Full Dataset Shows Additional Benefit for SMA With Higher Dose Nusinersen


A PK/PD model indicated that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP-INTEND score beyond that observed with the approved 12-mg dose.

Richard Finkel, MD

Richard Finkel, MD

Using data from the phase 2 CS3A (NCT01839656) and ENDEAR studies (NCT02193074), investigators found that treatment with nusinersen (Spinraza; Biogen) at doses higher than the approved 12-mg dose may lead to additional clinically meaningful improvement in patients with infantile-onset spinal muscular atrophy (SMA).1

Led by Richard Finkel, MD, director, Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, the mean percentage reductions from baseline in plasma phosphorylated neurofilament heavy chain (pNF-H) levels among those treated with 6-mg and 12-mg nusinersen loading doses in CS3A at day 85 were 25.0% and 62.7%, respectively. In those studies, patients received 3 loading doses, whereas in ENDEAR, a 12-mg nusinersen regimen with 4 loading doses resulted in the greatest decrease (71.4%) in plasma pNF-H levels at day 64.

The full findings, published in Annals of Clinical and Translational Neurology, come less than a year after the original analysis was presented at the 2021 SMA Research and Clinical Care Meeting. Each trial differed slightly in dosing, as mentioned previously. More specifically, in CS3A, participants received 3 loading doses of 6-mg or 12-mg equivalent doses of nusinersen on days 1, 15, and 85, followed by 12-mg equivalent doses on day 253. Participants with SMA in ENDEAR received 4 loading doses of 12-mg equivalent doses on days 1, 15, 29, and 64, followed by 12-mg equivalent doses on days 183 and 302.

As expected, the lowest nusinersen cerebral spinal fluid (CSF) levels were observed in the CS3A group treated with the 6-mg, 3 loading dose regimen (1.1 ng/mL at day 85). In contrast, higher nusinersen CSF levels were seen in the CS3A group treated with 3, 12-mg loading doses (3.7 ng/mL at day 85), and the highest levels were observed in the ENDEAR group treated with the 12-mg, 4 loading dose regimen (6.1 ng/mL at day 64).

Using nusinersen CSF levels obtained at the same time as Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) assessments, investigators created a pharmacokinetic/pharmacodynamic (PK/PD) model to further assess dose–response relationship. Based on data from participants with 2 SMN2 copies, the nusinersen concentration attained with the 12-mg ENDEAR dosing regimen (5 ng/mL) was associated with an estimated improvement of 7.5 points from baseline in CHOP-INTEND score, which was consistent with the mean 9.1-point improvement observed in the ENDEAR study.

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Finkel et al also modeled several dosing regimens that would be expected to lead to nusinersen CSF levels associated with a clinically meaningful increase (≥4 points on CHOP INTEND) above the 12-mg dose. A selected regimen of 2 loading doses of 50 mg separated by 2 weeks and maintenance doses of 28 mg resulted in nusinersen CSF steady-state levels of 12 ng/mL, a 2.4-fold increase in nusinersen CSF concentrations over the 12-mg approved dose. Based on the PK/PD model, this higher concentration was estimated to lead to a 5.2-point increase in CHOP-INTEND score above that observed with the approved dosage.

The response to treatment with nusinersen has been shown to fluctuate based on weight, according to previous analyses.2 To account for this, Finkel and his colleagues separated the data according to median participant age at first dose (ie, 150 days) and plotted the PK/PD curve for data of participants below and above median age at first dose. Similar PK/PD curves in both groups were observed, with mean change in CHOP-INTEND total score greater in the group that was younger at first dose than in those dosed at a later stage. This applied for both exposures associated with steady state of 12 mg and a higher dose of nusinersen (28 mg).

"Importantly, the additional improvement in CHOP-INTEND score expected with the higher dose of nusinersen above that seen with the 12-mg regimen was similar in both younger and older participants based on age at first dose with 5.2- and 5.1-point improvement in CHOP-INTEND scores, respectively,” Finkel et al wrote.1 "This analysis suggests that while age at first dose is an important contributing factor to change in CHOP-INTEND score from baseline, it is not a contributor to the higher efficacy predicted in this model with the higher dose of nusinersen."

In September 2021, Biogen announced plans to initiate a phase 3b trial, ASCEND, to study the safety and efficacy of higher doses of nusinersen in patients with SMA who were previously treated with risdiplam (Evrysdi; PTC Therapeutics). The study is expected to enroll approximately 135 later-onset, nonambulatory individuals with SMA who will be treated with the drug across a 2.5-year stretch. 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.3

1. Finkel RS, Ryan MM, Pascual SI, et al. Scientific rationale for a higher dose of nusinersen. Ann Clin Transl Neurol. Published online May 13, 2022. doi:10.1002/acn3.51562
2. Osmanovic A, Schreiber-Katz O, Petri S. Nusinersen Wearing-Off in Adult 5q-Spinal Muscular Atrophy Patients. Brain Sci. 2021;11(3):367. doi:10.3390/brainsci11030367
3. 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 May 18, 2022. https://investors.biogen.com/news-releases/news-release-details/biogen-plans-initiate-phase-3b-study-evaluating-potential
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