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Tesamorelin FDA Briefing Document pdf attached
 
 
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Glucose metabolism - Summary and Conclusions:
 
During the Main Phase of the trials:
· There were no clinically meaningful changes in mean values for fasting blood glucose, fasting insulin, HOMA-IR and HbA1c at Week 26 between tesamorelin- and placebo-treated patients.
 
· At post-baseline evaluations, there was a trend of worsening glucose status in individual patients treated with tesamorelin as indicated by the larger proportions of patients who shifted from normal fasting blood glucose or HbA1c to abnormal values (in the range of glucose intolerance, prediabetes, or DM) relative to placebo.
 
· There was a statistically significant difference in the proportion of patients who developed DM in the tesamorelin group relative to placebo: Odds Ratio (95%CI) of 3.4 (1.3, 11.5) or 3.6 (1.5, 12.0) depending on whether baseline DM cases were excluded or not.
 
During the Extension Phase of the trials there were no convincing data to indicate deterioration in the glucose status in patients who were continued on tesamorelin, while patients who were switched to placebo seemed to remain stable or slightly improve. This observation has to take into consideration that the potential effect of dropouts is not known.
 
Additional analyses of glucose metabolism
 
Main Phase

 
Table A21 illustrates shifts in FBG over the 26 weeks of the Main Phase based on patients' baseline state of glycemic control (normal BG, IFG/IGT, or DM). Among patients who started with normal BG at baseline, tesamorelin-treated patients had a greater tendency to shift into a "more severe" category of glucose tolerance at Weeks 13 and 19. At Week 13, 66.9% of patients in the tesamorelin group who started in the normal category remained normal, as opposed to 80.0% of patients in the placebo group. At Week 19, the proportion of patients in the tesamorelin group who started and remained in the normal category had dropped to 60.8%, as opposed to 70.7% of patients in the placebo group. However, by Week 26, the proportions were similar in the tesamorelin (70.7%) and placebo groups (70.0%).
 

Among patients who were considered to have IFG/IGT at baseline, as a whole, patients in the placebo group tended to shift into a "better" category (i.e. toward normal BG) compared to those in the tesamorelin group. At Weeks 6, 13, 19, and 26, 36.4%, 44.6%, 27.5% and 34.2% of placebo patients who started with IFG/IGT had shifted into the normal group. In comparison, at these timepoints 24.0%, 28.9%, 20.1% and 19.5% of tesamorelin-treated patients had shifted from IFG/IGT to the normal group. At Weeks 13 and 19, a greater proportion of tesamorelin-treated patients who started with IFG/IGT had shifted into the DM group compared with placebo-treated patients (9.3% and 9.2% for tesamorelin patients compared with 3.6% and 2.7% for placebo patients). However, by Week 26 the proportions of patients who started with IFG/IGT and shifted into the DM group were similar between the tesamorelin (13.7%) and placebo groups (15.1%).
 
Although the data seems to indicate that a greater proportion of tesamorelin-treated patients compared with placebo-treated patients who started in the DM category stayed in the same category over the course of the Main Phase, the number of patients who started with DM in each treatment arm is too small to draw conclusions.
 
Table A22 lists all the individual patients who had at least one FBG value of ≥126 mg/dL (i.e. DM range) during the Main Phase of the Pivotal Studies. The table displays all the FBG values that these patients had in addition to the ≥126 mg/dL measurements, which are marked with an asterisk. Its purpose is to give a visual display of what the patterns of FBG changes were for these patients. For instance, because patients with FBG in the DM range at baseline are presented at the beginning of the list for each treatment group, one can visually observe that for patients in the placebo group most post-baseline observations were within the normal range. For the tesamorelin group it appears that post-baseline values were about equally split between diabetic and non-diabetic categories. Visual inspection of FBG values ≥126 mg/dL observed for the first time in at post-baseline, indicates a larger number of individual patients with such values in the tesamorelin group. The patterns are quite variable with some patients developing FBG in the diabetes range which persist throughout the trial, while others return to non-diabetic values.
 
Table A23 looks at shifts in HbA1c over the 26 weeks of the Main Phase based on patients' baseline state of glycemic control (normal BG, pre-diabetes, or DM). Among patients who started with normal BG at baseline, tesamorelin-treated patients had a greater tendency to shift into a "more severe" category of glucose tolerance at Weeks 13 and 26. At Week 13, 84.5% of patients in the tesamorelin group who started in the normal category remained normal, as opposed to 91.7% of patients in the placebo group. At Week 26, the proportion of patients in the tesamorelin group who started and remained in the normal category had dropped to 82.2%, as opposed to 86.3% of patients in the placebo group.
 
Among patients who were considered to have pre-diabetes at baseline, as a whole, patients in the placebo group tended to shift into a "better" category (i.e. toward normal HbA1c) compared to those in the tesamorelin group. At Weeks 13 and 26, 32.5 and 30.6% of placebo patients who started with pre-diabetes had shifted into the normal group. In comparison, at these timepoints 21.5% and 19.4% of tesamorelin-treated patients had shifted from pre-diabetes to the normal group. Similarly, at Weeks 13 and 26, a greater proportion of tesamorelin-treated patients who started with pre-diabetes had shifted into the DM group compared with placebo-treated patients (19.0% and 25.4% for tesamorelin patients compared with 5.0% and 11.1% for placebo patients).
 
Although the data seems to indicate that a greater proportion of tesamorelin-treated patients compared with placebo-treated patients who started in the DM category stayed in the same category over the course of the Main Phase, the number of patients who started with DM in each treatment arm is too small to draw conclusions.
 

Table A24 evaluates each individual patient who had at least one HbA1c value of ≥6.5% (i.e. DM range) during the Main Phase of the Pivotal Studies and displays their HbA1c trends over time. It clearly indicates that there were more patients in the tesamorelin group who developed post-baseline HbA1c values >6.5% and overwhelmingly they tended to stay that way.
 
Extension Phase
 
Table A25 looks at shifts in FBG over the 26 weeks of the Extension Phase (T-T and T-P groups) based on patients' baseline state of glycemic control (normal BG, IFG/IGT, or DM). Among patients who started with normal BG at baseline, T-T patients had a greater tendency to shift into a "more severe" category of glucose tolerance at Weeks 45 but were otherwise similar to T-P patients. At Week 45, 74.0% of patients in the T-T group who started in the normal category remained normal, as opposed to 87.3% of patients in the T-P group. However, at all other timepoints by Week 26, the proportions were similar in the T-T and T-P groups.
 
Among patients who were considered to have IFG/IGT at baseline, as a whole patients in the T-P group tended to shift into a "better" category (i.e. toward normal BG) midway through the Extension Phase compared to those in the T-T group, before equalizing by Week 52. Although proportions who had shifted into the normal category were similar at Week 32, at Weeks 39 and 45, 55.6% and 41.0% of T-P patients who started with IFG/IGT had shifted into the normal group. In comparison, at these timepoints 45.6%, and 24.5% of T-T patients had shifted from IFG/IGT to the normal group. However, by Week 52 the proportions of patients who started with IFG/IGT and shifted into the normal group were similar between the T-T (35.9%) and placebo groups (37.1%).
 
The number of patients who started with DM in each treatment arm is too small to draw conclusions for the FBG shift data.

Table A26 lists all the individual patients who had at least one FBG value of ≥126 mg/dL (i.e. DM range) during the Extension Phase of the Pivotal Studies and displays their FBG trends over time, in addition to the ≥126 mg/dL measurements, which are marked with an asterisk. Its purpose is to give a visual display of what the patterns of FBG changes were for these patients. There were more patients with FBG ≥126 mg/dL at the beginning of the extension phase in the T-T group. The overall pattern of changes was variable.
 
Table A27 looks at shifts in HbA1c over the 26 weeks of the Extension Phase based on patients' baseline state of glycemic control (normal BG, pre-diabetes, or DM). Among patients who started with normal BG at baseline, results for both T-T and T-P patients were similar, with the vast majority remaining in the normal category at Weeks 39 and 52. Specifically, at Week 39, 96.0% of patients in the T-T group who started in the normal category remained normal, as did 92.8% of patients in the placebo group. At Week 52, the proportion of patients in the T-T group who started and remained in the normal category was 93.0%, as did 95.7% of patients in the placebo group.
 
Among patients who were considered to have pre-diabetes at baseline, patients in the T-P group tended to shift into a "better" category (i.e. toward normal HbA1c) compared to those in the T-T group. At Weeks 39 and 52, 57.1% and 35.0% of T-P patients who started with pre-diabetes had shifted into the normal group. In comparison, at these timepoints 42.0% and 29.5% of T-T patients had shifted from pre-diabetes to the normal group. There were too few patients who had shifted into the DM group to draw conclusions. Similarly, the number of patients who started with DM in each treatment arm is too small to draw conclusions.
 

Table A28 evaluates each individual patient who had at least one FBG value of ≥6.5% (i.e. DM range) during the Main Phase of the Pivotal Studies and displays their FBG trends over time.
 
 
 
 
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