Risdiplam May Halt Motor Impairment in SMA Patients, Interim Clinical Data Suggests

The investigational treatment risdiplam (RG7916) improved motor function in patients with type 1, 2 or 3 spinal muscular atrophy (SMA), according to preliminary results from the first part of two Phase 2/3 clinical studies.

Risdiplam, being developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation, is a once-daily oral treatment designed to boost production of SMN, the protein that is severely lacking in SMA patients.

This small molecule is intended not only to bypass the blood-brain barrier and effectively reach the central nervous system, but also to be distributed throughout the body, which may be a more effective approach.

Risdiplam is a splicing modifier, which means it can change the way pre-mRNA molecules are spliced, or “edited”, so that full-length SMN mRNA is produced, which can encode for functional SMN protein.

Two multicenter, two-part, Phase 2/3 studies, called FIREFISH (NCT02913482) and SUNFISH (NCT02908685), are evaluating the therapeutic benefits of risdiplam in patients with different types of SMA. Their first parts were designed to evaluate the safety, tolerability and pharmacological profile of several risdiplam doses to identify an optimal dose for the second part, which assesses the safety and effectiveness of the selected dose.

Earlier this year, results from the first part of these studies showed that risdiplam treatment increased SMN protein levels among SMA patients.

Preliminary functional results from the first part of these trials were presented earlier this month at the Annual Congress of the World Muscle Society in Mendoza, Argentina.

FIREFISH results were presented in a scientific poster, “FIREFISH: Risdiplam (RG7916) improves motor function in babies with Type 1 SMA.”

In this study, researchers gave risdiplam once a day to 21 babies 1 to 7 months old with SMA type 1, the most severe form of the disease. Infants at this age usually do not show motor improvement over time, and instead often show decline and have reduced survival. The median age at first dose was 6.7 months and median treatment duration was 9.5 months.

Ask questions and share your knowledge of SMA in our forums.

As of Sept. 7, 2018, 19 infants were still alive – three of them now more than 2 years old – and the two deaths were not considered therapy-related. No infant needed permanent ventilation or lost the ability to swallow.

In addition, many of the 14 infants who were treated for eight months achieved several motor milestones – assessed through the Hammersmith Infant Neurological Examination (HINE) Module 2 – such as kicking (7 infants, or 50%), sitting with or without support (6 infants, or 43%), upright head position (6 infants, or 43%), and rolling to the side (4 infants, or 29%).

Of note, of the six babies who were able to sit with or without support, three achieved unassisted sitting, something type 1 SMA babies never achieve when considering the natural history of SMA.

After eight months of treatment, the median change in the CHOP-INTEND score – a measure of motor skills that ranges from 0 to 64, with zero meaning no response – in these infants was 16 points, with 93% of them showing a greater than four-point improvement, and 57% having a score higher than 40.

Among the most common adverse events was fever (52.4%), diarrhea (26.8%), and upper respiratory tract infections (19%), while 10 babies (47.6%) had at least one serious adverse event.

“We are highly encouraged by these data showing infants treated with risdiplam surviving and achieving developmental milestones beyond the natural history of this devastating disease,” Sandra Horning, MD, Roche’s chief medical officer and head of global product development, said in a press release.

Results of the randomized, placebo-controlled, double-blind, SUNFISH study involving 51 type 2 or 3 SMA patients (milder forms of the disease) with ages 2-25 years were presented in another poster, titled “SUNFISH Part 1: Risdiplam (RG7916) treatment results in a sustained increase of SMN protein levels and improvement in motor function in patients with Type 2 or 3 SMA.”

Thirty-five patients were randomized to receive risdiplam for at least one year, and 30 of them had their motor function evaluated using the Motor Function Measure (MFM)-32 – a validated scale to assess motor function in neuromuscular diseases.

After one year of treatment, 19 patients (63.3%) showed motor improvements, including 13 out of 17 (76.5%) younger than 12, and 6 out of 13 (46.2%) 12 or older. Six patients (11.8%) had at least one serious adverse event – such as respiratory tract infection, nausea, or vomiting – but they were reported to be unrelated to treatment and resolved.

No patient had stop therapy due to treatment-related adverse events in both studies.

“The emerging results from FIREFISH and SUNFISH trials support the broad clinical benefit of a systemic oral treatment for SMA patients,” Stuart W. Peltz, Ph.D., CEO of PTC Therapeutics, said in a press release.

“Patients with Type 2 and 3 SMA typically decline over the course of a year and the increase in motor function by over 3 points in SUNFISH when compared to natural history is exceptionally encouraging,” said Peltz. “We are excited by the gains in developmental motor milestones exhibited by Type 1 babies in FIREFISH. The observation of six babies sitting to date in a dose finding study is remarkable. SMA is a systemic disease, and risdiplam which is an oral treatment that reaches all affected organs has the potential to be a best-in-class therapy.”

Participants of the first part of the FIREFISH and SUNFISH studies are expected to continue treatment in an open-label extension study. Up to 40 babies with type 1 SMA are currently being recruited for the second part of FIREFISH, while 168 patients with SMA type 2 have already been enrolled for the second part of SUNFISH.