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Growth Hormone Releasing Factor Tesamorelin Reduces Visceral Fat in HIV Positive People with Lipodystrophy

The growth hormone releasing factor tesamorelin (brand name Egrifta, formerly TH9507)reduced the amount of visceral abdominal fat in HIV positive people with central fat accumulation and led to improved feelings about body image, researchers reported in the March 1, 2010 Journal of Acquired Immune Deficiency Syndromes. Tesamorelin lowered total cholesterol and did not cause significant side effects, including blood glucose abnormalities.

Abdominal fat accumulation -- an aspect of lipodystrophy syndrome -- is a concern for many HIV positive people, both in terms of body image and cardiovascular risk. Administration of human growth hormone has been shown to reduce visceral adipose tissue (fat deep within the abdomen), but it can lead to side effects including elevated blood glucose, swelling, bone pain, and carpal tunnel syndrome.

In contrast to administering growth hormone directly, tesamorelin is a growth hormone releasing factor that stimulates the pituitary gland in the brain to secrete more growth hormone. Investigators hypothesized that it might provide similar benefits with fewer adverse effects, and this was supported by initial studies.

Julian Falutz from McGill University School of Medicine and colleagues investigated the effects of tesamorelin in 404 HIV positive participants on antiretroviral therapy (ART) who had excess abdominal fat.

This double-blind Phase 3 trial consisted of 2 sequential parts. During the first 6 months, patients were randomly assigned (2:1) to receive daily subcutaneous injections of 2 mg tesamorelin or placebo. In the extension phase (months 6-12), participants initially receiving tesamorelin were randomly assigned (1:1) to either continue on the same tesamorelin regimen or switch to placebo, while patients initially randomized to placebo switched to tesamorelin.

The primary endpoint was changes in visceral adipose tissue, assessed with both CT and DEXA scans. Secondary endpoints included other body composition measurements, body image, levels of insulin-like growth factor-1 (a protein produced in response to growth hormone stimulation), and safety parameters.

Results

• Visceral adipose tissue decreased by 10.9% (21 cm2 or about 1 kg) on average in the tesamorelin group versus a 0.6% (1 cm2 or about 0.2 kg) decrease in the placebo group during the first 6 months (P < 0.0001).
• Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-to-hip ratio (P = 0.001) all improved significantly, with no changes in limb or subcutaneous abdominal fat.
• Patients reported significantly less distress about belly appearance in the tesamorelin group compared with the placebo group (P = 0.02).
• Physicians' ratings of patient belly appearance also improved significantly (P = 0.02).
• Among participants who continued on tesamorelin for 12 months, visceral adipose tissue decreased by 17.5% (P < 0.001).
• However, the visceral adipose tissue improvements of the first 6 months were rapidly lost in patients who switched from tesamorelin to placebo.
• Patients receiving tesamorelin did not experience a significant decrease in triglycerides compared with placebo (as was seen in a prior Phase 3 study), but there was a trend in this direction.
• Participants who received tesamorelin for 12 months experienced a significant decrease in total cholesterol.
• Tesamorelin was well-tolerated overall.
• Levels of insulin-like growth factor-1 increased significantly, but there was no apparent change in glucose parameters.
• About 4% of participants experienced hypersensitivity reactions, which were generally mild; a few discontinued therapy prematurely for this reason.

Based on these findings, the study authors concluded, "Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose."

With these new data, they added, "there are now consistent results from two large Phase 3, randomized, placebo-controlled studies to suggest that [tesamorelin] is a potentially useful clinical strategy to selectively reduce visceral adipose tissue and improve body image among HIV-infected patients with abdominal fat accumulation in the context of antiretroviral therapy."

Montreal-based developer Theratechnologies has requested approval of tesamorelin from the U.S. Food and Drug Administration; and the agency will told a public meeting on May 27, 2010 to discuss the topic.

Affiliations: Department of Medicine, Montreal General Hospital and McGill University School of Medicine, Montreal, Canada; Massachusetts General Hospital and Harvard Medical School, Boston, MA.

4/2/10

Reference

J Falutz, D Potvin, JC Mamputu, and others. Effects of Tesamorelin, a Growth Hormone-Releasing Factor, in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Placebo-Controlled Trial With a Safety Extension. Journal of Acquired Immune Deficiency Syndromes 53(3): 311-322. March 1, 2010.