ARTICLE IN BRIEF
Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy for spinal muscular atrophy, researchers reported in The Lancet.
Babies treated with an antisense oligonucleotide for the treatment of spinal muscular atrophy type 1 (SMA-1) are meeting major developmental milestones such as crawling and sitting, and in some cases, are even standing and walking — improvements never seen with any other class of experimental treatments for SMA-1, according to a study published online December 6, 2016, in The Lancet.
The US Food and Drug Administration (FDA) has accepted the new drug application for nusinersen, developed by Ionis Pharmaceuticals and Biogen, and the drug has been fast-tracked for priority review. If approved, it would be the first therapy for SMA.
“This treatment holds great promise for children with spinal muscular atrophy,” said Richard S. Finkel, MD, division chief of neurology at Nemours Children's Hospital in Orlando, FL, and the lead study investigator. Interim data analysis on two subsequent phase 3 studies of nusinersen in infant and childhood onset SMA were so positive that the studies were stopped early to offer those infants in the placebo arm earlier access to the drug.
“This phase 2 open-label study demonstrated improved survival [for these babies], free of permanent dependence on ventilation support, and rather remarkable improvements in motor function. Even with optimal supportive care we can increase lifespan, but these babies usually become dependent upon feeding tubes and ventilation support. They fail to improve in their motor function, with many becoming effectively quadriplegic,” Dr. Finkel said.
“Many of these babies were rolling over and sitting, a few are standing, and two of the babies are walking. They look more like infants with less severe forms of the disease,” he added. “The entire community is quite excited at the prospect of having a drug available that improves the chance of these babies living longer and better, and having improved motor function.”
SMA is caused by homozygous deletions/mutation in the survival motor neuron 1 (SMN1) gene. Humans have a backup copy, the SMN2 gene, but in the absence of the normal SMN1 gene the babies are dependent on the SMN2 gene. But it is not identical. They differ in one critical place: a single nucleotide substitution that alters splicing and as a result usually excludes exon 7 in the mRNA. As a result, there isn't enough normal SMN protein produced.
In 2007, two teams of scientists independently discovered that they could take small segments of nucleotides and target a specific site on the SMN2 gene that modulates splicing to promote increased inclusion of exon 7 in the full-length transcript. This action in turn increases the amount of normal protein produced in motor neurons, the target in SMA. This same strategy of using antisense nucleotides to modulate splicing of the pre-mRNA is being explored for treatment of other genetic disorders.
STUDY METHODS, FINDINGS
An open-label phase 2 study tested the safety, tolerability, pharmacokinetics, and efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg) in 20 newborns with SMA. The babies were between three weeks and seven months old, and were followed closely at the four research centers involved in the trial (Nemours Children's Hospital in Orlando; Stanford University Medical Center in Palo Alto; Columbia University Medical Center in New York; and Hospital for Sick Kids in Toronto). The primary outcome measures included event-free survival and change from baseline on two motor function tests: The Hammersmith Infant Neurological Exam-Part 2 (HINE-2), which measures infant developmental motor milestones, and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), which assesses motor function in children with SMA.
Four of the 20 infants who had received at least one dose of the drug died. One was an accidental death, and the parents of two of the others removed their babies from life support. Dr. Finkel said that the deaths were related to the disease, not the drug. The high number of serious adverse events — 77 in the 16 patients who survived — were also thought to be unrelated to the drug. Two of 20 had transient side effects possibly related to the drug. The age at death or requirement for permanent ventilation were compared with natural history of the disease.
Among findings from the interim analysis, the researchers reported that infants taking the 12-mg dose showed incremental achievements of motor milestones (p<.0001), improvements in CHOP-INTEND motor function scores (p=.0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=.0103) and peroneal nerve (p<.0001), compared with their baseline measures.
The families of three babies who died agreed to donate autopsy tissue to the study investigators. The analysis showed that therapeutic concentrations of the drug were achieved in target motor neurons throughout the spinal cord and into other neurons and cell types in the brain stem and other regions. There was also increased full-length SMN2 mRNA, with inclusion of exon 7, and SMN protein concentrations in the spinal cord, said Dr. Finkel. These results were used in the design of two ongoing, sham-controlled, phase 3 clinical studies of nusinersen for SMA — ENDEAR and CHERISH.
ENDEAR is a 13-month study in 122 patients with infantile-onset SMA who developed symptoms by six months old. The study was stopped after an interim analysis showed significant benefit to those on the drug. The patients were transitioned into an open-label study (SHINE) where they all received the drug. CHERISH is a 15-month study in 126 non-ambulatory patients with later-onset SMA. Symptoms began after six months and children ranged in age from two to 12 years old.
Nusinersen is also being used in two other ongoing phase 2 studies. EMBRACE is studying a small subgroup of SMA patients who did not meet the criteria for the other studies, and NURTURE is an open-label study in pre-symptomatic infants who were given the initial dose by six weeks of age. An interim analysis of the NURTURE study has already shown that children treated for up to one year are reaching age-appropriate developmental milestones. The intrathecal treatment is given once every four months.
The FDA has had the data from several of these trials. If approved, the company will market it under the name Spinraza. Biogen's head of research and development, Michael Ehlers, MD, PhD, said that the company is now “focused on working with the agencies (US and the European Union) to hopefully bring this investigational treatment to the SMA community as quickly as possible.”
EXPERTS WEIGH IN
“This is the first truly effective drug for our profoundly weak SMA patients,” said Kathryn J. Swoboda, MD, director of the neurogenetics unit in the Center for Human Genetics Research at Massachusetts General Hospital. “Even five years ago, none of us would have predicted that these children would have such a positive response. By six months, many of them would have had swallowing and breathing problems, and now we are seeing improved motor functions and they are living longer without these supports.”
“We were concerned that the treatment would make these babies stronger but that we were not going to give them enough function,” Dr. Swoboda continued. “This is not what has happened. Now we will see how much benefit these children will continue to have.”
Dr. Swoboda said that the findings have “energized all of us. I am excited about the future for our SMA patients.”
Anne M. Connolly, MD, professor of neurology and pediatrics in the division of pediatric neurology at Washington University School of Medicine, said, “It is an exciting study.” She added, however, that it would be helpful to know if the age at treatment correlated with the outcomes, as well as how many of the children were able to maintain feeding by mouth as opposed to a feeding tube.
Hopefully, answers to these and other questions will come from the ongoing trials, she and other experts said.