Tuclar Phase 2 Programs

Phase II Program: Design and Results

We conducted an extensive Phase II clinical program for Tuclar. The full program included four separate studies and enrolled 77 men with low testosterone (T).

In our 30-day and seven-day repeat-dose Phase II studies, we treated men twice daily with the same Tuclar dose that we intend to evaluate in our pivotal Phase III study. In these two studies, 77% and 87% of our patients, respectively, achieved serum T levels in the normal range. These results were achieved without dose adjustments, thereby satisfying the guidance we have received from the Food and Drug Administration (FDA) that > 75% of men achieve serum T levels within the normal range of 300 to 1,000 ng/dL.

Our pivotal Phase III study endpoints are the same as the two completed Phase II study endpoints. Although we met the FDA guidance for peak serum T in both of our two Phase II studies, the results of these Phase II studies may not be predictive of the results we obtain in our pivotal Phase III study.

Phase II 30-Day Repeat-Dose Study

In late 2009, we completed a 30-day repeat-dose study of Tuclar dosed twice daily at 200 mg T in 15 hypogonadal men. The purpose of this study was to determine whether men treated with Tuclar twice-daily dosing reached serum T steady-state by day seven, as was found in our seven-day repeat-dose Phase II study described below. Regression analysis of the serum T data over time indicated men reached steady state between days seven and ten of the study. We also noted the pharmacokinetic results observed in the 30-day repeat-dose study correlated well with the results observed in our seven-day repeat-dose study. The Cavg concentration of T of the 15 men in this study on day 28, which was the last day of this study, was 516 ng/dL. Moreover, the serum T results from our 30-day study satisfied the efficacy guidance the FDA provided to us for our pivotal Phase III study, in that at least 75% of men obtained a serum T Cavg in the normal range.

We observed a decrease in high-density lipoprotein cholesterol, consistent with other T-replacement products and no meaningful changes to low-density lipoprotein cholesterol, triglycerides, or total cholesterol. No treatment-related significant adverse effects, or SAEs, were observed in this study.

Phase II Seven-Day Repeat-Dose Study

In 2008, we completed a seven-day repeat-dose Phase II study of four different T formulations in hypogonadal men. Twenty-nine men were enrolled in the four-arm crossover study, five of whom withdrew for reasons unrelated to the treatment. Men were washed out of current T-replacement therapy before being dosed with oral T in our study to ensure that their prior T-replacement therapy did not affect the results of our study. Men were dosed with one T formulation for seven days followed by 14 days of washout without any T-replacement therapy before being dosed with the next T formulation. The four treatment arms were as follows:

Arm 1 - Tuclar at a dose of 300 mg T, administered twice daily (N=28);
Arm 2 - 400 mg T, as 200 mg T as TE and 200 mg T as TU, administered twice daily (N=26);
Arm 3 - Tuclar at a dose of 200 mg T, twice daily, with food measured on day 7, and in fasted state measured on day 8 (N=26); and
Arm 4 - 300 mg T, as 150 mg T as TE and 150 mg T as TU, administered twice daily (N=24).

This study was designed to determine the serum T response over time in men treated with two doses of oral T and to determine the number of men that achieved serum T in the normal range with each formulation. In addition, Arm 3 evaluated the effect of food, specifically a diet containing 50% dietary fat or a high-fat diet, on Tuclar twice daily at a dose of 200 mg T. In addition to assess whether or not our study met the FDA’s previously stated efficacy guidance of greater than or equal to 75% of men with a serum T Cavg in the normal range, we also evaluated peak serum T levels.

Serum T results consistent with the FDA’s previously stated efficacy guidance were achieved in Arm 3 of the study, in which men received Tuclar twice daily at a dose of 200 mg T. Seventy-seven percent (77%) of men had average serum T in the normal range. Notably, these results were achieved without dose adjustment. Our pivotal Phase III study will include an opportunity for dose adjustments at days 30 and 60 to mimic clinical practice of men being treated for low T and to maximize the likelihood that the primary efficacy endpoint will be achieved. There were no treatment-related SAEs in this study.

Phase II Food Effect Study

In late 2009, we completed a five-way crossover study to further evaluate the effect of differing levels of dietary fat on Tuclar. The FDA requested that we perform this study because of the fatty nature of TU and the possibility that TU’s bioavailability could be impacted if administered with a meal. We conducted the study in accordance with published FDA guidance regarding the design of food effect studies. Sixteen hypogonadal men were dosed with the maximum anticipated Tuclar twice-daily oral dose of 300 mg T without food or with very low fat, low fat, normal fat and high fat meals. There was a trend toward increased bioavailability of Tuclar with increasing fat content of a meal. However, using the normal fat diet as the comparator, we determined that the differences between normal fat and each of low fat and high fat meals relative to serum T response were not statistically significant (p<0.05). Only in the absence of food or when administered with a very low fat meal was the serum T response to Tuclar statistically less (p<0.05) than the normal diet. Based on the results of this food effect study and based on our discussions with the FDA, men in our pivotal Phase III study will be instructed to take Tuclar with a meal. We do not anticipate sufficient food-induced variations to occur over repeat dosing in our pivotal Phase III study such that the average serum T response or the peak serum T levels would be adversely affected.

Phase II Dose Response Study

In 2008, we completed a Phase II clinical evaluation of five different T formulations in hypogonadal men. The study was designed to evaluate dose response, or the linearity of serum T levels, after an oral T dose. Twelve men were enrolled in the five-arm crossover study, with men washing out of current T-replacement therapy before beginning treatment in our study. Men received one or two oral T doses as TE or TU formulations. Each treatment day was followed by five to 14 days of washout without any T-replacement therapy before another oral T formulation was dosed. The five formulations were as follows:

400 mg T as TE, administered once daily;
Tuclar at a dose of 200 mg T, administered once daily;
Tuclar at a dose of 100 mg T, administered twice daily;
Tuclar at a dose of 200 mg T, administered twice daily; and
400 mg T as TE, administered twice daily.

We evaluated serum T pharmacokinetics for each formulation and determined that 200 mg T delivered as TU, administered twice daily, yielded optimal serum T levels. By only dosing men for a single day and then washing them out before administering the next formulation, we did not expect men to achieve serum T levels in the normal range because men cannot reach steady-state levels of T after a single day of treatment. Nonetheless, 75% of the 12 men achieved non-steady-state average serum T levels in the normal range, with a Cavg of 385 ng/dL. There were no treatment-related serious adverse events in this study.