#AANAM – Risdiplam Improves Survival, Motor Function in Infants with Type 1 SMA, According to Data

Risdiplam (RG7916) can improve both survival and motor function in patients with type 1 spinal muscular atrophy (SMA) beyond that expected in the natural history of the disease, according to recent clinical data.

These data were presented during the 2019 annual meeting of the American Academy of Neurology, currently taking place in Philadelphia.

SMA is caused by mutations in the SMN1 gene, which prevent it from functioning properly. Although people typically have multiple copies of a second SMN gene, named SMN2, this gene makes very low levels of the SMN protein and cannot compensate for the lack of a functional SMN1.

Risdiplam is an oral medicine that works by altering the way SMN2 messenger RNA (a molecule that carries instructions to make proteins) is processed. This allows higher levels of functional SMN protein to be produced, which may help treat SMA.

Risdiplam can be reconstituted, which means the powder form is reconstituted to liquid so it can be given orally to babies. If patients are already having trouble swallowing, it can be given through a gastric tube directly into the stomach. A liquid form makes it potentially easier to consume.

Under a 2011 licensing agreement, Roche and Genentech are leading the work on risdiplam in partnership with PTC therapeutics and the SMA Foundation.

In the study “FIREFISH Part 1: 1-Year Results on Motor Function in Babies with Type 1 SMA,” Giovanni Baranello presented one-year interim results from part 1 of the Phase 2/3 FIREFISH trial (NCT02913482).

This trial is divided into two parts: the first one is assessing the safety and tolerability of different doses of risdiplam (low dose and a higher therapeutic dose), as well as its pharmacokinetics and pharmacodynamics — how the medicine acts and is processed within the body. The second part is assessing the safety and efficacy of risdiplam.

The trial included 62 babies (21 in part 1; 41 in part 2) 1–7 months old at the time of study enrollment and with two copies of the SMN2 gene.

Of the 21 babies who participated in the first part of the trial, 86% showed a four-point or higher improvement in CHOP-INTEND scores — a measure of motor function — at one year after treatment, as compared to the beginning of the study.  This was true for 75% of all infants in the low-dose group and 88% of all infants in the therapeutic-dose group.

Fifty-six percent of babies who received the higher dose achieved a CHOP-INTEND score of over 40 points, “which is never achieved in the natural history [of SMA],” Baranello, the trial’s lead investigator, said in an onsite interview with SMA News Today.

Among the babies in part 1 who received the dose selected for the second part of the trial (high dose, 17 infants), seven (41.2%) were able to sit without support for at least 5 seconds, 11 (64.7%) were able to sit (with or without support) and nine (52.9%) achieved upright head control at one year of treatment.

One child was able to stand up supporting their weight.

“That’s quite important for this patient-population age. First of all, 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,” Susan Begelman, vice president for Rare Disease and Neuroscience Medical Unit, U.S. Medical Affairs at Genentech/Roche, told SMA News Today.

Baranello said, “Part 1 of the study was mainly a dose-timing study. Its main objective was not in terms of efficacy. But if we consider the primary endpoint of part 2 (safety and efficacy), we can see that up to 41% of patients receiving the higher dose achieved motor milestones which, by definition, are never achieved by a typical SMA type 1 patient. This means a lot in terms of efficacy.”

In the study “FIREFISH Part 1: Survival, Ventilation and Swallowing Ability in Infants with Type 1 SMA Receiving Risdiplam (RG7916),” Laurent Servais revealed that after one year, there were no drug-related safety findings leading to withdrawal and 90.5% (18 of 21) of participants were alive and event-free (defined as surviving and not requiring permanent ventilation).

None of the three fatal complications has been attributed by researchers as related to risdiplam.

Both Baranello and Servais stressed the importance of early treatment and emphasized that these data are particularly impressive, given that these infants were treated with risdiplam close to 7 months of age, which is late considering type 1 SMA.

All infants experienced at least one adverse event reflective of the underlying disease. Ten children had at least one serious adverse event, the most common being pneumonia (reported in three patients).

As of February 2019, no infant required tracheostomy, permanent ventilatory support (for more than 16 hours per day) or lost the ability to swallow. In fact, 85% were able to be fed orally after 12 months of treatment.

“We are highly encouraged by our latest findings for risdiplam, which take us one step closer to potentially bringing the first oral treatment option to the SMA community,” Sandra Horning, MD, chief medical officer and head of global product development, said in a press release. “While SMA has seen important advances over the past few years, significant medical need remains for people living with all types of SMA across multiple age groups. We look forward to sharing additional data from our broad development program for risdiplam as it emerges.”

Part 2 of the FIREFISH study is currently ongoing and results are expected by the beginning of next year.