The U.S. Food and Drug Administration has approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.
Nusinersen, marketed as Spinraza, is the first drug approved by Food and Drug Administration for use in treating spinal muscular atrophy. Nusinersen is a proprietary antisense oligonucleotide developed by Ionis Pharmaceuticals and licensed to Biogen. The drug is authorised for use in all types of spinal muscular atrophy regardless of age and disease stage. It is administered directly to the central nervous system using intrathecal injection once every 4 months.
"There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life," said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. "As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease."
SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.
The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based.
The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose.
Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.
The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.
Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.
The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.
The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.
Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL - SOURCE Cold Spring Harbor Laboratory.
'A perfect example of why we do basic research,' says Dr. Bruce Stillman, CSHL president
Within a week of Christmas day, a drug called nusinersen will be in the hands of doctors across the nation, who will use it, most urgently, to treat young children with a severe and potentially fatal illness called spinal muscular atrophy (SMA).
The leading genetic cause of infant mortality, SMA is a motor neuron disease that leads to the wasting of young muscles, impairing the ability of newborns and toddlers to walk, crawl, or even hold their heads up, and in the most severe cases, failure of muscles that enable them to breathe.
Nusinersen (to be sold by Biogen under the brand name Spinraza) was conceived and tested over several years in mouse models of SMA by Professor Adrian Krainer, Ph.D., and his colleagues, at Cold Spring Harbor Laboratory (CSHL), in collaboration with drug developers led by Dr. Frank Bennett at Ionis Pharmaceuticals. Their collaboration began a dozen years ago.
"Some are understandably calling the FDA's announcement of nusinersen's approval 'a Christmas surprise,'" Dr. Krainer commented. "For those of us who have had the thrilling experience of working on this drug from the very beginning, and have watched it succeed in reversing SMA pathology in animals - and more recently in young people with the illness - news of the approval is simply thrilling. Most gratifying to me is the thought that thousands of families will now be able to see their loved ones benefit from the drug's therapeutic effects."
"This drug will save lives of young people with severe SMA, and will improve the lives of many thousands of older children and adults who have disabling forms of the disease," said Bruce Stillman, Ph.D., President and CEO of CSHL. "This is a fantastic example of how fundamental research exploring the mechanisms of cells can lead to important clinical developments."
Ionis says nusinersen's FDA approval clears it for use in both pediatric and adult SMA patients. The drug performed impressively in clinical trials testing its impact across a wide range of SMA patients, from just after birth to age 12 and beyond. The earlier the drug is administered in patients, the more it appears to help them.
SMA patients no longer have a working copy of a gene called SMN1 ("survival of motor neuron"), which encodes a protein essential for the development of motor neurons. Without it, patients must rely on a nearly identical gene called SMN2. It's a poor backup, though: the SMN2 gene (in all people) has a DNA error that usually prevents cells from manufacturing functioning SMN protein. [click here to see a cartoon explaining the problem and how the drug fixes it]
Dr. Krainer, a world authority on a cellular process called RNA splicing - the editing of RNA "messages" copied from our genes - conceived of a way to compensate for the error in SMN1 by correcting the defect in SMN2, which is caused by a failure of the splicing mechanism to "edit" the gene's RNA message properly.
With Ionis scientists, Krainer's team designed, synthesized and tested tiny molecules of modified RNA called antisense oligonucleotides (ASOs), which, when delivered to cells, bind at a specific site on the unedited RNA message made from the SMN2 gene. The ASO's binding has the effect of fixing the splicing error responsible for non-functional SMN protein. Human testing sponsored by Ionis began in 2011.
One child who has benefited is Emma Larson, a lively 3½-year-old from Long Island, whose parents sought Dr. Krainer's counsel when she was diagnosed with Type 2 SMA. Dianne and Matthew Larson later enrolled Emma in a clinical trial, when she reached her 2nd birthday, at which point she was losing the ability to crawl and to hold her head up without assistance. Within 2 months of receiving her first injections of nusinersen, Emma began to improve. "It was a miracle," Dianne Larsen recalls. Today, Emma continues to improve, graduating from a walker to crutches and getting ready to join her peers in preschool.
"We are in tears over here, along with the rest of the community! Amazing! Still numb," Dianne said in an email the morning after the drug's FDA approval. "Thank god for Adrian Krainer and all the people who made this drug possible!"
Dr. Stillman, echoing Dianne Larson's joy, took the occasion to note that the applied research leading to nusinersen was preceded, in Krainer's case, by some 15 years of basic research to determine the mechanisms that underlie RNA splicing. And those discoveries, Stillman noted, followed closely upon another great scientific triumph, occurring simultaneously at CSHL and MIT almost exactly 40 years ago.
"In the spring of 1977, Drs. Richard Roberts of CSHL and Phillip Sharp, then of MIT, first described RNA splicing - a fundamental mechanism in cells that regulates how our genes are expressed." Roberts and Sharp shared the 1993 Nobel Prize for that work, which provided a point of departure for investigators like Adrian Krainer who worked on the mechanism. "This is a perfect example of how basic research - with no specific purpose other than uncovering the mysteries of life - is the precondition for all the marvels of applied science that we enjoy, wonders that now include the development of nusinersen."
Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. Visit www.cshl.edu