A new modeling study predicts that higher doses of Spinraza (nusinersen) may improve its effectiveness compared with the approved 12 mg dose.
The study used data from two clinical trials that evaluated the disease-modifying therapy in infants with spinal muscular atrophy (SMA).
“The [pharmalogical] model indicates that the higher dose of [Spinraza] may be associated with a clinically meaningfully increase in efficacy above that seen with the 12-mg approved dose,” the researchers wrote, noting that the larger dose is now being tested for safety and effectiveness in a clinical trial.
Titled “Scientific rationale for a higher dose of nusinersen,” the modeling study was published in the Annals of Clinical and Translational Neurology.
Spinraza, by Biogen, is an approved treatment that’s designed to increase the levels of SMN, a protein lacking in people with SMA. SMN is essential for the health of motor neurons, the specialized nerve cells that control voluntary movement.
A deficiency in SMN is primarily caused by defects in the SMN1 gene, which carries instructions for the SMN protein. Disease onset and severity are dictated mainly by the activity of a second SMN2 gene, which can produce SMN protein and partially compensate for the SMN1 defects.
Several clinical studies have demonstrated significant and clinically meaningful benefits from Spinraza that continue with long-term treatment. Because of the favorable safety profile — consistent for over seven years of therapy — higher doses beyond the approved 12 mg have been considered. Researchers have suggested that a higher dose may provide enhanced benefits.
To that end, the ongoing Phase 2/3 DEVOTE study (NCT04089566) is currently recruiting participants to evaluate the efficacy, safety, and pharmacological properties of a higher Spinraza dose. That trial is enrolling an estimated 172 participants at 51 locations worldwide.
The launch of the DEVOTE study was supported, in part, by two past studies that tested Spinraza in infantile-onset SMA: the Phase 3 ENDEAR study (NCT02193074) and the Phase 2 CS3A study (NCT01839656). As reported by Biogen at an SMA conference last year, data from these trials suggested a higher Spinraza dose may provide meaningful improvements in motor function.
Now, scientists at Biogen, collaborating with several clinical sites worldwide, conducted a modeling study using data from both ENDEAR and CS3A. The goal was to investigate the potential for higher Spinraza doses. Data were assessed from 93 participants from both studies who carried two copies of the SMN2 gene.
In summary, ENDEAR participants received four loading doses of 12-mg equivalent doses on days 1, 15, 29, and 64 — with the last dose coming just after the two-month mark. The loading doses were followed by 12-mg equivalent doses on days 183 (six months) and 302 (10 months).
Those in the CS3A study received three loading doses of 6- or 12-mg equivalent doses on days 1, 15, and 85 (2.8 months). For these patients, follow-up doses of a 12-mg equivalent dose were given on day 253 (8.3 months).
The team then examined potential dose-response relationships. First, they investigated a possible link between levels of Spinraza in the cerebrospinal fluid (CSF), a colorless liquid found around the brain and spinal cord, and levels of bloodstream pNF-H, a biomarker of neurodegeneration. Trough concentrations were used, or the steady-state Spinraza levels in the CSF between doses.
The lowest CSF Spinraza trough levels were seen in the CS3A group given the 6-mg three-loading dose regimen at 2.8 months. The highest concentrations, meanwhile, were found in the CS3A group treated with three 12-mg loading doses. Likewise, the highest levels were observed in the ENDEAR group, among patients who received three 12-mg loading doses at two months.
Higher trough CSF Spinraza corresponded with a greater mean reduction in pNF-H levels. In CS3A, the 12 mg dose led to a 62.7% drop in pNF-H, while the 6 mg dose reduced the marker by 25%. In ENDEAR, the greatest pNF-H decline was 71.4% at 12 mg by two months.
Next, a pharmacological model was developed using Spinraza CSF levels obtained at the same time that participants were assessed with CHOP INTEND — a validated motor outcome measure designed for infants with SMA. Fully, the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, CHOP INTEND is an easy-to-use assessment created by the hospital in 2010.
The model showed that Spinraza in the CSF reached with 12-mg in ENDEAR was associated with an estimated motor improvement of 7.5 points in the CHOP INTEND score. That increase “is consistent with the mean 9.1-point improvement observed in the ENDEAR study,” the team wrote.
To simulate a higher dosing regimen, the team selected two loading doses of 50 mg, separated by two weeks, followed by maintenance doses of 28 mg. The pharmacological model showed these higher doses led to an estimated 5.2-point increase in the CHOP INTEND score above that seen with 12-mg.
Because the patient’s age at the first dose is an essential determining factor of the therapeutic response, the team separated the model data into four different age groups at first dose. There was no clear pattern of age and CSF levels, suggesting that “age at first dose of [Spinraza] does not impact the predicted additional increase in CHOP INTEND score with a higher dose of [Spinraza] compared with 12-mg,” the researchers said.
Although ENDEAR and CS3A patients had different dosing regimens and doses, which led to different Spinraza concentrations over time, the model still predicted an additional increase of approximately 5.0 CHOP INTEND points with a higher dose.
Finally, further analysis indicated that higher CHOP INTEND scores would be obtained at a high dose of Spinraza regardless of body weight or sex.
“A higher dose of [Spinraza] is expected to lead to higher concentrations of [the therapy] across broad SMA populations, which may in turn lead to additional clinical benefit,” the team concluded.
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