Metreleptin

MYALEPT is a 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. ( 1 ) Limitations of Use The safety and effectiveness of MYALEPT for the treatment of complications of partial lipodystrophy have not been established. ( 1 ) The safety and effectiveness of MYALEPT for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established. ( 1 ) MYALEPT is not indicated for use in patients with HIV-related lipodystrophy. ( 1 ) MYALEPT is not indicated for use in patients with metabolic disease, without concurrent evidence of generalized lipodystrophy. ( 1 )

1.1 Patients with Generalized Lipodystrophy MYALEPT (metreleptin) for injection 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. Limitations of Use The safety and effectiveness of MYALEPT for the treatment of complications of partial lipodystrophy have not been established. The safety and effectiveness of MYALEPT 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. MYALEPT is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.

For Injection: 11.3 mg of metreleptin supplied in a vial as a sterile, white, solid, lyophilized cake (delivers 5 mg per mL of metreleptin when reconstituted with 2.2 mL of BWFI or WFI). MYALEPT is supplied as a sterile, white, solid, lyophilized cake of 11.3 mg metreleptin per vial to deliver 5 mg per mL when reconstituted in 2.2 mL of BWFI or WFI. ( 3 )

General obesity not associated with congenital leptin deficiency. ( 4.1 ) Hypersensitivity to metreleptin. ( 4.2 )

4.1 General Obesity 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 [see Warnings and Precautions (5.1) ].

4.2 Hypersensitivity MYALEPT is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included anaphylaxis, urticaria and generalized rash [see Warnings and Precautions (5.6) ].

Anti-metreleptin antibodies with neutralizing activity: Could inhibit endogenous leptin action and/or result in loss of MYALEPT efficacy. Test for neutralizing antibodies in patients with severe infections or loss of efficacy during MYALEPT treatment. ( 5.1 ) T-cell lymphoma: Carefully consider benefits and risks of treatment with MYALEPT in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy. ( 5.2 ) Hypoglycemia: A dose adjustment, including possible large reductions, of insulin or insulin secretagogue may be necessary. Closely monitor blood glucose in patients on concomitant insulin or insulin secretagogue therapy. ( 5.4 ) Autoimmunity: Autoimmune disorder progression has been observed in patients treated with MYALEPT. Carefully consider benefits and risks of MYALEPT treatment in patients with autoimmune disease. ( 5.5 ) Hypersensitivity: Hypersensitivity reactions (e.g., anaphylaxis, urticaria or generalized rash) have been reported. Patient should promptly seek medical advice regarding suspected reactions. ( 5.6 ) Benzyl Alcohol Toxicity: Preservative-free sterile WFI recommended for neonates and infants. ( 5.7 )

5.1 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 HbA 1c 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. Contact Chiesi Farmaceutici S.p.A. at 1-866-216-1526 for neutralizing antibody testing of clinical samples [see Adverse Reactions (6.2) ].

5.2 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 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). 5.3 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 (5.1, 5.2) ]. Notable requirements of the MYALEPT REMS Program include the following: Prescribers must be certified with the program by enrolling and completing training. Pharmacies must be certified with the program and only dispense MYALEPT after receipt of the MYALEPT REMS Prescription Authorization Form for each new prescription. Further information is available at www.myaleptrems.com or 1-855-669-2537.

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 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 [see Dosage and Administration (2.4) and Adverse Reactions (6.1) ]. 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.

5.5 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. 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.

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

5.7 Benzyl Alcohol Toxicity MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with sterile Water for Injection (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 in pediatric patients, particularly in neonates and premature infants [see Use in Specific Populations (8.4) ].

Most common in clinical trials (≥10%): headache, hypoglycemia, decreased weight, abdominal pain. ( 5.4 , 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi Farmaceutici S.p.A. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Open-Label, Single-Arm Study The safety of MYALEPT was evaluated in 48 patients with generalized lipodystrophy in a single-arm, open-label study [see Clinical Studies (14.1) ]. The median duration of exposure in this trial was 2.7 years with a range of 3.6 months to 10.9 years. The most frequent adverse reactions are summarized in Table 3. Table 3: Adverse Reactions of 5% or Greater Incidence in Patients with Generalized Lipodystrophy Receiving MYALEPT in an Open-Label, Single-Arm Study All Subjects N=48 (%) 1. Hypoglycemic events were assessed as mild, moderate, severe, or life threatening based on the protocol specified definitions: Mild: Documentation of low plasma glucose values with no symptoms; Moderate: Presence of clinical symptoms requiring ingestion of glucose, self-alleviated; Severe: Presence of neuroglycopenic symptoms requiring assistance from others for alleviation; Life threatening: Loss of consciousness and/or requiring intervention by administration of intravenous glucose or intramuscular glucagon. Headache 6 (13) Hypoglycemia 1 6 (13) Decreased weight 6 (13) Abdominal pain 5 (10) Arthralgia 4 (8) Dizziness 4 (8) Ear infection 4 (8) Fatigue 4 (8) Nausea 4 (8) Ovarian cyst 4 (8) Upper respiratory tract infection 4 (8) Anemia 3 (6) Back pain 3 (6) Diarrhea 3 (6) Paresthesia 3 (6) Proteinuria 3 (6) Pyrexia 3 (6) In patients with generalized lipodystrophy receiving MYALEPT in this study, 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.

6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Anti-metreleptin antibodies were detected in 84% (36/43) of generalized lipodystrophy patients studied in the MYALEPT trials. Total anti-metreleptin antibody titers ranged between 1:5 and 1:1,953,125. The incompleteness of the current immunogenicity database precludes understanding of the magnitude and persistence of the observed anti-drug antibody responses. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of MYALEPT efficacy were observed in 6% (2/33) of the patients with generalized lipodystrophy tested. Adverse events reported in these two patients included severe infections and worsening of metabolic control (increases in HbA 1c and/or triglycerides). 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 Chiesi Farmaceutici S.p.A. at 1-866-216-1526 for testing of clinical samples. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The immunogenicity assays utilized in clinical trials lacked sensitivity, resulting in potential underestimation of the number of samples positive for anti-metreleptin antibodies with neutralizing activity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MYALEPT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Incorrect dose administered, accidental overdose [see Dosage and Administration (2.1 , 2.3) ] Injection site reaction, including inflammation and hyperpigmentation

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.

8.1 Pregnancy Pregnancy Exposure Registry There is a program that monitors outcomes in women exposed to MYALEPT during pregnancy. Women who become pregnant during MYALEPT treatment are encouraged to enroll. Patients or their physicians should call 1-855-669-2537 to enroll. Risk Summary Available pharmacovigilance reports with the use of MYALEPT in pregnant women are insufficient to evaluate for any drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. These reports describe similar adverse pregnancy outcomes as those documented in women with lipodystrophy (see Clinical Considerations ) . In an animal reproduction study, no adverse developmental effects were observed with subcutaneous administration of metreleptin to pregnant mice during organogenesis at doses 7- and 15-fold the maximum recommended clinical dose, based on body surface area of a 20- and 60-kg patient, respectively. In a pre- and postnatal development study in mice, subcutaneous administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose (see Data ) . MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with WFI. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4) ]. Therefore, if therapy with MYALEPT is needed during pregnancy, consider using preservative-free WFI when reconstituting [see Dosage and Administration (2.2) ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and Fetal Risk Lipodystrophy in pregnancy can result in an increased rate of gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage. Labor and Delivery The effects of MYALEPT on labor and delivery in pregnant women are unknown. In a published in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. In animal studies with metreleptin, prolonged gestation and dystocia were observed (see Data ) . Data Animal Data Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7- and 15-fold the maximum recommended clinical dose, based on body surface area of a 20- and 60-kg patient, respectively. In a pre- and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose. Placental transfer of metreleptin into the fetus was low (approximately 1%) following subcutaneous dosing.

8.2 Lactation There are no available data on the presence of metreleptin in human milk; however, endogenous leptin is present in human milk. There are no available data on the effects of metreleptin on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MYALEPT and any potential adverse effects on the breastfed child from MYALEPT or from the underlying maternal condition.

8.4 Pediatric Use The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years [see Clinical Studies (14.1) ]. No clinically meaningful differences were observed in the efficacy and safety of MYALEPT between pediatric and adult patients. 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 contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.

8.5 Geriatric Use Clinical trials of MYALEPT did not include sufficient numbers of subjects aged 65 and over (n=1) to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities. MYALEPT (metreleptin) for injection exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.