Type of information: Granting of a Market Authorisation in the EU
Product name: Spinraza™
Compound: nusinersen - antisense oligonucleotide targeted to the SMN2 gene
Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases
Action mechanism: antisense oligonucleotide. The SMN protein is made by two genes, the SMN1 and SMN2 genes. Most patients with spinal muscular atrophy lack the SMN1 gene but have the SMN2 gene, which mostly produces a ‘short’ SMN protein which cannot work properly on its own. Nusinersen (ISIS-SMNRx ) is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein. It is expected to make the SMN2 gene produce adequate levels of the SMN protein of normal length, thereby increasing the survival of motor neurons.
Spinraza™ was discovered and developed by Ionis and Biogen. Biogen exercised its option to worldwide rights to nusinersen in August 2016. Biogen is responsible for future development, manufacturing, and commercialization of Spinraza™ .Under the terms of the January 2012 agreement, Ionis is responsible for global development and Biogen Idec has the option to license the compound until completion of the first successful Phase 2/3 study or the completion of two Phase 2/3 studies. Both the U.S. and EU have granted nusinersen Orphan Drug status. Additionally, both the U.S. and EU regulatory agencies have granted special status to nusinersen, including Fast Track Designation and Priority Review in the U.S. and Accelerated Assessment in the EU.
Company: Biogen (USA - MA) Ionis Pharmaceuticals (USA - CA)
Disease: spinal muscular atrophy (SMA)
- • On May 30, 2017, the European Commission has granted a marketing authorisation for Spinraza® to treat patients with spinal muscular atrophy .
- • On April 21, 2017, the European Medicines Agency (EMA) has recommended granting a marketing authorisation in the European Union for Spinraza® to treat patients with spinal muscular atrophy. Spinraza® is to be given by lumbar puncture injection into the fluid surrounding the spinal cord once every four months.There is currently no approved therapy in the EU for the treatment of spinal muscular atrophy. Patients receive supportive treatment to help them and their families cope with the symptoms of the disease. This includes chest physiotherapy and physical aids to support muscular function, and mechanical ventilators to help with breathing. There is therefore a significant unmet medical need for these patients. The recommendation from the CHMP is based on the results of one completed clinical trial and a number of ongoing trials in patients with spinal muscular atrophy with different stages of disease severity. These included patients with infantile-onset, as well as later childhood-onset of the disease, as well as patients in the pre-symptomatic phase.
- The clinical trial providing the main body of data for the assessment was conducted in 121 patients with infantile-onset who were randomised to receive an injection of Spinraza into the fluid surrounding the spinal cord, or undergo a mock procedure without an injection (a skin prick). The trial assessed the percentage of patients who had a pre-defined level of improvement (responders) in their motor milestones such as head control, rolling, sitting, crawling, standing and walking.
- Fifty one per cent of patients met the criteria as responders to treatment with Spinraza, compared to none receiving the mock injection (controls). Sixteen patients (22%) achieved full head control, six patients (8%) achieved independent sitting, and one patient (1%) achieved standing with support, whereas no subjects in the control group achieved any of these milestones. In the same trial, the risk of death or permanent ventilation was 47% less in patients treated with Spinraza. Unfortunately, 49% of the patients treated with Spinraza in the trial were not considered to be motor milestone responders.
- These effects are considered to be of considerable clinical importance as patients with infantile-onset spinal muscular atrophy typically fail to achieve independent sitting, do not see any improvement in their motor skills beyond those present at the time of diagnosis, and usually die within the first two years without intensive supportive care, as a result of progressive muscle weakness.
- Additional data were obtained from a separate, ongoing clinical trial conducted in 126 patients with later childhood-onset spinal muscular atrophy who were randomised to receive Spinraza or undergo a mock procedure without an injection. The trial compared the motor skills of the patients assessed at 15 months after treatment with those assessed when they entered the trial, using the Hammersmith Functional Motor Scale – Expanded (HFMSE). The group of patients treated with Spinraza improved by four points on the scale at 15 months, while controls declined by 1.9 points. This is an important outcome in patients who typically experience a gradual decline in their motor ability over time.
- The results obtained in these two randomised, double-blind, sham controlled clinical trials were supported by results from clinical trials with no comparators. In one of these trials, infants genetically diagnosed with the disease, but who did not yet have symptoms, received injections of Spinraza and seemed to achieve motor milestones comparable to normal development.
- Because patients treated with Spinraza have not yet been followed for a long period of time, it is not yet known whether the effects of Spinraza will be maintained in the longer term, or whether Spinraza may be able to provide a cure in some of the SMA patients. More information on these aspects will become available with time.
- Data are very limited in the milder forms of SMA associated with later age of onset and less severe outcomes. Nevertheless an effect of Spinraza can be assumed in these patients because it works in the same way as in more severely affected patients. Data will be collected post approval to confirm that this is the case.
- The most common side effects found in participants in the clinical trials for Spinraza were upper respiratory infection, lower respiratory infection and constipation. Spinraza must be administered by healthcare professionals experienced in doing lumbar punctures.
- • On December 23, 2016, Ionis Pharmaceuticals announced that the FDA has approved Spinraza™ (nusinersen) under Priority Review for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. Spinraza™ is the first and only treatment approved in the U.S. for SMA, a leading genetic cause of death in infants and toddlers that is marked by progressive, debilitating muscle weakness. The FDA approval of Spinraza™ was based on positive results from multiple clinical studies in more than 170 patients. Ionis and Biogen conducted an innovative clinical development program that moved Spinraza™ from its first dose in humans in 2011 to its first regulatory approval in five years. The data package included the interim analysis of ENDEAR, a Phase 3 controlled study evaluating Spinraza™ in patients with infantile-onset SMA, as well as open-label data in pre-symptomatic and symptomatic patients with SMA, or likely to develop, Types 1, 2 and 3 SMA.
- In conjunction with approval in the U.S., Ionis earned a $60 million milestone payment from Biogen and is eligible to receive $90 million in additional milestone payments based on regulatory approvals in Europe and Japan. Ionis is also eligible to receive tiered royalties on sales of Spinraza™ up to a percentage in the mid-teens. To date, Ionis has earned nearly $320 million from Biogen related to Spinraza™.
- Biogen plans to make Spinraza™ available for shipment in the U.S. to healthcare providers in approximately one week. Biogen anticipates there may be variation in time to treatment as institutions and treatment centers learn about Spinraza™. Biogen also plans to present results from the interim analysis of the Phase 3 ENDEAR study at the British Pediatric Neurology Association conference being held in Cambridge, UK January 11-13, 2017.
- Spinraza™(nusinersen) is under regulatory review with the European Medicines Agency (EMA), which has validated Biogen's Marketing Authorization Application (MAA) and granted Accelerated Assessment status. Biogen has also submitted regulatory filings in Japan, Canada and Australia and is initiating regulatory filings in additional countries in 2017
- • On October 28, 2016, Biogen announced that its New Drug Application (NDA) for nusinersen, an investigational treatment for spinal muscular atrophy, has been accepted by the FDA for Priority Review, and that the company’s Marketing Authorization Application (MAA) has been validated by the European Medicines Agency (EMA). Nusinersen had previously been granted Accelerated Assessment status by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The regulatory review process for these applications has now been initiated in the U.S. and EU. Biogen intends to market nusinersen under the brand name Spinraza™. This name has been conditionally accepted by the FDA and the CHMP and will be confirmed upon approval. Biogen is initiating regulatory filings in other countries in the coming months.
- • On September 26, 2016, Biogen and Ionis announced that Biogen has completed the rolling submission of a New Drug Application (NDA) to the FDA for the approval of nusinersen, an investigational treatment for spinal muscular atrophy (SMA). Biogen has also applied for Priority Review which, if granted, would shorten the review period of nusinersen following the Agency’s acceptance of the NDA. In addition to the NDA filing with FDA, Biogen plans to submit a Marketing Authorization Application (MAA) for nusinersen to the European Medicines Agency (EMA) in the coming weeks. The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently granted Accelerated Assessment to nusinersen, which can reduce the standard review time. Biogen will initiate regulatory filings in other countries in the coming months. The regulatory submissions are comprised of results from the pre-specified interim analysis of ENDEAR, the controlled Phase 3 study evaluating nusinersen in infantile-onset (most likely to develop Type 1) SMA, as well as all other clinical and preclinical data currently available, which includes open-label data in other patients types. The ENDEAR interim analysis demonstrated that infants receiving nusinersen experienced a statistically significant improvement in the achievement of motor milestones compared to those who did not receive treatment. Biogen anticipates hearing from regulatory authorities regarding the acceptance and validation of these submissions within the next couple of months.
- The nusinersen clinical trial program is comprised of two controlled studies, ENDEAR and CHERISH. ENDEAR was designed as a thirteen-month study investigating nusinersen in 122 patients with infantile-onset SMA; the onset of signs and symptoms of SMA less than or equal to 6 months of age and age less than or equal to 7 months at screening. Based on the results of the pre-specified interim analysis, the ENDEAR study will be stopped; patients who elect to are currently being transitioned to the SHINE open-label study where they will all receive nusinersen. Results from the ENDEAR interim analysis will be presented at future medical congresses. CHERISH is a fifteen-month study investigating nusinersen in 126 non-ambulatory patients with later-onset SMA, consistent with Type 2; onset of signs and symptoms greater than 6 months and age 2 to 12 years at screening. CHERISH was fully enrolled in May 2016 and remains ongoing. Additionally, the SHINE open-label extension study, for patients who previously participated in ENDEAR and CHERISH, is open and is intended to evaluate the long-term safety and tolerability of nusinersen.
- Two additional Phase 2 studies, EMBRACE and NURTURE, were designed to collect additional data on nusinersen. The EMBRACE study is designed to collect additional data on a small subset of patients with infantile or later-onset SMA who do not meet the age and other criteria of ENDEAR or CHERISH. Due to the evidence demonstrated in the infantile-onset SMA (most likely to develop Type 1) population, the sham arm of the EMBRACE study is being stopped and patients are being given the option to receive nusinersen through an open-label extension study. NURTURE is an open-label, ongoing study in pre-symptomatic infants who are less than or equal to 6 weeks of age at time of first dose to determine if treatment before symptoms begin would prevent or delay onset of SMA symptoms.
Submission of marketing authorization application USA : 2016-09-26
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2016-12-23
UE authorization: 2017-05-30
Favourable opinion UE: 2017-04-21
Favourable opinion USA:
Orphan status USA: 2011-04-18
Orphan status UE: 2012-04-02
Pediatric exclusivit _USA:
Pediatric exclusivity UE: