Long-term Safety and Effectiveness of Growth Hormone Releasing Factor Tesamorelin for Lipodystrophy

By Liz Highleyman

Central fat accumulation is a concern for many HIV positive people taking antiretroviral therapy. Human growth hormone (GH) has been shown to reduce visceral adipose tissue (VAT), but it can lead to side effects including elevated blood glucose, swelling, bone pain, and carpal tunnel syndrome.

Visceral Fat.

Buffalo Hump

Growth hormone releasing factor (GHRF) -- a hormone produced by the hypothalamus that stimulates the pituitary to secrete more GH -- has also been studied for lipodystrophy, in the hope that it would provide similar benefits with fewer side effects than direct GH administration.

Tesamorelin (TH9507) is a GHRF analog being developed by Theratechnologies as a treatment for excess VAT in people with HIV. As previously reported, patients receiving tesamorelin for 26 weeks experienced a significant decrease in VAT and improved blood lipid levels. Longer-term findings were recently published in the September 12, 2008 issue of AIDS.

Initially, 273 HIV positive individuals on HAART with central fat accumulation were randomly assigned to receive 2 mg TH9507 once daily by subcutaneous injection, while 137 received placebo injections for 26 weeks. At that point, 111 patients originally assigned to placebo switched to tesamorelin, while those who originally received tesamorelin were re-randomized to receive either tesamorelin (n = 154) or placebo (n = 50) for an additional 26 weeks.

The primary purpose of the extension study was to determine the safety of 52 weeks of tesamorelin. Secondary objectives were to determine the durability of effect after treatment discontinuation in individuals who were initially treated with tesamorelin for 26 weeks and then with placebo for 26 weeks, as well as the sustainability of response in those treated with tesamorelin for the full 52 weeks.

Results

• The change in VAT -- a reduction of 18% from baseline -- was sustained over 52 weeks of treatment in patients who remained on tesamorelin (P < 0.001).

• The decrease in triglycerides (-51 mg/dL from baseline) was also sustained over 52 weeks (P < 0.001).

• Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein (HDL or "good") cholesterol decreased minimally over 52 weeks.

• Tesamorelin was generally well tolerated.

• The prevalence of adverse events and serious adverse events during the extension phase was comparable to that seen during the initial 26 weeks.

• 6 patients who stayed on tesamorelin experienced urticarial skin rash, similar to the number in the first 26-week phase.

• All but 1 rash was self-limiting; patients with rash discontinued tesamorelin and did well with no known negative outcomes.

• Changes in glucose parameters over 52 weeks were not clinically significant, and were similar to those after 26 weeks.

• Upon discontinuation of tesamorelin, VAT levels again increased toward the baseline levels in patients who switched to placebo.

Based on these findings, the researchers concluded, "Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose."

However, they continued, "Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment."

In their discussion, the authors noted that with long-term use of both GH and tesamorelin, levels of IGF-1 increased by approximately the same amount, but the effect on VAT with tesamorelin was almost twice that seen with GH, and side effects -- especially with respect to glucose levels -- "were not seen with tesamorelin as they were with even physiological GH dosing."

Montreal General Hospital, McGill University Health Centre, Montreal, Canada; Theratechnologies Inc., Montreal, Canada; St Luke's-Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons, New York, NY; Desert Regional Medical Center, Palm Springs, CA; Northstar Healthcare, Chicago, IL; AIDS Research Alliance, West Hollywood, CA; Kaiser Foundation Research Institute, San Francisco, CA; Phase V Technologies Inc., Wellesley Hills, MA; Massachusetts General Hospital and Harvard Medical School, Boston, MA.

9/16/08

Reference
J Falutz, S Allas, J-C Mamputu, and others. Long-term safety and effects of tesamorelin, a growth hormone-releasing factor analogue, in HIV patients with abdominal fat accumulation AIDS 22(14): 1719-1728. September 12, 2008.
(Abstract).