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Isis Initiates Phase 1 Clinical Study of ISIS-SMNRx in Patients With Spinal Muscular Atrophy


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Isis Pharmaceuticals, Inc. announced that it has initiated a Phase 1 study of ISIS-SMNRx in patients with spinal muscular atrophy (SMA).  SMA is a severe motor-neuron disease that is the leading genetic cause of infant mortality. Isis is developing ISIS-SMNRx as a potential treatment for all Types of SMA.

"SMA is a devastating disease that leads to the loss of motor neurons resulting in muscle weakness and respiratory failure in children.  The genetic cause of this disease is well understood, but there are currently no effective disease-modifying therapies.  Currently, treatment of SMA is entirely symptomatic and focuses on preserving muscle strength and lung function by physical therapy and assisted ventilation.  This supportive approach has improved the natural history of SMA by extending life expectancy, but muscle weakness and atrophy are not affected.  A disease-modifying drug like ISIS-SMNRx that specifically targets the cause of the disease could, for the first time, restore muscle strength and respiratory function and dramatically improve the children's function and quality of life," said Darryl C. De Vivo, M.D., Sidney Carter Professor of Neurology and Pediatrics and Co-Director of the Motor Neuron Center at Columbia University Medical Center.

SMA is a severe genetic disease that affects approximately 30,000 – 35,000 patients in the United States, Europe and Japan.  One in 50 people, approximately 6 million people in the United States, are carriers of the SMA gene.  Carriers experience no symptoms and do not develop the disease, however, when both parents are carriers, there is a one in four chance that their child will have SMA.

SMA is caused by a loss of, or defect in, the survival motor neuron 1 (SMN1) gene leading to a decrease in the protein, survival motor neuron (SMN).  SMN is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular growth and function. The severity of SMA correlates with the amount of SMN protein.  Infants with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and have shortened life expectancy.

Children with Type II and Type III have greater amounts of SMN protein and less severe, but still life-altering forms of SMA.  ISIS-SMNRx is designed to treat all types of childhood SMA by altering the splicing of a closely related gene (SMN2) that leads to the increased production of fully functional SMN protein.

"Our strategy to treat SMA relies on a simple, powerful antisense method that boosts SMN protein levels by fixing a genetic RNA splicing glitch.  Working with Isis, we have successfully redirected splicing to increase functional SMN production.  We have thoroughly validated this approach in multiple animal models, observing marked improvement in modifying the disease course in both mild and severe models of SMA," said Adrian Krainer, Ph.D., Professor of Molecular Genetics at Cold Spring Harbor Laboratory in Long Island, NY.  "We look forward to translating this important discovery into an effective treatment for this serious disease."

"SMA represents a serious unmet medical need with no currently available treatments.   ISIS-SMNRx is our first drug to intervene in the splicing of RNA to increase the production of a normal protein, SMN.  Together with Dr. Krainer's lab, we have validated the antisense approach to treating this disease and are now advancing this program into clinical studies," said C. Frank Bennett, Ph.D., Senior Vice President of Research at Isis.  "We are committed to quickly developing this drug and are finalizing what we believe will be a rapid development path for this drug in all types of SMA.  Once we evaluate ISIS-SMNRx as a single dose in children with SMA, we will move to multiple doses in our Phase 1 studies and eventually evaluate the drug in Phase 2 studies in children with SMA, including infants with Type I SMA."

The Phase 1 study of ISIS-SMNRx is a single-dose, dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile of the drug in children with SMA between the ages of 2-14 who are medically stable.  In this study, ISIS-SMNRx will be administered intrathecally as a single injection directly into the spinal fluid.  Intrathecal administration of an antisense drug, ISIS-SOD1Rx, has been shown to be safe and well tolerated in an ongoing Phase 1 study in patients with amyotrophic lateral sclerosis.

"SMA is a heartbreaking disease. Children with SMA are bright and engaging, but often never achieve the simplest motor milestones like walking, crawling, and sitting up. Many do not live to reach kindergarten. In milder cases, SMA patients inexorably grow weaker and experience the loss of the few abilities they did acquire. In addition to motor losses, SMA patients young and old are at constant risk of tragic consequences from simple respiratory infections that you and I take in stride," said Karen S. Chen, Ph.D., Chief Scientific Officer at the SMA Foundation. "If you consider that this is the normally bleak clinical outlook for these patients, you can understand why the ISIS-SMNRx trial represents such a watershed moment for SMA. The landmark science behind ISIS-SMNRx is compelling and it has a chance to fill the therapeutic void for SMA and transform the hopes and futures of thousands of patients and families."

"We are very pleased to see the great milestone of a disease-modifying drug treatment advancing into clinical trials in SMA patients," said Kenneth Hobby, President of Families of SMA.  "Our community has worked for a long time to reach the goal of moving specific therapies for SMA from the bench and into the clinic.  This has been made possible by close interactions between basic researchers, families, clinicians, and industry.  Families of SMA applauds Isis for investing in and leading drug development efforts for this devastating, orphan disease."

"We see real promise in therapeutic strategies for SMA that increase production of the SMN protein," said Muscular Dystrophy Association Executive Vice President Research and Medical Director Valerie Cwik, M.D. "We're delighted Isis Pharmaceuticals is moving forward with a Phase 1 dose-escalation study of its antisense drug in children with SMA."

Isis acknowledges support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, Families of SMA and intellectual property licensed from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.

The United States Food and Drug Administration granted Orphan Drug Designation with Fast Track Status to ISIS-SMNRx for the treatment of patients with SMA.

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