A potential oral treatment for children with type 1 spinal muscular atrophy (SMA) called RG7916 was able to safely raise levels of the crucial SMN protein that is lacking in these patients, early results of a two-part clinical trial show.
Data from the study, “RG7916 significantly increases SMN Protein in SMA Type 1 Babies,” was part of the “Emerging Science Platform Session” given at the 2018 American Academy of Neurology (AAN) Annual Meeting on Tuesday. The event runs through April 27 in Los Angeles.
SMA is characterized by the loss of motor neurons, a type of nerve cell that transmits impulses from the brain to muscle cells. Type 1 SMA is the most severe and most common disease form, with symptoms — generalized muscle weakness and difficulties breathing — present at birth or within the first six months of life.
The disease results from a mutated or missing SMN1 gene that is responsible for SMN protein levels. Another gene, SMN2, also instructs production of the SMN protein, but only at 20 percent of the levels of SMN1 due to alternative splicing (editing) of a premature version of its messenger RNA (mRNA), the molecule that guides protein formation. Most of the protein generated from SMN2 is shorter and unstable.
RG7916, a once-daily liquid solution, is designed to increase production of full-length SMN2 mRNAs to increase the levels of functional SMN protein available for motor neuron health.
Researchers designed FIREFISH, a multicenter, open-label Phase 2/3 study (NCT02913482), to explore treatment with RG7916 in an estimated 48 babies, ages 1 to 7 months, with type 1 SMA and two copies of the SMN2 gene. On average, untreated SMA type 1 babies live for 10.5 months before needing permanent ventilation or dying.
In the study’s first part, 21 babies were given RG7916 every day for four weeks at different dose levels to assess its safety and tolerability. Results showed that treatment induced, in a dose-dependent manner, a greater amount of SMN protein in the blood. The higher the dose, the higher the SMN protein levels.
At its highest dose, the potential treatment after four weeks led to a 6.5-fold increase in SMN — an increase its researchers thought quite notable.
Ninety-four percent of babies had a greater than 4-point improvement from baseline in the CHOP INTEND score, a measure of motor skills that ranges from 0 to 64 (0 means no response). In fact, 7 of 16 patients had a CHOP-INTEND score higher than 40 at day 119 after treatment.
Nineteen of the 21 babies enrolled were still alive at the time of the analysis, and the two deaths were not considered therapy-related. No safety issues observed required discontinuing treatment, the scientists reported.
All treated infants also maintained an ability to swallow throughout this first part, and none had breathing difficulties that led to a tracheostomy or permanent ventilation.
RG7916’s effectiveness in addressing the disease’s impact on motor, respiratory, and other skills will be evaluated in FIREFISH’s second phase. Patients will receive open-label RG7916 (now being called risdiplam) for 24 months, at the dose selected in Part 1.
Enrollment is ongoing at sites in the U.S., Europe, and China; more information is available here.
“These results are exciting, as children with SMA type 2, which is less severe than type 1, have approximately twice as much SMN protein as those with type 1 so to see an increase of up to 6.5 times the amount of protein is very encouraging and supports the possibility to see improved function in these babies,” Giovanni Baranello, MD, the study’s lead author, said in a press release.
“This research is continuing and much more needs to be done to determine whether this treatment will provide meaningful benefits for children with [SMA],” he said.
These FIREFISH trial results are in line with those of the SUNFISH Phase 2/3 trial (NCT02908685) and the JEWELFISH Phase 2 study (NCT03032172) in types 2 and 3 SMA, also presented at AAN 2018, which also showed that RG7916 treatment increases SMN protein levels in patients.