Risdiplam, formerly known as RG7916, is a potential therapy being developed by Roche and Genentech, in collaboration with PTC Therapeutics and the SMA Foundation, for the treatment of spinal muscular atrophy (SMA).
How Risdiplam works
SMA is caused by a defect in the SMN1 gene, which codes for the survival of motor neuron (SMN) protein. Another gene, called SMN2, also codes for SMN protein, but most of the protein produced by SMN2 is shortened and unstable. The nerve damage in SMA occurs because cells do not produce enough functional SMN.
Messenger RNA (mRNA) is the molecule that guides protein formation. Pre-mRNA is a less mature version of mRNA. Before pre-mRNA becomes mRNA, the genetic material in pre-RNA is edited, a process called splicing where some sections are removed. RG7916 is a splicing modifier. It changes the way the pre-mRNA is spliced so that full-length SMN mRNA is produced, which can encode for functional SMN protein.
Risdiplam in clinical trials
A Phase 1 study (NCT02633709) investigating the safety, tolerability, pharmacokinetics (how a therapy moves in the body), and pharmacodynamics (the therapy’s effect in the body) of increasing doses of RG7916 in healthy volunteers was completed in August 2016. The goal of the study was to collect data that will help determine the optimal dose of the therapy to be used in people with SMA.
Three Phase 2 studies of risdiplam — FIREFISH, SUNFISH, and JEWELFISH — are currently underway and are recruiting participants.
FIREFISH (NCT02913482) is evaluating the effectiveness of risdiplam in infants with SMA type 1. The study is divided into two parts. The first part is exploratory, with participants receiving multiple ascending doses of risdiplam administered orally once daily for four weeks, followed by an open-label extension phase.
The second part is confirmatory, where participants receive risdiplam administered orally at the maximum tolerated dose identified in Part 1, with treatment continuing for up to 24 months. The primary endpoint is the percentage of infants who are able to sit without support at 12 months. Secondary endpoints include the percentage of infants who experience adverse events and changes in blood biomarkers, and the assessment of a number of milestones related to child development. The estimated primary completion date of the trial is September 2019.
There are two groups in this trial, which is also divided into two parts. The first group includes adolescents and adults (ages 12-25) who receive either risdiplam or placebo for 12 weeks to determine the optimal dose (Part 1). In Part 2, participants are treated for up to 24 months at the dose decided in the first 12 weeks. At the end of the 24-month period, the participants are offered the opportunity to enter an open-label extension study.
The second group includes children (ages 2-11 years) who are also randomized to receive either risdiplam or placebo and follow the same treatment schedule as the adult/adolescent group. The primary endpoint for both age groups is the change in total motor function after 12 months. Secondary endpoints include changes in blood biomarkers and measures of different motor functions. The estimated primary completion date of this trial is May 31, 2019.
In July 2017, PTC Therapeutics presented preliminary results from Part 1 of the SUNFISH trial. It reported a four-fold increase (from baseline) in the functional copy of the SMN2 gene in treated patients. The findings suggest that risdiplam does promote the correct splicing of the gene in SMA patients. Because low levels of the SMN protein are related to the loss of muscle and nerve function in SMA, the effects of risdiplam on SMN2 gene splicing confirms that the therapy is targeting the underlying cause of SMA in patients.
JEWELFISH (NCT03032172) is an open-label study evaluating the safety and tolerability of risdiplam in adults and children with SMA. All participants receive multiple doses of risdiplam once daily for 24 months. Primary endpoints are the percentage of participants who experience adverse or serious events, or suicidal ideation or behaviors, or clinically significant changes in blood biomarkers. The estimated primary completion date of this trial is December 2020.
In January 2017, PTC announced that risdiplam was granted orphan drug status by the U.S. Food and Administration (FDA). The purpose of this designation is to promote the development of drugs that may help patients with rare diseases. The benefits it extends to pharmaceutical companies include grant funding opportunities, clinical trial cost and tax advantages, FDA user-fee benefits, and FDA guidance during the drug approval process.
Another therapy, RG7800, was also under development for the treatment of SMA. But its Phase 1 clinical trial (NCT02240355, called MOONFISH) was terminated after an unexpected toxicology finding was identified in an animal study exploring the effects of long-term treatment.
Roche and Genentech are developing risdiplam with a joint steering committee that includes members from PTC and the SMA Foundation.
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