Spinal muscular atrophy (SMA) is a genetic condition caused by mutations in the survival motor neuron 1 (SMN1) gene and the retention of SMN2, a related gene that is unable to express sufficient levels of SMN protein.

RG3039 is an investigational drug developed by Repligen (in association with Pfizer), designed to promote survival and movement in SMA patients. It has been shown to strongly inhibit DcpS, an enzyme that promotes the degradation of mRNA (messenger RNA). Scientists believe that inhibiting the DcpS enzyme could lead to the stabilization of SMN2 mRNA and to the production of higher levels of SMN protein from the SMN2 gene.

The use of RG3039 to treat severely affected mice has produced positive results — the animals had higher survival rates and an increase in body weight and motor functions. The compound is available as a drug that could be taken by mouth. Importantly, it can penetrate the brain.

History of RG3039

In June 2011, a Repligen announced that the U.S. Food and Drug Administration (FDA) granted the drug candidate Fast Track designation (designed to accelerate the review of new drugs with the potential to attend unmet medical conditions). The European Medicines Agency (EMA) also gave the drug a positive opinion regarding orphan status.

How DcpS inhibition works

Insufficient levels of the SMN protein causes SMA, and patients with SMA have a deletion/mutation in the SMN1 gene. Patients also have a second SMN gene called SMN2. However, there is a single nucleotide (letter in the DNA) change in the SMN2 gene. This causes the protein expression machinery of the cell to sometimes stop reading the gene too early. The result is a truncated, dysfunctional protein that is rapidly degraded by the cell.

The low levels of protein produced by the SMN2 gene are not able to compensate for the loss of SMN production from the SMN1 gene. There is a positive correlation between the inhibition of the DcpS enzyme and the increase of SMN expression. However, the exact mechanism of how the inhibition of DcpS leads to an increase in SMN expression is still unknown.

Research involving RG3039

The drug has been tested in severely affected mice. A study of protein extracts from mouse brains, treated in vitro with different doses of the drug, has shown a dose-dependent ability of successful DcpS inhibition.

In order to estimate the tolerability of RG3039, SMA mice were treated daily with doses ranging from 3 to 40 mg/kg. The highest dose (40 mg/kg) showed some toxicity, shortening the survival periods and reducing weight gain. Mice treated with 10 mg/kg showed increased weight and survival, which was not increased in those treated with 20 mg/kg.

To assess the distribution of the drug in the body, the tissue of the central nervous system and skeletal muscle were tested and the results revealed similar concentrations of the drug in all the tissues.

Clinical trials involving RG3039

Phase 1 clincal trial evaluating the safety, tolerability, pharmacokinetics (how the drug moves within the body) and pharmacodynamics (the mode of action) of RG3039 in healthy volunteers started in June 2012 and finished in August 2014.

The trial consisted of two parts: The first part was blinded and a single ascending dose of the drug was tested in 32 healthy volunteers. The main objective was to test the pharmokynetics, safety and tolerability of the drug.

The results showed that RG3039 was well tolerated in all participants, and that doses up to 3 mg/kg successfully inhibited DcpS. However, the results provided mixed reviews given the fact that the actual levels of SMN did not change.

The second part of the study was double-blinded and placebo-controlled and used multiple ascending doses of the drug in 32 new volunteers. The same tests from part 1 were repeated and the inhibitory plasma concentration for the target enzyme were also determined.

Next steps for RG3039

Currently there are no active clinical trials regarding RG3039 and the partnership between Repligen and Pfizer has been terminated.

Note: SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.