Repros Therapeutics has received further clarification from the Food and Drug Administration (FDA) on the Full Clinical Hold status of Proellex.
As announced in early August 2009, and after voluntarily suspending dosing of all patients in its clinical trials, the company received verbal notice from FDA that the company’s Investigational New Drug Applications (INDs) for Proellex had been placed on clinical hold for safety reasons, due to the observation of increased liver enzymes in a number of patients treated with Proellex.
Following this verbal notice, written notice was received from FDA which outlined the specific clinical deficiency and the information that would be needed from the company to resolve the Full Clinical Hold. Further clarification on this matter was received during a teleconference with FDA’s Division of Reproductive and Urologic Products on September 23, 2009.
Reportedly, FDA’s letter outlined the type of information Repros needs to provide, at a minimum, to resolve the Full Clinical Hold. FDA asked for follow-up information from all subjects treated with Proellex who exhibited any laboratory changes indicative of liver injury, and whether these liver enzyme elevations have resolved or stabilised. Pharmacokinetic analyses to try and identify a serum concentration of Proellex below which there was no increase in liver enzymes.
It also asked for any information regarding the likely mechanism(s) for the Proellex-induced liver toxicity and processes/steps that will be implemented to minimise the risk of liver toxicity if the Full Clinical Hold is removed. After the aforementioned points have been satisfactorily addressed, the company may propose a dosing regimen to investigate the efficacy of Proellex, which will provide a sufficient margin of safety below the serum drug concentrations that were associated with liver toxicity.
Furthermore, FDA, opined in the letter that they doubted whether the company would be able to identify a dosing regimen for Proellex that will be both effective for any of the intended indications and free of an unacceptable risk of serious liver toxicity based on available information, which includes a small number of mild liver enzyme elevations of < 1.6xULN at the 12.5mg dose.
During the September 23, 2009 meeting with FDA, the company provided an update on the incidence of liver enzyme elevations, including subjects with confirmed liver injury, as defined by liver transaminase elevations >3xULN.
Discussions with FDA also focused on the potential types of pharmacokinetic analyses that could be performed with the objective of trying to identify a lower dose going forward that would provide an adequate safety margin versus doses that have exhibited signs of liver toxicity. An appropriate low dose would still be required to show efficacy in the treatment of uterine fibroids and/or endometriosis to support an overall positive benefit/risk profile for Proellex. The company believes a relatively small study of limited duration could serve as proof of concept to identify a lower, safe dose, as well as provide guidance for efficacy at such a dose.