New high-dose Spinraza regimen may offer added benefits in SMA
SMA expert says patients on original dose may consider switching
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- A new high-dose Spinraza regimen is approved for SMA, with safety findings broadly consistent with the original 12 mg regimen.
- An SMA expert says patients already taking Spinraza may discuss switching to the high-dose regimen with their doctors.
- Clinical trial data suggest the high-dose regimen may offer greater motor benefits and fewer loading doses for infants starting treatment.
A new high-dose regimen of Spinraza (nusinersen) was recently approved in the U.S. as a treatment for spinal muscular atrophy (SMA), with clinical trial data showing a safety profile broadly consistent with the original 12 mg regimen, first approved a decade ago, and suggesting the potential for greater motor benefits.
Richard Finkel, MD, director of the Center for Experimental Neurotherapeutics (CENT) at St. Jude Children’s Research Hospital, told SMA News Today that he sees a strong case for patients already taking Spinraza to consider the new high-dose regimen.
“Because the safety profile of high dose SPINRAZA is similar to that of the 12 mg regimen, I don’t see the rationale for keeping patients on the 12 mg regimen if there’s potential to achieve more with the higher dose,” Finkel said. He stressed that treatment decisions need to be made in consultation between individual patients and their doctors, but said he plans to move his patients on Spinraza to the new high-dose regimen.
High-dose regimen may help optimize Spinraza treatment
Spinraza, which is sold by Biogen, was the first treatment ever proven to slow the progression of SMA. It was approved in the U.S. in 2016 and has since been approved in many other countries.
The therapy is given intrathecally, or by injection into the spinal canal. Under the original approval, each injection delivers 12 mg. In the original schedule, patients first receive a series of four loading injections over the course of about two months, after which injections are given every four months.
For patients starting Spinraza, the new high-dose regimen involves two loading doses of 50 mg given two weeks apart, followed by injections of 28 mg every four months. Patients already receiving Spinraza can switch with a single 50 mg dose at least four months after their last 12 mg maintenance dose, then receive 28 mg maintenance doses every four months. The high-dose regimen was approved in the U.S. in March and has also been approved in the European Union, Switzerland, and Japan.
SMA is marked by abnormally low levels of SMN, a protein that’s vital for the survival of motor neurons, the nerve cells that control movement. Spinraza is designed to increase levels of SMN protein by modifying the activity of a backup gene called SMN2, thereby improving motor neuron survival. Based on how the therapy works, it’s reasonable to think that a higher dose might provide more benefit for patients, Finkel said. He noted that the original trials of Spinraza were not designed to optimize the therapy’s dose.
“I’ve seen firsthand how transformative the first generation of SMA treatments has been, but an important question remains: how to optimize the dose and dosing regimen to get this drug to as many motor neurons as possible and as quickly as possible. While we don’t yet have a definitive answer, the availability of high dose SPINRAZA represents a meaningful step in this direction,” Finkel said.
DEVOTE trial supported high-dose Spinraza approvals
Approvals of the high-dose Spinraza regimen were based in part on data from DEVOTE (NCT04089566), a clinical trial that tested the high-dose regimen in previously untreated children with SMA. Safety findings were broadly consistent with the known profile of the 12 mg Spinraza regimen.
“We were encouraged to see a similar safety profile to the 12 mg regimen, which was a key focus in the DEVOTE study,” said Finkel, who served as an investigator in the study. “You don’t want to sacrifice safety for better benefit – ultimately, you need both.”
In previously untreated infants with SMA who were given high-dose Spinraza, scores on a standard motor function measure, the CHOP-INTEND, improved by an average of 15.1 points after six months. By comparison, babies with SMA given a sham procedure, or placebo, in an earlier study saw an 11.1-point worsening of CHOP-INTEND scores in the same timeframe.
“A 4-point increase in this 64-point scale has been demonstrated to reflect a clinically meaningful response. Achieving a 15.1-point improvement on CHOP-INTEND, therefore, is significant, both statistically and clinically, as it indicates many patients saw substantial improvements,” Finkel said.
“It also appears that patients were still improving at the end of the 10-month follow-up period, which makes it encouraging to consider how much further benefit might be seen over a longer timeframe,” he added. Finkel also noted that the high-dose regimen may be more convenient for infants starting treatment, since it requires fewer loading doses that usually need to be given under sedation.
Motor function was stable or improved after switching
DEVOTE and a follow-up study called ONWARD (NCT04729907) also tested the impact of switching from the 12 mg Spinraza regimen to the high-dose regimen. Safety findings were broadly consistent with Spinraza’s known profile, and patients showed stable or improved motor function after making the switch.
“Based on what we know about a typical experience using 12 mg SPINRAZA, seeing patients improve this much after being on SMA therapy for this long was a pleasant surprise,” Finkel said. “Based on feedback from both my patients and fellow investigators, the higher dose may provide a more sustained response between doses.”
Finkel said the findings with high-dose Spinraza highlight the importance of continued research and innovation to improve care for people with SMA.
“The science indicates we haven’t reached the ceiling yet – there’s still meaningful opportunity to build upon what we’ve achieved so far in treating SMA. I’m encouraged by the progress we’re seeing in optimizing Spinraza dosing and in the development of next-generation SMA therapies,” he said. “It’s important that we continue to push boundaries, exploring what’s possible and how we can do even more for people living with SMA.”
