Indevus submits new drug application for NEBIDO

Aug 29 2007

Indevus Pharmaceuticals, Inc. has announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for NEBIDO (testosterone undecanoate) intramuscular injection, a long-acting testosterone therapy intended to treat male patients with primary and secondary hypogonadism.

Each 1000 mg injection of NEBIDO would only need to be provided once every 12 weeks, as compared to the current injectable therapies which typically require an injection every two to three weeks.

The NDA submission follows the June 2007 announcement of positive results from the Company's Phase III pharmacokinetic trial for NEBIDO. In addition to the data from this U.S. trial, the NDA includes the results of the European clinical trials database (originally generated by the Company's partner, Bayer Schering Pharma AG, Germany) which has formed the basis for the approval of NEBIDO in over 75 countries to date.

The U.S. testosterone therapy market is currently estimated to be in excess of $550 million. Of the approximately 340,000 men currently receiving therapy, approximately 130,000 utilize the existing injectable therapies that must be given every two to three weeks.

The NDA contains data from six clinical studies in which over 400 patients received at least one dose of NEBIDO, with over 300 of these patients treated for more than one year. In total, over 3,000 injections of NEBIDO have been given to hypogonadal males during the clinical development program. In addition, the NDA includes post-marketing data from safety reporting through June 2007, reflecting the world-wide experience from over 260,000 injections of NEBIDO.

"The submission of the NEBIDO NDA is a very important milestone for the Company," said Glenn L. Cooper, M.D., chief executive officer and chairman of Indevus. "We strongly believe that NEBIDO can greatly improve the treatment options for men who suffer from hypogonadism."

In June 2007, the Company announced positive results of its Phase III pharmacokinetic trial with NEBIDO. The purpose of the trial was to evaluate NEBIDO under U.S. Food and Drug Administration (FDA) pharmacokinetic guidelines for the approval of testosterone therapy products for male hypogonadism. The trial met its primary endpoints: a responder analysis based on the average testosterone concentrations during the steady-state dosing interval and an outlier analysis based on the maximum testosterone concentrations during the steady-state dosing interval.

The Phase III pharmacokinetic trial was a randomized open-label (unblinded) study that included the evaluation of the pharmacokinetics of NEBIDO dosed as either 1000 mg every 12 weeks or as 750 mg every 12 weeks, both via intramuscular injection. The primary endpoints included a responder analysis (based on guidelines provided from the FDA for average testosterone concentrations over the steady state dosing interval) and an outlier analysis (based on the maximum testosterone concentrations during the steady state dosing interval). Specifically, a responder was defined (per the FDA) as a patient who, at steady-state conditions, had an average concentration of serum total testosterone (Cavg) within the normal range (300 to 1000 ng/dL). The primary response endpoint was met if at least 75% of patients achieved a Cavg within this normal range. FDA also provided guidelines related to maximum testosterone (Cmax) levels, including thresholds that no patient should exceed a testosterone concentration of 2500 ng/dL, no more than 5% of patients should exceed a concentration of 1800 ng/dL, and no more than 15% of patients should exceed a concentration of 1500 ng/dL.

In addition, secondary outcomes included measurements evaluating the general health and well-being of the patients by questionnaires and assessment tools.

The trial randomized a total of 237 male hypogonadal patients (117 patients treated in the 1000 mg dose arm and 120 patients treated in the 750 mg dose arm). The patient completion rate of all 5 injections with NEBIDO was over 80%, demonstrating very high treatment compliance for a one-year study. Reasons for discontinuation were similar between the treatment groups.

Of the 97 patients in the 1000 mg arm receiving their steady-state injection, 94% had a Cavg over the course of the 12-week period that was within the normal range, demonstrating that treatment with NEBIDO successfully maintained therapeutic testosterone levels in hypogonadal men with injections given only once every 12 weeks (just 4 to 5 times per year). Further, no patients in the 1000 mg arm exceeded a testosterone concentration of 2500 ng/dL; four of 97 (4.1%) patients had a peak level over 1800 ng/dL; and 11 of 97 (11.3%) patients had a peak level exceeding 1500 ng/dL. The duration of time any patient had a concentration over these Cmax thresholds was brief.

Of the 102 patients in the 750 mg arm receiving their fourth injection, 86% had a Cavg within the normal range. No patients in the 750 mg arm exceeded a testosterone level of either 2500 ng/dL or 1800 ng/dL, and only four of 102 (3.9%) patients had a peak level exceeding 1500 ng/dL. For those few patients exceeding the 1500 ng/dL threshold, the duration of time above the threshold was brief.

Both treatment arms demonstrated improvements from baseline in key secondary clinical outcome variables.

Both doses of the drug were well-tolerated as indicated by the analysis of the safety measurements collected and the persistence with study treatment. Further, the spectrum of adverse events reported were comparable to other injectable hypogonadism treatments reported in the literature. There were no significant adverse changes in laboratory parameters with NEBIDO treatment.