Tuesday, January 24, 2017

Nusinersen for spinal muscular atrophy 2

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.



  1. "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.

    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.

    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."


  2. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended approval for two orphan drugs given accelerated review that is designed to facilitate access to medicines meeting an unmet medical need.

    The CHMP also recommended approval of nusinersen for treatment of 5q SMA, a rare autosomal-recessive disorder characterized by progressive weakness of motor neurons that typically begins between 6 and 12 months of age.

    The product is an antisense oligonucleotide that makes the SMN2 gene produce adequate levels of full-length SMN protein, thus improving neuronal survival, the EMA said in a news release.

    "The benefits with Spinraza are its ability to allow achievement of motor milestones and improvement in muscle function which is not observed during the natural course of the disease. The most common side effects are related to its administration via lumbar puncture," the EMA said.

    Recommendation for approval was based on the CHMP's assessment of two pivotal controlled studies, ENDEAR in infantile-onset SMA and CHERISH, a trial including patients with later-onset SMA, "which both demonstrated the clinically meaningful efficacy and favorable safety profile," Biogen reported in a news release.

    The drug will be available as a 2.4-mg/mL solution for injection and should be initiated only by a physician with experience in the management of SMA, the EMA said.

    Detailed recommendations for the use of cerliponase alfa and nusinersen will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages after the European Commission grants marketing authorization.


  3. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732.

    Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.

    We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.

    In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.

    Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.