SMA New Today recently published the following information from the Jewelfish trial.

Treating teenagers and adults with oral risdiplam, a potential therapy for spinal muscular atrophy (SMA), led to sustained increases in blood levels of the key SMN protein missing in these patients, the lead investigator for a Phase 2 clinical trial said in an interview.

Claudia A. Chiriboga, MD, also said these early results in the first 12 SMA patients enrolled in the open-label JEWELFISH study (NCT03032172) showed risdiplam to be well-tolerated. JEWELFISH is now enrolling up to 180 infants through adults with types 1, 2, and 3 disease at sites in the U.S., U.K., Switzerland, and Italy; more information is available here.

In an interview with SMA News Today, Chiriboga, a pediatric neurologist and a professor at Columbia University Irving Medical Center (CUIMC), discussed these early findings, while also sharing her thoughts on possible future trial outcomes, what makes risdiplam stand apart, and who might benefit from combination treatment.

Data regarding risdiplam’s clinical effectiveness in these patients is not yet available.

SMA is caused by a faulty SMN1 gene, which reduces the levels of the SMN protein in motor nerve cells and leads to cell loss. Similar to Spinraza (nusinersen, by Biogen), the first approved SMA therapy, risdiplam is designed to boost the ability of an alternative gene — SMN2 — to produce full-length and functional SMN, unlike the shorter and unstable protein it normally produces.

JEWELFISH, as of Dec. 1, 2018, had six patients with type 2 and six with type 3 disease, two SMA forms whose symptoms typically become evident in the first years of life. Their median age was 20, ranging from 13 to 52 years old. “So many of those patients are quite advanced,” Chiriboga said.

After a median 14 months of treatment, data showed that SMN protein levels in the blood peaked within four weeks and were maintained at about two times the levels recorded at baseline or the study’s start.

Chiriboga, who is following JEWELFISH participants being treated at CUIMC, noted that a similar profile has been seen in other ongoing Phase 2/3 trials of risdiplam, namely FIREFISH (NCT02913482) in infants with type 1 SMA and SUNFISH (NCT02908685) in patients ages 2–25 with types 2 or 3.

Whether these SMN increases lead to significant improvements has not yet been analyzed, but Chiriboga mentioned preclinical animal data supporting such a link, with protein levels in the blood correlating with those in the brain, and risdiplam efficiently reaching the central nervous system (spinal cord and brain).

“I’m dying to see those data because I’m sure it’s going to show an association,” she said.

Safety, like efficacy, is also yet to be assessed, and enrolling more patients may enable a comparison between SMA types, Chiriboga added.

Existing data show that risdiplam, a liquid given orally once in the morning, is well-tolerated and “the children don’t seem to mind it.” JEWELFISH’s dose was based on determinations made in the first part of SUNFISH, which showed motor improvements regardless of disease severity or age at treatment start.

Its oral delivery means that risdiplam is distributed throughout the body, setting it apart from the specific effect on motor neurons of Zolgensma (onasemnogene abeparvovec-xioi, by Novartis and AveXis), and from Spinraza’s intrathecal (spinal canal) infusion. The benefits of systemic distribution are “probably most obvious in the younger patients … who have a lower level of SMN protein to the point that it can affect other organs much more strongly,” Chiriboga said.

Recent results from FIREFISH appear to support this, with most of its 21 infants showing meaningful motor benefits at 12 months of treatment, including seven (41.2%) in the proposed therapeutic dose group able to sit without support for at least five seconds.

Considering the rapid progression in babies with this most severe form of SMA and that treatment started at a relatively late age (a median close to 7 months old), these benefits are even more impressive, Chiriboga said.

“To see the magnitude of response was really surprising to me because we know that the later we treat them, the worse the response is,” she said. “I am persuaded myself … that [systemic delivery] is one of the reasons why [risdiplam] works so well in these infants.”

You can read more about the results by clicking here