Rare Disease Report

SMA Treatment, Risdiplam, Yields Positive Interim Data

OCTOBER 03, 2018
Krista Rossi
Interim clinical data from Genentech’s 2-part pivotal FIREFISH and SUNFISH trials evaluating risdiplam (RG7916), a potential spinal muscular atrophy (SMA) treatment, have been released.

In the preliminary data gleaned from Part 1 of FIREFISH, 6 out of 14 infants (43%) were able to sit with or without support. After 8 months of treatment, 3 of those 6 patients (21%) were able to achieve unassisted stable sitting.

Additionally, 7 infants (50%) showed signs of kicking, 6 (43%) achieved upright head control, and 4 infants (29%) rolled to the side.

Among the results, developmental milestones were met in FIREFISH, and improvements in motor function were displayed in SUNFISH. In addition, no trial withdrawals due to drug-related safety findings occurred in either trial. 

“We are highly encouraged by these data showing infants treated with risdiplam surviving and achieving developmental milestones beyond the natural history of this devastating disease,” said Sandra Horning, MD, chief medical officer and head of Global Product Development, in a recent statement. “SMA therapies that produce a sustained increase in SMN protein in both the CNS and periphery may provide comprehensive benefits to people diagnosed with SMA, and we look forward to sharing additional data on risdiplam as the clinical program progresses.”

The FIREFISH clinical trial includes 2 parts, with Part 1 assessing the safety, tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and efficacy of risdiplam in infants with Type 1 SMA; and Part 2 assessing risdiplam for 24 months at the dose selected in Part 1.

The current primary outcome measure of Part 1 includes establishing the recommended Part 2 dose of risdiplam.

The observed milestones were assessed in accordance with the Hammersmith Infant Neurological Examination (HINE) Module 2 and serve as key secondary endpoints in the confirmatory part of the FIREFISH trial.

In accordance with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), a scale created to evaluate motor function in infants with Type 1 SMA, 8 out of 14 infants in FIREFISH (57%) scored 40 or above at their 8-month visit. Over time, the median CHOP-INTEND scores increased (37.5 at 6 months [n=20] compared to 41.5 at 8 months [n=14]).

At first dose in the FIREFISH, the median age was 6.7 months and median treatment duration was 9.5 months. To date, 19 out of 21 infants enrolled (90%) are alive, and 3 have progressed to an age over 24 months. Two participants discontinued treatment due to the fatal progression of their disease.

Neither tracheostomy or permanent ventilation has been required in infants since the study’s initiation. All infants also maintained the ability to swallow.

Fever (pyrexia; 52.4%), diarrhea (26.8%), upper respiratory tract infections (19%), ear infections (14.3%), pneumonia (14.3 percent), constipation (14.3%), vomiting (14.3 percent), cough (14.3%) and upper respiratory tract inflammation (14.3%) were the most common adverse events.

The SUNFISH clinical trial includes 2 parts, with Part 1 assessing the safety, tolerability, PK, PD, and efficacy of risdiplam in adult and pediatric participants with Type 2 and Type 3 SMA;
and Part 2 assessing risdiplam for 24 months at the dose selected in Part 1.

The current primary outcome measure of Part 1 includes the change from baseline in the Total Motor Function Measure 32 (MFM-32) Score at month 12.

In the preliminary data gleaned from Part 1 of SUNFISH, patients aged between 2 and 24 years ranging in functional status from weak non-ambulant to strong ambulant and with varying degrees of scoliosis from none to severe were included. Initially, 21 patients were administered lower doses of risdiplam for a minimum of 12 weeks.

After 12 months and as measured in the blood, SMN protein median increases of greater than 2-fold.

A 3.1-point improvement was also observed in the patients treated with risdiplam for at least 1 year (n=30), according to the median change from baseline in Motor Function Measure (MFM), the primary endpoint in the confirmatory part of SUNFISH, and a scale used to assess motor function in neuromuscular diseases.

An improvement in MFM over baseline of 3 points or more after 1 year was observed in 63%, which included patients under 12 years old (76%; n=17) and over 12 years old (46%; n=13).

Overall, the number of patients who experienced any amount of improvement over baseline was 70%. For the younger age group, it was 76%; and for the older patients, it was 62%.

Nausea (4%), upper respiratory tract infection (4%) and vomiting (4%) included serious adverse events that occurred in two or more of the 51 patients treated with risdiplam.

No drug-related safety findings leading to withdrawal from any study have been reported thus far.

Follow-ups for both FIREFISH and SUNFISH are ongoing for the confirmatory Part 2 portions.

The interim Part 1 data was presented at the 23rd International Annual Congress of the World Muscle Society in Mendoza, Argentina. 

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