Risdiplam (formerly known as RG7916) is an experimental oral therapy for the treatment of spinal muscular atrophy (SMA), a neurodegenerative disease characterized by progressive muscle weakness and atrophy. Risdiplam is being developed by Roche and Genentech, in collaboration with PTC Therapeutics and the SMA Foundation.
How does risdiplam work?
The investigational therapy works by potentially rectifying the underlying cause of SMA: the deficiency of survival motor neuron (SMN) protein. That protein is essential for maintaining the health of motor neurons, or the nerve cells that control muscle movement. The brain and spinal cord relay messages to the muscles via the motor neurons. The correct relay of those messages is vital for muscle health because they instruct muscles to contract and move. Any defect in SMN leads to the breakdown of the nerve cells and impedes their function, leading to muscle atrophy.
Two genes — SMN1 and SMN2 — carry instructions to make SMN protein. The majority of the functional protein in the body is produced from the SMN1 gene. The protein produced by SMN2 is usually short and unstable.
SMA is primarily caused by mutations in the SMN1 gene, while the number of copies of the SMN2 gene determines the severity of SMA.
Messenger RNA (mRNA) is the molecule that 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 the steps affect the overall production of the protein. The unstable nature of the SMN protein made from the SMN2 gene is caused by such a problem.
A gene can have 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. Many molecular steps have to happen even before the mRNA is formed from the DNA.
Pre-mRNA, which is first generated from the DNA, is a less mature version of mRNA. Before pre-mRNA becomes mature mRNA, the genetic material is edited, a process called splicing, in which 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. That increases the level of SMN protein inside cells.
According to the results of an animal study published in December 2018, daily administration of risdiplam for 39 weeks resulted in a significant increase in SMN protein levels body-wide —including in muscles, the brain, the spinal cord, and peripheral tissues — in mice, rats, and monkeys. That study was published in the scientific journal Pharmacology Research & Perspectives
Risdiplam in clinical trials
A Phase 1 study (NCT02633709) investigating the safety and tolerability of increasing doses of risdiplam in healthy volunteers was completed in August 2016. That study also evaluated risdiplam’s pharmacokinetics — its movement in the body — and its pharmacodynamics, or its effect on the body. The goal of the study was to collect data that will help determine the optimal dose of the therapy to be used for SMA patients.
Four Phase 2 studies of risdiplam — FIREFISH, SUNFISH, JEWELFISH, and RAINBOWFISH — are currently underway to test the effect of the treatment in people with SMA.
The first trial, called 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 part is exploratory and is assessing the safety, tolerability, and pharmacokinetics of multiple ascending doses of risdiplam, administered orally once daily for four weeks. The second part is an open-label extension phase intended to evaluate any improvements in muscle function. 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 the number of milestones reached in the children’s development.
The 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. Both type 2 and type 3 are later onset than type 1.
Participants are divided into two groups based on their age for this second trial. The first group includes adolescents and adults, ages 12 to 25, while the second group includes children ages 2 to 11. The study has two subsequent parts. In part 1, patients are randomly selected to receive either risdiplam or placebo for 12 weeks to determine the optimal dose of treatment. In Part 2, participants are treated for up to two years 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.
For both age groups, the primary endpoint is the change in total motor function after 12 months. Secondary endpoints include changes in blood biomarkers and measures of different motor functions.
PTC Therapeutics presented preliminary results from part 1 of the study in July 2017. It reported a 400% increase from the start of the study in full-length SMN mRNA from the SMN2 gene in treated patients. The findings suggest that risdiplam does promote the correct splicing of the SMN2 gene in people with SMA. 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 confirm that the therapy is targeting the underlying cause of SMA.
The third trial, called JEWELFISH (NCT03032172), is an open-label study evaluating the safety and tolerability of risdiplam in SMA patients ages 6 months to 60 years. The study is currently enrolling patients with SMA types 1, 2, and 3 in the U.S., the U.K., and Europe. 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 trial aims to enroll 180 participants.
Data was presented on all three of these trials at the 24th International Annual Congress of the World Muscle Society, held recently in Copenhagen, Denmark. According to these preliminary results, risdiplam appears to be safe and well-tolerated at every dose tested in all three studies, without any treatment-related withdrawals. A two-fold increase in SMN protein levels in the blood was noted in patients receiving risdiplam treatment. The SUNFISH study also showed clinically relevant improvement in motor function with risdiplam therapy.
RAINBOWFISH (NCT03779334), the fourth study, is evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of risdiplam in newborns to infants ages up to 6 weeks who have been genetically diagnosed with SMA but do not yet show any symptoms. The study plans to enroll 25 patients. Enrollment is ongoing at multiple centers across the world.
The proportion of infants with two copies of the SMN1 gene mutation who are able to sit up without support after 12 months is the study’s primary outcome. Secondary endpoints include mortality, the number of children who develop clinical manifestations of SMA, and time to permanent ventilation.
A final Phase 1 study (NCT03920865) is examining the effects of risdiplam in healthy volunteers and patients with mild-to-moderate liver dysfunction. Under evaluation is the participants’ ability to tolerate and process the oral therapeutic. This multi-center, open-label study will assess the effect of a single oral dose of risdiplam in these patients. People ages 18 to 70 will be included in the study, which plans to enroll 32 participants. Enrollment is ongoing at sites in Florida and Texas.
Risdiplam was granted orphan drug status by the U.S. Food and Administration (FDA) in January 2017. It then received priority medicine or PRIME designation from the European Medicines Agency (EMA) in December 2018. The purpose of both designations is to promote the development of treatments that may help patients with rare diseases. The benefits to the pharmaceutical companies come in the form of grant funding opportunities, clinical trial cost and tax advantages, FDA user-fee benefits, and FDA guidance during the drug-approval process.
Another therapy, RG7800, also was 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 long-term effects of the treatment.
Last updated: Nov. 1, 2019
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