FDA denies approval for higher dose of nusinersen for SMA
Biogen calls decision on Spinraza medication 'unexpected,' will resubmit
The U.S. Food and Drug Administration (FDA) has declined to approve a higher dose of nusinersen — the medication in Biogen’s long-approved therapy Spinraza — for the treatment of spinal muscular atrophy (SMA).
According to Biogen, no issues were raised with the clinical data in the company’s submission seeking regulatory approval of the higher dosage. Instead, the FDA’s Complete Response Letter requested that an update to technical information be included in the Chemistry Manufacturing and Controls module of Biogen’s supplemental New Drug Application.
The company is planning to resubmit the application promptly, using readily available information, and says the regulatory agency provided options for resolution.
“While this outcome was unexpected, we remain committed to bringing the high dose regimen to people living with SMA,” Priya Singhal, MD, head of development at Biogen, said in a company press release. “We are working diligently to provide the necessary information to the FDA.”
SMA is mostly caused by mutations in the SMN1 gene that lead to a shortage of SMN, a protein needed for the maintenance and functioning of motor neurons — the nerve cells that control muscles involved in movement. Without enough SMN, motor neurons progressively die, causing muscle weakness and other symptoms.
Spinraza, the first disease-modifying therapy approved for SMA, works by increasing the amount of SMN produced from SMN2, a backup gene for SMN1. The first three doses are given once every two weeks, while the fourth is administered 30 days later. Maintenance doses are then given every four months. The therapy is given by intrathecal injection, or directly into the spinal canal.
MDA ‘hopeful’ new nusinersen dose will soon be available to patients
The high-dose regimen involves faster loading — two doses of 50 mg given 14 days apart — and a higher maintenance dose of 28 mg every four months instead of the previously approved 12 mg.
Clinical testing has shown that it may provide further benefits relative to the previously approved dosing regimen.
This outcome … underscores both the complexity and importance of regulatory processes..
Regarding the FDA’s rejection, the Muscular Dystrophy Association (MDA) said in a statement that “this outcome … underscores both the complexity and importance of regulatory processes.”
In its statement, posted on LinkedIn, the MDA also noted that “the SMA community has more treatment options today than ever before.” Still, “there remains a vital need to expand and refine therapies that improve strength, function, and quality of life,” the nonprofit wrote.
Noting that “time is muscle,” the MDA added: “We remain hopeful this additional dosing option will become available to families in the near future.”
Biogen’s application based on positive data from Phase 3 clinical trial
The application filed by Biogen was based on data from DEVOTE (NCT04089566), a now-completed three-part Phase 3 clinical trial. It tested how safe a higher dose of nusinersen is and how well it works in 145 patients of all ages and main types of SMA.
In Part A, six patients ages 6 to 12 received three loading doses and two maintenance doses, all of 28 mg. The regimen was well tolerated, with four patients experiencing mostly mild side effects.
Part B mainly compared the higher-dose regimen with the currently approved dose in 75 patients with infantile-onset SMA who had never received treatment for SMA. As untreated controls, it included patients from ENDEAR (NCT02193074), the Phase 3 clinical trial that provided the basis for approval of the 12 mg dose.
After six months, patients on the higher dose experienced significant improvements in motor function, measured by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), compared with the untreated controls. In addition, reductions in blood levels of a marker of nerve cell damage, called neurofilament light chain, were greater in the high-dose group than in both the 12 mg dose group and the external controls.
The higher dose was also linked to a lower risk of death or permanent ventilation to help with breathing, as well as fewer hospitalizations and serious respiratory events, compared with the external group of untreated patients. It also tended to be better than the 12 mg dose on these measures, while resulting in fewer serious side effects.
The open-label Part C tested how safe it is to transition to the higher-dose regimen in 40 children and adults who had been receiving Spinraza at the approved regimen for at least one year. Patients aged 4 to 65 received a single dose of 50 mg, followed by two doses of 28 mg spaced by four months.
The higher-dose regimen resulted in further gains in motor function in children and adults who had been on the approved 12 mg dose for a median of 3.9 years. None of the serious side effects seen in six patients in part C were deemed related to treatment or its administration.
While the high-dose regimen has already been approved in Japan, similar applications are under review by the European Medicines Agency and other global regulators, Biogen noted.
About the Author
