Isis Pharmaceuticals announced the initiation of a pivotal phase 3 study evaluating ISIS-SMNRx in approximately 120 non-ambulatory children with spinal muscular atrophy (SMA).  SMA is a severe and rare genetic neuromuscular disease characterised by muscle atrophy and weakness.  The phase 3 study, CHERISH, is the second phase 3 study Isis has initiated in a global late-stage clinical development programme for ISIS-SMNRx.  Isis earned a $27 million milestone payment from its development partner, Biogen Idec, for the dosing of the first patient in this study. Isis is also evaluating ISIS-SMNRx in the phase 3 study, ENDEAR, in infants with SMA.  Isis is conducting both phase 3 studies with agreement from the US Food and Drug Administration (US FDA) for special protocol assessments, or SPAs.

"CHERISH is the second pivotal Phase 3 study of ISIS-SMNRx we have initiated this year.  The speed at which we have moved this drug from a preclinical development candidate to a late-stage development reflects the successful collaboration we have with Biogen Idec and the support from the SMA community.  It is our hope that this study will build upon the encouraging results we observed in our open-label phase 2 studies.  Both phase 3 studies are designed to evaluate the efficacy of ISIS-SMNRx in either infants or children with SMA and to further assess the safety profile in these patients. We are further encouraged by the FDA's agreement on the trial design and planned analysis for both of these Phase 3 studies on ISIS-SMNRx," said B. Lynne Parshall, chief operating officer at Isis Pharmaceuticals.  "Together with our partner Biogen Idec, we are also in the planning stages for additional clinical studies as part of our commitment to the clinical programme for ISIS-SMNRx."  

"SMA is a devastating disease that robs people of physical strength by affecting the motor nerve cells in the spinal cord.  SMA is the number one genetic cause of death for infants.  Children with SMA grow weaker as their disease progresses.  Although the genetic cause of SMA is well understood, currently there are no effective drugs available for children with SMA," said Kenneth Hobby, president of Cure SMA.  "We applaud Isis for investing in and leading drug development efforts for SMA.  We remain hopeful that potential treatments, like ISIS-SMNRx, will be able to provide therapeutic benefit."

CHERISH, a phase 3 study of ISIS-SMNRx, is a randomised, double-blind, sham-procedure controlled fifteen month study in approximately 120 children who are non-ambulatory with SMA between the ages of 2-12.  The study will evaluate the efficacy and safety of a 12 mg dose of ISIS-SMNRx with a primary endpoint of a change in the Hammersmith Functional Motor Scale-Expanded (HFMSE), a validated method to measure changes in muscle function in patients with SMA.  Additional efficacy endpoints are also included in the study.

In addition to the current phase 3 clinical studies ENDEAR and CHERISH, Biogen Idec plans to conduct two additional ISIS-SMNRx studies, which could begin in the first half of 2015:

NURTURE will be a phase 2 clinical study evaluating ISIS-SMNRx in up to 25 pre-symptomatic newborns that are genetically predisposed to the disease.

EMBRACE will be a Phase 2 clinical study evaluating safety and exploratory efficacy of ISIS-SMNRx in approximately 20 patients with infantile or childhood-onset SMA. This study will bridge the gap in a small subset of patients that do not meet the age and inclusion criteria of the current phase 3 studies ENDEAR and CHERISH.  

ISIS-SMNRx is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein.  The FDA granted orphan drug status and fast track designation to ISIS-SMNRx for the treatment of patients with SMA.  Isis is currently in collaboration with Biogen Idec to develop and potentially commercialise the investigational compound, ISIS-SMNRx, to treat all types of SMA.  Under the terms of the January 2012 agreement, Isis is responsible for global development and Biogen Idec has the option to licence the compound until completion of the first successful Phase 2/3 study or the completion of two phase 2/3 studies.  Isis is conducting two phase 3 studies with agreement from the FDA for special protocol assessments, or SPAs. A SPA is a written agreement between the FDA and a drug sponsor intended to confirm that the clinical trial protocol is adequate to meet current scientific and regulatory requirements for a potential new drug application.

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

SMA is a severe genetic disease that affects approximately 30,000-35,000 patients in the United States, Europe and Japan. SMA is caused by a loss of, or defect in, the survival motor neuron 1 (SMN1) gene leading to a decrease in the survival motor neuron (SMN) protein. SMN is critical to the health and survival of nerve cells in the spinal cord responsible for neuromuscular growth and function. One in 50 people, the equivalent of about 6 million people in the United States, are carriers of a defective SMN1 gene, which is unable to produce fully functional SMN protein. 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. The severity of SMA correlates with the amount of SMN protein. Infants with Type I SMA, the most severe form of the disease, produce very little SMN protein and have a life expectancy of less than two years. Children with Type II have greater amounts of SMN protein but still have a shortened lifespan and are never able to stand independently. Children with Type III have a normal lifespan but accumulate life-long physical disabilities as they grow.