RG3039 (quinazoline) is an investigational, disease-modifying oral therapy for spinal muscular atrophy (SMA) that was being developed by Repligen, in partnership with Pfizer. Work on RG3039 was suspended after Pfizer terminated the partnership in January 2015.
How RG3039 works
SMA is an inherited condition, caused by mutations in the survival motor neuron 1 (SMN1) gene that results in insufficient production of SMN protein. This leads to a progressive loss of nerve cells involved in controlling muscles, and decreasing muscle strength and control, among other symptoms.
A related gene, SMN2, also provides instructions for generating SMN protein. But this gene mostly produces a shortened, unstable version of SMN that  quickly degrades. So, the amount of functional SMN protein produced from the SMN2 gene is not enough to compensate for mutated SMN1.
RG3039 is designed to boost the amount of functional SMN protein by inhibiting a protein called DcpS. DcpS is an RNA processing enzyme that can trigger the breakdown of SMN2 mRNA, which is a copy of the gene that is processed and sent to the cell’s protein-making machinery with instructions to produce the protein. By blocking DcpS, RG3039 should boost levels of mRNA that potentially could produce functional SMN protein.
The results of two preclinical studies in mice models of SMA were published in the journal Human Molecular Genetics.
The first study showed that RG3039 could pass successfully through the blood-brain barrier to reach affected neurons in the brains of mice with severe SMA. These mice showed an increase in motor function and survival corresponding with increasing doses of RG3039.
The second study examined RG3039 in mice with SMA of varying severity. Similar results were observed, with the animals living much longer and showing increased motor control.Â
Researchers used these studies to estimate initial doses of RG3039 to be tested in human clinical trials.
RG3039 in clinical trials
Scientists investigated RG3039 in a Phase 1a and a Phase 1b clinical trials. Both trials, which ended in August 2014, evaluated the compound’s safety, tolerability, movement within the body, and mode of action in healthy volunteers. Â
The blinded Phase 1a study examined a single ascending dose of RG3039 in 32 healthy volunteers. The results were positive, demonstrating that RG3039 was well-tolerated and inhibited more than 90% of DcpS for at least 48 hours. Following this success, researchers initiated their placebo-controlled, double-blind, Phase 1b trial to assess the effect of multiple ascending doses of the compound in 32 additional healthy volunteers.
Pfizer presented the results of the Phase 1b trial at the 2014 Cure SMA conference. While RG3039 successfully blocked DcpS in the blood, levels of SMN protein did not change. Since increased levels of SMN were seen as essential in helping patients, Pfizer concluded that RG3039 would be ineffective in SMA patients at this dose and suspended all further work on RG3039.
Other information
Cure SMA initially identified the compound as part of efforts to discover new treatments that may boost SMN2 expression and licensed it to Repligen in 2009. In June 2011, Repligen announced that the U.S. Food and Drug Administration (FDA) had granted the therapy fast-track designation, which accelerates the review of new compounds that potentially could fill unmet medical needs.
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