Phase 3b Study of Higher-Dose Nusinersen in Patients With SMA Announced


Initiated by Biogen, the study will evaluate the effectiveness of the treatment in patients previously treated with risdiplam (Evrysdi; PTC Therapeutics).

Maha Radhakrishnan, MD, chief medical officer, Biogen

Maha Radhakrishnan, MD

Biogen announced plans to initiate a phase 3b trial, ASCEND, to study the safety and efficacy of higher doses of nusinersen (Spinraza; Biogen) in patients with spinal muscular atrophy (SMA) who have been treated previously with risdiplam (Evrysdi; PTC Therapeutics). 

The ASCEND trial is anticipated to begin enrolling its first patients in 2021, with the study spanning approximately 2.5 years and including 135 patients with later-onset, nonambulatory SMA between the ages of 5 and 39 years. Participants will be given 2 loading, 50-mg doses of nusinersen 2 weeks apart, and a 28-mg maintenance dose at 4-month intervals for the duration of the study. 

“We believe that lower drug exposure may be contributing to less-than-optimal treatment outcomes for some patients treated with Evrysdi,” Maha Radhakrishnan, MD, chief medical officer, Biogen, said in a statement.1 “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.”

The protocol has been submitted to the FDA, with inclusion criteria including being previously treated with the maximum 5-mg dose of risdiplam and falling within a specific Revised Upper Limb Module (RULM) measurement range, which will then be used to assess efficacy. Safety, Hammersmith Functional Motor Scale Expanded (HFMSE), and caregiver burden are additional clinical outcomes to be evaluated. 

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The global clinical study will include children, teenagers, and adults with SMA, as data suggest those treated with risdiplam may have remaining unmet needs. Data have suggested exposure to risdiplam decreases as patients grow and age, and when comparing adult patients to children, adults saw a 40% reduction in drug concertation. Once patients’ weight reaches 20 kg, dosage of the treatment is capped at 5 mg. 

“There have been significant advances in SMA treatment; however, there is still no cure and unmet medical needs remain,” Tim Hagenacker, MD, head, Neuromuscular Diseases Unit, Essen University, in Germany; and member, ASCEND study steering committee, said in a statement.1 “As part of my clinical practice, we’ve observed an opportunity to potentially further improve patient outcomes. With a higher dose of nusinersen, we are positioned to explore what may be possible.”

The current approved dose of nusinersen is 12 mg, administered intrathecally, with patients seeing similar motor neuron exposure to the treatment as they age. Across patients of different ages and with varying SMA types, nusinersen has further shown safety and efficacy according to long-term data from patients treated with the drug for over 7 years. 

The long-term impact of nusinersen is currently being evaluated in 2 open-label extension studies, with recently reported findings from the phase 2, open-label, dose-escalation study (NCT01839656) finding that the treatment improved survival and attainment of motor milestones over 3 years in patients with infantile-onset SMA.

Originally approved in December 2016, nusinersen became the first FDA-approved therapy to treat SMA types 1, 2, and 3. Since the approval, several trials have been initiated to study safety and efficacy of the treatment. 

Datasets from those who transitioned from the CHERISH study (NCT02292537), a randomized control study of nusinersen, to the open-label SHINE extension study (NCT02594124), presented at the American Academy of Neurology 2020 Annual Meeting, also showed that the treatment has sustained efficacy and long-term safety in patients with infantile-onset SMA, as well as later-onset SMA. In that analysis, the HFMSE score at the modified maintenance dosing regimen Day 1 for patients with later-onset SMA was 26 (standard deviation, 11.01) for those who received nusinersen in CHERISH/SHINE and 21.2 (SD, 7.75) for those randomized to sham-procedure in CHERISH and then nusinersen in SHINE.3

1. Biogen plans to initiate phase 3b study evaluating potential benefit of a higher dose of nusinersen in patients previously treated with Evrysdi (risdiplam). News release. Biogen. September 15, 2021. Accessed September 15, 2021.
2. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health. 2021;5(7):491-500. doi:10.1016/S2352-4642(21)00100-0
3. Chirboga CA, Darras BT, Farrara MA, et al. Longer-term treatment with nusinersen: results in later-onset spinal muscular atrophy from the SHINE study. Neurology. 2020;94(15 Suppl):166
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