U.S. FDA approves orphan drug MyaleptTM (metreleptin for injection)

  U.S. FDA approves orphan drug MyaleptTM (metreleptin for injection)

Business Wire

WILMINGTON, Del. -- February 25, 2014

AstraZeneca (NYSE: AZN) today announced that the U.S. Food and Drug
Administration (FDA) has approved Myalept™ (metreleptin for injection), which
is indicated as an adjunct to diet as replacement therapy to treat the
complications of leptin deficiency in patients with congenital or acquired
generalized lipodystrophy. MYALEPT, a recombinant analog [laboratory-created
form] of human leptin, is the first and only treatment approved by the FDA for
these patients.

AstraZeneca is working to complete the transfer of the Biologics License
Application (BLA) for MYALEPT from Bristol-Myers Squibb Company to AstraZeneca
as part of the acquisition of the diabetes alliance assets (including MYALEPT
and Amylin Pharmaceuticals, LLC), which was completed on February 1, 2014.

Lipodystrophy is a group of rare syndromes characterized by loss of fat
tissue. In some patients, it is genetic, and in others it may be acquired for
different pathophysiological, and in some cases unknown reasons. Generalized
lipodystrophy is characterized by a widespread loss of fat tissue under the
skin. This loss of fat tissue causes a deficit in the hormone leptin leading
to multiple metabolic complications.

The safety and effectiveness of MYALEPT for the treatment of complications of
partial lipodystrophy or for the treatment of liver disease, including
non-alcoholic steatohepatitis (NASH), have not been established. MYALEPT is
not indicated for use in patients with HIV-related lipodystrophy or for use in
patients with metabolic disease, including diabetes mellitus and
hypertriglyceridemia, without concurrent evidence of congenital or acquired
generalized lipodystrophy.

MYALEPT has Boxed WARNINGS regarding the risk of anti-metreleptin antibodies
with neutralizing activity and risk of lymphoma. Anti-metreleptin antibodies
with neutralizing activity have been identified in patients treated with
MYALEPT. The consequences of these neutralizing antibodies are not well
characterized but could include inhibition of endogenous leptin action and/or
loss of MYALEPT efficacy. Severe infection and/or worsening metabolic control
have been reported. Healthcare professionals should test for anti-metreleptin
antibodies with neutralizing activity in patients who develop severe
infections or show signs suspicious for loss of MYALEPT efficacy during
treatment. T-cell lymphoma has been reported in patients with acquired
generalized lipodystrophy, both treated and not treated with MYALEPT.
Healthcare professionals should carefully consider the benefits and risks of
treatment with MYALEPT in patients with significant hematologic abnormalities
and/or acquired generalized lipodystrophy. Because of these risks associated
with the development of anti-metreleptin antibodies that neutralize endogenous
leptin and/or MYALEPT (metreleptin for injection) and the risk for lymphoma,
MYALEPT is available only through a restricted program under a Risk Evaluation
and Mitigation Strategy (REMS) called the MYALEPT REMS PROGRAM.

“We are pleased that MYALEPT will be available to patients in the U.S. MYALEPT
is the first approved therapy, as an adjunct to diet, to help treat the
complications of leptin deficiency affecting the lives of children and adults
with generalized lipodystrophy,” said Briggs Morrison, M.D., executive vice
president, Global Medicines Development and chief medical officer,
AstraZeneca.“MYALEPT represents a significant treatment advancement for
people living with this serious and rare disorder. We are committed to
supporting this patient community and are dedicated to ensuring the
appropriate patients who are prescribed MYALEPT will also have a comprehensive
patient support program available to them.”

MYALEPT is for subcutaneous injection only and is available in an 11.3 mg vial
that requires reconstitution.

MYALEPT is contraindicated in patients with general obesity not associated
with congenital leptin deficiency. MYALEPT has not been shown to be effective
in treating general obesity, and the development of anti-metreleptin
antibodies with neutralizing activity has been reported in obese patients
treated with MYALEPT. MYALEPT is also contraindicated in patients with prior
severe hypersensitivity reactions to metreleptin or any of the product
components. Known hypersensitivity reactions have included urticaria and
generalized rash.

AstraZeneca is working to make MYALEPT available to patients as soon as
possible in the U.S. MYALEPT has been granted orphan drug status by the FDA.

INDICATION and IMPORTANT SAFETY INFORMATION

for Myalept™ (metreleptin for injection)

INDICATION

Myalept™ (metreleptin for injection) is a recombinant human leptin analog
indicated as an adjunct to diet as replacement therapy to treat the
complications of leptin deficiency in patients with congenital or acquired
generalized lipodystrophy.

LIMITATIONS OF USE

  *The safety and effectiveness of MYALEPT (metreleptin for injection) for
    the treatment of complications of partial lipodystrophy or for the
    treatment of liver disease, including nonalcoholic steatohepatitis (NASH),
    have not been established.
  *MYALEPT is not indicated for use in patients with HIV-related
    lipodystrophy or in patients with metabolic disease, including diabetes
    mellitus and hypertriglyceridemia, without concurrent evidence of
    congenital or acquired generalized lipodystrophy.

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF ANTI-METRELEPTIN ANTIBODIES WITH NEUTRALIZING ACTIVITY AND
RISK OF LYMPHOMA

  *Anti-metreleptin antibodies with neutralizing activity have been
    identified in patients treated with MYALEPT. The consequences of these
    neutralizing antibodies are not well characterized but could include
    inhibition of endogenous leptin action and/or loss of MYALEPT efficacy.
    Severe infection and/or worsening metabolic control have been reported.
    Test for anti-metreleptin antibodies with neutralizing activity in
    patients who develop severe infections or show signs suspicious for loss
    of MYALEPT efficacy during treatment. Contact Bristol Myers-Squibb at
    1-866-216-1526 for neutralizing antibody testing of clinical samples
  *T-cell lymphoma has been reported in patients with acquired generalized
    lipodystrophy, both treated and not treated with MYALEPT. Carefully
    consider the benefits and risks of treatment with MYALEPT in patients with
    significant hematologic abnormalities and/or acquired generalized
    lipodystrophy
  *Because of these risks associated with the development of anti-metreleptin
    antibodies that neutralize endogenous leptin and/or MYALEPT and the risk
    for lymphoma, MYALEPT is available only through a restricted program under
    a Risk Evaluation and Mitigation Strategy (REMS) called the MYALEPT REMS
    PROGRAM

CONTRAINDICATIONS

MYALEPT (metreleptin for injection) is contraindicated in patients with:

  *General obesity not associated with congenital leptin deficiency. MYALEPT
    has not been shown to be effective in treating general obesity, and the
    development of anti-metreleptin antibodies with neutralizing activity has
    been reported in obese patients treated with MYALEPT
  *Prior severe hypersensitivity reactions to metreleptin or to any of the
    product components. Known hypersensitivity reactions have included
    urticaria and generalized rash.

WARNINGS AND PRECAUTIONS

Risk for Development of Antibodies that Neutralize Endogenous Leptin and/or
MYALEPT

Anti-metreleptin antibodies with in vitro neutralizing activity to leptin
associated with adverse events consistent with loss of endogenous leptin
activity and/or loss of efficacy have been identified in two patients with
generalized lipodystrophy treated with MYALEPT (severe infections, increases
in HbA1c and triglycerides), and in three patients without lipodystrophy who
received MYALEPT in clinical studies (excessive weight gain, development of
glucose intolerance or diabetes mellitus). The clinical implications
associated with development of anti-metreleptin antibodies with neutralizing
activity are not well-characterized at this time due to the small number of
reports. Test for anti-metreleptin antibodies with neutralizing activity in
patients who develop severe infections or show signs suspicious for loss of
MYALEPT efficacy during treatment.

Lymphoma

  *Three cases of T-cell lymphoma have been reported in the MYALEPT
    lipodystrophy program; all three patients had acquired generalized
    lipodystrophy. Two of these patients were diagnosed with peripheral T-cell
    lymphoma while receiving MYALEPT. Both had immunodeficiency and
    significant hematologic abnormalities including severe bone marrow
    abnormalities before the start of MYALEPT treatment. A separate case of
    anaplastic large cell lymphoma was reported in a patient receiving MYALEPT
    (metreleptin for injection)  who did not have hematological abnormalities
    before treatment.
  *Lymphoproliferative disorders, including lymphomas, have been reported in
    patients with acquired generalized lipodystrophy not treated with MYALEPT.
    A causal relationship between MYALEPT treatment and the development and/or
    progression of lymphoma has not been established. Acquired lipodystrophies
    are associated with autoimmune disorders, and autoimmune disorders are
    associated with an increased risk of malignancies including lymphomas.
  *The benefits and risks of MYALEPT treatment should be carefully considered
    in patients with acquired generalized lipodystrophy and/or those with
    significant hematologic abnormalities (including leukopenia, neutropenia,
    bone marrow abnormalities, lymphoma and/or lymphadenopathy).

MYALEPT REMS Program

MYALEPT is available only through a restricted distribution program under a
REMS, called the MYALEPT REMS Program, because of the risks associated with
the development of anti-metreleptin antibodies that neutralize endogenous
leptin and/or MYALEPT and the risk for lymphoma [see Warnings and Precautions
section].

Further information is available at www.myaleptrems.com or 1-855-6MYALEPT.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Dosages adjustments, including possible large reductions, of insulin or
insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to
minimize the risk of hypoglycemia. Closely monitor blood glucose in patients
on concomitant insulin therapy, especially those on high doses, or insulin
secretagogue (e.g., sulfonylurea), when treating with MYALEPT.

Autoimmunity

Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are
associated with autoimmune disorders including autoimmune hepatitis and
membranoproliferative glomerulonephritis. Cases of progression of autoimmune
hepatitis and membranoproliferative glomerulonephritis (associated with
massive proteinuria and renal failure) were observed in some patients with
acquired generalized lipodystrophy treated with MYALEPT (metreleptin for
injection). A causal relationship between MYALEPT treatment and the
development and/or progression of autoimmune disease has not been established.
The potential benefits and risks of MYALEPT treatment should be carefully
considered in patients with autoimmune disease.

Hypersensitivity

There have been reports of generalized hypersensitivity (e.g., urticaria or
generalized rash) in patients taking MYALEPT. If a hypersensitivity reaction
occurs, patient should promptly seek medical advice regarding discontinuation
of MYALEPT.

Benzyl Alcohol Toxicity

MYALEPT contains benzyl alcohol when reconstituted with Bacteriostatic Water
for Injection (BWFI). The preservative benzyl alcohol has been associated with
serious adverse events and death in pediatric patients, particularly in
neonates and premature infants. Preservative-free Water for Injection (WFI),
that does not contain benzyl alcohol, is recommended for use in neonates and
infants.

ADVERSE REACTIONS

  *In an open label, single arm study (N=48), the most common adverse
    reactions reported in ≥5% in patients with generalized lipodystrophy
    receiving MYALEPT were:

       *Headache (13%), hypoglycemia (13%), decreased weight (13%), abdominal
         pain (10%), arthralgia (8%), dizziness (8%), ear infection (8%),
         fatigue (8%), nausea (8%), ovarian cyst (8%), upper respiratory tract
         infection (8%), anemia (6%), back pain (6%), diarrhea (6%),
         paresthesia (6%), proteinuria (6%), pyrexia (6%)

  *Less common adverse reactions included injection site erythema and
    urticaria (N=2 [4%]).
  *Six patients (13%) had 7 adverse reactions of hypoglycemia, 6 of which
    occurred in the setting of concomitant insulin use, with or without oral
    antihyperglycemic agents.
  *Two patients (4%) had events of pancreatitis, both of whom had a medical
    history of pancreatitis.

Immunogenicity

  *Anti-metreleptin antibodies were detected in 84% (36/43) of generalized
    lipodystrophy patients studied in the MYALEPT (metreleptin for injection) 
    trials. The magnitude and persistence of the observed anti-drug antibody
    responses is not understood. Anti-metreleptin antibodies with neutralizing
    activity associated with adverse events consistent with loss of endogenous
    leptin activity and/or loss of MYALEPT efficacy was observed in 6% (2/33)
    of the patients with generalized lipodystrophy tested including severe
    infections and worsening of metabolic control (increases in HbA1c and/or
    triglycerides) was seen in these two patients.
  *Test for anti-metreleptin antibodies with neutralizing activity in
    patients who develop severe infections or show signs suspicious for loss
    of MYALEPT efficacy during treatment.

DRUG INTERACTIONS

  *No formal drug interaction studies were performed.
  *Leptin is a cytokine and may have the potential to alter the formation of
    cytochrome P450 (CYP450) enzymes. This should be taken into account when
    prescribing concomitant drugs metabolized by CYP450 (e.g., oral
    contraceptives and drugs with a narrow therapeutic index). The effect of
    metreleptin on CYP450 enzymes may be clinically relevant for CYP450
    substrates with narrow therapeutic index, where the dose is individually
    adjusted. Upon initiation or discontinuation of MYALEPT, in patients being
    treated with these types of agents, therapeutic monitoring of effect
    (e.g., warfarin) or drug concentration (e.g., cyclosporine or
    theophylline) should be performed and the individual dose of the agent
    adjusted as needed.

USE IN SPECIFIC POPULATIONS

Pregnant Women

  *There are no adequate and well-controlled studies of MYALEPT in pregnant
    women. MYALEPT should be used during pregnancy only if the potential
    benefit justifies the potential risk to the fetus. There is a program that
    monitors outcomes in women exposed to MYALEPT during pregnancy.
  *Disease-Associated Maternal and Fetal Risk: The contribution of MYALEPT
    (metreleptin for injection)  to obstetrical risks and complications is
    unknown compared with those already documented in the lipodystrophy
    patient population (e.g., gestational diabetes, macrosomia, eclampsia,
    intrauterine growth retardation, intrauterine death, and miscarriage).
  *Labor or Delivery: The effects of MYALEPT on labor and delivery in
    pregnant women are unknown.

Nursing Mothers: It is not known if MYALEPT is present in human milk.
Endogenous leptin is present in human milk. Because of the potential for
serious adverse reactions (including possible adverse reactions related to
passage of anti-metreleptin antibodies) in nursing infants from MYALEPT a
decision should be made whether to discontinue nursing or discontinue the
drug, taking into account importance of drug to the mother.

Pediatric Use

  *MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT
    contains no preservative when reconstituted with WFI. Preservative-free
    WFI is recommended for use in neonates and infants. The preservative
    benzyl alcohol has been associated with serious adverse events and death,
    particularly in pediatric patients. The "gasping syndrome" (characterized
    by central nervous system depression, metabolic acidosis, gasping
    respirations, and high levels of benzyl alcohol and its metabolites found
    in the blood and urine) has been associated with benzyl alcohol dosages
    >99 mg/kg/day in neonates and low-birth weight infants. Additional
    symptoms may include gradual neurological deterioration, seizures,
    intracranial hemorrhage, hematologic abnormalities, skin breakdown,
    hepatic and renal failure, hypotension, bradycardia, and cardiovascular
    collapse.
  *Although normal therapeutic doses of this product deliver amounts of
    benzyl alcohol that are substantially lower than those reported in
    association with the "gasping syndrome," the minimum amount of benzyl
    alcohol at which toxicity may occur is not known. Premature and low-birth
    weight infants, as well as patients receiving high dosages, may be more
    likely to develop toxicity. Practitioners administering this and other
    medications containing benzyl alcohol should consider the combined daily
    metabolic load of benzyl alcohol from all sources. When reconstituted with
    2.2 mL of BWFI, MYALEPT (metreleptin for injection)  contains 1.76 mg of
    benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of
    reconstituted product.

ADDITIONAL CONSIDERATIONS

Dosage Adjustments of Medications Known to Cause Hypoglycemia

Dosage adjustments, including possible large reductions, of insulin or insulin
secretagogue (e.g., sulfonylurea) may be necessary in some patients to
minimize the risk of hypoglycemia. Closely monitor blood glucose in patients
on concomitant insulin therapy, especially those on high doses, or insulin
secretagogue (e.g., sulfonylurea) when treating with MYALEPT.

Discontinuation in Patients at Risk for Pancreatitis

When discontinuing MYALEPT therapy in patients with risk factors for
pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia),
tapering of the dose over a one-week period is recommended. During tapering,
monitor triglyceride levels and consider initiating or adjusting the dose of
lipid-lowering medications as needed. Signs and/or symptoms consistent with
pancreatitis should prompt an appropriate clinical evaluation.

Please click here for US Full Prescribing Information and click here for
Medication Guide for MYALEPT (metreleptin for injection), including Boxed
WARNINGS about the risks of anti-metreleptin antibodies with neutralizing
activity and lymphoma. Please click here for Instructions for Use.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that
focuses on the discovery, development and commercialization of prescription
medicines, primarily for the treatment of cardiovascular, metabolic,
respiratory, inflammation, autoimmune, oncology, infection and neuroscience
diseases. AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more information
please visit: www.astrazeneca.com.

Contact:

AstraZeneca
Media:
Andrew Davis,215-542-3378
andrew.davis@astrazeneca.com
or
Michele Meixell, 302-885-2677
michele.meixell@astrazeneca.com
or
Investors:
Karl Hard, 44-20-7604-8123
karl.j.hard@astrazeneca.com
or
Anthony Brown, 44-20-7604-8067
Anthony.brown@astrazeneca.com
or
Jens Lindberg, 44-20-7604-8414
jens.lindberg@astrazeneca.com
or
Colleen Proctor, 302-886-1842
colleen.proctor@astrazeneca.com
 
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