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Efficacy and Long-Term Safety of Tesamorelin (TH9507), a Growth Hormone-Releasing Factor (GRF) Analogue, in Sub-Populations of HIV-Infected Patients with Excess Abdominal Fat
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Reported by Jules Levin
ICAAC Sept 14 2010 Boston
Monika Zoltowska1 , Josee Morin1 , Steven Glyman2 , and Graziella Soulban1
1Theratechnologies Inc., Montreal, Canada; 2EMD Serono Inc., Rockland, Massachusetts, USA.
ICAAC: Reduction in Visceral Adipose Tissue (VAT) with Tesamorelin Correlates with Changes in Anthropometric, and Patient-Reported Outcome (PRO) Parameters in HIV+ Patients with Excess Abdominal Fat - (09/14/10)
From Medscape report: "A pooled analysis of 2 phase 3 clinical trials showed the efficacy of tesamorelin in reducing VAT, regardless of age, gender, race, hepatitis status, or antiretroviral regimen. Also, waist circumference measurements correlated with reductions in VAT seen on computed tomography [CT] scans," said Sophie Elise Michaud, PhD, an employee of Theratechnologies Inc. in Montreal, Quebec, who was coauthor of one of the studies. Tesamorelin is an investigative analog of growth-hormone-releasing factor and growth-hormone-releasing hormone. The drug is pending approval by the US Food and Drug Administration (FDA), but some investigators are not enthusiastic about using it, except perhaps for specific indications. "This drug has not been approved by the FDA yet," said Jens Lundgren, MD, from the University of Copenhagen HIV Programme in Denmark. "It may be that tesamorelin adversely affects other metabolic parameters, which is a concern. Are the cosmetic effects worth the side effects? The FDA will decide that," he noted. In Dr. Lundgren's opinion, even if tesamorelin is approved, it will not be used that often. "As soon as the drug is stopped, the fat comes back, so treatment would have to be lifelong," he explained. Patients with VAT could try diet and exercise for their bellies, he added. Tesamorelin might find a role as a treatment for the few patients with pathologic interabdominal fat that interferes with respiration, Dr. Lundgren continued. "If there is a niche for this drug, this might be it," he stated.
AUTHOR CONCLUSIONS
These results suggest that tesamorelin significantly reduces VAT in different sub-populations of HIV-infected patients with abdominal lipohypertrophy, including women, patients with hepatitis, patients with detectable viral load, and non-caucasian patients. Long term safety was similar between these subgroups and the main population of treated patients.
ABSTRACT
Background: Treatment with tesamorelin was consistently shown to significantly reduce visceral adipose tissue (VAT) in HIV- infected patients with lipohypertrophy, with an overall acceptable safety profile. The objective of this study was to determine the efficacy and safety of tesamorelin among different sub-populations of these patients.
Method: A total of 816 HIV-infected patients with excess abdominal fat were randomized in two phase 3 multicenter, randomized, double-blind, parallel-group trials, each consisting of a 26-week, placebo- controlled primary intervention phase followed by a 26- week extension phase to assess long-term safety and duration of effects. Subgroups were based on race, gender, age, hepatitis status (present or absent), antiretroviral therapy and viral load. The analyses were performed on combined results from the 2 trials, using an ANCOVA model controlling for each covariate for efficacy assessment and descriptive statistics for safety evaluation.
Results: Baseline subpopulation's characteristics were similar between tesamorelin and placebo groups. The mean age was 48 years, with the majority of patients being male (85%), Caucasian (76%), presenting no-hepatitis (78%) and with undetectable viral load (76%). At 26 weeks the effect of tesamorelin on VAT compared to placebo was consistent with the primary analyses across different subgroups with no statistically significant treatment-by-covariate interaction (P> 0.1 for all covariates). No important differences in AE profile were observed in any subgroups throughout the 52 weeks of treatment.
Conclusion: This data suggest that tesamorelin efficaciously reduces VAT in different sub-populations of HIV-infected patients with lipohypertrophy, without any clinically meaningful differences in long-term safety.
INTRODUCTION
A significant number of HIV-infected patients on antiretroviral therapy (ART) develop lipodystrophy, a condition characterized by body changes, including accumulation of fat in the visceral compartment, and multiple metabolic disturbances such as dyslipidemia and insulin resistance, and present an increased risk of cardiovascular diseases (1,2). Treatment with tesamorelin, a stabilized analogue of growth hormone-releasing factor (GRF), has been shown in two similar Phase 3 trials to significantly reduce visceral adipose tissue (VAT), and triglycerides levels and to improve patient-reported outcomes related to body image at 26 weeks in HIV- patients with excess abdominal fat (3). An additional 26 week-treatment showed a sustained VAT loss along with an overall acceptable long-term safety profile (4). Here we report additional data on efficacy on VAT following 26 weeks of treatment and long term-safety among different sub-populations of these patients.
RESULTS
Table 1. Baseline demographics and clinical characteristics of the patients entering the main phase of the study (N= 806) (0-26 weeks). Data are presented as Mean ± SD when applicable.
Figure 1. Forest plot of the effect size and 95% C.I. of the percent (%) change from baseline in VAT at week 26 among different subgroups. No statistically significant treatment-by-covariate interactions were observed for the percent change frombaseline in VAT at week 26 when age, gender, ethnic origin or hepatitis status (present or absent) were included as categorical covariates.
Figure 2. Percent (%) change in VAT per ART regimen after 26 weeks of treatment. The % change from BL in VAT was not statistically significant between tesamorelin groups on different ART regimen (Treatment-by-ART interaction P=0.82). Data are Mean ± SEM. *P<0.05 vs Placebo.**P<0.001 vs Placebo.
Table 2. Overall adverse events incidence rates (0-52 weeks). (1)The P-T group, which represents de novo treatment with tesamorelin is not presented since all safety data in this group consistently mirrors the observations made for the tesamorelin group in the main phase; (2) The proportion of subjects who reported at least one AE was comparable between tesamorelin and placebo groups during the main phase (78.3 % vs. 71.1 %, respectively) as well as between the T-T and T-P groups during the extension phase (62.6 % vs. 60.0 %, respectively). (3) The majority of AEs were of mild or moderate severity in all treatment groups. (4) The incidence of AEs was greater during 0-26 weeks than during 27-52 weeks. No AEs were identified that might occur primarily after extended treatment. (5) Subpopulations analyses of AEs indicated that, in general, there were no clinically notable differences in the overall incidence nor in pattern of AEs among the subgroups. * 47 years is the median age among 18-64 old year age group in the main phase and 48 years is the median age among 18-65 year old age group in the extension phase.
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