor function in treated patients against placebo. 

RAINBOWFISH (NCT03779334), the fourth study, is evaluating risdiplam’s safety, efficacy, pharmacokinetics, and pharmacodynamics in presymptomatic newborns up to 6 weeks old, genetically diagnosed with SMA but without any evident symptoms. This open-label study in up to 25 babies is still enrolling at multiple centers worldwide. The number of infants able to sit up without support after 12 months of treatment is the study’s primary outcome. Secondary goals include adverse events, the number of children who go on to develop clear SMA symptoms, and time to which they need permanent ventilation.

This study expects to finish in October 2025.

A final Phase 1 study (NCT03920865) examined the effects of a single dose of risdiplam in healthy volunteers and in people with mild-to-moderate liver injury  (chronic stable liver disease). Particularly, it assessed participants’ ability to tolerate and process the oral treatment. The study completed in January 2020 and recruited 26 participants, ages 18 to 70. The results are expected soon. 

Other information

Risdiplam was granted orphan drug status by the U.S. Food and Administration (FDA) in January 2017, and designated a priority medicine or PRIME by the European Medicines Agency (EMA) in December 2018. The purpose of both designations is to advance in developing possible treatments for people with rare diseases. Benefits to the pharmaceutical companies come in the form of grant funding opportunities, clinical trial costs and tax advantages, FDA user fees, and FDA guidance during the drug-approval process.

Another SMN2 splicing therapy, called RG7800, was under development as a potential SMA treatment. But its Phase 1 clinical trial (NCT02240355), called MOONFISH, was terminated after a safety warning was identified, affecting the eyes, in an animal study exploring the long-term treatment effects. No similar problems were seen in treated MOONFISH patients; doses given these animals were higher than those used in people.

The brand name under which risdiplam will be marketed in the U.S., and possibly elsewhere, will be released if the therapy is approved to treat SMA, Roche and Genentech said.


Last updated: Jan. 23, 2020


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