Isis Pharmaceuticals, Inc. has initiated a phase 2 study of ISIS-SMNRx in infants with spinal muscular atrophy (SMA).   SMA is a severe and rare genetic neuromuscular disease characterized by muscle atrophy and weakness and is the most common genetic cause of infant mortality.  The study, which will begin enrolling patients soon, is a phase 2 study in eight patients with infantile-onset SMA. The study, which initiates the phase 2/3 program for ISIS-SMNRx in infants, is designed to provide data to allow Isis to define the optimal dose for the larger planned phase 2/3 study in infants and to provide safety and tolerability data.  Isis will earn a $3.5 million milestone payment from Biogen Idec when the first infant is dosed in the study, which is projected for May 2013.  

The phase 2 study of ISIS-SMNRx is an open-label, multiple-dose, dose-escalation pilot study, which will include eight infants who have been diagnosed with SMA.  To meet enrollment criteria, infants must be between the ages of three weeks and seven months, live in close proximity to a study site and pass screening evaluations conducted at study sites.  The study will be conducted at centers in the United States and Canada.  

"We are very pleased with the progress Isis has made in advancing this new potential therapeutic agent, which could fill the therapeutic void for SMA and transform the hopes and futures of patients and families with this devastating disease.  It is a testament to the commitment of Isis that, in just a few years, this program has moved rapidly from research to late-stage clinical development.  We look forward to continuing to support the SMA community with the goal of accelerating a treatment for children with SMA," said Karen S. Chen, Ph.D., chief scientific officer at the SMA Foundation.

"We are very pleased with the achievement of this clinical milestone of advancing a potentially disease-modifying drug treatment into later-stage clinical trials.  This achievement is a culmination of the 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," said Jill Jarecki, Ph.D., research director of Families of SMA.

Isis completed an open-label phase 1 study evaluating ISIS-SMNRx in children (age 2 and older) with SMA, in which ISIS-SMNRx was well tolerated at all dose levels when administered intrathecally as a single dose directly into the spinal fluid. Although the study was not designed to provide evidence of functional activity improvements in the Hammersmith Functional Motor Scale-Expanded, a measure of muscle function, were observed in a number of these children.  In addition to the infant pilot study, Isis is also completing a multiple-dose, dose-escalation phase 1b/2a study of ISIS-SMNRx in children with SMA.  Data from the phase 1b/2a study will provide information to determine the dose for the phase 2/3 registration-directed study in children (age 2 and older) with SMA.

"SMA represents a serious unmet medical need with no currently available treatments. Based on its mechanism of action and encouraging preclinical and clinical data, ISIS-SMNRx could be an effective treatment for these very sick children, though additional work still needs to be done.  The rapid advancement of this drug to this stage in development reflects the support from the SMA community and the success of the collaboration between Isis and Biogen Idec.  Isis and Biogen Idec are committed to advancing the program for children with SMA," said C. Frank Bennett, Ph.D., senior vice president of research at Isis.  "ISIS-SMNRx is our first drug designed to intervene in the splicing of RNA to increase the production of a normal protein, SMN.  Antisense drugs could offer novel new therapeutics for a number of severe neurodegenerative diseases.  The encouraging safety data from this program and our preclinical and clinical experience in other neurodegenerative diseases support the broadening of our efforts to develop antisense drugs to treat such diseases."

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.

ISIS-SMNRx is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein.  The United States Food and Drug Administration 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 commercialize 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 license the compound until completion of the first successful Phase 2/3 study.  ISIS-SMNRx is currently being evaluated in a Phase 1b/2a multiple-dose, dose-escalation study in children with SMA.  In this study, children will either receive two or three doses of ISIS-SMNRx over the course of the study.