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November 12, 2010 ??? The US Food and Drug Administration (FDA) has approved tesamorelin acetate injection (Egrifta; Theratechnologies, Inc, and marketed by EMD Serono) as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy.
Tesamorelin is a synthetic analog of growth hormone???releasing factor ??? a hypothalamic peptide that acts on pituitary cells in the brain to stimulate the production and release of endogenous growth hormone.
"The FDA recognizes the need for therapies to treat patients with HIV-lipodystrophy," said Curtis Rosebraugh, MD, MPH, director of the Office of Drug Evaluation II in the FDA's Center for Drug Evaluation and Research, in an agency news release. "The presence of excess fat with this condition may contribute to other health problems as well as affect a patient's quality of life, so treatments that demonstrate they are safe and effective at treating these symptoms are important."
FDA approval followed a positive endorsement from the Endocrinologic and Metabolic Drugs Advisory Committee and was based on data from 2 multicenter, randomized, double-blind, placebo-controlled phase 3 studies of 816 patients, showing that once-daily treatment with tesamorelin significantly reduced visceral adipose tissue (VAT) at 26 weeks.
Mean VAT at baseline ranged from 178 cm2 to 186 cm2 for the active-treatment group and 171 cm2 to 195 cm2 for patients randomly assigned to placebo, as assessed by computed tomography scan at the L4???L5 vertebral level.
Computed tomography scan results of the first study showed that tesamorelin therapy yielded an 18% least-squares mean decrease from baseline in VAT compared with an increase of 2% for placebo (Δ, −20%; 95% confidence interval [CI], −24% to −15%). In the second study, tesamorelin-treated patients experienced a likewise significant 14% decrease from baseline in VAT compared with a 2% decrease among those given placebo (Δ, −12%; 95% CI, −16% to −7%).
Both studies also showed significant decreases in VAT as measured by least-squares mean decreases from baseline in waist circumference (study 1, −3 cm vs −1 cm; Δ, −2 cm; 95% CI, −2.8 cm to −0.9 cm; study 2, −2 cm vs −1 cm; Δ, −1 cm; 95% CI, −2.5 cm to −0.3 cm).
The decreases in VAT and waist circumference were sustained in patients who received extended therapy with tesamorelin for 52 weeks.
The recommended dose of tesamorelin is 2 mg (2 vials) injected subcutaneously once daily in the abdomen. Adverse events most commonly reported in tesamorelin-treated study patients included arthralgia (13% vs placebo, 11%), pain in extremity (6.1% vs 4.6%), myalgia (5.5% vs 1.9%), injection-site erythema (8.5% vs 2.7%), injection-site pruritus (7.6% vs 0.%), and peripheral edema (6.1% vs 2.3%).
FDA officials note that the long-term cardiovascular benefit and safety of tesamorelin have not been studied, and there are no data to support improved compliance with antiretroviral therapies. Also, tesamorelin should not be used for weight-loss management.
"As HIV-infected patients are living longer, a substantial number may develop metabolic complications associated with HIV, such as abdominal lipohypertrophy," said Morris Schambelan, MD, professor of medicine from the University of California???San Francisco, in a company news release. "With the approval of Egrifta, doctors are now able to provide appropriately selected patients with a treatment option shown to reduce [VAT]."
Because tesamorelin induces the release of endogenous growth hormone, it should not be used in patients with active malignancy, whether newly diagnosed or recurrent. Tesamorelin increases serum levels of insulin-like growth factor 1 (IGF-1), which has an unknown effect on the development or progression of malignancies. Discontinuation of therapy should be considered in patients with persistent IGF-1 elevations greater than 3 standard deviations, particularly if the efficacy response is not robust. In clinical trials, IGF-1 levels were measured every 3 months.
Tesamorelin therapy may also result in glucose intolerance and an increased risk for diabetes mellitus. Glucose status should be carefully evaluated before initiating therapy and monitored periodically thereafter. Caution is advised when treating patients who develop glucose intolerance or diabetes, and discontinuation of therapy should be considered in those who do not demonstrate a clear efficacy response. Diabetic patients should be monitored at regular intervals for the potential development or worsening of retinopathy.
Treatment with tesamorelin is contraindicated in patients with disruption of the hypothalamic???pituitary axis resulting from hypophysectomy, hypopituitarism, or pituitary tumor/surgery; active malignancy; or pregnancy and in patients with known hypersensitivity to tesamorelin and/or mannitol.
The safety and efficacy of tesamorelin have not been established in pediatric patients and in those with renal or hepatic impairment; discontinuation of therapy should be considered in critically ill patients.
As a condition of approval, the company is required to conduct a clinical trial to assess whether tesamorelin has an effect on diabetic retinopathy, and a long-term observational safety study for a single-vial formulation of the drug (tesamorelin).
Tesamorelin is a synthetic analog of growth hormone???releasing factor ??? a hypothalamic peptide that acts on pituitary cells in the brain to stimulate the production and release of endogenous growth hormone.
"The FDA recognizes the need for therapies to treat patients with HIV-lipodystrophy," said Curtis Rosebraugh, MD, MPH, director of the Office of Drug Evaluation II in the FDA's Center for Drug Evaluation and Research, in an agency news release. "The presence of excess fat with this condition may contribute to other health problems as well as affect a patient's quality of life, so treatments that demonstrate they are safe and effective at treating these symptoms are important."
FDA approval followed a positive endorsement from the Endocrinologic and Metabolic Drugs Advisory Committee and was based on data from 2 multicenter, randomized, double-blind, placebo-controlled phase 3 studies of 816 patients, showing that once-daily treatment with tesamorelin significantly reduced visceral adipose tissue (VAT) at 26 weeks.
Mean VAT at baseline ranged from 178 cm2 to 186 cm2 for the active-treatment group and 171 cm2 to 195 cm2 for patients randomly assigned to placebo, as assessed by computed tomography scan at the L4???L5 vertebral level.
Computed tomography scan results of the first study showed that tesamorelin therapy yielded an 18% least-squares mean decrease from baseline in VAT compared with an increase of 2% for placebo (Δ, −20%; 95% confidence interval [CI], −24% to −15%). In the second study, tesamorelin-treated patients experienced a likewise significant 14% decrease from baseline in VAT compared with a 2% decrease among those given placebo (Δ, −12%; 95% CI, −16% to −7%).
Both studies also showed significant decreases in VAT as measured by least-squares mean decreases from baseline in waist circumference (study 1, −3 cm vs −1 cm; Δ, −2 cm; 95% CI, −2.8 cm to −0.9 cm; study 2, −2 cm vs −1 cm; Δ, −1 cm; 95% CI, −2.5 cm to −0.3 cm).
The decreases in VAT and waist circumference were sustained in patients who received extended therapy with tesamorelin for 52 weeks.
The recommended dose of tesamorelin is 2 mg (2 vials) injected subcutaneously once daily in the abdomen. Adverse events most commonly reported in tesamorelin-treated study patients included arthralgia (13% vs placebo, 11%), pain in extremity (6.1% vs 4.6%), myalgia (5.5% vs 1.9%), injection-site erythema (8.5% vs 2.7%), injection-site pruritus (7.6% vs 0.%), and peripheral edema (6.1% vs 2.3%).
FDA officials note that the long-term cardiovascular benefit and safety of tesamorelin have not been studied, and there are no data to support improved compliance with antiretroviral therapies. Also, tesamorelin should not be used for weight-loss management.
"As HIV-infected patients are living longer, a substantial number may develop metabolic complications associated with HIV, such as abdominal lipohypertrophy," said Morris Schambelan, MD, professor of medicine from the University of California???San Francisco, in a company news release. "With the approval of Egrifta, doctors are now able to provide appropriately selected patients with a treatment option shown to reduce [VAT]."
Because tesamorelin induces the release of endogenous growth hormone, it should not be used in patients with active malignancy, whether newly diagnosed or recurrent. Tesamorelin increases serum levels of insulin-like growth factor 1 (IGF-1), which has an unknown effect on the development or progression of malignancies. Discontinuation of therapy should be considered in patients with persistent IGF-1 elevations greater than 3 standard deviations, particularly if the efficacy response is not robust. In clinical trials, IGF-1 levels were measured every 3 months.
Tesamorelin therapy may also result in glucose intolerance and an increased risk for diabetes mellitus. Glucose status should be carefully evaluated before initiating therapy and monitored periodically thereafter. Caution is advised when treating patients who develop glucose intolerance or diabetes, and discontinuation of therapy should be considered in those who do not demonstrate a clear efficacy response. Diabetic patients should be monitored at regular intervals for the potential development or worsening of retinopathy.
Treatment with tesamorelin is contraindicated in patients with disruption of the hypothalamic???pituitary axis resulting from hypophysectomy, hypopituitarism, or pituitary tumor/surgery; active malignancy; or pregnancy and in patients with known hypersensitivity to tesamorelin and/or mannitol.
The safety and efficacy of tesamorelin have not been established in pediatric patients and in those with renal or hepatic impairment; discontinuation of therapy should be considered in critically ill patients.
As a condition of approval, the company is required to conduct a clinical trial to assess whether tesamorelin has an effect on diabetic retinopathy, and a long-term observational safety study for a single-vial formulation of the drug (tesamorelin).
