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

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.