Treatment with the experimental oral therapy risdiplam has been enabling patients with spinal muscular atrophy (SMA) to achieve key development milestones and clinically meaningful motor improvements beyond the natural history of the disease.
Susan Begelman, MD, vice president, Neurology, Nonmalignant Hematology, Influenza, U.S. Medical Affairs at Genentech, and Giovanni Baranello, MD, PhD, the lead investigator of the Phase 2/3 FIREFISH trial (NCT02913482), discussed the latest results, as well as what lies ahead in risdiplam’s clinical development, in interviews with SMA News Today at the recent 2019 American Academy of Neurology (AAN) annual meeting.
Data presented at AAN addressed one year of treatment in both the FIREFISH study in type 1 SMA — the most severe and common form of the disease — and the Phase 2/3 SUNFISH trial (NCT02908685) in types 2 and 3.
Overall, seeing the benefits across risdiplam’s trials is “really becoming quite exciting … potentially [representing] an oral treatment agent to patients,” Begelman said. “We hope to submit data to health authorities in the second half of this year.”
‘Impressive and unexpected’ improvements
Risdiplam — being developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is intended to boost the ability of the SMN2 gene to generate a full-length and functional SMN protein, unlike the shorter and unstable version it normally produces.
Specifically, risdiplam is a splicing modifier, changing the way pre-messenger RNA molecules — those generated from DNA in protein production — are edited to generate full-length mature RNA.
Risdiplam’s powder form can be reconstituted into a liquid, making it potentially easier to administer and able to be taken at home.
“There’s enough burden on the patients, the infants, their families and caretakers and other members, [so] to be able to do it on an outpatient basis is great,” Begelman said.
Results of part 1 of FIREFISH in 21 infants showed improved survival, and among the 17 infants who received the dose selected for the second part of the trial, seven were able to sit upright without support for at least five seconds.
“That’s quite important,” Begelman said. “What parent doesn’t want to see their kid sit upright? So that’s a very important thing for the families. But also by being able to sit upright, you’re also able to move your arms, perhaps eventually feed yourself. That’s a critical milestone.”
Other key improvements included nine infants with head control, one able to stand up, and 41% of the patients on the higher dose reaching motor milestones “never achieved by a typical SMA type 1 patient. This means a lot in terms of efficacy,” said Baranello, a neurologist with the Carlo Besta Neurological Research Institute Foundation in Italy.
Considering that most patients were treated at close to 7 months of age — which is late, given the typical SMA type 1 progression — these results “are even more impressive” and unexpected, Baranello added.
Part 1 of SUNFISH, in types 2 and 3 showed that 58% of the 43 patients had clinically meaningful motor improvements, as assessed by increases of at least three points on the Motor Function Measure-32 scale.
Such motor changes were “really rare” in a similar group of SMA patients who were part of a natural history study in France, Belgium, and Germany, according to Baranello.
The 2-to-11-year-old group had a higher proportion of motor improvements than patients ages 12–25 (71% vs. 42%). Although Begelman cautioned that the trial was not designed to address the potential benefits of earlier treatment, “you can look at those subgroups and you see who’s potentially going to benefit more greatly,” she said.
As with FIREFISH, these results need to be confirmed in part 2, which will include 180 participants, a sufficient number to enable definitive conclusions. But the benefits seen to date, together with the more than twofold increase in blood SMN protein found in part 1, suggest a meaningful effect with risdiplam, Begelman said.
As for safety, there were no risdiplam-related withdrawals from either trial. Most adverse events were mild or moderate and reflected the underlying disease.
Looking at the broad SMA patient population
Other clinical trials of risdiplam are now recruiting participants. The Phase 2 RAINBOWFISH study (NCT03779334) will assess presymptomatic treatment and plans to include 25 infants up to 6 weeks of age at first dose.
Enrollment is ongoing in the U.S., Italy, Poland, and Russia, with other locations expected to open in Australia, Belgium, Brazil, China, and Saudi Arabia up to the third quarter of this year. More information on trial sites and contacts is available here.
The Phase 2 JEWELFISH trial (NCT03032172) is recruiting a broad range of participants, ages 6 months to 60 years. They may have been on another therapy, including Spinraza (nusinersen, by Biogen) — the only approved SMA treatment to date — or a gene therapy, or olesoxime, which is no longer being developed after disappointing results.
“[The] goal is to really cover the wide range of patients and all types of SMA,” Begelman said.
Similar to risdiplam, Spinraza is an SMN2-targeting therapy, but Begelman noted they are “different molecules.” Also, unlike the oral delivery of risdiplam, Spinraza is given by intrathecal (spinal canal) infusion.
“When you think about oral, perhaps you have both delivery into central nervous system [brain and spinal cord] and throughout the body,” she said.
Another potential advantage of oral delivery is that it may be an option for patients with scoliosis — curvature of the spine — or spinal stenosis (narrowing), who may not be able to receive intrathecal therapies such as Spinraza, Begelman said.
Risdiplam has been designed as a stand-alone therapy. But with Zolgensma (by Novartis) expected to expand SMA treatment options, “the potential for combination therapies is on everyone’s mind, healthcare providers certainly, certainly ours. But that would have to be studied,” Begelman said.
The key question, she noted, is whether SMA treatments enable “full normalcy” compared with unaffected people: “Our goal right now is getting this investigational medicine hopefully to patients, and the next step would be to see what can we build on that.”
Looking back, the SMA community has seen rapid changes since Sprinraza’s U.S. approval in December 2016. “If you really put that in context … back a few years there was nothing for a disease that was so devastating,” Begelman said. “To see such tremendous advances in a short amount of time is really a thrill to be able to do that for patients. I’m really happy for the community.”