Growth hormone release factor (TH9507) reduces central fat adiposity

Stephen Grinspoon, from Massachusetts General Hospital, presented 26 weeks results from a Phase 3 study of TH9507, a growth hormone releasing factor analogue (GHRF) produced by Theratechnologies (Canada), in patients with central fat hypertrophy.

The study randomised 410 patients on stable HAART (80% <50 copies/mL) with central fat accumulations (mean waist:hip ratio 1.1 +/-0.1; waist circumference 104 +/- 10 cms) 2:1 to either 2mg/day TH9507 (n=273) or placebo (n=137) subcutaneously for 26 weeks. The primary endpoint was the percentage of change in visceral adipose tissue (VAT) by abdominal CT at L4-L5. Secondary endpoints included triglycerides, cholesterol-to-HDL ratio, and IGF-I. Based on FDA requirements, the study had 90% power to detect an 8% reduction in VAT between TH9507 and placebo. The group was 86% male, with an average age of 48 years (+/-9). 19% patients at baseline had type-2 diabetes or glucose intolerance.

There was approximately 20% drop out in both arms of the study: 211 patients in the GHRF and 115 patients in the placebo group completed the study.

At week 26, absolute VAT decreased significantly by 27.8cm3 in the GHRF group compared to an increase of +4.9 in the placebo group (p <0.001). Trunk fat by DEXA also decreased (1.0±1.9 vs +0.4±1.6 kg, p <0.001), with a smaller impact on abdominal SAT (+0.4±15.8 vs +1.8±14.5%, p = 0.05) and limb fat (0.0±0.8 vs +0.2±1.0 kg, p = 0.01). The lipid profile improved in the GHRF group with significant reduction in triglycerides (0.6±1.7 vs +0.1±1.3 mmol/L, p <0.001) and in cholesterol to HDL ratio (0.3±1.0 vs +0.2±1.0, p <0.001).

The side effect profile was similar between the two arms (ie headache 16% vs 17 %; arthralgia 13% vs 10%). A higher proportion of patients in the GHRF arm reported drug-related side effects (53% vs 34%) and discontinued due to side effects (12% vs 3%), but not for serious side effects (5% vs 2%). Approximately 2% patients had skin reactions, generally after four months treatment. There were no effects on glucose or insulin parameters in the study, nor increase in percentage of patients shifting to impaired glucose tolerance.

Earlier studies have shown that recombinant Human Growth Hormone (rHGH) has a similarly beneficial impact on central fat accumulation, although the dose-dependent response at the higher dose of 6mg/day was associated with unacceptable levels of side effects including hyperglycemia, though lower doses may have a therapeutic role with more acceptable tolerability.

Comment

Changes of 20% vs placebo over 6 months is a significant change. Changes in waist:hip ratio were reported but not detailed. An ongoing roll-over study is looking at tolerability out to week 48.

TH9507 will be studied in UK trial sites, due to start in March or April including at the Chelsea and Westminster and Royal Free Hospitals, and both sites will accept patient referrals from other clinics.

Entry criteria include increased waist circumference and specific waist-hip limits plus viral load under 10,000 copies/mL.

Participants will be randomised 2:1 to TH9507 vs placebo for 6 months, followed by an extension study where placebo patients will receive active drug.