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Theratechnologies (TSX: TH), Montreal, has announced preliminary results for a Phase II study testing ThGRF, its growth hormone-releasing factor analogue, in patients suffering from chronic wasting, or muscle depletion, secondary to chronic obstructive pulmonary disease (COPD). Highlights included positive effects on body composition (increased muscle and decreased fat), a series of converging positive findings in functional measures, and a very good safety profile. Taken together, the company considers that the results suggest an improvement in clinical condition and provide a rationale for moving ThGRF into late-stage development in COPD wasting.

Dr. Annemie Schols is associate professor of Pulmonology at the Department of Respiratory Medicine at Maastricht University in the Netherlands. She is a leading authority on COPD wasting, an advisor to Theratechnologies, and an investigator in this study. "The results of this study are promising, because they demonstrate that ThGRF has the potential to bring clinical benefit in COPD patients with muscle wasting. The effects on body composition are impressive because the patients were not receiving any other rehabilitation therapy, such as exercise or nutritional intervention. Furthermore, the functional parameters that seem to respond to a short period of ThGRF treatment are those that you would expect to respond to anabolic treatment. What's also very interesting is that the clinical benefits appear to extend to patients who have progressed into severe wasting. This is a large body of patients who are in a very serious clinical condition without satisfactory treatment alternatives. It will be very exciting, if the next large-scale clinical trial is focused on this patient group, with a longer term treatment," Dr. Schols concluded.

According to Dr. Thierry Abribat, Theratechnologies' vice president and chief scientific officer, the study findings are significant in many ways. "The effect of growth hormone on body composition has been known for more than ten years but trials in adults have surfaced safety concerns and evidence of a corresponding improvement in muscle function has been inconsistent. As such, the results we are announcing today represent a significant advance in growth hormone therapeutics and a major turning point for our product, ThGRF. Not only do the results support proceeding with COPD wasting as an indication but these data are promising with respect to other indications associated with chronic wasting such as congestive heart failure or chronic renal failure. This is also encouraging news for our two ongoing Phase II studies in hip fracture wasting and HIV-related lipodystrophy", Dr. Abribat noted.

Luc Vachon, vice president, Drug Development, at Theratechnologies, oversaw the study and is pleased with the outcome. "With this study, we have added valuable information to our already extensive knowledge of ThGRF. In terms of primary activity, we now have confirmed that our product builds lean body mass, or muscle, and reduces fat mass. We have also obtained evidence of a set of positive clinical outcomes, which make sense from a physiological perspective; and with well over 300 patients and healthy volunteers already exposed to the product, we have a very good safety profile. We have consulted with our advisors on the results of this study and on the unmet medical need that ThGRF could address in COPD wasting. Taking all of this into consideration, we believe that there is a strong case to be made for ThGRF as a potential treatment for COPD wasting and an opportunity to move forward to a later-stage of development in this indication," Dr. Vachon concluded.

Relevant findings

In the overall population, a three-month ThGRF treatment induced significant changes in body composition:

- A 50 % increase in IGF-1 levels at 1 mg (p less than 0.001 vs. placebo) and 92% increase at 2 mg (p less than 0.001 vs. placebo), as compared with a 6% decrease on placebo;

- A significant increase in muscle mass (lean body mass; LBM), with a net average gain of 1.3 kg muscle mass in the 1 mg group (P less than 0.01 vs. placebo) and 0.9 kg in the 2 mg group (P less than 0.02 vs. placebo), as compared to an average loss of 0.1 kg in the placebo group.

- A significant loss in fat mass (FM), with a net average loss of 0.7 kg fat at 1 mg (p less than 0.01 vs. placebo) and 0.5 kg at 2 mg (p less than 0.05 vs. placebo), as compared to an average gain of 0.4 kg in the placebo group.

- There were no differences observed between the treatment groups in terms of safety assessments, and no sign of immunogenicity (antibody formation) was detected in any of the patients.

Interestingly, the effect of ThGRF on body composition was at least as strong in patients with the most severe wasting, which is a clinically defined group, based on their body mass index, who represented 23% of the total patient population:

- An average gain in LBM of 1.1 kg muscle mass in the 1 mg group (p less than 0.02 vs. placebo) and 1,8 kg in the 2 mg group (p less than 0.01 vs. placebo), as compared to an average loss of 0.1 kg in the placebo group.

- An average loss in FM of 1.1 kg fat in the 1 mg group (p less than 0.05 vs. placebo) and 0.9 kg in the 2 mg group (p less than 0.05 vs. placebo), as compared to a gain of 0.4 kg in the placebo group.

Additional assessments were conducted in order to investigate whether the expected changes in body composition translated into a functional improvement over the 3-month study period. From a preliminary evaluation of the data, including exploratory analyses, some reached statistical significance while some did not. Amongst these, the following converging findings suggest that ThGRF improved the clinical condition of these patients:

- A decrease in leg fatigue during exercise endurance test (Borg Scale) at 2 mg in the overall population (p less than 0.01; placebo NS, vs. baseline);

- A decrease in breathing discomfort during exercise endurance test (Borg Scale) at 2 mg in the overall population (p (equal sign) 0.01; placebo NS, vs. baseline);

- A trend for an increase in the physical function score of SF-36, a quality of life questionnaire, at 2 mg in the overall population (p (equal sign) 0.09; placebo NS; vs. baseline);

- An increase in muscle strength at the quadriceps level at 1 mg and a trend for an increase at 2 mg in patients with the most severe wasting (1 mg: p (equal sign) 0.05; 2 mg: p (equal sign) 0.11; placebo NS, vs. baseline);

- A trend for an increase in maximal pulmonary inspiratory pressure (PImax) at 2 mg in patients with the most severe wasting (p (equal sign) 0.09; placebo NS; vs. baseline).

These parameters are highly relevant to anabolic treatment and the objectives of this study. This is true of quadriceps strength because in COPD wasting, muscle weakness affects the leg more than the arm. Similarly, PIMax is more dependent on respiratory muscle functionality than other pulmonary parameters and both the PIMax improvement and the increase in quadriceps strength would support the observed improvement in the Borg scales (leg and breathing discomfort). Finally, the SF-36 subscale that improved is related to muscle functionality.

The next steps for ThGRF

Theratechnologies has two additional Phase II studies underway. The first is measuring the efficacy of ThGRF in the recovery of wasting patients following hip fracture surgery with results expected in December 2003. The second is measuring the lipolytic effect of ThGRF in HIV-related lipodystrophy, a metabolic syndrome, with results expected in the first quarter of 2004.

Looking to the future, Luc Tanguay, president and CEO of Theratechnologies said, "Today's results add to the already promising profile of ThGRF. Our strategy has been to capitalize on the product's unique safety profile by targeting indications above and beyond the existing US $1.7 billion market for growth hormone deficiency (GHD). We believe we now have the basis to pursue COPD wasting as an initial indication for ThGRF and our analysis indicates that this is potentially a very large market. We estimate that there are approximately three million patients with severe COPD wasting in North America, Europe and Japan.

"I want to acknowledge the hard work of our advisors, the investigators and everyone at Theratechnologies who contributed to this project and to congratulate them on the results announced today. We still have a lot to do but, with one potential indication in hand and the results of two ongoing Phase II studies to come, we are increasingly confident that ThGRF will be a very important drug in the years ahead," Tanguay concluded.

About the study

Conducted in 20 centers in Canada and Europe, this double-blind, randomized, parallel group and placebo-controlled Phase II study was aimed at evaluating the efficacy and safety of two doses of ThGRF (1 mg and 2 mg), administered daily over a three-month period, on body composition, functional status, respiratory function and quality of life in 90 patients of 50 years of age and over.

The overall patient population was representative of a non-obese COPD population and included patients with various degrees (mild to severe) of COPD severity, the pulmonary component of the disease, as defined by the American Thoracic Society criteria, and various degrees of muscle depletion, or wasting, the peripheral component of the disease, as defined by Body Mass Index (BMI) or Fat-Free Mass Index (FFMI).

About COPD wasting

COPD is a multi-component disease, implying two major components, the pulmonary and the periphery (muscle mass). The evolution of these two components is not parallel. Several prospective and retrospective studies have clearly demonstrated that involuntary weight loss or a loss in lean body mass are independent predictors of mortality, and are associated with diminished endurance exercise capacity, impaired quality of life and increase utilization of health care costs. In this regard, ThGRF is currently developed as the first compound for the treatment of muscle depletion, or wasting, associated with COPD.

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.

The results studies conducted to date, involving over 400 healthy subjects and patients, have established a safety profile for ThGRF that differentiates it from growth-hormone-based products. In addition, its emerging pharmacological profile identifies two distinct mechanisms of action and two therapeutic fields, each with attractive market potential.

- Because of its positive effect on the secretion of an anabolic factor known as IGF-1, ThGRF may have a therapeutic effect on catabolic states characterized by a reduction in the ability to synthesize proteins, as well as muscle wasting and cachexia, which often lead to loss of autonomy and death. The company has undertaken two efficacy studies in this field. The first concerns catabolic states related to chronic obstructive pulmonary disease (COPD) and is the subject of this press release; the second concerns catabolic states following hip fracture in elderly patients with results expected in December 2003.

- Because of its cholesterol-lowering effect and the direct lipolytic effect of growth hormone, ThGRF also has therapeutic potential in certain metabolic diseases. The company is currently conducting a Phase II study targeting lipodystrophy related to HIV. Positive results in this indication could enlarge the field of investigation for ThGRF to include the metabolic syndrome (Syndrome X). The results of this study are expected in the first quarter of 2004.

About Theratechnologies

Theratechnologies (TSX:TH) is a Canadian biotechnology company engaged in the discovery and development of therapeutic products in the field of endocrinology and metabolism. The company has and is developing a portfolio of peptides at various stages of development for the treatment of catabolic (loss of the body's synthesis and regeneration capacity) and metabolic disorders, as well as osteoporosis and type II diabetes. In addition, Theratechnologies is expanding its peptide portfolio through proven, proprietary technologies. Its subsidiary, Celmed BioSciences, develops cell-based therapies for the treatment of hematological, immune and neurodegenerative disorders.

For more information, visit or call 514/336-4804, ext. 234.
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Publication:Worldwide Biotech
Date:Dec 1, 2003

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