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Good Safety Profile, Clear Positive Effect on Body Composition Highlight Phase II Results for ThGRF

MONTREAL, April 15 /PRNewswire-FirstCall/ -- Theratechnologies (TSX:TH) today announced exciting results for its Phase II clinical trial, testing ThGRF in patients with HIV-associated lipodystrophy, a medical condition characterized by body composition changes and metabolic abnormalities. Highlights include a good safety profile, a clear positive effect on body composition and a clinically relevant reduction in visceral fat while subcutaneous fat was preserved. While this selectivity of action on fat distribution appears to have prevented the study from meeting one of its primary endpoints, it likely would be an advantage in treating HIV-associated lipodystrophy patients who generally experience an accumulation of visceral fat (lipohypertrophy), associated with higher risk of cardiovascular disease, coupled with a loss of subcutaneous fat (lipoatrophy).

Of particular importance in this study was good glycemic control, including in glucose-intolerant and diabetic patients, who represented 28% of the subjects enrolled. It is estimated that approximately 40% of all HIV- associated lipodystrophy patients are either glucose intolerant or diabetic.

Based on these positive results, the Company and its clinical experts consider that ThGRF is well suited for Phase III testing as a novel approach to treat HIV lipodystrophic patients with excessive visceral fat, an unmet clinical need.

"The results of this study are important and suggest ThGRF as a potentially beneficial treatment for HIV-associated lipodystrophy", said Dr. Steven Grinspoon, Director, Program in Nutritional Metabolism, Associate Professor of Medicine, Harvard Medical School and Lead Investigator for the US. "The selectivity on visceral fat mass as well as the decrease in the VAT/SAT ratio are noteworthy in this regard, and suggest that the physiological mode of action of ThGRF translates into clinical advantages over other approaches for patients with HIV-associated lipodystrophy. ThGRF may also prove useful to alter fat distribution from the trunk and viscera in non- HIV-infected patients with the metabolic syndrome."

Preliminary Results
Effects on IGF-1 and body composition - a key objective of the study was to determine if ThGRF had the desired endocrine activity and overall effects on body composition in this patient population. The results indicate that it does. At the 2 mg dose:

- Marked increase in IGF-1 levels (+80%, P less than 0.01 vs placebo).

- Highly significant effects on body composition (lean body mass: +1.7 kg, P less than 0.01 vs placebo; total body fat mass: -1.4 kg, P less than 0.02 vs placebo).

Efficacy and primary endpoints - the two primary endpoints of the study were visceral fat (VAT) and the trunk/limb fat ratio. VAT is the fat specifically located within the abdominal cavity and is the fat most associated with cardiovascular disease, whereas the trunk/limb fat ratio is a measure of the relative amount of total trunk to extremity fat. These parameters were selected based on previous trials performed with high doses of recombinant human growth hormone (rhGH). The results indicate that ThGRF may be more selective than originally expected, concentrating all of its effect on visceral fat, while preserving subcutaneous fat, both at the abdominal and the peripheral levels. At the 2 mg dose:

- Body fat was preferentially lost at the trunk level (-1.1 kg, P less than 0.02 vs placebo), with no significant change in limb fat.

- Within the trunk, this fat loss took place solely in the visceral compartment (VAT, -15.7%, P less than 0.05 vs baseline, NS vs placebo; placebo: -5.4%, NS vs baseline), whereas no change or trend thereof was observed at the subcutaneous level (SAT).

- The trunk/limb fat ratio was only modestly reduced in the treated patients. This result reflects the selectivity of ThGRF, which did not reduce subcutaneous fat at the trunk level. In line with these findings, VAT/SAT, a ratio that more accurately reflects the specificity of the treatment on visceral vs subcutaneous fat, was decreased by 17.5% (P less than 0.05 vs baseline; NS vs placebo), as compared with a reduction of 1.7% in the placebo group (NS vs baseline).

Lipid Profile - the results suggest that the lipid profile improved during treatment, based on a statistically significant overall treatment effect (P less than 0.02 vs placebo) over the study period in the total cholesterol to HDL cholesterol ratio (known as atherogenic index), which was reflected at Week 12 by an average decrease of 0.34 in the 2 mg group compared to an average increase of 0.21 in the placebo group.

Globally, time and dose-related effects between the 1 mg and 2 mg groups were seen for most efficacy parameters during the treatment period.

Safety - due to the fact that a significant portion of the HIV-associated lipodystrophy patient population is glucose intolerant, the safety profile of growth hormone therapy is a limiting factor in this indication. It was therefore important to confirm the safety profile of ThGRF in this regard.

- 28 percent of the patients presented with impaired glycemic control at entry into the study. No patients discontinued treatment due to deterioration in this condition or required medical intervention for their impaired glucose tolerance or diabetes condition.

- No significant or clinically relevant change in fasting blood glucose or on glucose levels 2 hours following an Oral Glucose Tolerance Test was observed, suggesting that ThGRF did not clinically alter the glycemic control in the study patients.

- The number of patients experiencing adverse events or clinical laboratory abnormalities was similar between the three groups. Apart from a possible higher incidence of headache and paresthesia, no clear treatment effects were observed. A similar number of patients prematurely discontinued the study across the three groups.

- No ThGRF antibodies were found in any of the patients at the end of the treatment period.

"Despite the relatively low number of patients, this study provides us with the important information that we were looking for at the time of its inception approximately one year ago," said Dr. Julian Falutz, Director, HIV Metabolic Clinic, Montreal General Hospital, Assistant Professor, McGill University Medical School, and Lead Investigator for Canada. "Based on these preliminary results, ThGRF presents the essential components of a potential treatment for the management of HIV patients with lipodystrophy and increased abdominal girth, a major risk factor for premature cardiovascular disease, and altered body image. The absence of major safety concerns, particularly in patients with impaired glucose tolerance, as well as the apparent lack of significant toxicities, in conjunction with the positive selective effects on body composition, makes this treatment very attractive. I fully anticipate further positive developments in the ongoing investigation of this new addition to our therapeutic armamentarium against the challenge of the HIV lipodystrophy syndromes."

Luc Tanguay, President and Chief Executive Officer of Theratechnologies, concluded, "We launched this study less than a year ago in order to determine quickly whether our ThGRF could be a novel treatment strategy for HIV- lipodystrophy. The idea was to assess safety and obtain preliminary efficacy data. We ended up with much more: the reduction in visceral fat, the selectivity of action, and a good safety profile, even among glucose intolerant patients. In our minds, ThGRF is clearly a promising candidate for late-stage development in this indication."

About HIV-associated Lipodystrophy
HIV-associated lipodystrophy is a metabolic syndrome that afflicts a significant percentage of HIV patients undergoing antiretroviral therapy to control their HIV infection. Although the exact cause of this syndrome is unknown, it is suspected to be partly due to the HIV treatment itself. It is characterized by changes in distribution of adipose tissue (fat-containing tissue), dyslipidemia and glucose intolerance. The changes in fat distribution include: lipohypertrophy, which is the accumulation of visceral adipose tissue, a risk factor for cardiovascular disease and type II diabetes; and lipoatrophy, which is the loss of subcutaneous fat, generally in the limbs and facial area. In addition to the direct health risks, the resulting body abnormalities can stigmatize patients and discourage compliance with their HIV regimens. There is currently no approved treatment for this condition, and although some new HIV treatments have shown signs of reducing dyslipidemia and the lipoatrophy components of the disease, the lipohypertrophy component remains an important unmet medical need. It is estimated that, among the 1.4 million HIV- positive patients in North America and Europe, as many as 250,000 suffer from HIV-associated lipodystrophy with excess visceral fat.

About the HIV-associated lipodystrophy study
The double-blind, randomized, placebo-controlled study was conducted in seven centers in Canada and the United States. In total, 61 patients were enrolled in parallel groups who received a daily subcutaneous injection of 1 mg, 2 mg or placebo, over a period of 12 weeks. The study population consisted of 89% of male patients with a mean age of 45 years. All patients were on stable antiretroviral therapy. Their average BMI was 28 kg/m2, their mean waist circumference 101 cm and their mean waist/hip ratio 1.0.

About ThGRF
ThGRF is a stabilized analogue 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 related to aging and obesity, as these conditions are characterized by a significant reduction in growth hormone secretion.

Source: Theratechnologies

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