New Drug 'Transforming' Outlook in Spinal Muscular Atrophy

January 17, 2017

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."

SMA affects approximately 1 in every 11,000 births. It is a progressive motor neuron disorder, causing muscle weakness and difficulties breathing and eating. About 60% of patients with SMA are born with the severe form — infantile-onset type 1 — developing profound limb and trunk weakness before 6 months of age and failing to roll over or achieve independent sitting. Less than a quarter of these infants survive beyond 2 years of age without dependence on ventilation support.

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.

The primary endpoint was improvement in motor function, as measured on the Hammersmith Infant Neurological Examination part 2 score. Dr Finkel explained that this includes eight items of motor function in infants: hand grasp, kicking of legs, rolling over, sitting, crawling, standing, walking, and head control. He added that the study excluded head control from the score because this has developmental aspects and is not just a measure of strength, but deficits in the other items are characteristic of SMA type 1. To be classified as having improvement in motor function in the study, the infants had to show more items improving than declining from baseline.

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. These data have not yet been presented but were also part of the FDA approval application.

"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."

A Question of Reimbursement

So with all these exciting results, and nusinersen now commercially available in the United States, how can families access the drug? And will its extremely high price limit its use?

Dr Finkel said it is too early to know for sure, but he is hopeful that all patients with SMA will be able to get the drug. "The FDA approved it for all types of SMA. Because it has such a broad indication, it will be difficult for insurance companies not to pay for it. In my state — Florida — Medicaid has just approved it.

"Yes, it is very expensive, but there is an argument that it will result in fewer hospitalizations," he added. "These infants have multiple stays in intensive care for pulmonary infections and these are very costly."

Kenneth Hobby, president of Cure SMA, a nonprofit SMA patient advocacy organization, is also optimistic about funding for nusinersen. "The data from clinical trials are really very good. The FDA has made very supportive comments about the data — we believe this will support the case for payment by insurance companies."

Hobby pointed out that under the Affordable Care Act, insurance companies have to take on patients with existing conditions, although he admitted there is some uncertainty whether this will continue with the new presidential administration.

He noted that Biogen also has a program to help families sort out insurance and help with copays and other issues. "I don't think cost will be a major issue for families," he added. "I don't think anyone will have to go into massive debt in order to get this drug for their child."

But not everyone is so upbeat. Geoffrey Porges, a biotech analyst with Leerink, said nusinersen could be "the straw that breaks the camel's back in terms of the US market's tolerance for rare disease drug pricing." He believes the high cost of the drug is likely to renew questions from patients, insurers, and the government about how drug companies set prices.

"At the very least the price is going to force payers to closely scrutinize which patients receive access and limit the overall access provided," Porges writes. "To us, it seems certain that patients who have the less severe forms of the disease or who are older with relatively milder symptoms will find it difficult to obtain treatment."

A Biogen spokesperson told Medscape Medical News that the price of the drug "was determined through a rigorous and thoughtful process that evaluated a range of information and strived to achieve an appropriate balance among three key pricing principles — clinical value, impact to the healthcare system, and commitment to patients and advancing science through the funding of research and development."

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.

Delivering the New Drug

Hobby pointed out that other issues need to be addressed, including awareness and delivery of the nusinersen.

"We are trying to make sure families with children with this condition are aware that there is now a drug available that could make a big difference, and also help guide them through the steps needed to be taken to get the drug," he said.

"We are also trying to raise awareness of this new drug among the medical community. The development of this drug has happened very fast. The approval came sooner than expected — probably because the data was so good. It is important for infants to get the diagnosis as soon as possible so the treatment can be started as soon as possible."

He also noted that administering nusinersen is not straightforward, and this may limit accessibility to start with. The drug is given by intrathecal injection, with an initial loading dose regimen of 4 doses over the first 2 months, then a maintenance phase of 1 dose every 4 months.

"Giving an intrathecal injection — often to very young babies — takes specialist training. And the injection may require sedation in some cases and/or an overnight stay. At present there are only about 30 or 40 centers in the US able to give the drug. We need several hundred to cope with the demand. We need to get more pediatric neurologists trained up to administer the drug. This will happen but it make take some time."

He added: "It is thought this drug will be most beneficial the earlier it is given, so families are desperate to get it. We are trying to help the process happen — help guide families through the steps they need to take to get a definitive diagnosis and get a physician to prescribe the drug. This will then trigger insurance payments and support from Biogen and then to find a hospital to administer the drug."

Genetic Test for All Newborns?

Hobby noted other exciting events on the horizon. "Because of the spectacular results being seen in presymptomatic babies with nusinersen, we would like to see the SMA genetic test conducted in all newborns as part of the heel prick test. We will be applying for this to happen soon."

Many other drugs for SMA are in development: 6 in clinical trials and 12 in preclinical development. Some of these agents act in a similar way to nusinersen — on the backup gene — but others are gene therapy aiming to replace the missing gene itself. Some of these are orally available so will be much easier to give.

Hobby explained that because SMA is caused by a single gene mutation and backup genes can make the depleted protein, it has been an attractive target for pharmaceutical companies.

"There was an obvious strategy to develop effective therapies, and it has been successful," he said. "The availability of nusinersen is a scientific success story, but we are hopeful that it is only the first step in eradicating this disease."

Kenneth Hobby has no personal relationships with Ionis or Biogen, but Cure SMA does receive sponsorships from both companies and from all others developing potential treatments for SMA. Dr Finkel reports grants and personal fees from Ionis Pharmaceuticals and Biogen and also from Roche outside the submitted work. He also serves in an advisory capacity to the nonprofit organizations, such as the SMA Foundation, Cure SMA, SMA Reach (UK), and SMA Europe, and serves on the data safety monitoring board for the AveXis gene transfer study.

British Pediatric Neurology Association 2017 Annual Conference. Presented January 13, 2017.

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