Infants Receiving Evrysdi Continue to Improve and Achieve Motor Milestones, Phase 2/3 Trial Data Show

Infants with spinal muscular atrophy (SMA) type 1 receiving the therapeutic dose of Evrysdi (risdiplam) continue to improve and achieve motor milestones, according to two-year data from the first part of the Phase 2/3 FIREFISH clinical trial.

Updated data from FIREFISH (NCT02913482) showed that nearly all infants who received the highest (therapeutic) dose of Evrysdi were alive and did not require permanent ventilatory support after two years. Also, more than half of them were able to sit unaided for at least five seconds, maintain their head in an upright position, and achieve a CHOP-INTEND score of 40 points or more — corresponding to nearly normal motor function — by the second year of the study.

“We are highly encouraged by the results we are seeing in the second year of treatment with Evrysdi,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a press release.

“These results build on the efficacy and safety demonstrated by Evrysdi in pivotal trials, and we look forward to continued assessments of both survival and motor function during long-term follow up for this first-of-its-kind treatment,” Garraway said.

Trial findings were presented at the 25th International Annual Congress of the World Muscle Society (WMS), held online, Sept. 28–Oct. 2.

Developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation, Evrysdi was the first oral therapy to be approved in the U.S. to treat patients 2 months and older with all types of SMA.

The medication, which is meant to be taken as a liquid every day at home, works by increasing the production of functional survival of motor neuron (SMN) protein, which is missing in people with SMA and is crucial for muscle health. Like Spinraza (nusinersen), Evrysdi does this by boosting the ability of the SMN2 backup gene, which usually remains unaffected in SMA patients, to produce the SMN protein.

The safety and effectiveness of Evrysdi have been assessed in several Phase 2 and Phase 3 clinical trials enrolling patients from several age groups with different types of SMA.

FIREFISH, one of the trials that supported Evrysdi’s approval in the U.S., focused on evaluating the safety and effectiveness of the medication in infants ages 1–7 months with type 1 SMA, who had two copies of the SMN2 gene.

The study was divided into two parts: an initial part that enrolled a total of 21 infants and sought to evaluate the safety, tolerability, and pharmacological properties of different doses of Evrysdi; and a second part that enrolled 41 infants and sought to evaluate the most effective and safest dose of Evrysdi as determined in the previous phase.

From the 21 infants who participated in the first part of the trial, 17 were treated with the highest dose of Evrysdi, which later was determined to be the best dose at which the medication should be given.

One-year data from the first part of FIREFISH showed that 10 of the 17 infants (59%) who received the highest therapeutic dose of Evrysdi attained a CHOP-INTEND score of at least 40 points. By the end of the first year of treatment, seven of these infants (41%) were able to sit unaided for at least five seconds, nine (53%) could maintain their head upright, two (12%) could turn over, and one (6%) could stand supporting their weight.

Two-year data from FIREFISH now announced by Genentech showed that infants treated with the highest therapeutic dose of Evrysdi in the first part of the study continued to improve and achieve motor milestones. At the time of this analysis, the youngest infant participating in the study was 28.4 months (almost 2.5 years), and the oldest was 45.1 months (about 3.7 years).

After two years of treatment, 12 infants (71%) achieved a CHOP-INTEND score of at least 40 points, with all of them having their scores increase from the first to the second year of treatment. Moreover, after two years of treatment, 10 of these infants (59%) managed to sit without support for at least five seconds, 11 (65%) maintained control of their head, five (29%) turned over by themselves, and five (30%) could stand upright with help or supporting their own weight.

This exploratory analysis also estimated that by the second year of the study, 88% of infants treated with Evrysdi were still alive and required no permanent ventilatory support. All 14 infants who were still alive after two years of treatment with the therapeutic dose, maintained their ability to swallow, and 13 (93%) were still able to feed orally.

The safety profile of Evrysdi during FIREFISH was consistent with previous reports, with no new safety signals identified. The most common side effects observed during the trial included fever (71%), upper respiratory tract infection (52%), cough (33%), vomiting (33%), diarrhea (29%) and respiratory tract infection (29%). Pneumonia, which was the most common serious side effect observed during the study, occurred in 24% of infants.

Two of the 17 infants who received the highest dose of Evrysdi in the first part of the trial died from SMA complications, and one who withdrew from the study died a few months later. However, none of these deaths were found to be related to the medication.

“The results from the long-term FIREFISH trial demonstrate that SMA patients continue to improve in motor function and gain additional developmental milestones,” Stuart W. Peltz, PhD, CEO of PTC Therapeutics, said in a press release.

“In addition, the results further validate the safety and durable efficacy profile of Evrysdi and reinforce the continued benefit of the therapy. Since its approval in August, Evrysdi has demonstrated a strong commercial launch signifying the need for an oral treatment for SMA patients, especially one that can be taken at home amidst the global pandemic,” Peltz added.

In addition to FIREFISH, three other clinical trials — SUNFISH (NCT02908685), JEWELFISH (NCT03032172), and RAINBOWFISH (NCT03779334) — are assessing the safety and effectiveness of Evrysdi in SMA patients. In total, more than 450 SMA patients with ages ranging from a few months old to 60 years, are currently receiving the medication in one of these studies.