The Therapeutic Effects of RG3039 in Severe Spinal Muscular Atrophy Mice and Normal Human Volunteers (SC01.002)

Objective: To investigate the therapeutic effects of RG3039 in spinal muscular atrophy (SMA). Background Spinal muscular atrophy (SMA) is an autosomal recessively inherited motor neuron disease that frequently results in early mortality. SMA is caused by homozygous mutation of the SMN1 gene and retention of SMN2, a highly similar gene that expresses insufficient levels of SMN protein. Currently there is no disease modifying treatment to offer patients. SMN2 copy number inversely correlates with disease severity in humans and robust increases in SMN expression prevents SMA in mice. RG3039, a quinazoline derivative, increases SMN2 promoter activity (Jarecki et al., 2005) and inhibits the scavenger decapping enzyme DcpS (Singh et al., 2008). Design/Methods: Severe SMA mice were treated with 0, 3, or 10 mg/kg of RG3039 daily beginning on the day of birth (P1). Behavioral, biochemical, and histological outcomes were assessed. A Phase I safety study of RG3039 in healthy human volunteers is ongoing. Results: RG3039 improves median survival by 29%, maximum body weight achieved by 15%, and motor behavioral outcomes in severe SMA mice. These effects are associated with increased SMN2 transcript levels, improved neuromuscular junction (NMJ) morphology and physiology, increased muscle and myofiber area, and increased number of vGluT1 synapses onto lumbar motor neurons. Interim phase I clinical results in healthy volunteers indicate no adverse effects at drug exposure that inhibits DcpS enzyme completely in circulating PBMC. Conclusions: RG3039 improves survival, motor behavior, and motor unit structure and function in severe SMA mice. Dosing in humans has produced no adverse effects to date. Phase I trials in SMA patients will be initiated in early 2012 and will represent the first clinical trial of a compound developed solely for the treatment of SMA. Supported by: Funding from the Repligen Corporation and grant support from the MDA, Families of Spinal Muscular Atrophy to CK and the National Institutes of Health (R01NS062869 to CJS). Disclosure: Dr. Van Meerbeke has nothing to disclose. Dr. Gibbs has nothing to disclose. Dr. Plasterer has received personal compensation for activities with Repligen Corporation as an employee. Dr. Feng has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Wee has nothing to disclose. Dr. Xia has received personal compensation for activities with Repligen Corporation as an employee. Dr. Jacques has received personal compensation for activities with Repligen Corporation as an employee. Dr. Rusche has received personal compensation for activities with Repligen Corporation as an employee. Dr. Ko has nothing to disclose. Dr. Sumner has nothing to disclose.