Interim results from a phase 1 clinical trial of RG2833 in people with Friedreich’s ataxia (FA) show that the experimental drug is well-tolerated, and that it appears to increase the activity of the gene for the frataxin protein.
RG2833, which belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, is designed to work by "turning on" an abnormally “turned-off” frataxin gene (DNA). This allows cellular machinery to "read" the DNA and produce the otherwise deficient frataxin protein. (For more about the causes of FA, read FA: A Case of Impaired Ironworks.)
Jim Rusche, senior vice president of research and development at Repligen Corp., presented the results as a “snapshot before the end of the study,” April 24, 2013, at MDA’s Scientific Conference in Washington, D.C.
While the encouraging results are an important step forward in finding new drugs, Rusche said, more tests will be required before a drug like RG2833 can be available as a safe and effective treatment for FA.
According to the trial design, 20 adults with FA were assigned to one of four groups, or cohorts:
Reported results to date include data covering the first three groups, as well as the fourth group after the first of two scheduled treatments.
So far, RG2833 has been well-tolerated, Rusche reported. No drug-related severe adverse events have been reported, and none of the participants have dropped out of the trial.
Data show that amounts of RG2833 measured in participants’ blood cells increased as increasing doses of the oral drug were administered. Investigators also saw evidence that the drug engaged its target, inhibiting the deacetylaseactivity that causes the frataxin gene to be “turned off.”
In addition, RG2833 increased levels of frataxin messenger RNA in trial participants in a dose-dependent manner in all five participants in group 3 and in four of five participants in group 4. Evidence suggested a possible increase in frataxin protein levels in three out of the 10 participants that comprised the third and fourth groups.
The study demonstrates “proof of principle,” Rusche said, that an HDAC inhibitor can increase frataxin production in people with FA.
Biopharmaceutical company Repligen, headquartered in Waltham, Mass., launched the phase 1 trial— the first to test a therapy specifically developed to treat the underlying molecular cause of FA — in March 2012. It remains ongoing at San Luigi Gonzaga University Hospital in Turin, Italy, under the direction of principal investigator Luca Durelli.
The main aim of the trial is to assess the safety of RG2833 in people with FA. However, investigators also will evaluate the drug's pharmacokinetics profile (how the drug is absorbed, distributed, metabolized and excreted by the body) and its pharmacodynamics (the effects the drug has on the body).
Results from the trial will help with the design of future, longer-term trials aimed at examining safety and efficacy— a necessary step in obtaining U.S. Food and Drug Administration (FDA) approval of RG2833 or similar compounds for the treatment of FA.
MDA has awarded Repligen two grants to fund development of HDAC inhibitors for FA. The first, awarded in late 2007, totaled nearly $1 million. In December 2009, MDA awarded Repligen a supplemental grant of $731,534 to support ongoing development and completion of the preclinical testing required to advance the experimental drug toward human clinical trials. The awards were made through MDA's translational research program.
GoFAR, a Friedreich's ataxia patient advocacy group based in Italy, and the European Union 7th Framework Program EFACTS (European Friedreich's Ataxia Consortium for Translational Studies) also directly funded a portion of the phase 1 clinical trial.
Previous MDA-supported studies in mice with a disease resembling FA have confirmed that RG2833 targets the enzyme HDAC3, and that blocking or inhibiting that enzyme increases frataxin production.