Risdiplam Use ‘Meaningful’ to Broadest SMA Group Ever in Clinical Trial, Genentech Exec Says

Risdiplam treatment has led to “clinically meaningful” improvements — whether gains or disease stabilization — in the broadest range of spinal muscular atrophy (SMA) patients, by age and disability level, yet enrolled in a clinical trial.

More than one-third of those in the second part of the SUNFISH trial (NCT02908685) were ages 12 or older — an under-represented group in SMA clinical trials — and had no previous disease-specific treatments.

In an interview with SMA News Today, Susan Begelman, MD, vice president of the rare disease and neuroscience medical unit in U.S. medical affairs at Genentech, discussed SUNFISH’s latest results, their implications for different age and disability groups, and what distinguishes this trial from all others to date.

SMA is caused by mutations in the SMN1 gene, which disrupts production of the survival motor neuron (SMN) protein that’s essential for muscle health. A second survival motor neuron gene — SMN2, with an identical sequence — only partly compensates for the loss of SMN1-produced SMN.

Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral liquid therapy designed to boost the ability of the SMN2 gene to produce a functional SMN protein, primarily in motor neurons but elsewhere as well.

Benefits in broadest patient range

The two-part, global Phase 2/3 SUNFISH study is evaluating the safety and effectiveness of risdiplam given once a day to people with type 2 or 3 SMA, ages 2 to 25.

“SUNFISH is the first clinical trial to include such a diverse and heterogeneous SMA patient population,” with a wide range of ages and SMA disease characteristics, and a “broad geographic diversity, including clinical trial sites in the U.S., Europe, China, Japan, and the rest of the world,” Begelman said.

“Many of the patients in this study have not been considered, enrolled, or able to participate in other clinical studies of medicines, based on the type of disease they have, the age they are, the underlying scoliosis, and even some of their other baseline characteristics,” she said.

SUNFISH’s first part determined the best dose of risdiplam — focusing on achieving a sustained two-fold increase in SMN levels — in 51 ambulatory (able to walk) and non-ambulatory patients.

In part 2, the focus of this interview, 180 wheelchair-bound participants were randomly assigned to receive either risdiplam (120 people) at that optimal dose or a placebo (60 people) for 12 months. Begelman declined to specify the dose given; risdiplam is now under U.S. Food and Drug Administration (FDA) review for possible approval.

Most (71.1%) of the part 2 patients had been diagnosed with SMA type 2, with a mean age of 15.5 months at disease onset, and a median disease length of nine years at enrollment. About half were male, and 66.7% had scoliosis, many with a severe curve to the spine.

The risdiplam and placebo groups largely maintained a similar sex and SMA-type ratio to that of the whole patient population.

Begelman emphasized that 37.8% were at least 12 years old, 31.7% had severe scoliosis, and 41% had severe disability — features that would typically make patients ineligible for an SMA clinical trial.

“So, in the conduct of this study, we’re also learning about the types of tools and assessments, as well as what the impact of treatment has on this patient population,” she said.

After one year of treatment, data showed that SUNFISH met most of its goals, with risdiplam’s use bringing significantly superior benefit to patients’ motor abilities (whether as functions gained or stabilized) compared with placebo.

The trial’s primary and secondary goals were chosen together with the SMA community “to better understand the nature of their disease and what scales might reflect improvement and/or stabilization in these patients,” Begelman said.

SUNFISH’s primary goal was changes in motor function assessed using the Motor Function Measure-32 (MFM32), a validated test able to measure motor skills across a range of patients with neuromuscular diseases, including SMA.

MFM32 evaluates 32 changes from a study’s start (baseline) in skills that include sitting, standing, walking, running, and hopping. It also assesses head support, upper limb function, and hip and knee flexion. Flexion is movement that decreases the angle between the bones that converge at the joint — basically, how much patients can bend their legs at the knees or how closely they can bring the knee up to the chest.

Higher scores indicate better motor function, and an increase of at least three points on the MFM32 scale — rarely seen in SMA’s natural history — is considered clinically meaningful.

Secondary goals included other functional measures, such as the Revised Upper Limb Module (RULM) score, the Hammersmith Functional Motor Scale Expanded (HFMSE), and the SMA Independence Scale (SMAIS).

The SMAIS is a 22-item test develop by Roche that measures the amount of assistance required to complete daily living activities, mainly related to upper limb function. These activities include feeding oneself, brushing one’s teeth and other hygiene tasks, getting dressed, picking up and moving objects, writing, and using a computer.

This test was completed by caregivers for all study participants, and also by patients 12 or older.

Those on risdiplam showed clinically meaningful and statistically significant changes in both MFM32 and RULM scores compared with patients receiving the placebo. However, motor improvements seen in the HFMSE score were not statistically significant, meaning they are still likely to be a result of chance rather than treatment.

Begelman said that the HFMSE test “mostly assesses growth in motor movement,” and may be less sensitive than is MFM32 for patients with poorer motor abilities and longer disease duration.

A scale needs to capture “different changes in a patient population,” she added. And it needs to detect changes in patients “who may be weaker, as well as looking at specific subsegments like upper limb function in someone who’s already lost the ability to ambulate.

“MFM32 is probably a more sensitive [tool] than Hammersmith” in people with more advanced disease, “which is why it was chosen” as SUNFISH’s primary goal, Begelman said.

Risdiplam-treated patients and their caregivers reported greater independence in daily tasks at one year than did those on placebo, whose independence fell over the year. Caregivers were the most optimistic, reporting greater gains in independence than did the treated patients in their charge.

“The mean change was slightly higher by the caregivers assessing than by the patients, but both were higher than placebo, which declined,” Begelman said.

Whether risdiplam’s optimal dose continued to raise by a median of two times SMN protein levels in patients’ blood will likely be disclosed when the subgroup analyses are complete, Begelman said.

SUNFISH will continue for another year, with all enrolled being treated with risdiplam. Patients can then choose to continue with treatment in an open-label extension study.

Different expectations for different age groups

The greatest motor improvements were seen in the youngest age group, those 2-5 years old, an exploratory subgroup analysis of MFM32 score changes with risdiplam’s use showed. A large proportion of people in the oldest group, ages 18 to 25, achieved stabilization, meaning no further loss in motor skills due to disease progression.

Among the youngest patients, clinically meaningful improvements — a three-or-more-point gain on MFM32 — were seen in 78.1% of those given risdiplam and 52.9% of those on a placebo. Stabilization was observed in 57.1% on risdiplam in the oldest group and 37.5% of those on a placebo.

“In older SMA patients, stabilization — lack of disease progression — is as important to them as [improvements are] in a very young patient, someone trying to achieve new motor milestones like sitting,” Begelman said. “For different ages, one’s expectations may need to be different.”

Begelman didn’t “specifically know what to conclude” about the more than 50% of young placebo patients showing clinically meaningful gains in MFM32 scores.

“We have a lot of data yet to still process,” she said. “In the body of the data, we might have more insights than we do today.”

Motor gains seen with risdiplam’s use appeared to lessen with age at treatment initiation, though greater across-the-board benefit was seen in those on treatment across all age groups: 2–5, 6–11, 12–17, and 18–25.

Data capturing changes within specific sections of the MFM32 by age group is still being analyzed, Begelman said.

Risdiplam’s safety profile also was consistent with that reported in previous trials.

Serious adverse events — those that pose a threat to a patient’s life or ability to function — were slightly more frequent in risdiplam-treated patients (20%) than in those on placebo (18.3%). These included serious lower respiratory tract infections (10% vs. 2%) and bacteremia, or bacteria in the bloodstream (1.7% vs 0%), but none were considered related to treatment and all resolved without any changes in therapy. Grade 3 (severe) and 4 (life-threatening) adverse events, while not specified, were 17.5% in the risdiplam group and 13.3% among those on the placebo.

“Many of the AEs [adverse events] and SAEs [serious adverse events] reported are commonly seen in patients with this disease,” Begelman said. “There was a trend toward more grade 3 and 4 AEs [in the risdiplam group], but these AEs resolved without any changes to study medication.”

In addition to the approval request submitted to the FDA, Genentech and Roche filed such requests with health authorities in Chile, Indonesia, and Taiwan. Data updates are continuously being submitted, she said, and other worldwide filings are planned, including one with the European Medicines Agency expected in mid-year.

The FDA’s decision is due on or before May 24.

“We’re excited about this study,” Begelman said. “It was a pretty ambitious study, to really reflect the real-world population of individuals with [later-onset] SMA, many of whom were not receiving treatment or haven’t had access to clinical trials or treatment.”