Biogen moving ‘rapidly’ in quest to bring salanersen to SMA patients
In Q&A, company official notes therapy's 'striking' results in Phase 1 trial
Biogen is very pleased with the “striking” results seen thus far in clinical testing with its therapy candidate salanersen — designed to have high efficacy in people with spinal muscular atrophy (SMA) — and is engaging with health authorities on the design of further trials that might provide data supporting applications for its regulatory approval, a company official shared in a written Q&A with SMA News Today.
Salanersen is intended to have effectiveness similar to the higher dose regimen of Biogen’s long-approved therapy Spinraza (nusinersen), but with less frequent, annual dosing, per the developer. Its early efficacy was demonstrated in a Phase 1 clinical trial involving already treated children with SMA, according to early study data.
Now, Stephanie Fradette, Biogen’s head of the neuromuscular development unit, said in the Q&A that the company is “committed to moving as rapidly as possible to potentially bring salanersen to market.”
“Salanersen leverages the same mechanism of action as Spinraza … but was designed with novel antisense chemistry to enhance potency, stability and durability, enabling the potential for high efficacy with once yearly dosing,” Fradette said.
The interim data from that Phase 1 trial showed that salanersen improved motor function in children with SMA previously treated with the gene therapy Zolgensma (onasemnogene abeparvovec). Some children gained the ability to able to sit, crawl, stand, or walk, which they could not do before or needed assistance to do.
“Given the age at first salanersen dose, baseline function, and time since receiving Zolgensma [median of 28 months], achievement of new milestones for any of these participants would be unexpected,” Fradette said. “Therefore, it was quite striking when we observed that many participants achieved these milestones, in some cases within [three] months of starting salanersen.”
Some SMA children given salanersen in trial now crawl, stand, walk
SMA is mostly caused by mutations in the SMN1 gene, which result in little to no production of the SMN protein and the progressive loss of motor neurons, the nerve cells that control voluntary movements. Salanersen is an experimental injectable therapy that, like Spinraza, is designed to increase SMN levels produced from the SMN2 gene, a backup gene for SMN1.
The newer treatment, however, was designed to have greater potency and durability — and also to be dosed once per year. Spinraza’s currently approved regimen involves three loading doses every 14 days, and a fourth 30 days later. After that, patients are given maintenance doses once every four months.
A higher-dose regimen of Spinraza that involves fewer loading doses is currently under review in the U.S.
With salanersen, the safety and efficacy of a single administration of one of two doses (40 and 80 mg), given by intrathecal injection, or administration into the spinal canal, is now being tested in a Phase 1 clinical trial (NCT05575011). Besides the achievement of World Health Organization (WHO) motor milestones in four of eight children given a single 40 mg administration of salanersen, preliminary results also showed clinically meaningful improvements in scales of motor abilities and motor performance in the upper limbs.
According to Fradette, “the magnitude of improvement on these scales is notable, though it is sometimes hard to translate numbers into impacts on an individual’s daily life. Looking at the WHO motor milestones achieved can be illustrative in this regard.”
Additionally, the use of salanersen led to significantly lower amounts of neurofilament light chain among children with previously elevated levels of this biomarker of nerve cell damage. Fradette added that this “[gives] us confidence that salanersen is slowing the neurodegenerative process.”
The magnitude and consistency of the observed changes … are highly suggestive that salanersen is having a robust clinical effect. … Achieving a new motor milestone is a high bar, because it requires strength and coordination across multiple muscle groups.
Two children who had not completed the first year of follow-up were seen to achieve new motor milestones in the trial. Another three children attained the ability to sit without support within three to six months after treatment.
Other children in the study, including one unable to crawl, one who could not stand, and another who did not walk independently, reached such milestones.
“The magnitude and consistency of the observed changes across these endpoints are highly suggestive that salanersen is having a robust clinical effect,” Fradette said. “Achieving a new motor milestone is a high bar, because it requires strength and coordination across multiple muscle groups.”
Children who did not achieve a new motor milestone did show higher scores in motor function scales and less neurodegeneration, Fradette noted.
Gains still seen among children not reaching new motor milestones
Salanersen was generally well tolerated at both doses tested, with most adverse events being mild to moderate in severity. In the interim analysis, four participants experienced at least one adverse event considered related to the treatment by the investigator. Among these side effects were fatigue, fever, excessive saliva production, vomiting, back pain, headache, night sweats, and low blood levels of neutrophils, an immune cell type.
The trial will continue following children with SMA for up to two years after salanersen administration; the children then have the opportunity to join a long-term extension for five more years. More data from the trial will be shared at a future scientific congress, Fradette said.
Biogen is now in discussions with health authorities on the design of Phase 3 studies that could potentially provide data supporting applications for the treatment’s regulatory approval. According to Fradette, these trials will evaluate salanersen across a broad range of individuals, including those not previously treated and treatment-experienced patients.
“Driven by these encouraging Phase 1 results, we are eager to initiate our registrational studies for salanersen as quickly as possible,” Fradette said. “We are immensely grateful for the study participants, their families, investigators and site staff whose commitment to advancing new research for SMA makes this progress possible.”
Biogen’s Spinraza was the first therapy approved for SMA, in September 2016. Since then, both Zolgensma and Evrysdi, a gene therapy, have been widely approved. Still, according to Fradette, more work is needed to develop new treatments.
“While we’re thrilled about the progress in SMA over the past decade with the approval of three disease-modifying therapies, it has become increasingly clear there are critical remaining unmet medical needs to be addressed. Given the progressive nature of the disease, we continuously strive to optimize efficacy outcomes for people living with SMA,” Fradette said.
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