Long-term results show Spinraza (nusinersen) is of unprecedented benefit to a broad range of spinal muscular atrophy (SMA) patients, said Wildon Farwell, executive director of clinical development at Biogen, which markets this approved treatment.
With clinical development that spans “presymptomatic infants, to symptomatic infants, to symptomatic children,” Spinraza has “demonstrated … a really broad efficacy in all patient groups,” Farwell said in an interview with SMA News Today at the recent annual meeting of the American Academy of Neurology (AAN).
“That’s led to rapid approvals around the world, rapid reimbursement.”
Equally important, real-world experience is in line with results seen in studies that date back to December 2011 and the dosing of a first SMA patient, both in terms of efficacy and safety.
“We believe that … it’s important to factor in the size of the program and the overall length of the program. To be able to say we know how Spinraza can impact children not just over a year or two years, but three, four more years,” Farwell said.
“It’s been a long journey, but it’s been very exciting to see where we are.”
‘Remarkable’ and long-term benefits
Data presented at AAN included findings from the open-label and ongoing SHINE Phase 3 trial (NCT02594124), assessing Spinraza’s safety and efficacy in patients who took part in prior studies.
Eighty-nine children with infantile-onset SMA, most likely to have SMA type 1, the disease’s most severe and common form, started in the Phase 3 ENDEAR study (NCT02193074) that opened in 2014 before moving to SHINE. ENDEAR had a placebo, or untreated, control group.
CHOP-INTEND scores of motor skills rose by 16.8 points after about three years in the 65 children given treatment in ENDEAR, an increase that Farwell called “remarkable.” Among the 24 who were controls and only began using Spinraza in SHINE, scores increased by 8.2 points over 1.5 years.
These motor benefits were significant in both groups, Farwell said, and “well above” the four-point increase deemed clinically meaningful.
“You’re talking about improvement in multiple domains … multiple limbs or multiple functions,” he said. “It really is a meaningful improvement.”
He underscored the importance of gains in those 24 SMA patients who “were much older … much more progressed in their disease” when starting on Spinraza.
“There was a question around whether all patients with infantile-onset really could benefit” from treatment, Farwell said. “I think the data from SHINE provides a good answer.”
A greater proportion of patients treated before age 6 months also achieved skills like sitting without support than those who started at later ages (60% to 38%), and greater increases in CHOP scores (19.4 points vs. 13.8).
Similar differences linked to earlier treatment among later-onset SMA patients — those most likely to develop type 2 or 3, and first enrolled in the CHERISH Phase 3 trial (NCT02292537) — are also a “key finding” of SHINE.
“All the [later-onset] patients that we studied we believe are demonstrating benefit,” Farwell said. “For some patients that means stability, the ability to maintain the function that you have; for most of the patients that means gaining functions.”
Motor improvements in these children, enrolled at ages 2 to 12, were assessed by the Hammersmith Functional Motor Scale and upper limb measures, because of the importance of upper limb strength to daily life in people with more advanced SMA.
‘Time is motor neuron’
NURTURE, a Phase 2 study (NCT02386553), treated pre-symptomatic newborns diagnosed at less than 6 weeks of age. All 25 babies were given Spinraza intrathecally (via the spinal canal) every four months, as were treated patients in other studies.
All were able to swallow, sit without support, and none required permanent ventilation as of May 2018, the cut-off date for data collected and presented at AAN.
“We have been saying from the very beginning that time is motor neuron,” Farwell said. “The importance of treating as soon after a diagnosis is possible is reflected by the data we see in NURTURE.”
Because Spinraza works to increase the ability of the SMN2 gene to produce a full-length and functional survival motor neuron (SMN) protein, essential for the health of motor nerve cells, greater motor milestones are being seen those with three SMN2 copies compared to those with two.
“We are seeing patients with two copies sitting, we’re seeing them standing, we’re seeing them walking. That’s never seen in the absence of treatment,” Farwell said. “Patients with three copies … [are] walking in timelines consistent with normal development.
“These are findings that are just not seen outside of NURTURE. There are really no parallels for it.”
A search for an SMA biomarker
Biogen also presented results on a potential SMA biomarker called phosphorylated neurofilament heavy subunit (pNF-H) at AAN. pNF-H is a key component of motor nerve cells, cells damaged or lost in SMA, and its levels were studied in plasma.
“The data from neurofilament is quite encouraging, [suggesting] that it may be a biomarker for SMA,” Farwell said, and as such a tool may help in both treatment development and patient care.
“What we see is that, even in a presymptomatic period, patients with SMA have markedly elevated neurofilament compared” to healthy controls.
What’s more, SMA patients given Spinraza — in the NURTURE, ENDEAR and CHERISH trials — had a rapid decline in pNF-H “more close to non-SMA control levels,” which stabilized with further treatment.
Farwell doubted that plasma levels might one day more easily diagnose SMA. But, if confirmed with further study, pNF-H might help in gaining a better understanding of SMA, tracking disease activity, and predicting a person’s likely future motor function. “I think it’s a very promising potential biomarker,” he said.
“Biomarkers are very common in chronic diseases,” Farwell added. “Hopefully, one day we’ll be able to have a tool like that for SMA.”