Latest results from a phase 3 trial with the new drug for spinal muscular atrophy (SMA), the most common genetic cause of childhood mortality, show that it can bring about large improvements in both motor function and survival in infants with this condition.
The drug, nusinersen (Spinraza; Ionis Pharmaceuticals/Biogen), was approved by the US Food and Drug Administration (FDA) in late December after a fast-track review and has been given a broad label for all individuals with all types of SMA. It is the first agent to be made available for the condition and is now commercially available, albeit at an extremely high price — $750,000 in the first year, when loading doses are given, reduced to half that in subsequent years.
The data from the phase 3 trials were part of the FDA application but had not been publicly presented at the time of approval. Results from one of the two phase 3 studies, ENDEAR, were presented formally for the first time last week at the British Pediatric Neurology Association Annual Conference in Cambridge, United Kingdom.
"Nusinersen really is a transformative treatment for SMA," pediatric neurologist Richard Finkel, MD, Nemours Children's Hospital, Orlando, Florida, lead investigator of the ENDEAR trial, told Medscape Medical News. "The ENDEAR results show it has major effects on both motor function and survival. These results are extremely promising, with this drug making a meaningful difference to these babies and children."
He added that even more exciting observations are coming from a study in which the drug is given very early in life to babies with the genetic defect for SMA but before symptoms have started to develop. "This raises the question as to whether giving treatment in the first few weeks of life may stop the disease developing at all."…
The disease is caused by deletions or mutations in the survival motor neuron (SMN1) gene, rendering it incapable of generating functional SMN protein. The severity of the disease depends on how many backup copies of gene are present. Those with two backup copies have the worst symptoms (usually type 1), with survival of less than a year, while those with three copies can manufacture more protein and therefore usually develop the condition later, in early childhood, and have a less severe form (type 2) and normally live longer. Some patients can have more than three backup copies of the defective gene, and they have a less severe form of the disease again (type 3) and a normal lifespan.
It is estimated that about 20,000 patients are living with SMA in the United States and about 24,000 in Europe.
Nusinersen is an antisense oligonucleotide that has been designed to bring about increased production of the SMN protein by the backup genes.
The ENDEAR trial was a double-blind, sham-controlled study in 121 patients with infantile-onset (most likely to develop type 1) SMA who were randomly assigned on a 2:1 basis to nusinersen or control.
The study was stopped in June 2016 after an interim analysis because of convincing benefit in the treated group. All babies were then switched to open-label nusinersen…
Forty-one percent of patients in the treatment group showed improvement from baseline vs 0% in the control group (P = .002).
"The response was variable, with some infants only improving by a couple of points while others had an improvement of 15 points," Dr Finkel said. "Some infants are rolling and sitting and a few are actually managing to stand, and that does not happen in type 1 SMA. And we haven't seen the maximal response yet."
The second endpoint, survival, was also highly significantly improved in the treatment group. "More than 50% of infants given the drug were living by the end of the study vs 30% in the control group," Dr Finkel reported.
A Biogen press release states that nusinersen showed a statistically significant 47% reduction in the risk for death or permanent ventilation (P < .01), with 68% of the control group having died or requiring permanent ventilation by the end of the study period compared with 39% of infants in the treatment group.
Dr Finkel cautioned, however, that "this is not a cure. These infants are still weak."
A second phase 3 study — CHERISH — has been conducted in older children with type 2 SMA. Dr Finkel explained that although this form of SMA is not as severe as type 1, these children also have many problems with pulmonary infections, scoliosis, and feeding issues. "They do normally manage to sit but generally don't walk."
This study, which had a design similar to that of ENDEAR, was also stopped after an interim analysis and has also shown an improvement in motor function with the drug, with an approximately 4-point improvement on the Expanded Hammersmith Functional Motor Scale vs a 2-point reduction in the control group…
"The most exciting of results of all have been seen in a study known as NURTURE, in which the drug has been given to babies before they develop symptoms," Dr Finkel commented. These babies are known to carry the defective gene and have usually been identified because they have had an older sibling with the condition. "In this study we are seeing even more remarkable changes than in ENDEAR, which suggests that the earlier the treatment the better."
Dr Finkel added: "So far three infants from my site have been included in this NURTURE trial — two are of the age that normal infants start to walk and they are both walking. One is thought to be type 2 and one is thought to be type 1. Infants with type 1 SMA are never able to sit up, let alone walk."…
The United States is the first country to approve nusinersen. The drug is awaiting approval in Europe, Japan, Canada, and Australia, and Biogen plans to initiate additional filings in other countries in 2017. Each country will have to address pricing and reimbursement issues separately. Expanded-access programs in some countries can help families obtain the drug before it becomes commercially available.