Encouraging Results in Nusinersen Trial for Infantile-Onset SMA

In a joint statemlogosent today, Biogen and Ionis Pharmaceuticals announced encouraging interim results from the late-stage ENDEAR clinical trial to test the experimental drug nusinersen in infants with type 1 spinal muscular atrophy (SMA). Based on the results, investigators have stopped the trial to allow all participants to transition into an open-label trial called SHINE, in which all infants will be treated with the drug.

Biogen plans to file for regulatory approval for nusinersen in the United States and Europe by the end of 2016. In addition, the company is working to open a global expanded access program (EAP) for eligible patients with infantile-onset SMA in the coming months.

Nusinersen is designed to modify SMA

In SMA, very little full-length SMN protein is made. Instead, most of the SMN is in the form of a short, unstable protein. Full-length SMN is needed by muscle-controlling nerve cells, known as motor neurons, in the spinal cord. Without the protein, loss of motor neurons from the spinal cord occurs, with resulting weakness and atrophy of the voluntary muscles. In the severest forms of the disease, premature death may occur due to failure of the respiratory (breathing) muscles.

Infants with type 1 SMA can’t sit or hold their heads up, and progressively lose what movement ability they have. Death typically occurs before the age of 1 year, often due to respiratory failure, unless the infant is placed on a ventilator. Other, milder forms of SMA (types 2, 3 and 4) involve difficulties with movement and are associated with normal or somewhat reduced lifespan.

Nusinersen is a disease-modifying antisense drug, one of a class of experimental therapeutic molecules designed to target genetic instructions at the RNA stage (an intermediate step between DNA and protein manufacturing stage inside cells). It is designed to increase production of the needed SMN protein.

Interim analysis from the phase 3 ENDEAR trial, conducted in 120 infants with type 1 SMA, found that the drug was safe and well-tolerated and that infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment.

Nusinersen clinical trials

Ionis and Biogen have been testing nusinersen both in blinded and open-label studies, and in patients with types 1, 2 and 3 SMA. In rare instances, as with the ENDEAR trial, when evidence of efficacy is sufficiently strong a blinded trial can be halted so all patients can benefit from treatment. Along with ENDEAR participants, patients in the control sections of a phase 2 study called EMBRACE will be able to transition to the SHINE open-label study.

Other studies of nusinersen will continue as planned. These include CHERISH, which is testing the drug in later-onset SMA, and NURTURE, for infants with a genetically-confirmed diagnosis of with SMA who are not yet showing symptoms.

The drug has been granted orphan drug status in both the U.S. and European Union and fast track designation in the United States. If approved, it would be the first disease-modifying drug approved for the treatment of SMA.

MDA has funded foundational work in SMA and invested nearly $750,000 in awards to Adrian Krainer at Cold Spring Harbor Laboratory in New York for early-stage development of nusinersen. Since its inception, MDA has invested more than $45 million in SMA research.

“Today marks an important day for the Spinal Muscular Atrophy (SMA) community in our collective pursuit of a meaningful treatment for this life-threatening disease,” said MDA Scientific Program Officer Amanda Haidet-Phillips, Ph.D. “These encouraging results are an important step, not only in making nusinersen available as quickly as possible as an approved therapy for infants with type 1 SMA, but also in allowing eligible SMA infants not currently participating in the ongoing ENDEAR clinical trial to receive nusinersen this fall.

“MDA is proud to have been part of early-stage research that helped lay the groundwork for this development that’s brought us to this meaningful moment and closer to our ultimate goal of helping all those with SMA live longer and grow stronger.”

“The latest news from the ENDEAR trial are extremely encouraging, and it’s very heartening that the infants in the trials who were getting sham injections can now be administered the actual drug,” said Adrian R. Krainer, Ph.D., MDA Grantee and St. Giles Professor of molecular genetics and Program Chair of Cancer & Molecular Biology, Cold Spring Harbor Laboratory in Cold Spring Harbor, NY. “In addition, many new patients will very soon have access to nusinersen through an expanded-access program. I remain extremely grateful to MDA for their generous support for the research in my lab at Cold Spring Harbor Laboratory; this crucial funding, from 2007-2010, made possible the preclinical development of nusinersen, in a very productive collaboration with Ionis Pharmaceuticals.”

For more information on today’s news, read the Q&A provided by Biogen and Ionis below.


On August 1, 2016 Biogen and Ionis Pharmaceuticals announced that nusinersen, our investigational treatment for Spinal Muscular Atrophy (SMA), met the primary endpoint pre-specified for the interim analysis of ENDEAR, the Phase 3 clinical trial evaluating nusinersen in infantile-onset (consistent with Type 1) SMA.

We recognize this exciting program milestone may bring certain questions to mind. Below we hope you’ll find answers to some of these questions. If you need additional information, please feel free to contact Biogen’s Patient Center at patientcenter@biogen.com.

  1. What is the ENDEAR study?

The ENDEAR study was originally designed to be a 13-month clinical trial including approximately 110 patients with infantile-onset (consistent with Type 1) SMA. The purpose of the trial was to collect well-controlled data for regulators to assess the safety and efficacy of nusinersen in this patient population. Initially, the study was designed with a primary endpoint of ventilation-free survival. As we gained more insight from our open-label studies, it became increasingly clear that measuring motor milestones could be a useful indicator of nusinersen’s potential efficacy in the ENDEAR study. As such, the primary and secondary endpoints were updated in May of 2016.

  1. Why did you conduct an interim analysis? What does this mean?

When designing the ENDEAR study, we consulted extensively with regulators, experts in field and members of the community to design a protocol that would allow us to collect the necessary well-controlled data in the shortest time possible.

We designed the ENDEAR protocol to include an option for an interim analysis prior to the formal conclusion of the trial in order to evaluate if a significant treatment effect was detectable ahead of the full data collection. The interim analysis has showed that infants taking nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment.

Because of the positive results of the interim analysis in the infantile-onset (consistent with Type 1) SMA population,  all ENDEAR and EMBRACE study participants can elect to receive nusinersen by enrolling in the extension studies.

  1. What happens next?

We will continue to collect data on all of the participants enrolled in the clinical trial through their next office visit as we work to submit our regulatory filings.   The regulatory filings will include the ENDEAR interim analysis data and all other clinical and preclinical data currently available. We anticipate we will be able to submit our marketing applications to both the FDA and the EMA in the coming months, with filings in other countries to follow.

  1. When will nusinersen be approved?

Once the filing packages are submitted, they must be accepted or validated by each regulatory agency before the review period starts. In the U.S., companies are notified of an acceptance 60 days after submission. In the EU, companies are notified that the submission has been validated approximately 30 days after submission. Once accepted or validated, the review periods start.

We are exploring expedited review options with both agencies and do not yet have a specific timeline for review and potential approval of nusinersen in either region.  Review and approval varies by country, but, in general once accepted or validated, standard review in the U.S. is 10 months and review time averages between 13-15 months in the EU.

  1. What are your plans for the CHERISH study? Will you conduct an interim analysis with this trial, too?

Based on our ongoing conversations with regulators, data from a well-controlled study in later-onset (consistent with Type 2) SMA will be needed in order for them to assess the safety and efficacy of nusinersen in this population. Once we are able to collect enough well-controlled data to have a pathway to approval in that population, and we are able to end the CHERISH sham-controlled study arm, we will be able to make a determination about how to proceed.

We are working to complete our CHERISH studies as quickly as possible and continue to explore all opportunities to shorten the timeline to review and potential approval.

  1. Are you opening an Expanded Access Program (EAP)?

Given the positive data from the interim analysis, Biogen is working to open an expanded access program (EAP) for eligible patients with infantile-onset SMA (consistent with Type 1). We hope this program will mark the initial phase in our effort to enable expanded access to nusinersen for patients with SMA.

Existing clinical trial sites, because of their experience in administering nusinersen, can participate in the EAP in countries where EAPs are permitted according to local laws and regulations, can be operationalized and there is a path that can support long-term availability of nusinersen.  Once the EAP is open and required local approvals are in place, individual participating sites may start enrollment after they have transitioned ENDEAR study participants to the open-label extension study.

  1. How can I find out if I am or my child is eligible for the EAP?

In the coming weeks, eligibility criteria and additional details on the infantile-onset (consistent with Type 1) EAP will be posted on clinicaltrials.gov. This will be the best place for you and your physician to obtain the most up-to-date information on the program.

To participate in the EAP, physicians at eligible clinical trial sites must make a formal request on behalf of the patient to Biogen or to Idis, Biogen’s partner company running the EAP program. The requesting physician is responsible for the patient’s care and all legal and regulatory requirements for medically monitoring the patient while that patient is receiving the investigational therapy.

We understand the EAP will not meet the needs of the entire SMA community. We intend to open an EAP for later-onset SMA (consistent with Type 2) in the future,  if and when we are able to collect enough well-controlled data to enable regulators to assess the safety and efficacy in nusinersen in this population and we are able to close the CHERISH sham-controlled study.

  1. Will you charge for the EAP?

Biogen will supply nusinersen free of charge for the period in which patients are being treated under the expanded access program. Any other healthcare related costs are not covered under the EAP.

  1. How will we find out more information about what’s happening next?

The interim analysis represents an important milestone for the program, but we still have work to do as we move towards our number one goal of advancing nusinersen toward approval. We are committed to open and transparent communications with the SMA community whenever possible and will continue to update the community as the program progresses.