Biogen Announces First Patient Dosed in Phase 4 Trial of Nusinersen in SMA


The phase 4 study will use total score on the Hammersmith Infant Neurological Examination Section 2 motor milestones as the primary end point over a 2-year period.

Julie Parsons, MD

Biogen announced that the first patient has been treated in the phase 4 RESPOND study (NCT04488133), which will evaluate nusinersen (Spinraza) in infants and children with spinal muscular atrophy (SMA) who still have unmet needs following treatment with gene therapy onsemnogene abeparvovec (Zolgensma; Novartis).1

The study is evaluating 60 patients up to 3 years old using total score on the Hammersmith Infant Neurological Examination (HINE) Section 2 motor milestones score as the primary end point. Researchers will seek to understand if the proven efficacy of nusinersen and its mechanism of action, which leads to continuous production of survival motor neuron (SMN) protein, may also benefit patients who have been insufficiently treated with gene therapy.

"SMA treatments have changed what is possible for children born with the disease but they have also raised new questions,” Nicole Gusset, president, SMA Europe, said in a statement. “We appreciate that the RESPOND study will collect data to help provide answers so individuals living with SMA can make informed treatment decisions.”

The primary study group will include 40 infants aged 9 months or younger (at the time of first nusinersen dose) who have 2 copies of SMN2 and received nusinersen at 6 months and older. A second study group will include 20 children within a broader age range (up to 3 years old at the time of first nusinersen dose).

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According to the trial registration information, patients will receive nusinersen 12 mg administered through intrathecal injection as loading doses on days 1, 15, 29, and 64 followed by maintenance doses every 4 months, on days 183, 302, 421, 540, and 659 over a 2-year study period.

Investigators will be looking at a number of secondary outcome measures, mainly the number of participants with adverse events (AEs) and serious AEs (SAE), as well as change from baseline in clinical laboratory parameters, electrocardiograms (ECGs), and in vital signs.

Other secondary end points such as achievement of motor milestones assessed by World Health Organization (WHO) criteria, change from baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score, and change from baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) score will all be assessed.

"In some patients treated with gene therapy, we have recognized that further motor neuron protection may be needed. Our hope is that results from RESPOND will demonstrate if Spinraza can optimize treatment for some of our youngest patients,” Julie Parsons, MD, professor of clinical pediatrics and neurology, Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders, Children’s Hospital Colorado, and primary investigator of the study, said in a statement.

Nusinersen became the first FDA approved drug for the treatment of SMA in pediatric and adult patients in December 2016. The approved recommended dosage of the injection is 12 mg per intrathecal administration.2

The drug is an antisense oligonucleotide that targets the root cause of SMA by continuously increasing the amount of full-length SMN protein produced in the body. It is administered directly into the central nervous system, where motor neurons reside, to deliver treatment where the disease starts.

Observational cohort data published in March 2020 suggested that nusinersen can be administered safely, with efficacious results, in the real-world treatment of adults with 5q SMA, the indication for which the therapy was FDA-approved.3 The study, which included 139 eligible screened patients, showed mean HFMSE scores increase from baseline by a mean difference of 1.73 (95% CI, 1.05–2.41; P <.0001) at 6 months, 2.58 (95% CI, 1.76–3.39; P <.0001) at 10 months, and 3.12 (95% CI, 2.06–4.19; P <.0001) at 14 months.

When the phase 4 RESPOND study was announced in July, Crystal Proud, MD, pediatric neuromuscular neurologist, Children’s Hospital of The Kings Daughters, and member of the RESPOND steering committee, sat down with NeurologyLive to discuss the goals of the study as well as the greatest unmet needs for the SMA patient population.

1. Biogen announces first patient treated in RESPOND study evaluating benefit of Spinraza (nusinersen) in patients treated with Zolgensma (onasemnogene abeparvovec). News release. Biogen. January 8, 2021. Accessed January 11, 2021.
2. FDA approves spinraza (nusinersen) for the treatment of spinal muscular atrophy in pediatric and adult patients. News release. FDA. December 23, 2016. Accessed January 11, 2021.
3. Hagenacker T, Wurster CD, Gunther R, et al. Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Lancet Neurol. 2020;19(4):317-325. doi: 10.1016/S1474-4422(20)30037-5
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