FDA Approves EGRIFTA™ (tesamorelin for injection): First and Only Treatment for the Reduction of Excess Abdominal Fat in HIV-infected Patients with Lipodystrophy

ROCKLAND, Mass., Nov. 11, 2010 /PRNewswire/ -- EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, today announced that the U.S. Food and Drug Administration (FDA) has approved EGRIFTA™ (tesamorelin for injection) as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy (abdominal lipohypertrophy). EGRIFTA™ (tesamorelin for injection), developed by Theratechnologies, a Canadian biopharmaceutical company, will be marketed in the United States exclusively by EMD Serono.

To view the Multimedia News Release, go to http://multivu.prnewswire.com/mnr/emdserono/47019  

There are limitations of use associated with EGRIFTA™ (tesamorelin for injection). Since the long-term cardiovascular safety and potential long-term cardiovascular benefit of EGRIFTA™ (tesamorelin for injection) treatment have not been studied and are not known, careful consideration should be given whether to continue EGRIFTA™ (tesamorelin for injection) treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue (VAT) measured by waist circumference (WC) or CT scan.  EGRIFTA™ (tesamorelin for injection) is not indicated for weight loss management (weight neutral effect).  There are no data to support improved compliance with antiretroviral therapies in HIV-positive patients taking EGRIFTA™ (tesamorelin for injection).

The efficacy and safety of EGRIFTA™ (tesamorelin for injection) was evaluated in two Phase 3 multi-center, randomized, double-blind, placebo-controlled clinical trials, which demonstrated statistically significant decreases in visceral adipose tissue and waist circumference versus placebo in HIV-infected patients who suffer from excess abdominal fat associated with lipodystrophy. HIV-associated lipodystrophy refers to abnormalities in body fat distribution and metabolism.  

"As HIV-infected patients are living longer, a substantial number may develop metabolic complications associated with HIV, such as abdominal lipohypertrophy," said Dr. Morris Schambelan, Professor of Medicine, University of California, San Francisco.  "With the approval of EGRIFTA™, doctors are now able to provide appropriately selected patients with a treatment option shown to reduce visceral adipose tissue."

"While antiretroviral therapy is extremely important in the management of patients with HIV infection, some patients are experiencing excess abdominal fat associated with lipodystrophy, which can be difficult to manage," said Fereydoun Firouz, President and CEO, EMD Serono, Inc. "EMD Serono has maintained a commitment to advancing science and medicine in this area of unmet medical need, and it will continue to remain a focus for the organization.  We are committed to making a difference in people's lives, and look forward to making EGRIFTA™ available for patients as soon as possible."

"Theratechnologies is very pleased to receive marketing approval for EGRIFTA™ from the FDA.  We are one of very few Canadian biotechnology companies to have successfully discovered, developed and brought a drug to the market on our own.  This milestone represents a significant achievement which will benefit both patients and our shareholders," commented Mr. Yves Rosconi, President and CEO of Theratechnologies.

"We are confident that EMD Serono will successfully commercialize EGRIFTA™ in the United States, given their track record and expertise with other metabolic disorders," noted Paul Pommier, Chairman of the Board of Directors of Theratechnologies. "Theratechnologies will continue to focus on signing partnerships outside of the United States in order to access additional markets for EGRIFTA™ in HIV-infected patients with excess abdominal fat associated with lipodystrophy," he concluded.

The FDA has requested the following three postmarketing requirements: a long-term observational safety study for tesamorelin acetate (EGRIFTA™), a single vial formulation – the development of a new presentation of the same formulation, and a clinical trial to assess whether EGRIFTA™ (tesamorelin for injection) has an impact on diabetic retinopathy in diabetic HIV-infected patients with lipodystrophy and excess abdominal fat.

About EGRIFTA™ (tesamorelin for injection) Phase 3 Trials

The FDA approval of EGRIFTA™ (tesamorelin for injection) was based on two multi-center, randomized, double-blind, placebo-controlled Phase 3 studies consisting of a 26-week main phase and a 26-week extension phase of 816 HIV-infected patients with excess abdominal fat associated with lipodystrophy.  

The primary endpoint of the 26-week main phase was the percent change in VAT from baseline, as assessed by computed tomography (CT) scan at the L4-L5 vertebral level.  

In both Phase 3 studies, patients received either EGRIFTA™ (tesamorelin for injection) or placebo for 26 weeks. Patients initially randomized to EGRIFTA™ (tesamorelin for injection) were then re-randomized to receive either EGRIFTA™ (tesamorelin for injection) or placebo for an additional 26-week treatment period, whereas patients receiving placebo were switched to EGRIFTA™ (tesamorelin for injection). In the first study, at baseline, mean VAT was 178 cm(2) for the patients who received EGRIFTA™ (tesamorelin for injection) and was 171 cm(2) for the patients who received placebo. In the second study, at baseline, mean VAT was 186 cm(2) for the patients who received EGRIFTA™ (tesamorelin for injection) and was 195 cm(2) for the patients who received placebo. Patients treated with EGRIFTA™ (tesamorelin for injection) experienced a statistically significant least-squares mean decrease from baseline in VAT of 27 cm(2) compared to an increase of 4 cm(2) for patients on placebo [(95% CI for the mean treatment difference of -31 cm(2) (-39 cm(2), -24 cm(2))] in the first study, and a statistically significant decrease from baseline in VAT of 21 cm(2) compared to no change in VAT for patients on placebo [(95% CI for the mean treatment difference of -21 cm(2) (-29 cm(2), -12 cm(2))] in the second study during the 26-week main phase.  

This represents a statistically significant least-squares mean decrease from baseline in VAT of 18% for patients treated with EGRIFTA™ (tesamorelin for injection) compared to an increase of 2% for patients on placebo [(95% CI for the mean treatment difference  of -20%  (-24%, -15%)] in the first study, and a statistically significant decrease from baseline of 14% for patients treated with EGRIFTA™ (tesamorelin for injection) compared to a decrease of 2% for patients on placebo [(95% CI for the mean treatment difference of -12% (-16%, -7%)] in the second study during the 26-week main phase.  

In the first study, at baseline, mean waist circumference was 104 cm for the patients who received EGRIFTA™ (tesamorelin for injection) and was 105 cm for the patients who received placebo. In the second study, at baseline, mean waist circumference was 105 cm for the patients who received EGRIFTA™ (tesamorelin for injection) and for the patients who received placebo. Treatment with EGRIFTA™ (tesamorelin for injection) resulted in a statistically significant least-squares mean decrease from baseline in waist circumference of -3 cm compared to a decrease of -1 cm for patients on placebo [(95% CI for the mean treatment difference of -2 cm  (-2.8 cm, -0.9 cm)] in the first study, and a statistically significant decrease from baseline of -2 cm compared to a decrease of -1 cm for patients on placebo [(95% CI for the mean treatment difference of -1 cm (-2.5 cm, -0.3 cm)] in the second study during the 26-week main phase. The decreases in VAT and waist circumference observed after 26 weeks of treatment were sustained in patients who received EGRIFTA™ (tesamorelin for injection) over 52 weeks.

Important Risk Information

EGRIFTA™ (tesamorelin for injection) is contraindicated in women who are pregnant, in patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma, in patients with known hypersensitivity to tesamorelin and/or mannitol (excipient) and in patients with active malignancies (either newly diagnosed or recurrent). Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with EGRIFTA™ (tesamorelin for injection). If pregnancy occurs, EGRIFTA™ (tesamorelin for injection) therapy should be discontinued.

EGRIFTA™ (tesamorelin for injection) induces the release of endogenous growth hormone, a known growth factor, thus patients with active malignancy should not be treated with EGRIFTA™ (tesamorelin for injection). For patients with a history of non-malignant neoplasms, EGRIFTA™ (tesamorelin for injection) therapy should be initiated after careful evaluation of the potential benefit of treatment.  For patients with a history of treated and stable malignancies, EGRIFTA™ (tesamorelin for injection) therapy should be initiated only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy. In addition, the decision to start treatment with EGRIFTA™ (tesamorelin for injection) should be considered carefully based on the increased background risk of malignancies in HIV-positive patients.

EGRIFTA™ (tesamorelin for injection) stimulates growth hormone production and increases serum IGF-1. Given that IGF-1 is a growth factor and the effect of prolonged elevations in IGF-1 levels on the development or progression of malignancies is unknown, IGF-1 levels should be monitored closely during EGRIFTA™ (tesamorelin for injection) therapy. Careful consideration should be given to discontinuing EGRIFTA™ (tesamorelin for injection) in patients with persistent elevations of IGF-1 levels (e.g., >3 Standard Deviation Score (SDS)), particularly if the efficacy response is not robust (e.g., based on visceral adipose tissue changes measured by waist circumference or CT scan). During the clinical trials, patients were monitored every three months. Among patients who received EGRIFTA™ (tesamorelin for injection) for 26 weeks, 47.4% had IGF-1 levels greater than 2 SDS, and 35.6% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on EGRIFTA™ (tesamorelin for injection) for a total of 52 weeks, at the end of treatment 33.7% had IGF-1 SDS >2 and 22.6% had IGF-1 SDS >3.

Fluid retention may occur during EGRIFTA™ (tesamorelin for injection) therapy and is thought to be related to the induction of GH secretion. It manifests as increased tissue turgor and musculoskeletal discomfort resulting in a variety of adverse reactions (e.g. edema, arthralgia, carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment.

EGRIFTA™ (tesamorelin for injection) treatment may result in glucose intolerance. During the Phase 3 clinical trials, the percentages of patients with elevated HbA1c (greater than 6.5%) from baseline to Week 26 were 4.5% and 1.3% in the EGRIFTA™ (tesamorelin for injection) and placebo groups, respectively. An increased risk of developing diabetes with EGRIFTA™ (tesamorelin for injection) (HbA1c level greater than 6.5%) relative to placebo was observed [intent-to-treat hazard odd ratio of 3.3 (CI 1.4, 9.6)].  Therefore, glucose status should be carefully evaluated prior to initiating EGRIFTA™ (tesamorelin for injection) treatment. In addition, all patients treated with EGRIFTA™ (tesamorelin for injection) should be monitored periodically for changes in glucose metabolism to diagnose those who develop impaired glucose tolerance or diabetes. Diabetes is a known cardiovascular risk factor and patients who develop glucose intolerance have an elevated risk for developing diabetes.  Caution should be exercised in treating HIV-positive patients with lipodystrophy with EGRIFTA™ (tesamorelin for injection) if they develop glucose intolerance or diabetes, and careful consideration should be given to discontinuing EGRIFTA™ (tesamorelin for injection) treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue by waist circumference or CT scan measurements. Since EGRIFTA™ (tesamorelin for injection) increases IGF-1, patients with diabetes who are receiving ongoing treatment with EGRIFTA™ (tesamorelin for injection) should be monitored at regular intervals for potential development or worsening of retinopathy.

Hypersensitivity reactions may occur in patients treated with EGRIFTA™ (tesamorelin for injection). Hypersensitivity reactions occurred in 3.6% of patients with HIV-associated lipodystrophy treated with EGRIFTA™ (tesamorelin for injection) in the Phase 3 clinical trials. These reactions included pruritus, erythema, flushing, urticaria, and other rash.  In cases of suspected hypersensitivity reactions, patients should be advised to seek prompt medical attention and treatment with EGRIFTA™ (tesamorelin for injection) should be discontinued immediately.

EGRIFTA™ (tesamorelin for injection) treatment may cause injection site reactions including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 24.5% in EGRIFTA™ (tesamorelin for injection) treated patients and 14.4% in placebo-treated patients during the first 26 weeks of treatment in the Phase 3 clinical trials. For patients who continued EGRIFTA™ (tesamorelin for injection) for an additional 26 weeks, the incidence of injection site reactions was 6.1%.  In order to reduce the incidence of injection site reactions, it is recommended to rotate the site of injection to different areas of the abdomen.

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. EGRIFTA™ (tesamorelin for injection) has not been studied in patients with acute critical illness. Since EGRIFTA™ (tesamorelin for injection) stimulates growth hormone production, careful consideration should be given to discontinuing EGRIFTA™ (tesamorelin for injection) in critically ill patients.

EGRIFTA™ (tesamorelin for injection) is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes.  Modifying this physiologic change of pregnancy with EGRIFTA™ (tesamorelin for injection) offers no known benefit and could result in fetal harm.  Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue EGRIFTA™ (tesamorelin for injection) therapy.  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving EGRIFTA™ (tesamorelin for injection) should be instructed not to human milk-feed. It is not known whether EGRIFTA™ (tesamorelin for injection) is excreted in human milk.

Safety and effectiveness in pediatric patients have not been established. EGRIFTA™ (tesamorelin for injection) should not be used in children with open epiphyses, among whom excess GH and IGF-1 may result in linear growth acceleration and excessive growth.

There is no information on the use of EGRIFTA™ (tesamorelin for injection) in patients greater than 65 years of age with HIV and lipodystrophy.

Safety, efficacy, and pharmacokinetics of EGRIFTA™ (tesamorelin for injection) in patients with renal or hepatic impairment have not been established.

The most commonly reported adverse reactions (>5% and more frequent than placebo) are arthralgia [13.1% of patients receiving EGRIFTA™ (tesamorelin for injection) and 11.0% of patients receiving placebo], pain in extremity [6.1% of patients receiving EGRIFTA™ (tesamorelin for injection) and 4.6% of patients receiving placebo], myalgia [5.5% of patients receiving EGRIFTA™ (tesamorelin for injection) and 1.9% of patients receiving placebo], injection site erythema [8.5% of patients receiving EGRIFTA™ (tesamorelin for injection) and 2.7% of patients receiving placebo], injection site pruritus [7.6% of patients receiving EGRIFTA™ (tesamorelin for injection) and 0.8% of patients receiving placebo], and peripheral edema [6.1% of patients receiving EGRIFTA™ (tesamorelin for injection) and 2.3% of patients receiving placebo].

During the first 26 weeks of treatment (main phase), discontinuations as a result of adverse reactions occurred in 9.6% of patients receiving EGRIFTA™ (tesamorelin for injection) and 6.8% of patients receiving placebo. Apart from patients with hypersensitivity reactions identified during the studies and who were discontinued per protocol (2.2%), the most common reasons for discontinuation of EGRIFTA™ (tesamorelin for injection) treatment were adverse reactions due to the effect of GH (4.2%) and local injection site reactions (4.6%).

About EGRIFTA™

EGRIFTA™ (tesamorelin for injection) is a synthetic analogue of growth hormone releasing factor (GRF), shown to reduce visceral fat in HIV-infected patients with excess abdominal fat associated with lipodystrophy. GRF is a hypothalamic peptide that acts on the pituitary cells in the brain to stimulate the synthesis and release of endogenous growth hormone.  

About HIV-Associated Lipodystrophy

Several factors, including a patient's antiretroviral drug regimen and the HIV virus itself are thought to contribute to HIV-associated lipodystrophy, which is characterized by body composition changes. The changes in body composition may include excess abdominal fat accumulation, which is known as abdominal lipohypertrophy.

Please see full prescribing information for EGRIFTA™ (tesamorelin for injection) at www.emdserono.com.

About EMD Serono, Inc.

EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, is a leader in the US biopharmaceutical arena, integrating cutting-edge science with unparalleled patient support systems to improve people's lives. The company has strong market positions in neurodegenerative diseases, with Rebif® (interferon beta-1a), as well as in endocrinology, with Saizen® (somatropin (rDNA origin) for injection) and Serostim® (somatropin (rDNA origin) for injection). EMD Serono is a leader in reproductive health, with Gonal-f® (follitropin alfa for injection), Luveris® (lutropin alfa for injection) and Ovidrel® Prefilled Syringe (choriogonadotropin alfa injection). In addition, EMD Serono is growing its expertise and presence in the area of oncology, with more than 10 projects currently in development. With a clear focus on the patient and a leadership presence in the biopharmaceutical industry, EMD Serono's US footprint continues to grow, with more than 1100 employees around the country and fully integrated commercial, clinical and research operations in the company's home state of Massachusetts.

For more information, please visit www.emdserono.com

About Merck KGaA

Merck KGaA is a global pharmaceutical and chemical company with total revenues of Euro 7.7 billion in 2009, a history that began in 1668, and a future shaped by approximately 40,000 (including EMD Millipore) employees in 64 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.  

For more information, please visit www.merckserono.com or www.merck.de

About Theratechnologies

Theratechnologies (TSX: TH) is a Canadian biopharmaceutical company that discovers and develops innovative therapeutic products, with an emphasis on peptides, for commercialization. The Company targets unmet medical needs in specialty markets where it can retain all or part of the commercial rights to its products. Its most advanced compound, tesamorelin, is an analogue of the human growth hormone releasing factor. Tesamorelin will be exclusively commercialized in the U.S. by EMD Serono, under the brand name EGRIFTA™. The Company's growth strategy is centered on the commercialization of EGRIFTA™ in the United States through an agreement with EMD Serono, Inc. for the reduction of excess abdominal fat associated with lipodystrophy in HIV-infected patients. Moreover, Theratechnologies' growth will also derive from the commercialization of EGRIFTA™ in other markets for HIV-associated lipodystrophy, as well as the development of clinical programs for EGRIFTA™ in other medical conditions.

SOURCE EMD Serono, Inc.

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