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November 11, 2010 – 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
treatmentindicated to reduce excess abdominal fat in
HIV-infected patients with
lipodystrophy(abdominallipohypertrophy) EGRIFTA
developed by Theratechnologies, a Canadian biopharmaceutical
company, will be marketed in the United States exclusively byEMD
Serono.
There are limitations of use associated with
EGRIFTA. Since the long-term cardiovascular safety and
potential long-term cardiovascular benefit of EGRIFTA
treatment have not been studied and are not known,
carefulconsideration should be given whether to continue
EGRIFTA treatment in patients who do not show a clear
efficacy response as judged by the degree ofreduction in
visceral adipose tissue (VAT) measured by waist circumference
(WC) or CT scan. EGRIFTA 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 .
The efficacy and safety of EGRIFTA was evaluated in two
Phase 3 multi-center, randomized, double-blind,
placebo-controlled clinical trials, which
demonstratedstatistically significant decreases in visceral
adipose tissue and waist circumference versus placebo in
HIV-infected patients who suffer from excess abdominal fat
associated withlipodystrophy. HIV-associated lipodystrophy
refers to abnormalities in body fat distribution and metabolism.
“As HIV-infected
patients are living longer, a substantial number may develop
metaboliccomplications 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.”
About EGRIFTA (tesamorelin for injection)
Phase 3 Trials
The FDA approval of EGRIFTA
was based on two multi-centerrandomized,
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 or
placebo for 26 weeks. Patients initially randomized to
EGRIFTA were then re-randomized to receive either EGRIFTA
or placebo for an additional 26-week treatment period, whereas
patients receiving placebo were switched to EGRIFTA).
In the first study, at baseline, mean VAT was 178 cm2 for the
patients who received EGRIFTA and was 171 cm2 for the
patients who received placebo. In the second study, at baseline,
mean VAT was 186 cm2 for the patients who received EGRIFTA
and was 195 cm2 for the patients who received placebo.
Patients treated with EGRIFTA experienced a statistically
significant least-squares mean decrease from baseline in VAT of
27 cm2 compared to an increase of 4 cm2 for patients on placebo
[(95% CI for the mean treatment difference of -31 cm2 (-39 cm2,
-24 cm2)] in the first study, and a statistically significant
decrease from baseline in VAT of 21 cm2 compared to no change in
VAT for patients on placebo [(95% CI for the mean treatment
difference of -21 cm2 (-29 cm2, -12 cm2)] 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 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 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 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 and for the patients who received placebo. Treatment
with EGRIFTA 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 over 52 weeks.
Important Risk Information
EGRIFTA 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 If
pregnancy occurs, EGRIFTA therapy should be discontinued.
EGRIFTA induces the release of
endogenous growth hormone, a known growth factor, thus patients
with active malignancy should not be treated with EGRIFTA.
For patients with a history of non-malignant neoplasms,
therapy should be initiated after careful evaluation of the
potential benefit of treatment. For patients with a history of
treated and stable malignancies, EGRIFTA) 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 should be considered carefully
based on the increased background risk of malignancies in
HIV-positive patients. EGRIFTA 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 therapy. Careful consideration
should be given to discontinuing EGRIFTA 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 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 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
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) treatment may result in glucose
intolerance. During the Phase 3 clinical trials, the percentages
of patients with elevated HbA 1c
(≥
6.5%) from baseline to Week 26 were
4.5% and 1.3% in the EGRIFTA and placebo groups,
respectively. An increased risk of developing diabetes with
EGRIFTA (HbA1c level
≥
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 treatment. In addition, all
patients treated with EGRIFTA 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 if they develop
glucose intolerance or diabetes, and careful consideration
should be given to discontinuing reatment 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 increases IGF-1, patients with diabetes who
are receiving ongoing treatment with EGRIFTA should be
monitored at regular intervals for potential development or
worsening of retinopathy.
Hypersensitivity reactions may occur in patients treated with
EGRIFTA. Hypersensitivity reactions occurred in 3.6% of
patients with HIV-associated lipodystrophy treated with
EGRIFTA 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
should be discontinued immediately.
EGRIFTA 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 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 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 has not been studied in patients
with acute critical illness. Since EGRIFTA stimulates
growth hormone production, careful consideration should be given
to discontinuing EGRIFTA in critically ill patients.
EGRIFTA 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 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 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 should be instructed not to human
milk-feed. It is not known whether EGRIFTA is excreted in
human milk.
Safety and effectiveness in pediatric patients
have not been established. EGRIFTA 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
in patients greater than 65 years of age with HIV and
lipodystrophy.
Safety, efficacy, and pharmacokinetics of
EGRIFTA 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 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)and 1.9% of patients receiving placebo],
injection site erythema [8.5% of patients
receiving EGRIFTA and 2.7% of patients receiving
placebo], injection site pruritus [7.6% of patients receiving
EGRIFTA and 0.8% of patients receiving placebo], and
peripheral edema [6.1% of patients receiving EGRIFTA™
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 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 treatment were adverse
reactions due to the effect of GH (4.2%) and local injection
site reactions (4.6%).
Please see full prescribing information for
EGRIFTA atwww.emdserono.com
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