Higher Dose Regimen of Nusinersen Approval Delayed by FDA Complete Response Letter

The FDA has issued a Complete Response Letter (CRL) for Biogen’s supplemental New Drug Application (sNDA) for a higher dose regimen of nusinersen, a spinal muscular atrophy (SMA) drug, according to a recent news release.

The CRL requested that a technical information update be included in the Chemistry Manufacturing and Controls (CMC) module of the sNDA.

The proposed higher dose regimen is two 50 mg doses administered 14 days apart, followed by a maintenance dose of 28 mg every 4 months.

This higher dose regimen was recently approved in Japan and is now under review by the European Medicines Agency.

Nusinersen was approved by the FDA in 2016 as a 12 mg injection under the brand name Spinraza for adults and pediatric SMA patients. It was the first drug ever to be approved for the treatment of SMA. More than 14,000 individuals worldwide have been treated with Spinraza since its approval.

Spinal muscular atrophy is a rare, progressive and genetic disease caused by mutations in the two survival motor neuron genes: SMN1 and SMN2. This causes progressive weakness in the arms, legs, face and throat. Weakness is often most severe in the trunk.

Depending on severity and symptom onset, patients may lose the ability to speak or walk. Secondary complications include respiratory infections, scoliosis and joint contractures, which is the chronic shortening of muscles and tendons.

The most severe form of SMA, called Type 1, generally manifests before 6 months of age. These children rarely live beyond the age of 2.
Approximately 10,000 to 25,000 Americans have SMA, and about 6 million Americans are carriers of SMN1, the primary gene associated with SMA. Although SMA gene carriers do not exhibit any symptoms, if both parents are carriers, their child has a 25% chance of having the disease.

Because it is considered the “backup” SMA gene, the number of SMN2 genes a patient has may also affect the severity of their SMA, with more copies leading to milder symptoms.

Spinraza is an antisense oligonucleotide that binds to the SMN2 gene, fixing errors to make a more complete protein, which lessens SMA symptoms. It is administered directly into the cerebrospinal fluid through the lower back via an intrathecal (IT) injection.

The sNDA submission for a higher dosing regimen was based on the findings from the phase 2/3 DEVOTE study, which demonstrated safety and efficacy in 145 SMA patients of varying SMA type and ages.

Results showed that patients who transitioned to the higher dose regimen had clinically significant motor function improvements and slowed neurodegeneration, including mean increases of 1.8 points on the Hammersmith Functional Motor Scale-Expanded and 1.2 points on the Revised Upper Limb Module at day 302. Adverse reactions were similar to ones observed with the lower dose regimen, the most common side effects being respiratory infection, fever and constipation.

“While this outcome was unexpected, we remain committed to bringing the high dose regimen to people living with SMA,” Priya Singhal, M.D., M.P.H., Head of Development at Biogen, said in the news release. “We are working diligently to provide the necessary information to the FDA.”