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, decreasing muscle strength and control, among other symptoms.

A second related gene, SMN2, encodes for SMN protein. But this gene mostly produces a shortened, unstable version of the SMN protein that quickly breaks down. And the amount of SMN protein it produces is not enough to compensate for mutated SMN1.

RG3039 boosts the amount of functional SMN protein by inhibiting a protein called DcpS. This DcpS is an RNA processing enzyme that can trigger the breakdown of SMN2 mRNA, which, in turn, is a copy of the gene that is processed and sent to a cell’s protein-making machinery as instructions to produce the protein. By blocking DcpS, RG3039 should boost levels of mRNA that could potentially produce functional SMN protein.

The results of two preclinical studies in mice models of SMA appeared in the journal Human Molecular Genetics.

The first showe that RG3039 could successfully pass through the blood-brain barrier to reach affected neurons in the brains of severe SMA mice. These mice showed an increase in motor function and survival in line 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. 

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 Phase 1a and 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.  

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 percent 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 had granted the therapy fast-track designation, which accelerates the review of new compounds that could potentially fill unmet medical needs.

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