Biogen Announces Phase 4 Study of SMA Therapy Nusinersen


The RESPOND study steering committee member and pediatric neuromuscular neurologist at Children’s Hospital of The King’s Daughters discussed the goals of the phase 4 trial of nusinersen in SMA.

Dr Crystal Proud

Crystal Proud, MD, pediatric neuromuscular neurologist, Childrens Hospital of The Kings Daughters

Crystal Proud, MD

Just this month, Biogen announced that it is launching a phase 4 study of its spinal muscular atrophy (SMA) therapy nusinersen (Spinraza), called RESPOND, with plans to submit the study protocol to regulatory agencies in the coming months and an aim to begin enrollment in early 2021.1

The trial will assess treatment with nusinersen in infants and children who have lingering unmet clinical needs after being treated with onasemnogene abeparvovec (Zolgensma; Avexis)—a patient population that has been reported to include up to 40% of those treated with the agent, based on the findings of a long-term study of Zolgensma.2 RESPOND is planned as a 2-year, open-label study with a target enrollment of 40 infants aged ≤9 months at time of first dose with 2 SMN2 copies.

To find out more about the goals of the study, what needs remain to be met with the participants, and how this may impact future clinical care, NeurologyLive inquired with a member of the RESPOND steering committee, Crystal Proud, MD, pediatric neuromuscular neurologist, Children’s Hospital of The King’s Daughters.

NeurologyLive: What is the goal of this phase 4 study and what end points are being assessed?

Crystal Proud, MD: SMA is a progressive, life-long disease requiring urgent treatment. Clinicians continue to pursue improved outcomes for infants and children with SMA, and we’ve observed that some patients treated with gene therapy need additional benefit.

In fact, in the long-term study of Zolgensma and real-world experience, some patients have moved on to treatment with Spinraza. We expect that the RESPOND study will generate valuable data to help inform future treatment decisions for our youngest SMA patients.

Based on the planned study design for RESPOND, efficacy will be assessed by change from baseline on motor function measures, additional clinical outcomes (e.g., swallowing) and caregiver burden. Neurofilament levels, an exploratory endpoint, will also be evaluated as a marker of biological disease activity.

What specific unmet needs might be addressed for patients who will be treated secondarily with nusinersen?

People with SMA do not produce enough survival motor neuron (SMN) protein that is critical for the maintenance of motor neurons that support sitting, walking and basic functions of life, including breathing and swallowing. Preclinical data show that not all motor neurons are treated by gene therapy.3,4 SPINRAZA has a different mechanism of action with regard to SMN protein production, acting on the SMN2 gene. The RESPOND study will seek to understand if the proven efficacy of SPINRAZA and its continuous production of SMN protein may also benefit patients treated with gene therapy.

The study will enroll children who are determined by study investigators to have the potential for additional clinical improvement after receiving Zolgensma. We will evaluate children using criteria that may include one or more of the following: suboptimal motor function (e.g., a score lower than 50 on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]); the need for respiratory support; abnormal swallowing or feeding ability or other factors deemed relevant.

Might this provide insight into the possibility of a multi-pronged, or multi-therapy approach to patients with SMA?

There is compelling clinical rationale for the potential of additional efficacy with SPINRAZA following Zolgensma. Additional data is needed from a clinical trial setting, and the RESPOND study aims to answer a question that’s very meaningful to the SMA community. It could certainly help inform future treatment decisions.

Transcript edited for clarity.


1. Biogen Plans to Initiate Phase 4 Study Evaluating Benefit of SPINRAZA® (nusinersen) in Patients Treated with Zolgensma® (onasemnogene abeparvovec) [press release]. Cambridge, MA. Biogen. Published July 21, 2020. Accessed July 23, 2020.

2. EMA. Zolgensma EU Summary of Product Characteristics (SmPC). Updated 2019. Accessed on July 23, 2020.

3. Foust KD, Nurre E, Montgomery CL, et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009;27:59—65. doi: 10.1038/nbt.15153.

4. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28:271—274. doi: 10.1038/nbt.1610

Related Videos
Michael Levy, MD, PhD
Michael Kaplitt, MD, PhD
Michael Kaplitt, MD, PhD
video 4 - "Amyloid Cascade Hypothesis of Alzheimer’s Disease"
Video 3 - "Amyloid Precursor Protein and Amyloid Beta Species in Alzheimer’s Disease"
Svetlana Blitshteyn, MD, FAAN, director and founder of Dysautonomia Clinic
© 2024 MJH Life Sciences

All rights reserved.