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Tesamorelin Reduces VAT: FDA Hearing
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reported by Jules Levin
In the public hearing section several HIV+ patients who benefited from tesamorelin spoke at the microphone who were of course emotionally moving including a community advocate urging approval of the drug. They ralked about how belly fat affected them, disfigured them, stigmatized them, made them feel bad, and use of tesamorelin reduced the size of their belly and improved self-image. A Theratechologies spokesman tried to mitigate the concerns about glucose abnormalities; discussed a 3.4% developing diabetes on tesamorelin vs 1% on placebo among people I think he said completing the study while I think the ITT analysis was 4% vs 1%. So in other words they are saying the risk for diabetes development is not great. The sponsor alluded to the point that Steve Grinspoon made before that glucose abnormalitis appear to reverse given more time. Grinspoon said a reduction in waist circumference is detectable by measure in the clinic and reflects a benefit for patient and reduced VAT by CT scan in the studies. So patients with a reduced waist circumference on drug can continue and feel they are receiving benefit & the clinician as well can feel the patient is benefiting but a patient without this reduction can stop the drug. I believe it was a pasnelist who just said patients on the drug with the highest levels of triglycerides appear to be achieving the greatest reductions o drug in triglycerides.
"among patients who discontinued, more patients discontinued due to adverse events in the tesamorelin group (40.0%) than placebo (32.1%) and more tesamorelin patients were non-compliant (10% vs. 1.8% placebo)."
Primary efficacy analysis
The primary efficacy analysis was a drug-to-placebo comparison of the percent change in VAT from baseline to Week 26 using an analysis of covariance (ANCOVA). The results, as analyzed by the FDA statistical reviewer, are presented in Table 4 for the intent-totreat (ITT) population. The mean absolute change from baseline in VAT for tesamorelin relative to placebo was -31.9 cm2 in Study 10 and -20.6 cm2 in Study 11. The prespecified primary efficacy analysis, the mean % change in VAT in the tesamorelin group relative to placebo, was statistically significant (p<0.001) in each of the studies. Specifically, the mean % change in VAT was -19.6% (95% CI: -23.7, -15.3) in Study 10 and -11.7% (95% CI: -16.2, -7) in Study 11.
An analysis of VAT % change conducted in completers indicated similar results (Table 5). It is not entirely clear why the two trials yielded quite different VAT reductions given the similarity in design, inclusion criteria, and baseline patient characteristics. Compliance does not seem to have played a part because the percentage of patients who were <80% compliant in the tesamorelin arm was actually lower in Study 10 (26.2%) versus Study 11 (39.5%), while they were similar in the placebo arms (25% in Study 10 and 20.6% in Study 11).
Efficacy data pooled from both studies is presented by time on trial in Table 6 (next page). The mean VAT at baseline was 182.36 cm2 for the tesamorelin group and 182.49 cm2 for the placebo group. After 13 weeks of treatment, the mean percent change from baseline in VAT was statistically significantly greater in the tesamorelin group (decrease of 10.32%) compared with the placebo group (increase of 1.36%). By week 26, the mean percent change in the tesamorelin group showed a decrease of 13.11% compared to an increase of 2.30% in placebo (p<0.001).
Secondary efficacy endpoints
Secondary endpoint analyses were the change from baseline in the IGF-1 level, total cholesterol: HDL-C ratio, TG level, and patient reported outcomes (PROs): belly size evaluation, belly appearance distress, and belly profile.
Triglycerides
Fasting triglycerides were measured at Weeks 0, 6, 13, 26 and were analyzed centrally. The statistical results were inconsistent between the two trials. In Study 10 tesamorelin was superior to placebo (mean reduction of 52.8 mg/dl relative to placebo, p<0.001). In Study 11 the placebo-subtracted triglyceride reduction of 19.9 mg/dl did not reach statistical significance (p=0.1). An ANCOVA analysis provided by the FDA statistical reviewer (using treatment, lipid lowering treatment (Y/N) as fixed effect and baseline TG as covariate) confirmed that the TG change from baseline was statistically significant in Study 10 but not in study 11 (Table 14).
Total Cholesterol: High-density Lipoprotein Cholesterol Ratio
Total cholesterol and HDL-C were measured from fasting blood samples which were analyzed centrally. Measurements were performed at Weeks 0, 6, 13, and 26. As shown in Table 15 the treatment group difference in Study 10 achieved statistical significance p<0.001 but this observation was not confirmed in Study 11 (p<0.094).
Non HDL-Cholesterol
Non-HDL-C was measured from fasting blood samples and was analyzed centrally. Fasting blood samples were collected at Weeks 0, 6, 13, and 26. The reduction observed in Study 10 reached statistical significance, but again this result was not confirmed in Study 11 (Table 16).
Other Endpoints
Table 17 describes the changes from baseline to Week 26 in various parameters of body composition.
The main findings from Table 17 are listed next:
· The mean change from baseline in abdominal subcutaneous tissue (SAT) was not significantly different between tesamorelin and placebo subjects. (see table to look at SAT reductions on reasmorelin although not statistically significant)
· The change from baseline in the VAT/SAT ratio was significantly different between tesamorelin and placebo subjects (p<0.001), as was the primary efficacy endpoint, VAT.
· The mean change in total fat at both Weeks 13 and 26 was significantly different (p<0.001) between tesamorelin and placebo patients; the mean changes from baseline at Weeks 13 and 26 were -0.93 and -0.98 kg, respectively, in the tesamorelin group and +0.26 and +0.46 kg, respectively, in the placebo group.
· The mean change from baseline in limb fat (total, lower limb, and upper limb fat) was statistically significantly different between the tesamorelin and placebo treatment groups at Week 26; however, this difference was not considered clinically significant.
· The mean change in trunk fat at both Weeks 13 and 26 was significantly different (p<0.001); the mean changes from baseline at Weeks 13 and 26 were -0.82 and 0.90
kg, respectively, in the tesamorelin group and +0.14 and +0.28 kg, respectively, in the placebo group. The results of mean change from baseline in trunk fat for the PP population were generally similar to those described for the ITT population.
· The mean change from baseline in lean body mass (LBM) was statistically significantly different between the groups at each time point (p<0.001); the tesamorelin group showed increased LBM, whereas the placebo group showed decreased LBM, at both Week 13 (+1.23 vs. -0.08 kg, respectively) and Week 26 (+1.27 vs. -0.14 kg, respectively).
Anthropometric Measurements
Waist and hip circumferences were measured at Weeks -4 (screening), 13, and 26. In summary:
· The mean waist circumference decreased from baseline in both treatment groups at Week 26, but a greater decrease was observed in the tesamorelin group; across both studies the mean change from baseline relative to placebo was approximately
1.5 cm (p<0.001) and it was statistically significant for each study (p<0.001 for Study 10, p=0.013 for Study 11).
· The mean hip circumference increased in both arms in Study 10 (p=0.021) and was not statistically different from placebo in Study 11 or in the pooled analysis.
· The mean waist:hip ratio was statistically significantly different in Study 11, in Study 10 and in the pooled analysis.
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