BOSTON -- More infants with spinal muscular atrophy (SMA) hit motor milestones with nusinersen (Spinraza) than with a sham spinal injection, researchers reported here.
In the final analysis of data from the phase III ENDEAR study, significantly more patients were considered motor milestone responders compared with the control group (51% versus 0%, P<0.0001), tracking well with earlier interim data, Nancy Kuntz, MD, of Children's Hospital of Chicago, reported at the .
Nusinersen, an antisense oligonucleotide drug that acts to induce expression of a protein called SMN, lack of which is responsible for SMA, was approved by the FDA to treat SMA in December.
Drugmaker Biogen conducted the ENDEAR study in symptomatic infants with SMA; it also assessed the effects of nusinersen in asymptomatic infants in a separate trial called NURTURE, and children with SMA ages 12 and under in the CHERISH study. Results from both of those trials will also be presented at the meeting.
Kuntz noted that pre-symptomatic treatment in the NURTURE trial offered higher motor milestone achievement scores than in symptomatic infants in ENDEAR, suggesting an advantage for earlier treatment.
For this study, Kuntz and colleagues enrolled 121 patients, 80 of whom were randomized to nusinersen and 41 to a sham injection group (nusinersen is delivered intrathecally, so the sham procedure was a lumbar puncture).
To be included, patients had to have a genetic diagnosis of SMA, only two copies of the SMN2 gene, onset of SMA symptoms at age 6 months or less, and no baseline hypoxemia.
Patients were given four loading doses over 2 months, followed by a maintenance phase with dosing every 4 months. The primary endpoint was the proportion of motor milestone responders, as measured by a modified version of the Hammersmith Infant Neurological Examination (HINE).
Interim results of ENDEAR showed that 41% of nusinersen infants were motor milestone responders compared with none of the controls (P<0.0001) -- and those results were strengthened in the final analysis.
Kuntz reported that none of the infants in the control group achieved any of the milestones -- but among those on nusinersen, 22% had full head control, 10% could roll from supine to prone position, and 8% could sit independently.
Still, Kuntz cautioned that results from the NURTURE trial, which enrolled pre-symptomatic infants, had higher total milestone scores. Thus, those treated early may benefit most, she said.
"Both the rate and range of their [presymptomatic infants'] motor skills were much greater than any group, suggesting that early treatment makes a difference," she added.
The ENDEAR study also showed significantly prolonged event-free survival (death or permanent ventilation) in nusinersen-treated infants over 56 weeks (HR 0.53, P=0.0046), with a significantly larger proportion being alive with no permanent ventilation by the end of the study (61% versus 32%).
They also saw a significantly prolonged overall survival in nusinersen-treated infants (HR 0.372, P=0.0041). At 56 weeks, more patients in the nusinersen group were alive overall (84% versus 61%).
Kuntz also noted that a significantly greater proportion of nusinersen-treated patients were CHOP responders (71% versus 3%, P<0.0001) and peroneal compact muscle action potential (CMAP) amplitude responders (36% versus 5%, P=0.0004).
There were more adverse events in the untreated group, which wasn't unexpected in a cohort of such sick children, Kuntz said.
Charlotte Sumner, MD, of Johns Hopkins, who wasn't involved in the study but has consulted for Biogen in the past, said the approval of nusinersen for SMA is an "incredible milestone" that advanced through the development and approval process much more quickly than many other compounds. She said the data show the drug is efficacious and that it offers a "sustained improvement."
She acknowledged that earlier treatment seems more effective, as when comparing data from ENDEAR and NURTURE "you can see that those treated presymptomatically experienced a much greater increase in motor milestone scores."
Sumner also noted that certain body segments respond more robustly to the drug than others: "It's possible that certain motor neuron pools are more susceptible to the disease or are better targeted by the drug. As a result, it's possible that some infants may have improved limb strength, but not as much bulbar symptom improvement."
Many questions remain unanswered, she cautioned. For instance, the magnitude of benefit in older patients with longer disease duration isn't known, as all patients enrolled in trials were age 12 or under at enrollment. It's also unclear if the treatment effect will be durable, although the early data "suggest that it will because some patients have now received the drug for four years and haven't shown any loss of effect."
Whether the drug can eventually be stopped is an important question -- especially as its price tag is among the highest of any drug, at $750,000 for the first year, then $375,000 per year (at about $125,000 per dose).
Despite financial challenges, well over 100 patients have been dosed commercially, Sumner said. That figure is likely to rise, given that teams are hard at work at making neonatal SMA screening standard of care.
Disclosures
The authors disclosed extensive financial relationships with industry.
Primary Source
American Academy of Neurology Meeting
Kuntz N "Final results of the phase III ENDEAR study assessing the efficacy ans safety of nusinersen in infants with spinal muscular atrophy (SMA)" AAN Meeting 2017.