[NATAP] TH9507, New Growth Hormone

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TH9507, New Growth Hormone

“A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulationâ€

AIDS: Volume 19(12) 12 August 2005 p 1279-1287

Falutz, na; Allas, Sorayae; Kotler, c; , d; Koutkia, Polyxenij; Albu, Jeanineb; Trottier, Benoith; Routy, Jean-Pierref; Cote, Pierreg; Abribat, Thierrye; Grinspoon, j

From the aMontreal General Hospital Immuno-Deficiency Treatment Centre, McGill University Health Center, Montréal, Quebec, Canada

bDivision of Endocrinology

cDivision of Gastroenterology, St Luke's Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons, New York, New York

dARCA (AIDS Research Consortium of Atlanta), Atlanta, Georgia, USA

eTheratechnologies, St. t

fDivision of Hematology and Immunodeficiency Service, Royal Hospital, Montreal

gClinique médicale du Quartier Latin, Montréal

hClinique Médicale l'Actuel, Montréal, Québec, Canada

jMass General Hospital Program in Nutritional Metabolism and Harvard Medical School, LON207, Mass General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT

Objective: To investigate the effects of TH9507, a novel growth hormone releasing factor, on abdominal fat accumulation, metabolic and safety parameters in HIV-infected patients with central fat accumulation.

Design and methods: Randomized, double-blind, placebo-controlled trial enrolling 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH9507 subcutaneously, once daily for 12 weeks. The primary outcome was change in abdominal fat, assessed by dual energy X-ray absorptiometry and cross-sectional computerized tomography scan. Secondary endpoints included change in insulin-like growth factor-I (IGF-I), metabolic, quality of life, and safety parameters.

Results:

--TH9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo).

--Trunk fat (DEXA) decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; placebo, 1 and 2 mg, respectively, P = 0.014 for 2 mg versus placebo), without significant change in limb fat. P-value=0.178 for 1 mg vs placebo, not significant.

--Visceral fat (VAT) decreased most in the 2 mg group (-5.4, -3.6 and -15.7%; placebo, 1 and 2 mg, respectively) but this change was not significant versus placebo.

--Subcutaneous fat (SAT) was preserved and did not change between or within groups.

--Lean body mass and the ratio of VAT to SAT improved significantly in both treatment groups versus placebo. Lean body mass increased in both treatment groups versus placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg, mean (SD) for placebo, 1 and 2 mg, respectively, P = 0.002 for change in 2 mg group versus placebo, P = 0.047 for the change in 1 mg group versus placebo

--Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo, but not significantly in the 1 mg group. LDL cholesterol did not change significantly.

--Treatment was generally well tolerated without changes in glucose. Adverse events listed below.

Conclusions:

--TH9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation.

--TH9507 may be a beneficial treatment strategy in this population, but longer-term studies with more patients are needed to determine effects on VAT, treatment durability, and safety.

RESULTS

Participant characteristics

Between May 2002 and November 2003, 88 patients were screened. Sixty-one subjects were randomized, 21 to placebo, 19 to TH9507 1 mg and 21 to TH9507 2 mg. Five subjects discontinued in the placebo group, two in the 1 mg group and six in the 2 mg group, for a 79% completion rate.

At baseline no significant differences were seen between the groups in demographic characteristics, including use of antiretroviral therapy. The percentage of patients with diabetes (2 h-glucose ≥ 11.1 mmol/l) and impaired glucose tolerance (7.8 mmol/l ≤ 2 h-glucose < 11.1 mmol/l) was not different between the groups. Among the entire study group, 20% of subjects demonstrated impaired glucose tolerance (IGT) and 5% demonstrated diabetes mellitus at baseline. Use of lipid-lowering medications did not differ among the groups.

Body composition

Body composition variables were not different between the groups at baseline. Trunk fat decreased in the 2 mg group versus placebo (0.8, -4.6 and -9.2%; for placebo, 1 and 2 mg groups, respectively, P = 0.014 for 2 mg group versus placebo), whereas extremity fat did not change in comparison to placebo. Visceral fat (VAT) decreased most in the 2 mg group [-5.4, -3.6 and -15.7%; for placebo, 1 and 2 mg, respectively, (P = 0.03 for change within group) but this change was not significant versus placebo]. Subcutaneous fat (SAT) did not change significantly between the groups and the ratio of VAT: SAT decreased more in the treatment groups versus placebo [0.01 (0.10), -0.23 (0.47), -0.14 (0.18); for placebo, 1 and 2 mg groups, respectively] (P = 0.008 for 2 mg versus placebo and P = 0.043 for 1 mg versus placebo]. The ratio of trunk to leg fat did not decrease compared to placebo, but decreased within the treatment groups.

Lean body mass increased in both treatment groups versus placebo [-0.5 (1.6) kg, 0.7 (2.0) kg, and 1.7 (2.3) kg, mean (SD) for placebo, 1 and 2 mg, respectively, P = 0.002 for change in 2 mg group versus placebo, P = 0.047 for the change in 1 mg group versus placebo, Table 2]. Total fat decreased in the 2 mg group compared to placebo [0.3 (1.7) kg, -0.4 (1.8) kg and -1.4 (2.0) kg; for placebo, 1 and 2 mg, respectively, P = 0.013 for 2 mg group versus placebo]. Weight did not change significantly between the groups.

Biochemical indices

Biochemical indices did not differ between the groups at baseline except for the ratio of total cholesterol: HDL, which was higher in the 1 mg group (Table 2). IGF-I increased significantly with the 1 and 2 mg dose versus placebo [21.8 (33.2) ng/ml, 79.0 (68.4) ng/ml, 102.5 (79.3) ng/ml; last observation values for placebo, 1 and 2 mg, respectively, P < 0.01 for each active group versus placebo]. Similar changes in IGF-I were seen using 12-week data.

Using last observation values, triglyceride levels decreased in the 2 mg group compared with placebo [-0.2 (1.3) mmol/l, -0.9 (4.2) mmol/l, -0.9 (1.2) mmol/l; for placebo, 1 and 2 mg, respectively, P = 0.013 for 2 mg versus placebo] and the ratio of cholesterol: HDL improved in both treatment groups versus placebo [0.3 (1.1), -0.3 (0.7), -0.3 (0.6); for placebo, 1 and 2 mg, respectively, P = 0.013 for 2 mg group versus placebo and P = 0.051 for 1 mg group versus placebo]. HDL increased within the 2 mg group, but did not change significantly compared to placebo in either treatment group. Changes in triglycerides, the ratio of total: HDL cholesterol, and HDL were not significantly different between the groups using 12-week data.

Changes in fasting and 120 min glucose were not significant between or within the treatment groups. Among subjects with normal glucose tolerance at baseline (n = 45), three subjects in the 2 mg group versus none in the 1 mg group versus three in the placebo group developed IGT and no patient developed DM. Among patients with IGT at baseline (n = 12), no subject developed DM. Changes in fasting insulin and HOMA-R were not different between the groups but fasting insulin and HOMA-R increased from baseline within the 2 mg group. HbA1C decreased within the placebo group [-0.3(0.5)% P = 0.03)] and increased within the 1 mg group [0.2 (0.4)%, P = 0.02 for within group change and P = 0.002 versus placebo]. No change was seen within the 2 mg group [-0.0 (0.5)%, P = 0.60] or in comparison to placebo.

Bone markers

Osteocalcin increased significantly within the 2 mg group, whereas no changes with NTX were seen.

Quality of life

Baseline quality of life indices were not different among the groups except for social well-being. Significant differences over time between groups were not seen for the six subscales of the general portion of the quality of life questionnaire [16]. Changes in reported abdominal bloating were significant between groups and bloating decreased significantly within the 2 mg group. Although not significant between groups, abdominal pain decreased significantly within the 1 mg group, and enlarged abdominal girth decreased significantly within the 2 mg group.

Immunologic parameters

CD4 cell counts [28(104), 24(147) and -40(77): for placebo, 1 and 2 mg, respectively] did not change significantly between (P = 0.126) or among groups. Viral load remained undetectable in the majority of patients and did not change significantly within treatment groups.

Adverse events and discontinuation

Discontinuation rates were not different between the groups (24, 11 and 29%; for placebo, 1 and 2 mg, respectively). One subject in the placebo group (arthritis), none in the 1 mg group and three in the 2 mg group (rash, arthralgia, paresthesia) experienced adverse events leading to treatment discontinuation. There were 18 severe adverse events that occurred in two patients (9%) in the placebo, 5 (26%) in the 1 mg group and three (14%) in the 2 mg group. Musculoskeletal adverse events such as pain and arthralgias were noted in 24, 26 and 29% of subjects in the placebo, 1 and 2 mg groups, respectively (Table 4). Carpal tunnel symptoms were not noted in any patient. Edema and/or peripheral swelling were noted in one patient in the 2 mg group only. Headache was noted in 14, 21 and 29% in the placebo, 1 and 2 mg groups, respectively. Paresthesias were noted in 0 (0%), 1 (5%) and 3 (14%) of subjects in the placebo, 1 and 2 mg groups, respectively. Blood pressure and heart rate did not change between or within the groups. One patient in the placebo group compared to three in the 2 mg group withdrew from the study related to adverse events.

Safety laboratory values, including hemoglobin, white blood cell, liver function tests, and creatinine did not differ between the groups (data not shown). Anti-TH9507 antibodies were not detected after 12 weeks in any patient.

Table 4. Adverse events seen in more than 5% of subjects, ranked by frequency.

AUTHOR DISCUSSION

HIV-infected patients on chronic antiretroviral therapy often demonstrate changes in fat distribution, including increased abdominal adiposity in association with insulin resistance and dyslipidemia [1,3], which may increase risk for CVD in this population [4,22,23]. Recent studies suggest that GH secretion is decreased in these patients in association with increased visceral adiposity [8,9]. Strategies using high dose, pharmacologic GH have been shown to decrease visceral fat but aggravate hyperglycemia in this population [11,12]. We hypothesized that a strategy to increase GH within the physiologic range would improve fat distribution and decrease truncal and visceral fat with fewer adverse effects. We therefore assessed the effect of TH9507, a growth hormone releasing factor (GRF) analog on abdominal fat accumulation and relevant metabolic indices in patients with HIV lipodystrophy. GH stimulating analogs increase GH pulsatility but may lead to less toxicity if feedback inhibition of IGF-I on the pituitary is intact. The GRF analog used in this study is not commercially available but was assessed under an Food and Drug Administration investigational new drug (FDA IND).

TH9507, a GRF analog, resulted in significant but physiologic increases in IGF-I, an integrated measure of GH secretion. Trunk fat demonstrated a graded dose-response effect, with a significant reduction in response to 2 mg. Visceral fat decreased most in the 2 mg group, but this change was not significant compared to placebo. In contrast, the ratio of VAT: SAT improved significantly compared to placebo. Larger studies are necessary to determine the statistical and clinical significance of reduced VAT in response to GRF, but the percent decrease in VAT in this study was similar in magnitude, 15% over 3 months, to that shown by GH in the recent STARS study of pharmacologic GH [10]. Furthermore, the lack of a significant effect on extremity and subcutaneous fat may be an advantage of GRF compared to other strategies using pharmacologic GH, in which both visceral and subcutaneous fat decrease [10]. Preservation of extremity and subcutaneous fat is of critical importance to patients with significant lipoatrophy