Infants with spinal muscular atrophy (SMA) continue to show better motor control and strength the longer they receive Spinraza (nusinersen), concludes a new and long-term analysis of final data from a Phase 3 clinical trial in babies with type 1 disease.
These infants are also less likely to be hospitalized for respiratory issues, a separate analysis indicates.
The end-of-trial findings were presented at the first International Scientific Congress on Spinal Muscular Atrophy, held Jan. 25-27 in Krakow, Poland.
Richard Finkel, a pediatric neurologist and lead researcher in many Spinraza studies, presented a third analysis. Finkel reported data from ENDEAR (NCT02193074) alongside results from the Phase 2 NURTURE (NCT02386553) trial, which studied Spinraza in asymptomatic newborns with genetic markers for SMA, and the CHERISH (NCT02292537) trial, which studied the therapy in children with late-onset SMA.
Together, these long-term studies add to the body of evidence showing Spinraza’s overall benefit for patients. This is the view of Wildon Farwell, Biogen‘s senior medical director of clinical development, who spoke with SMA News Today. Findings continue to demonstrate that earlier and prolonged treatment leads to the best clinical outcomes, he said.
Spinraza, marketed by Biogen, became the first treatment approved by the U.S. Food and Drug Administration for SMA patients in December 2016; the therapy received similar approval in Europe soon after for all types of this disease.
Spinraza’s Continued Efficacy
End-of-study ENDEAR data, given in an oral presentation Jan. 27 at the Krakow conference, showed that longer treatment with Spinraza makes patients more likely to reach motor milestones.
In agreement with data released previously, the analysis found that 51 percent of Spinraza-treated infants in the study were responders on the Hammersmith Infant Neurological Examination Section-2 (HINE-2), which measures motor milestones, after six months of treatment (183 days), compared to 9 percent of babies on placebo.
But the Krakow presentation also included greater numbers of treated infants who returned for follow-up at 302 days, finding that 61 percent were now responders — compared to zero percent of infants on a sham treatment. At 394 days, or 13 months, 77 percent of infants on Spinraza were HINE-2 responders while, again, none on placebo responded.
HINE-2 responders are defined as those showing improvements in kicking ability, head control, rolling, sitting, crawling, standing or walking.
The response rate to the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and another motor milestone marker, similarly increased over time.
This data builds on results published in the New England Journal of Medicine in November 2017. That study, “Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy,” reported the motor milestones reached both at the interim period of the trial and at the last visits made by patients. A group of the study infants in that analysis, however, had not yet reached six-month or later timepoints, Farwell said.
A slightly different subset of study patients are also in this new data:the analysis doesn’t include those who died or withdrew early. By narrowing patients included in this way, Farwell said, researchers can answer a slightly different question.
“You’re asking the clinical question, my patient has now been on treatment for six, or 10, or 13 months, and they’re in front of me, so what’s the likelihood of them being a responder,” he said. That is in contrast to intent-to-treat analysis, done for the November study, which looks at all patients in a study to distinguish likely responders at the treatment’s start.
Answers to the clinical question posed clearly shows that most patients alive and continuing to receive treatment throughout the study’s 13 months were motor milestone responders, Farwell said.
“These are large numbers, larger than what we’ve previously reported in the intention to treat analysis,” he said. “This is a broad benefit … clearly beyond what’s expected in the natural history” of SMA progression.
An Overall Measure of Health
Infants treated with Spinraza were also less likely to be hospitalized, and those who were spent a shorter amount of time there than those given a sham treatment during the course of the ENDEAR trial, data in a Friday presentation showed.
Hospitalization is a marker of overall health, Farwell said. “We wanted to look at the number of hospitalizations to see if [Spinraza] could have a broader impact on patients than just on motor function and survival alone.”
The adjusted annualized hospitalization rate (AAHR), which accounts for age and disease duration, among the 73 treated infants in this analysis was 4.378 hospitalizations per year. The 41 non-treated infants had an AAHR of 5.817 hospitalizations per year.
A range of reasons were behind these hospitalizations. But Farwell noted that patients receiving Spinraza had fewer hospitalizations for respiratory issues than did those on sham therapy. “For some of the specific areas of concern in the population, like respiratory infection, the trend for those is to have less,” he said.
Infants on Spinraza also spent less time hospitalized compared to sham group infants, again for multiple possible reasons. “It could suggest that the reason for hospitalization wasn’t as severe, and that the patient was able to respond to interventions more quickly,” he said, and it could also indicate that the patient was stronger upon arrival at a hospital.
Treating Early Counts
Finkel’s presentation, also on Jan. 27, compared ENDEAR data to findings from CHERISH and NURTURE, and again confirmed that beginning Spinraza therapy earlier leads to better outcomes.
After a year of treatment, the initially asymptomatic babies receiving Spinraza in NURTURE had a higher average response on the HINE scale than those given Spinraza in the ENDEAR trial, who were symptomatic when treatment began.
In ENDEAR, treated infants with a disease duration of less than 12 weeks had greater improvement on the Hammersmith Functional Motor Scale (HFMS) than those with a duration longer than 12 weeks.
In CHERISH, which enrolled children 2 to 12 years old, those treated within 25 months of disease onset showed greater improvement on the HFMS scale than those treated between 25 and 44 months of disease onset, or after 44 months. Children younger than age 6 when starting treatment also improved more than those who were 6 or older.
Based on this data, Farwell said, it appears that disease progression is a more critical reference than age when predicting treatment response. That is, intervening quickly after symptoms begin — or before they begin — is more likely to lead to greater improvement.
“It’s expected patients will lose motor function over time,” he said. “What we saw is that in the younger patients with shorter disease duration, there was more improvement after early initiation of treatment. In older patients with longer disease progression, we see stabilization.”
Researchers are continuing to follow children from the ENDEAR, CHERISH and NURTURE trials who went on to enroll in SHINE (NCT02594124), an open-label extension study. Findings from that study, which includes over 200 patients, should be released later this year.
“Our focus now is continuing to demonstrate the long-term safety and efficacy within SHINE,” Farwell said. “We’re continuing to think about what else can we do to improve upon what we’ve been able to demonstrate so far.”