TH-9507, a Growth Hormone Releasing Factor Shows Early Promise as an Effective and Safe Therapy for HIV-related Central Obesity

Despite much effort by researchers, there is as yet no known effective treatment for any aspect of the HIV-related lipodystrophy syndromes. The effects of these syndromes, due most likely to the use of antiretrovirals, have resulted in an increase in serious health risks for HIV patients on HAART, including increased risk of cardiovascular disease and myocardial infarction rates.

The syndromes also have adversely affected the quality of life of many HIV positive individuals on HAART by significantly altering the shape of the central trunk area of the body (central visceral adiposity) or the breasts (in women) or the back of the neck (buffalo hump).

The use of recombinant human growth hormone/ rhGH (Serostim) has been studied as a treatment for the reduction of central visceral fat accumulation in HIV patients. Studies using higher dose Serostim have resulted in reduced visceral adiposity in individuals with fat redistribution, but also are associated with increased insulin resistance and side effects, which has limited its potential as an treatment for this condition.

Researchers have continued to explore the potential of growth hormone, in other forms, to positively impact increased visceral and central fat accumulation in HIV patients. There is encouraging evidence for success from the results of a multi-center, dose-ranging study of TH-9507, a growth hormone releasing factor. The results of this Phase II dose-ranging study are promising enough to suggest that researchers may have found in TH-9507 the first agent with the capability to significantly reduce increased visceral and central fat accumulation without increasing insulin resistance and unwanted side effects.

TH-9507 (Theratechnologies, Inc, St-Laurent, Canada), a synthetic analog that comprises the 44-amino acid sequence of human growth hormone releasing factor (hGRF). The in vitro half-life of TH-9507 is 3-8 hours compared to 0.56 hours for hGRF. Daily 1 and 2 mg doses have been shown to increase IGF-I to the physiological range seen in younger adults. The drug, an injectible, is not yet available commercially. However, Theratechnologies is now actively recruiting patients for a Phase III registration trial of TH-9507.

TH-9507 also has been studied in 53 patients with Type II diabetes mellitus (DM), and was not shown to aggravate overall glycemic control when administered at a daily dose up to 2 mg. Administration of the 1 and 2 mg doses of TH-9507 for 3 months in 109 patients with chronic obstructive pulmonary disease resulted in similar overall incidence of adverse events in all groups, including placebo.

Results of the current dose-ranging study appear in the August 12, 2005 issue of AIDS. Preliminary results of this study were first presented at the 6^th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV held in Washington DC in 2004. The aim of the study was to evaluate the effects of TH-9507, a novel growth hormone releasing factor, on abdominal fat accumulation and on metabolic and safety parameters in HIV-infected patients with central fat accumulation.

This randomized, double-blind, placebo-controlled trial enrolled 61 HIV-infected patients with increased waist circumference and waist-to-hip ratio. Participants were randomized to placebo or 1 or 2 mg TH-9507 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

·   TH-9507 resulted in dose-related physiological increases in IGF-I (P < 0.01 for 1 mg (+48%) and 2 mg (+65%) versus placebo).

·   Trunk fat 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.

·   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.

·   Triglyceride and the cholesterol to high-density lipoprotein ratio decreased significantly in the 2 mg group versus placebo.

·   Treatment was generally well tolerated without changes in glucose, even among patients with impaired glucose tolerance.

·   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.

Based on these results, the authors conclude, “TH-9507 reduced truncal fat, improved the lipid profile and did not increase glucose levels in HIV-infected patients with central fat accumulation.”

“TH-9507 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.”

Discussion

TH-9507, 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.

Furthermore, say the study authors, “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. Preservation of extremity and subcutaneous fat is of critical importance to patients with significant lipoatrophy.”

The 2 mg GRF dose significantly improved triglyceride levels and the cholesterol: HDL ratio. This is a significant advantage of a GRF analog, not seen with other treatment strategies for HIV lipodystrophy. Similar beneficial effects on triglycerides were seen with lower, alternating day, but not higher doses of GH in a study reported by Kotler et al. In contrast, higher doses of GH were shown to reduce total and LDL cholesterol in patients with HIV lipodystrophy.

Growth hormone has been shown to decrease cholesterol and triglyceride levels in GH-deficient patients and among otherwise healthy men chosen for abdominal obesity. Taken together, the data suggest that treatment with TH-9507 resulted in an improved lipid profile in dyslipidemic, abdominally obese patients with HIV lipodystrophy.

An important issue regarding the use of GH or related strategies in HIV lipodystrophy is glucose control. Patients with HIV lipodystrophy are often insulin resistant, and a significant percentage, more than one-third, may have impaired glucose tolerance. In this study, even with the higher dose of 2 mg, there were no significant differences in fasting glucose or 2-h glucose in response to a standard glucose tolerance test.

Furthermore, there was no significant increase in the number of patients who went from normal glucose tolerance to impaired glucose tolerance. Of note, and in contrast to recently published studies with GH, patients with IGT were permitted to enter this study (e.g. 25% of subjects had IGT or diabetes at baseline), and among this subgroup, there was not a significant shift toward the development of diabetes mellitus.

TH-9507 was also associated with other benefits in this study. Osteocalcin, a marker of bone formation increased within the 2 mg group, whereas NTX, a marker of bone resorption did not, suggesting a net positive effect on bone turnover.

Quality of life assessment did not demonstrate significant differences between groups in global domains of physical and psychological functioning, but did suggest that patients receiving GRF, particularly at the 2 mg dose, felt improvement in abdominal fullness, bloating and girth, consistent with the decreases in truncal fat. This is an important consideration for HIV-infected patients for whom such complaints may affect quality of life.

Specific symptoms of GH excess, such as carpal tunnel syndrome, edema, swelling, pain and arthralgias were not noted in a larger proportion of the patients receiving active medication, but headaches and to a lesser extent paresthesias were seen more often in the subjects receiving the 2 mg dose, although not to a degree necessitating discontinuation from the study or therapeutic intervention.

Blood pressure did not increase. Discontinuation rates from the study were not different between the groups. Our data suggest that TH-9507 was generally well tolerated except for a dose-related increase in headaches, but larger studies of longer duration are needed to definitively determine the safety of GRF in the treatment of HIV-infected patients.

Summary

In summary, the authors write, “Treatment of HIV-infected patients with lipodystrophy and central obesity with TH-9507, a GRF analog, results in physiologic increases in GH secretion. At a 2 mg dose, this strategy results in significant reductions in truncal fat and increases in lean body mass, without reductions in extremity and subcutaneous fat.”

“VAT decreased 15% over 3 months in the 2 mg group, but changes in VAT were not significant compared to placebo. Glucose did not increase, even among patients with impaired glucose tolerance. In addition, triglyceride and cholesterol: HDL ratio improved in response to the 2 mg dose compared to placebo.”

“Further studies are needed to assess the utility of this novel treatment strategy for patients with HIV and central fat accumulation. “

Phase III Trials of TH-9507 Now Enrolling

Theratechnologies Inc. has recently announced the beginning of recruitment of patients for a Phase III clinical trial of TH-9507 in HIV patients with excess of abdominal fat accumulation as part of the HIV-associated lipodystrophy syndromes.

This multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial is investigating the safety and efficacy of TH-9507 in reducing excess VAT in approximately 400 patients, across the US and Canada, by administering 2 mg daily for a period of 26 weeks.  There will also be an extension phase of the study lasting an additional 26 weeks to assess long-term safety and the effects of discontinuing treatment.

About TH-9507
TH-9507 is a stabilized analog of the growth hormone-releasing factor (GRF) that induces the production and secretion of growth hormone in a specific, physiological, controlled and pulsatile fashion.  This property makes it a strong candidate as a potential treatment for many diseases characterized by a reduction in growth hormone secretion.

About Theratechnologies
Theratechnologies (TSX: TH) is a Canadian biopharmaceutical company engaged in the discovery and development of therapeutic peptides in the field of endocrinology and metabolism. The Company uses proprietary discovery technologies to expand its product portfolio. The most advanced clinical program (Phase III) targets HIV-associated lipodystrophy with its lead compound, TH-9507 (ThGRF). The Company is investigating other potential indications for TH-9507 and it also has an interesting product pipeline targeting type 2 diabetes.

Following are the details of the Phase III clinical trial.  The locations of US study sites along with their contact information and names of principal investigators are included at the end of this article.

Study TH-9507/ III/ LIPO/ 010

Study Type:  Interventional

Study Design:  Randomized, Double-Blind, Placebo-Controlled, Parallel Assignment

Official Title:  A Phase 3 Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Assessing the Efficacy and Safety of a 2 mg Dose of TH-9507, a Growth Hormone Releasing Factor Analog, in HIV Patients with Excess of Abdominal Fat Accumulation

Endpoints:  Safety/Efficacy

Primary outcomes:  Change in Visceral adipose tissue (VAT) after 26 weeks of treatment

Study Start Date:  June 2005

Study Completion Date:  December 2006 (last patient to complete 52 weeks)

Eligibility Criteria           

Inclusion Criteria:

a) Age 18 to 65 years inclusive;

b) HIV positive; CD4 cell counts >100 cells/mm³; viral load <10 000 copies/mL stable for 8 weeks;

c) On stable ART regimen for at least 8 weeks prior to randomization;

d) Have evidence of abdominal fat accumulation defined by the following anthropometric cut off values:

 · For males:  waist circumference > 95 cm and waist to hip ratio > 0.94;

· For females:  waist circumference > 94 cm and waist to hip ratio > 0.88;

e) Females of childbearing potential, not pregnant or lactating;

f) Female with normal mammography within 6 months of study;

g) Signed informed consent.

Exclusion Criteria:

a) Body Mass Index < 20 kg/m²;

b) Opportunistic infection; HIV-related disease within 3 months of study;

c)  History of malignancy; active neoplasm;

d)  PSA >5 ng/mL at screening;

e) Hypopituitarism; history of pituitary tumor/surgery; head irradiation; head trauma that has affected the somatotropic axis;

f) Untreated hypothyroidism;

g) Type 1 diabetics and Type 2 diabetics on oral hypoglycemic or insulin sensitizing agent within 6 months of study;

h) ALT or AST >3 x ULN; serum creatinine >133 mmol/L (1.5 mg/dL); hemoglobin more than 20 g/L below LLN; fasting blood glucose > 8.33 mmol/L (150 mg/dL); fasting triglycerides > 11.3 mmol/L (0.99 g/dL);

i) Untreated hypertension;

j) Change in anti-hyperlipemic regimen within 3 months prior to study;

k) Change in testosterone regimen and/or supraphysiological dose of testosterone;

l) Estrogen therapy;

m) Anoretics/anorexigenics or anti-obesity agents within 3 months of study;

n) Growth hormone (GH), GH secretagogues, growth hormone releasing factor (GRF) products, IGF-1, or IGFBP-3 within 6 months of study;

o)  Drug or alcohol dependence or use of methadone within 6 months of study entry;

p)  Participation in a clinical trial with any investigational drug/device within 30 days of screening.

From the Montreal General Hospital Immuno-Deficiency Treatment Centre, McGill University Health Center, Montreal, Quebec, Canada Division of Endocrinology Division of Gastroenterology, St Luke's Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons, New York, New York ARCA (AIDS Research Consortium of Atlanta), Atlanta, Georgia, USA Theratechnologies, St. Laurent Division of Hematology and Immunodeficiency Service, Royal Victoria Hospital, Montreal Clinique medicale du Quartier Latin, Montreal Clinique Medicale l'Actuel, Montreal, Quebec, Canada Mass General Hospital Program in Nutritional Metabolism and Harvard Medical School, LON207, Mass General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

08/03/05

Reference
J Falutz and others. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation. AIDS 19(12):1279-1287. August 12, 2005.

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