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Ionis Pharmaceuticals, Inc.

Partner : Biogen Idec, Inc.

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Biogen’s Regulatory Applications for Nusinersen as a Treatment for Spinal Muscular Atrophy Accepted by FDA and EMA
Nusinersen Granted Priority Review by FDA

EMA Plans to Follow Accelerated Assessment Timeline

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Oct. 28, 2016-- Biogen (NASDAQ: BIIB) today announced that its New Drug Application (NDA) for nusinersen, an investigational treatment for spinal muscular atrophy (SMA), has been accepted by the U.S. Food and Drug Administration (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. Both the Priority Review and Accelerated Assessment designations can reduce the standard review time. If approved, nusinersen would be the first therapy for SMA, a leading genetic cause of infant mortality.

Biogen intends to market nusinersen under the brand name SPINRAZATM. This name has been conditionally accepted by the FDA and the CHMP and will be confirmed upon approval.

"The FDA and EMA have acknowledged the potential for nusinersen to address the urgent need for an effective SMA treatment by granting special status to the applications, and FDA has shared that they plan to act early on our NDA under an expedited review," said Michael Ehlers, M.D., Ph.D., executive vice president, head of Research and Development at Biogen. "We are now focused on working with the agencies to hopefully bring this investigational treatment to the SMA community as quickly as possible."

The regulatory filing packages in the U.S. and EU are based on data that demonstrate the clinically meaningful efficacy and favorable safety profile of nusinersen from multiple studies. These include the results from the interim analysis of ENDEAR, the Phase 3 study evaluating nusinersen in infantile-onset (most likely to develop Type 1) SMA, as well as open-label data in other patient populations. 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 nusinersen. Data from the other endpoints analyzed were also consistently in favor of the treated infants. Nusinersen was generally well-tolerated, with a favorable safety profile. No adverse events (AEs) were considered related to nusinersen.

Biogen is initiating regulatory filings in other countries in the coming months.

The Nusinersen Clinical Trial Program
The nusinersen Phase 3 program is comprised of two registrational studies, ENDEAR and CHERISH. ENDEAR is a thirteen-month study investigating nusinersen in 122 patients with infantile-onset SMA, including patients with the onset of signs and symptoms of SMA at up to six months of age. The endpoint pre-specified for the interim analysis of the study evaluated the proportion of motor milestone responders from the motor component of the Hammersmith Infant Neurological Examination (HINE). Given the results of the interim analysis, the ENDEAR study is being stopped and participants are able to transition into the SHINE open-label study, in which all patients will receive nusinersen.

CHERISH is a fifteen-month study investigating nusinersen in 126 non-ambulatory patients with later-onset SMA, including patients with the onset of signs and symptoms at greater than 6 months and an age of 2 to 12 years at screening. CHERISH was fully enrolled in March 2016.

Additionally, the SHINE open-label extension study for patients who previously participated in ENDEAR or 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. EMBRACE is studying a small subset of patients with infantile or later-onset SMA who do not meet the age and other criteria of ENDEAR or CHERISH. NURTURE is an open-label, ongoing study in pre-symptomatic infants who are up to six weeks of age at time of first dose to determine if treatment before symptoms begin would prevent or delay the onset of SMA symptoms. An interim analysis of NURTURE showed that infants treated for up to one year with nusinersen achieved motor milestones in timelines more consistent with normal development than what is observed in the natural history of patients with Type 1 SMA. Three infants experienced adverse events considered possibly related to nusinersen, all of which resolved. In addition, no infants have discontinued or withdrawn from the study and no new safety concerns have been identified. NURTURE is currently active and enrolling. All studies are being conducted on a global scale.
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Source: press release, 10/28/16. http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2...

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Biogen Completes Rolling Submission of New Drug Application to FDA for Nusinersen as a Treatment for Spinal Muscular Atrophy
Submission of Marketing Authorization Application to the European Medicines Agency Planned in the Coming Weeks

CAMBRIDGE, Mass. & CARLSBAD, Calif.--(BUSINESS WIRE)--Biogen (NASDAQ: BIIB) and Ionis (NASDAQ:IONS) today announced that Biogen has completed the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (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.

“Since announcing the positive results of the ENDEAR interim analysis in infantile-onset SMA last month, we have heard from many families expressing their excitement about nusinersen. Their stories continue to inspire us and they are in the forefront of our minds as we work to support the FDA’s review of nusinersen,” noted Alfred Sandrock, M.D., Ph.D., executive vice president and chief medical officer at Biogen. “We appreciate the FDA’s collaboration with us during the application process, and we look forward to continuing this productive dialogue, with the goal of rapidly bringing the first treatment for SMA to as many patients as possible.”

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.

“Our ability to advance the nusinersen program as quickly as we have is largely due to the tremendous contributions of the entire SMA community, from the patients and families who participated in the clinical trials to the doctors, nurses and advocates who work tirelessly on their behalf,” said B. Lynne Parshall, chief operating officer at Ionis Pharmaceuticals. “We are deeply appreciative of their unwavering commitment to finding a treatment for SMA and today’s milestone is truly a collective achievement.”

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

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.
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Source: press release, 9/26/16. http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Nusinersen (IONIS-SMNRx)NeurologySpinal Muscular Atrophyantisense drugSMN-2 gene

Mechanism of action: Nusinersen (IONIS-SMNRx) is an antisense drug designed to treat spinal muscular atrophy. SMA occurs from a genetic deletion of the survival motor neuron 1 (SMN-1) gene. SMN-1 produces most of the SMN protein necessary for normal motor function. The severity of SMA is determined by the amount of SMN protein in the cell. Humans also have one or more copies of a related gene, SMN-2, which produces a small fraction of SMN protein due to inefficient RNA splicing. ISIS-SMNRx increases the production of SMN protein by modulating the splicing of SMN-2, thereby compensating for the underlying genetic defect.

Phase of Development: Filed

Event Type: Regulatory FDA: PDUFA DATE

Dates: 2017-04-28

Results:

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SPINRAZA™ (nusinersen) Approved in U.S. to Treat Broad Range of Patients with Spinal Muscular Atrophy
- First Treatment Approved for SMA -
- SPINRAZA Improved Motor Function in Patients with SMA; Greater Percentage of Infantile-Onset Patients on SPINRAZA Survived -
- FDA Approval Received Within 3 Months of Regulatory Filing -
CARLSBAD, Calif., Dec. 23, 2016 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) announced today that the U.S. Food and Drug Administration (FDA) has approved SPINRAZATM (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. SPINRAZA was discovered and developed by Ionis and Biogen, and licensed to Biogen who is responsible for future development, manufacturing, and commercialization of SPINRAZA.

In ENDEAR, a pivotal controlled clinical study, infantile-onset SMA patients treated with SPINRAZA achieved and sustained clinically meaningful improvement in motor function compared to untreated study participants. In addition, a greater percentage of patients on SPINRAZA survived compared to untreated patients. In open-label studies, some patients achieved milestones such as ability to sit unassisted, stand or walk when they would otherwise be unexpected to do so and maintained milestones at ages when they would be expected to be lost. The overall findings of these studies support the effectiveness of SPINRAZA across the range of SMA patients, and appear to support the early initiation of treatment.

"At Ionis, we have had the privilege of discovering and, together with Biogen, developing SPINRAZA. We are very pleased with today's announcement, which is an important milestone for the entire SMA community. Now we look forward to the benefit that SPINRAZA can bring to patients with SMA and their families. SPINRAZA is truly a precision medicine that works by altering the processing of a single cellular RNA. We are proud that SPINRAZA exists because Ionis created and validated a new platform for drug discovery, antisense technology," said Stanley T. Crooke, M.D., Ph.D., chief executive officer and chairman of Ionis. "We want to thank the families, physicians and their staff who participated in our clinical trials. Their dedication and support have been crucial to the approval of SPINRAZA for all those with SMA."

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.

"I believe SPINRAZA is a game changer for patients with SMA and their families," said John Day, M.D., Ph.D., director of the Neuromuscular Disorders Clinic at Lucile Packard Children's Hospital Stanford and professor of neurology and pediatrics at the Stanford University School of Medicine. "Until now we had to tell parents that the only treatment was to manage symptoms as their children became weaker. Now, SPINRAZA offers patients currently living with SMA hope for disease stabilization or improvement, and it raises the possibility that infants with SMA could be prevented from developing weakness if identified early enough. More generally, the success of SPINRAZA increases our optimism that antisense oligonucleotides could also control other neurodegenerative disorders."

"This is a watershed moment for the entire SMA community, which has worked tirelessly to finally see the day when a therapy for SMA would be made available. Cure SMA and our families have supported research into this terrible disease for more than 30 years, and many have participated in the critical clinical trials for SPINRAZA. We are excited to now have the first ever treatment option for SMA, and thank all our supporters and the dedicated researchers who made this possible," commented Kenneth Hobby, President, Cure SMA.

"SPINRAZA is the first of many antisense programs for neurological diseases in our discovery and clinical development pipeline with the potential to treat a variety of other severe neurological diseases that are not adequately addressed today," said C. Frank Bennett, Ph.D., senior vice president of research and leader of the neurological disease franchise at Ionis. "We are excited by the potential of our antisense technology to treat diseases that other therapeutic modalities are unable to address or adequately treat."

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.

"We are pleased with Biogen's preparations for launch and the speed with which they are implementing them," said B. Lynne Parshall, chief operating officer of Ionis. "We look forward to receiving the first commercial revenues from sales of SPINRAZA next year. These revenues will build on our current solid financial foundation and will add to the substantial revenues we expect to receive from our successful collaborations with Biogen and our other collaboration partners."

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.
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Source: press release, 12/23/16. http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=2...

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