[Editor’s note: An earlier version of this story did not specify in its opening statement that Spinraza’s use in this proposed trial would follow Evrysdi’s use.]
Biogen plans to launch a Phase 3b trial into the safety and efficacy of a higher dose of Spinraza (nusinersen) in children, teenagers, and adults with later-onset spinal muscular atrophy (SMA) previously treated with Evrysdi (risdiplam).
The trial, to be called ASCEND and to run for roughly 2.5 years, expects to enroll up to 135 patients, ages 5 to 39, who are unable to walk and likely to have SMA types 2 and 3, according to a Biogen press release that only specifies later-onset disease.
Enrollment is expected to start this year, the company said. Its protocol, which details how the study will be conducted, has been submitted to the U.S. Food and Drug Administration (FDA) for review and acceptance.
Eligible patients must have used Evrysdi at its approved 5 mg dose for those weighing 20 kg (about 44 lbs) or more, and have a pre-specific range of arm movement as determined by the Revised Upper Limb Module (RULM) test for SMA. They may or may not have been treated with Spinraza prior to starting with Evrysdi.
Those enrolled will be given two Spinraza loading doses at 50 mg each, delivered two weeks apart. This will be followed by a maintenance high dose — 28 mg — given every four months throughout the study period. Spinraza’s approved maintenance dose is 12 mg, delivered by intrathecal (spinal canal) injection every four months.
Treatment effectiveness at this higher dose, as assessed by RULM, will be a main study goal. Additional outcomes include the therapy’s safety, its impact on motor function — assessed with the Hammersmith Functional Motor Scale Expanded (HFMSE) — and caregiver burden.
In patients ages 13 and older, levels of neurofilament — a marker of nerve cell damage, indicating disease activity — will be assessed as an exploratory goal, as will upper limb fine motor function using the Konectom app for smartphones.
Evrysdi, given as a flavored liquid, is administered daily at home by mouth or feeding tube, and approved at up to its 5 mg dose for SMA patients ages 2 months and older (dosing is weight-based for those under 20 kg). It was developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation.
This disease-modifying therapy, like Spinraza, works by acting on the SMN2 gene, a “backup” gene that contains the information needed to make the SMN protein that is lacking or deficient in SMA patients. By doing so, it raises the levels in cells of functional SMN protein, which plays an essential role in motor neuron and muscle health.
Biogen in its release referred to data showing that Evrysdi’s exposure seems to fall as patients age and gain weight, with an approximately 40% reduction in therapy concentration in adults compared with youngest-treated infants. This lack of availability in older patients may diminish treatment effectiveness.
“We believe that lower drug exposure may be contributing to less-than-optimal treatment outcomes for some patients treated with Evrysdi,” said Maha Radhakrishnan, MD, chief medical officer at Biogen. “The ASCEND study seeks to understand if nusinersen may address that unmet medical need and will help inform the future of SMA treatment, with the hope of improving patients’ outcomes for the long term.”
At its 12 mg dose, motor neuron exposure to Spinraza “remains similar as patients age and grow,” the release stated.
Spinraza is approved for patients of all SMA types and ages, and data support its safety and sustained efficacy in patients treated for more than seven years, the company added.
An analysis of two past studies — the Phase 2 CS3A study (NCT01839656) and the Phase 3 ENDEAR study (NCT02193074), both in people with infantile-onset SMA — indicated that a higher dose of Spinraza may lead to meaningful improvements in motor function beyond those seen at the 12 mg dose, Biogen reported at a June SMA conference.
These data also supported the 2020 launch of the ongoing Phase 2/3 DEVOTE study (NCT04089566), evaluating Spinraza’s safety and efficacy at a 28 mg maintenance dose, compared with its approved dose, in SMA patients (ages 2 through 9 for part B, and all ages for part C). DEVOTE is enrolling eligible patients at sites across the U.S. and Canada, Europe, Asia, and South America; information is available here.
“There have been significant advances in SMA treatment; however, there is still no cure and unmet medical needs remain,” said Tim Hagenacker, professor at the Essen University in Germany, and a member of the ASCEND study’s steering committee.
“As part of my clinical practice, we’ve observed an opportunity to potentially further improve patient outcomes,” he added. “With a higher dose of nusinersen, we are positioned to explore what may be possible.”
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