Treatment with nusinersen demonstrated no clinically meaningful changes in vital signs or clinical laboratory parameters, including urine parameters, in those with spinal muscular atrophy.
Interim analysis from Part A of the ongoing phase 2/3 DEVOTE study (NCT04089566) showed that treatment with high-dose nusinersen (Spinraza; Biogen) is safe, with no treatment-related adverse events (AEs) observed, in participants with spinal muscular atrophy (SMA).
The results of the study were presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18. Based on the safety results from Part A, Part B has been initiated and 6 participants have enrolled thus far, though enrollment in Part B is still ongoing.
As of December 7, 2020, 6 participants had been included in the study and received 28-mg nusinersen for 161-257 days. At follow-up, AEs were observed in 4 participants, none of which were related to the study drug, and none of which were considered severe or serious.
Lumbar puncture (LP) was associated with AEs in 4 participants. The documented AEs related to LP were headache, vomiting, procedural headache, procedural pain, chills, decreased appetite, and paresthesia. Of 21 total LP procedures, 11 (52%) were associated with greater than 1 AE considered related to LP.
The current approved regimen for nusinersen calls for 4 loading doses within the first 2 months of initiating treatment, each of which is 12 mg. According to Richard Finkel, MD, director, Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, and principal investigator of the DEVOTE study, preclinical work helped influence the decision to use a new 28-mg maintenance dose. In April, when the first patient in DEVOTE was treated, he spoke with NeurologyLive on the study outline.
"By using pharmacokinetic-pharmacodynamic modeling, we were able to put together information from the preclinical testing as well as information that we've learned from treating patients with Spinraza and say, ‘How do we model the drug to be able to identify with what we think is an optimal dose?’” Finkel explained. “This decision ultimately came back to the idea of trying to optimize the response for each individual patient as much as possible.”
Finkel and colleagues also found that there were no clinically meaningful changes in vital signs or clinical laboratory parameters, including urine parameters, as well as no AEs associated with electrocardiograms. Furthermore, platelet counts for patients treated with nusinersen remained in the normal range.
Nusinersen did not demonstrate any clinically relevant change on patients’ blood chemistry, hematology, urinalysis, and physical or neurological examinations. Researchers also observed no clinically significant cerebrospinal fluid (CSF) abnormalities.
There was no evidence of an adverse effect on liver function tests, demonstrated by normal levels of alkaline phosphatase and aspartate aminotransferase. One patient had a high aspartate aminotransferase level at screening, and this remained constant with no associated AEs.
DEVOTE is a 3-part study to evaluate the clinical efficacy, safety/tolerability, and pharmacokinetics of nusinersen dosing regimens targeted to achieve higher CSF concentration more rapidly with fewer loading doses in patients with 5q SMA.
Finkel also told NeurologyLive in April 2020 that “if you’re sitting down with a parent or a patient and you’re trying to make a data-driven decision, you have the most information, at the end, on Spinraza. I think that’s very powerful. If Spinraza shows good safety and enhanced efficacy at this higher dosage, then the clinician will be able to discuss the potential extended role that it can play.”
Nusinersen was the first FDA-approved drug for the treatment of SMA in pediatric and adult patients in December 2016. 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 (CNS), where motor neurons reside, to deliver treatment where the disease starts.2
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