This is the medicine that we are trying to get compassionate use for: ISIS-SMNRx is an antisense drug we discovered in collaboration with Dr. Adrian R. Krainer at Cold Spring Harbor Laboratory. ISIS-SMNRx is designed to treat SMA, a severe motor-neuron disease that is the leading genetic cause of infant mortality. SMA affects approximately 30,000 to 35,000 patients in the United States, Europe and Japan. One in 50 people, approximately six million people in the United States, carry the gene mutation that causes SMA. Carriers experience no symptoms and do not develop the disease. When both parents are carriers, however, 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, or SMN1, gene leading to a decrease in the protein, survival motor neuron, or 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 I SMA, the most severe life-threatening form, produce very little SMN protein and have a significantly shortened life expectancy. Children with Type II and Type III SMA have greater amounts of SMN protein and have less severe, but still life-altering, forms of SMA. The FDA granted Orphan Drug Designation with Fast Track Status to ISIS-SMNRx for the treatment of patients with SMA. In January 2012, we and Biogen Idec entered into a preferred partner alliance that provides Biogen Idec an option to develop and commercialize ISIS-SMNRx. Under the agreement, we received an upfront fee and are responsible for developing ISIS-SMNRx. Biogen Idec has the option to license ISIS-SMNRx until completion of the first successful Phase 2/3 study or the completion of two Phase 2/3 studies. We are eligible to receive milestone payments from Biogen Idec as ISIS-SMNRx advances through development. We designed ISIS-SMNRx to potentially treat all types of childhood SMA by altering the splicing of a closely related gene, SMN2, which leads to the increased production of fully functional SMN protein. We developed a biomarker assay to measure levels of SMN protein in the cerebral spinal fluid of children and infants with SMA. In February 2014, we reported the first set of data using this biomarker assay. Using this assay, we observed dose-dependent increases in SMN protein levels in children with SMA treated with ISIS-SMNRx from both the single- and multiple-dose studies. In the single-dose study, SMN protein levels more than doubled in the two highest dose cohorts, 6 and 9 mg, with average increases of approximately 120 percent and 160 percent compared to baseline, respectively, approximately nine to 14 months after dosing. Similarly, in the multiple-dose study, we observed substantial increases in SMN protein levels in the 9 mg cohort of 115 percent compared to baseline approximately three months, or day 86, after the first dose. In March 2013, we reported encouraging data from a single-dose, open-label Phase 1 clinical study evaluating ISIS-SMNRx in children with SMA. In this study, we reported that ISIS-SMNRx was well tolerated when administered intrathecally as a single dose directly into the spinal fluid. In addition, the children tolerated the intrathecal injection procedure well. We also showed that concentrations of ISIS-SMN Rx measured in cerebral spinal fluid were consistent with levels predicted from preclinical studies, indicating that the drug half-life in nervous system tissues is very long and that dosing once every six to nine months is feasible. Although the study was not designed to provide evidence of functional activity, we observed increases in the Hammersmith Functional Motor Scale-Expanded, or HFMSE, a measure of muscle function, in a number of these children. The mean increase in the HFMSE scores observed in the highest dose cohort (9 mg) at 3 months was 3.1 points or a 17.6% increase from baseline, with six of ten patients experiencing an increase of greater than four points. Observed increases in HFMSE scores equal to or greater than a 4 point compared to baseline were distributed by age with half in children under the age of five and half in children five and older. In September 2013, we reported a follow-up analysis of the single-dose, open-label Phase 1 study of ISIS-SMNRx in children with SMA. In this study, we observed that most children with SMA who received a single dose of one of the two highest doses of ISIS-SMNRx, 6 mg or 9 mg, continued to show increases in muscle function scores up to 14 months after a single injection of the drug. We are evaluating ISIS-SMNRx in a Phase 2 open-label, multiple-dose, dose-escalation study in children with SMA. In this study, we are evaluating four dose levels, 3, 6, 9, and 12 mg in children with SMA ages two to 15. We reported interim results from the 3, 6 and 9 mg cohorts from this study in February 2014 showing that treatment with ISIS-SMNRx was well tolerated. In addition, we observed dose- and time-dependent increases in HFMSE scores in children treated with multiple doses of ISIS-SMNRx. Children in the 3 mg, 6 mg, and 9 mg cohorts achieved mean increases in HFMSE scores of 1.5, 2.3 and 3.7 points, respectively, nine months following the first dose of ISIS-SMNRx. Children in the 9 mg cohort achieved mean increases in HFMSE scores of 2.7 and 3.7 points three and nine months after the first dose of ISIS-SMNRx, respectively. We are also evaluating ISIS-SMNRx in a Phase 2 open-label, multiple-dose, dose-escalation pilot study in infants who have been diagnosed with SMA. In this study, we are evaluating two dose levels, 6 and 12 mg in infants with SMA. We reported interim results from this study in February 2014 showing that all four infants in the 6 mg cohort had been on study for over six months and are now approximately nine and a half to 16 months in age with an average age of approximately 12 and a half month. We reported that all four infants were alive and none had required permanent respiratory assistance. In addition, all four infants had tolerated intrathecal administration of ISIS-SMNRx well. We acknowledge support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, and Cure SMA. We have licensed intellectual property from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.
Posted on: Fri, 26 Dec 2014 18:17:04 +0000
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