Higher Dose Nusinersen Shows Greater Potential for Clinical Benefit in SMA


A pharmacokinetic/pharmacodynamic model indicated that the exposures predicted with a higher dose of nusinersen may lead to more clinically meaningful increases of at least 5 points on CHOP INTEND score.

Alfred Sandrock Jr., MD, PhD

Alfred Sandrock Jr., MD, PhD

Analysis presented at the 2021 Cure SMA Research & Clinical Care Meeting, June 9-11, showed that higher nusinersen (Spinraza; Biogen) levels are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with spinal muscular atrophy (SMA) and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.1,2

The pharmacokinetic/pharmacodynamic (PK/PD) model indicated that patients exposed to higher nusinersen cerebrospinal fluid (CSF) were correlated with greater efficacy, as measured by change from baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores. Furthermore, exposure levels also predicted clinically meaningful increases of at least 5 points on CHOP INTEND.

"Intervention with Spinraza can meaningfully impact the trajectory of SMA, and we remain relentless in our aim of improving outcomes for people with SMA. We continued to better understand and explore Spinraza’s potential with our new and ongoing global clinical studies,” Alfred Sandrock Jr., MD, PhD, head of Research and Development, Biogen, said in a statement.2

Data including plasma pNH-F and CSF PK measurements was collected from 99 participants with infantile-onset SMA in the phase 2 CS3A (NCT01839656) and phase 3 ENDEAR (NCT02193074) clinical studies. Patients in CS3A were treated with either 3 loading doses (LD) of 6-mg (n = 4) or 12-mg (n = 16) nusinersen, whereas those in ENDEAR were treated with 12-mg nusinersen for 4 LDs.

READ MORE: Nusinersen Shows Improved 3-Year Survival in Infantile-Onset SMA

CSF trough concentration (Ctrough) measurements, time-matched with CHOP INTEND scores in 80 participants, were higher in those dosed in ENDEAR compared with CS3A, which according to the investigators was expected. Similarly, those with higher nusinersen levels were associated with greater decreases of plasma pNF-H levels.

The validated population PK model was then applied to predict nusinersen Ctrough in CSF for patients within the phase 3 DEVOTE study (NCT04089566). Those in the study who received a higher-dose regimen of 2 LDs of 50 mg on Days 1 and 15, followed by 28-mg maintenance doses every 4 months, were stimulated to predict the anticipated exposure within CSF as a function of time. The investigators concluded that "the model predicts that steady-state Ctrough in CSF will increase at least 2-fold with higher doses of nusinersen compared with 12 mg.”1

DEVOTE is an ongoing 2-part study. Those in Part B, which was used in this analysis, received 2 LDs of 50 mg 14 days apart followed by 28-mg maintenance dose every 4 months. Results from Part A of DEVOTE, which evaluated 3 LD of nusinersen 28 mg followed by 2 maintenance doses of nusinersen 28 mg, were previously reported.3

After 303 days of follow-up in Part A, investigators found no severe or serious adverse events (AEs) and no AEs related to the study drug. There was no clinically relevant changes related to nusinersen in terms of blood chemistry, hematology, urinalysis, vital signs, physical or neurological exams, and electrocardiograms (ECGs).

Part C of the study, which was recently initiated, will evaluate safety and tolerability of transitioning from currently approved regimen to a higher dose of nusinersen in an open-label setting. Patients included in that analysis will receive 1 LD of 50 mg followed by 2 maintenance doses at 28 mg.

Nusinersen, an antisense oligonucleotide administered intrathecally, received FDA approval for the treatment of children and adults with SMA in December 2016.4 Since its approval, the drug has had a multitude of studies conducted to further confirm its efficacy and safety in this patient population.

NeurologyLive’s Peer Exchange, “The Changing Landscape in the Treatment of Spinal Muscular Atrophy,” featured Basil Darras, MD, who reviewed data from the ENDEAR trial and discussed the agent’s safety and efficacy in patients of differing age groups. Watch below for his commentary.


1. Finkel RS, Ryan MM, Pascual SI, et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting; June 9-11. Abstract P46
2. New data at Cure SMA 2021 highlight the long-term efficacy of Spinraza (nusinersen) and Biogen’s commitment to innovation in SMA therapy. News release. June 10, 2021. Accessed June 14, 2021. https://www.globenewswire.com/news-release/2021/06/10/2245119/0/en/New-Data-at-Cure-SMA-2021-Highlight-the-Long-Term-Efficacy-of-SPINRAZA-nusinersen-and-Biogen-s-Commitment-to-Innovation-in-SMA-Therapy.html
3. Pascual SI, Day JW, Finkel RS, et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021; March 15–18.
4. FDA approves spinraza (nusinersen) for the treatment of spinal muscular atrophy in pediatric and adult patients. News release. FDA. December 23, 2016. Accessed June 14, 2021. accp1.org/accp1/5publications_and_news/fda_approves_spinraza.aspx
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