• Development of insulin resistance and diabetes • Progression to poorly controlled diabetes and complications of diabetes • Patients with lipodystrophy may exhibit diabetes with a high insulin dose requirement.
Insulin resistance and diabetes
• Ectopic lipid deposition • Hepatic steatosis • Hepatomegaly • Steatohepatitis •Cirrhosis
Liver
• Proteinuric renal disease • Glomerulonephritis
Kidneys
• Chronic pain • Mood disturbances
Other effects
• Cardiomyopathy • Atherosclerosis •Arrhythmias
Heart
• Episodes of pancreatitis
Pancreas
• Infertility • Hyperandrogenism • Polycystic ovaries
Reproductive
Metabolic alterations and associated comorbidities
Key metabolic features Severely elevated triglycerides Ectopic lipid deposition Progression to poorly controlled diabetes, complications of diabetes Hyperphagia
• • • •
Kidney
Proteinuric renal disease Glomerulonephritis
Other general
Chronic pain Mood disturbances
Cardiomyopathy Atherosclerosis Arrhythmias
Hepatic steatosis Hepatomegaly Steatohepatitis Cirrhosis
Episodes of pancreatitis
Infertility Hyperandrogenism Polycystic ovaries
Leptin: A complex hormone
Leptin is an endogenous hormone produced by adipose (fat) tissue Leptin is the key hormone that informs the central nervous system (CNS) of the status of energy stores in the body It also has affects on many other systems and processes
• • •
Central actions
Hormone regulation Food intake Energy expenditure
Other targets
Kidney Bowel Pancreas Muscle
Reproduction
Placental function Trophoblast invasion Fetal function Gonadotrophins and gonadal hormones
Immune System Modulation
Cytokine induction Chemotaxis Macrophage activation Natural killer cytotoxicity TH1 stimulation TH2 inhibition Increase of maturation and survival of thymic T cells Increase of IL-2 Naïve T-cell proliferation Dendritic cells activation
Bone and Cartilage
Regulation of bone mass Rheumatoid arthritis Osteoarthritis Nitric Oxide Chondrocytes
Vascular function
Atherosclerosis Angiogenesis Oxidative stress
The safety and effectiveness of metreleptin for the treatment of complications of partial lipodystrophy or for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.
LIMITATIONS OF USE
INDICATION
Hyperphagia
• Severe elevated triglycerides • Low HDL Cholesterol • Atherogenic lipid profile
Lipid abnormalities
3
Understanding lipodystrophy
Safety of Metreleptin
Metreleptin is a recombinant human leptin analog for injection that binds to and activates the leptin receptor. Metreleptin decreases appetite and food intake resulting in improvements in metabolic parameters with positive impact on other physiological systems and processes
• •
Metreleptin: Clinical effects in LIPODYSTROPHY patients
Renal
• Reduction in proteinuria and hyperfiltration
Liver effects
• Improved hepatic steatosis • Reduced liver volume • Improvement in liver transaminases • Improved NASH
• Decreased appetite • Decreased food intake
• Normalised gonadotrophin secretion • Improved fertility • Clinical improvements in hyperandrogenemic women with PCOS
Metabolic improvements
• Reduction HbA1c • Reduction triglycerides • Improved insulin sensitivity
Immune system modulation
• Immunomodulatory effects • PBMC responsiveness
Other emerging data
• Improvement in QoL • Improvement in mortality and cardiovascular risk reduction
Direct effects
Potential effects of metreleptin
-71
-29
-45
-53
-46
-49
-13
-9
-21
4
-80%
-60%
-40%
-20%
0
20%
Hyperphagiaᵃ Pancreatitisᵇ Inability to perform work/school work Impaired Physical Appearance HbA1c > 8% Liver abnormality Progression of Organ Damage (fast) Triglycerides > 500mg/dL Disruption to female reproductive functioning (PCOS)ᶜ Triglycerides >200 mg/dL and ≤ 500 mg/dL HbA1c >6.5% and ≤ 8% Kidney abnormality Heart abnormalityᵈ Progression of Organ Damage (slow)
% Change in prevalence
QALY change after treatment
0.050
0.018
0.076
0.030
0.038
0.039
0.009
0.005
0.001
- 0.001
0.014
- 0.004
0.01
-0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Hyperphagia Pancreatitis Inability to perform work/school work Impaired Physical Appearance HBA1C > 8% Liver abnormality Progression of Organ Damage (fast) Triglycerides > 500mg/dL Disruption to female reproductive functioning (PCOS) Triglycerides >200 mg/dL and ≤ 500mg/dL HbA1c >6.5% and ≤ 8% Kidney abnormality Heart abnormality Progression of Organ Damage (slow)
QALY gains associated with 12 months of treatment with metreleptin: 0.313
Metreleptin: impact ON QUALITY OF LIFE in patients with GENERALIZED LIPODYSTROPHY
Adapted from Cook et al. 2021. Journal of the Endocrine Society; 5:1–16
Data based on N=68 patients with GL Data on hyperphagia were collected for 62 GL patients One patient with GL experienced a single episode of pancreatitis while on treatment with metreleptin. Only female patients of reproductive capacity (GL, n=27) were eligible for impairment; all other patients were considered unimpaired. Reproductive capacity was defined as female patients who were postpubescent and premenopausal who had not undergone surgical removal of reproductive organs at the time of starting metreleptin. Prevalence of heart abnormality can only increase as clinical resolution of abnormalities could not be determined with available data. GL, generalized lipodystrophy; HbA1c, glycated haemoglobin; PCOS, polycystic ovary syndrome; QALY, quality-adjusted life-year
1. Brown et al. Endocrine. 2018; 60(3):479–489. 2. Amryt Pharmaceuticals DAC, Data on file.
Lipid-lowering
76% - Continued (26/34)
24% - Discontinued (8/34)
Oral anti-diabetics
78% - Continued (25/32)
22% - Discontinued (7/32)
Insulin
28% - Discontinued within 1 years (11/39)
59% - Continued (23/39)
13% - Discontinued (other) (5/39)
Of clinical significance, >76% of GL patients treated with metreleptin discontinued key concomitant medications including: lipid-lowering therapies (LLTs), insulin and oral anti-diabetics.
Patient using (at baseline):
Generalized Lipodystrophy (GL) Patients: Reductions/Discontinuations of Concurrent Medication
Month 12 (n=24)
Baseline (n=25)
% change from baseline -72% p < 0.001
2803.6
644.8
6000
5000
4000
3000
2000
1000
Fasting Triglycerides (mg/dL)
Patients with baseline triglycerides ≥ 500 mg/dL
31.7
7.3
40
30
20
10
Fasting Triglycerides (mmol/L)
Patients with baseline triglycerides ≥ 5.65 mmol/L (≥ 500 mg/dL)
Change in Fasting Triglycerides
mmol/L
mg/dL
12
8
6
2
Month 12 (n=45)
Baseline (n=47)
Mean HbA1c (%)
9.6
Absolute change from baseline -2.8 p < 0.001
6.8
Change in HbA1c
Patients with baseline HbA1c ≥ 7%
HbA1c, n (%)*
Fasting Triglycerides, n (%)*
< 6.5%
15 (22.7)
49 (74.2)
13 (19.7)
50 (75.8)
24 (36.4)
26 (39.4)
≥ 6.5%
≥ 7.0%
< 200 mg/dL
≥ 200 mg/dL
≥ 200 to < 500 mg/dL
≥ 500 mg/dL
Baseline Characteristic
GL (n=66)
Generalized Lipodystrophy (GL) Patients with High Baseline Levels of HbA1c or Triglycerides: Efficacy results at Month 12
Month 24 (n=25)
Month 36 (n=17)
Month 12 (n=40)
3.5
7
10.5
14
-12.2
-9.1
-8.8
Mean reduction fasting Triglycerides (mmol/L)
300
600
900
1200
-1083.7
-806.5
-783.1
Mean reduction fasting Triglycerides (mg/dL)
P<0.001 for all parameters vs baseline
0.5
1.0
1.5
2.0
2.5
3.0
Moth 48 (n=11)
Month 12 (n=41)
Mean actual decrease in HbA1c (%)
-2.3
-2.1
-1.5
-2.2
In patients who remained on therapy, improvements in glycaemic control and triglyceride levels remained clinically significant over 48 months
Generalized Lipodystrophy (GL) Patients: Improvement in Metabolic Parameters Over Time
3500
2500
1500
500
Month 12 (n=12)
Baseline (n=21)
Mean Liver Volume (ml)
3357.7
Mean % change from baseline -33.8 (P<0.001)
2193.0
Liver Volume
150
100
50
Baseline (n=62)
Mean AST (U/L)
111.9
Mean change from baseline -53.1 (P=0.01)
76.3
ALT Levels
75.0
Mean change from baseline -23.8 (P = 0.291)
63.1
AST Levels
Generalized Lipodystrophy (GL) Patients: Effects on Serum ALT/AST and Liver Volumes
Month 12 (n=59)
183.0
Absolute change from baseline -53.2 p < 0.001
126.4
200
Fasting Glucose (mg/dL)
10.2
Absolute change from baseline -3.0 p < 0.001
7.0
15
5
Mean Fasting Glucose (mmol/L)
Change in Fasting Glucose
Month 12 (n=57)
Baseline (n=61)
1299.2
396.4
Mean of individual patient % change from baseline -32.1% p = 0.001
16
14.7
4.5
Mean Fasting Triglycerides (mmol/L)
% change from baseline -32.1% p=0.001
8.6
Absolute change from baseline -2.2 p < 0.001
6.4
Changes in HbA1c, fasting triglycerides and fasting glucose from baseline to Month 12
Generalized Lipodystrophy (GL) Patients: Efficacy results at Month 12
Age (N=66) • Median: 15.0 years of age • Range: 1–68 years of age • 68% of patients were <18 years of age at enrollment • 49 (74%) patients had HbA1c values of 6.5% or greater • 49 (74%) had HbA1c values of 7% or greater • 42 (64%) had HbA1c values of 8% or greater • 26 (39%) had fasting triglyceride values of 500mg/dL (i.e. ≥ 5.65 mmol/L) or greater
Race
12% - Other
47% - White
17% - Hispanic
24% - Black
Sex
77% - Female (51/66)
23% - Male (15/66)
LD Subtype
68% - CGL (45/66)
32% - AGL (21/66)
Hover for more info
AGL, acquired generalized lipodystrophy; CGL, congenital generalized lipodystrophy; HbA1c, glycosylated hemoglobin; LD, lipodystrophy; N, number of patients 1. Data on file, Amryt Pharma, DAC 2. Myalept (Metreleptin for injection) Package insert 2022/ Myalepta SmPC 2021 3. Brown et al. Endocrine. 2018; 60(3):479–4891
Patients were mostly adolescent and older, female, and white, reflecting the available patient pool and US patient characteristics.
Generalized Lipodystrophy(GL): Patient Demographics
1. National Institute of Health (NIH) Study 991265 [ClinicalTrials.gov: NCT00005905] 2. National Institute of Health (NIH) Study 20010769 [ClinicalTrials.gov: NCT00025883] 3. FHA101 [ClinicalTrials.gov: NCT00677313] 4. Amryt Pharmaceuticals DAC, Data on file. 5. Myalept, Prescribing Information, 2022
capture of data (focused on metabolic endpoints) by investigator using standardized conventions
collection of multiple endpoints by NIH
N=148
N=107
Integrated Analysis
Completed
FHA 101 Expanded-Access Long-Term Efficacy and Safety N=41
NIH 20010769 Long-Term Efficacy and Safety
NIH 991265 Proof-of-Concept
Initiated in 2000 (Investigator IND)
Initiated in 2009 (Sponsor Treatment IND)
FHA Study
NIH Studies
Two investigator-led open-label studies with an accumulated patient pool large enough to collect data on efficacy and tolerability
Metreleptin: Core Clinical Studies
To report SUSPECTED ADVERSE REACTIONS, contact Amryt Pharmaceuticals DAC at 1-855-303-2347 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
EFFICACY OF METRELEPTIN TREATMENT IN GENERALIZED LIPODYSTROPHY
Mean change over time in the full analysis set. Least-squares means and P-values for the change from baseline parameters computed using a mixed-effects model for repeated measures. P < 0.001 for the change from baseline for all time points.
a b c d
1-5
1,2
1
1-6
P-values generated using paired t-tests from evaluable baseline and Month 12 data. HbA1c, glycated hemoglobin
*evaluable baseline data: HbA1c (n=64) and Fasting Triglycerides (n=63) P-values generated using paired t-tests from evaluable baseline and Month 12 data. HbA1c, glycated haemoglobin
75
25
Month 48 (n=13)
-13.5
-1197.6
Metreleptin is not indicated for use in patients with HIV-related lipodystrophy. Metreleptin is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of generalized lipodystrophy.
Please see full Prescribing Information, including Boxed Warning.
Metreleptin for injection 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.
Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with metreleptin. The consequences are not well characterized but could include inhibition of endogenous leptin action and loss of metreleptin efficacy. Worsening metabolic control and/or severe infection have been reported. Test for anti-metreleptin antibodies with neutralizing activity in patients with severe infections or loss of efficacy during metreleptin treatment. Contact Amryt Pharmaceuticals DAC at 1-866-216-1526 for neutralizing antibody testing (Sections 4.1 , 5.1 of the prescribing information). T-cell lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and not treated with metreleptin. Carefully consider the benefits and risks of treatment with metreleptin in patients with significant hematologic abnormalities and/or acquired generalized lipodystrophy (Section 5.2 of the prescribing information). Metreleptin is available only through a restricted program under a risk management strategy (REMS) (Section 5.3 of the prescribing information).
WARNING: RISK OF ANTI-METRELEPTIN ANTIBODIES WITH NEUTRALIZING ACTIVITY AND RISK OF LYMPHOMA.
IMPORTANT SAFETY INFORMATION
Mean change from baseline based on evaluable baseline and Month 12 data. ALT, alanine aminotransferase; AST, aspartate aminotransferase;
1. Brown et al. Endocrine. 2018; 60(3):479–489 2. Amryt Pharmaceuticals DAC, Data on file.
1. Brown et al. Endocrine. (2018), 60(3): 479–489 2. Cook et al. (2021) The Journal of the Endocrine Society; 5:1–16 3. Cook et al. (2021) J. Clin. Endocrinol Metab;106:e2953–e2967 4. Oral et. J. Clin. Endocrinol. Metab (2006), 91:621–628 5. Myalept, Prescribing Information, 2022 6. Figure adapted from Akinci et al. Curr Diab Rep. 2018;18(12):14
HbA1c, glycated haemoglobin; NASH, nonalcoholic steatohepatitis; PBMC, peripheral blood mononuclear cells; PCOS, polycystic ovary syndrome; QoL, quality of life
Efficacy of Metreleptin in Generalized Lipodystrophy
How to use Metreleptin
Patient Support Services
Metreleptin in Partial Lipodystrophy (Reactive Use Only)
ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Amryt Pharmaceuticals DAC at 1-855-303-2347 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
SAFETY OF METRELEPTIN IN THE TREATMENT OF GENERALIZED LIPODYSTROPHY
Adverse reactions of 5% or greater incidence in patients with generalized lipodystrophy (GL) receiving metreleptin in an open-label, single-arm study (median duration of exposure, 2.7 years; range, 3.6 months to 10.9 years)
Headache
Pyrexia
Hypoglycemia¹
Decreased weight
Abdominal pain
Arthralgia
Dizziness
Ear infection
Fatigue
Nausea
Ovarian cyst
Upper respiratory tract infection
Anemia
Back pain
Diarrhea
Paresthesia
Proteinuria
3 (6)
4 (8)
5 (10)
6 (13)
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.
Myalept prescribing information 2022
CONTRAINDICATIONS
Metreleptin is contraindicated in patients with general obesity not associated with congenital leptin deficiency. Metreleptin 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 metreleptin
General Obesity
Metreleptin 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.
Hypersensitivity
WARNINGS AND PRECAUTIONS
There are warnings and precautions for the use of metreleptin in patients with generalized lipodystrophy
Myalept, prescribing information, 2022
Benzyl Alcohol Toxicity
Autoimmunity
Hypoglycemia
Risk Evaluation and Mitigation Strategy (REMS)
Lymphoma
Immunogenicity
Benzyl alcohol toxicity
Metreleptin contains benzyl alcohol when reconstituted with bacteriostatic water for injection (BWF) Metreleptin 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
There have been reports of generalised hypersensitivity (e.g. anaphylaxis, urticaria or generalised rash) in patients using metreleptin. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of metreleptin.
Autoimmune disease
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 metreleptin. A causal relationship between metreleptin treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of metreleptin treatment should be carefully considered in patients with autoimmune disease.
HYPOGLYCEMIA WITH CONCOMITANT USE OF INSULIN AND OTHER ANTI-DIABETICS
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 metreleptin.
Prescribers must be certified with the program by enrolling and completing training. Pharmacies must be certified with the program and only dispense metreleptin after receipt of the Metreleptin REMS Prescription Authorization Form for each new prescription.
Further information is available at www.myaleptrems.com or 1-855-669-2537.
Metreleptin is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS), called the Metreleptin REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or metreleptin and the risk for lymphoma Notable requirements of this REMS Program include the following:
Two patients were diagnosed with peripheral T-cell lymphoma while receiving metreleptin. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of metreleptin treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving metreleptin who did not have hematological abnormalities before treatment.
Three cases of T-cell lymphoma have been reported in the metreleptin lipodystrophy program; all three patients had acquired generalized lipodystrophy (AGL).
Lymphoproliferative disorders, including lymphomas, have been reported in patients with AGL not treated with metreleptin. A causal relationship between metreleptin 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 metreleptin 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).
•
Test: Initial test (1:80) Retest (1:80) Retest (1:800) Retest (1:8000)
Metreleptin-specific inhibitory activity by category
≤CP
>CP
A
B
C
D
E
The current methodology for testing for neutralizing antibodies in the US uses a cell-based program. This uses a Cut-Point (CP) analysis for threshold inhibition. The cut point of the immunogenicity screening assay is the level of response of the immunogenicity screening assay at or above which a sample is defined to be positive and below which it is defined to be negative. The Food and Drug Administration Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutics recommends the cut point to be an upper 95 percentile of the negative control patients (https://www.ncbi.nlm.nih.gov/pubmed/25356783).
Categorization approach for neutralizing activity results with the in vitro cell based neutralizing activity assay and interpretation of the results:
result is less than the assay cut-point on initial testing – Non-neutralizing
Category A
result is higher than the assay cut-point on initial testing, but is less than the assay cut-point on repea Non-neutralizing
Category B
result is higher than the assay cut-point on initial testing and re-testing, but is less than the assay cut-point after additional 1:10 dilution – Low-potency neutralizing activity
Category C
result is higher than the assay cut-point on initial testing and re-testing and after additional 1:10 dilution but not after 1:100 dilution – Medium/high-potency neutralizing activity
Category D
result is higher than the assay cut-point on initial testing and re-testing and after additional 1:10 dilution and 1:100 dilution – High-potency neutralizing activity
Category E
How is testing for neutralizing antibodies currently performed?
Process for anti-drug blocking and/or neutralizing antibody testing
Role
HCP
Physician reports a “Severe or Serious Infection” or “Loss of efficacy” SAE and requests testing
Physician requests antibody testing through Medical Information by contacting medinfo@amrytpharma.com or 1 855 303 2347
Amryt receives sample for testing
Amryt receives results
Physician Receives testing kit
Amryt shares test results and offers option to enroll in follow-up program
Enroll in follow-up program
Physician to reach out to Medical Information by contacting medinfo@amrytpharma.com or 1 855 303 2347 if they have questions
Amryt
Request/Processing
Sample Collection
Testing & Results Distribution
Follow-Up
Amryt sends testing kit
RISK FOR DEVELOPMENT OF ANTI-LEPTIN OR ANTI-METRELEPTIN ANTIBODIES
Anti-metreleptin antibodies were detected in 84% (36/43) of patients with generalized lipodystrophy studied in the metreleptin trials. Anti-metreleptin antibodies associated with adverse events consistent with loss of endogenous leptin activity and/or loss of metreleptin efficacy were observed in 6% (2/33) of the patients with GL tested. Adverse events reported in these two patients included severe infections and worsening of metabolic control (increases in HbA1c and/or triglycerides). 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 metreleptin efficacy during treatment. Contact Amryt Pharmaceuticals DAC at 1-866 216-1526 for testing of clinical samples
Myalept, Prescribing Information, 2022
As with all therapeutic proteins, there is potential for immunogenicity.
Cell-based assay (~4 weeks)
The testiing of individual patient samples can take up to 3 months. The timeline for testing is shown below.
When will I receive the results?
Assays run approx. every 90 days
~2 weeks
Delivery of paperwork and sample kit
~2-3 weeks
Collate report and send to physician
Testing has been designed according to the lastes regulatory guidance for immunogenicity surveillance.
In patients with GL receiving metreleptin 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.
INDICATIONS AND USAGE
INDICATION STATEMENT: 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 metreleptin for the treatment of complications of partial lipodystrophy have not been established. The safety and effectiveness of metreleptin for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established. Metreleptin is not indicated for use in patients with HIV-related lipodystrophy. Metreleptin is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.
RECOMMENDED DOSING
HOW TO USE METRELEPTIN
Males and females ≤ 40 kg
0.06 mg/kg (0.012 mL/kg)
2.5 mg (0.5 mL)
1.25 mg (0.25 mL) to 2.5 mg (0.5 mL)
10 mg (2 mL)
5 mg (1 mL)
0.02 mg/kg (0.004 mL/kg)
0.13 mg/kg (0.026 mL/kg)
Males > 40 kg
Females > 40 kg
Baseline weight
Starting daily dose (injection volume)
Dose adjustments (injection volume)
Maximum daily dose (injection volume)
Recommended daily dose and maximum recommended daily dose in adults and pediatric patients. Table 1 Metreleptin Recommended Dosage
5 kg 10 kg 15 kg 20 kg 25 kg 30 kg 35 kg 40 kg
Weight
Starting Dose
Dose Adjustments
Maximum Dose
In pediatric patients, small volumes for administration can result in medication errors when measured incorrectly. Table 2 provides example doses and volumes by weight. For patients using insulin syringes, the volume conversion is 100 Units/mL. Table 2: Example Dosing Chart for Patients Less than or Equal to 40 kg
0.30 mg (0.06 mL or 6 Units) 0.60 mg (0.12 mL or 12 Units) 0.90 mg (0.18 mL or 18 Units) 1.2 mg (0.24 mL or 24 Units) 1.5 mg (0.3 mL or 30 Units) 1.8 mg (0.36 mL or 36 Units) 2.1 mg (0.42 mL or 42 Units) 2.4 mg (0.48 mL or 48 Units)
0.10 mg (0.02 mL or 2 Units) 0.20 mg (0.4 mL or 4 Units) 0.30 mg (0.06 mL or 6 Units) 0.40 mg (0.08 mL or 8 Units) 0.50 mg (0.1 mL or 10 Units) 0.60 mg (0.12 mL or 12 Units) 0.70 mg (0.14 mL or 14 Units) 0.80 mg (0.16 mL or 16 Units)
0.65 mg (0.13 mL or 13 Units) 1.3 mg (0.26 mL or 26 Units) 1.95 mg (0.39 mL or 39 Units) 2.6 mg (0.52 mL or 52 Units) 3.25 mg (0.65 mL or 65 Units) 3.9 mg (0.78 mL or 78 Units) 4.55 mg (0.91 mL or 91 Units) 5.2 mg (1.03 mL or 103 Units)
STORAGE AND HANDLING
• • • • •
Metreleptin should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light until preparing for use. Keep metreleptin vials in the carton when not in use. Metreleptin should not be used past the expiration date. Do not freeze metreleptin . Do not use if the white lyophilized cake is discolored. Use with Bacteriostatic Water for Injection (BWFI): when metreleptin is reconstituted with BWFI, the vial can be used for multiple doses within 3 days when stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light.
Use with preservative-free sterile Water for Injection (WFI): when metreleptin is reconstituted with WFI, the vial can be used for a single dose should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded. After reconstitution, the vials should not be frozen (below 0°C) or shaken vigorously. If the reconstituted product is inadvertently frozen, it should be thrown away. After reconstitution, the mixture should be clear and colorless. Do not use if visible particulates are present in the solution. Keep out of the reach of children.
Metreleptin should be administered once daily at the same time every day. Metreleptin can be administered any time of day without regard to the timing of meals.
Instruct patients that if a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.
Based on clinical response (e.g., inadequate metabolic control) or other considerations (e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), metreleptin dosage may be decreased or increased to the maximum dosage listed in Table 1.
Dosing in patients ≤ 40 KG
Based on clinical response (e.g., inadequate metabolic control) or other considerations ([e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), metreleptin dose may be decreased or increased to the maximum dose listed in Table 1 above.
Dosage Adjustments of Medications Known to Cause Hypoglycemia
Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue may be necessary in some patients to minimize the risk of hypoglycemia. When treating patients concomitantly with metreleptin and insulin therapy, close monitoring of blood glucose levels is recommended
When discontinuing metreleptin, tapering the dose over a 1-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.
DOSE ADJUSTMENTS AND DISCONTINUATION
Discontinuation in Patients at Risk for Pancreatitis
DOSAGE FORMS AND STRENGTHS
This products 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 bacteriostatic water for Injection (BWFI) or preservative-free sterile Water for Injection (WFI).
SUPPORT ACCESS RESOURCES
For Medical Information, Product Complaints and to report Adverse Events related to Metreleptin, please contact: Email: Medinfo@amrytpharma.com Phone: 1 855 303 2347 (USA). A UK toll paid number (+44 1604 549 952) is available for use in all countries (English only) For Medical information numbers for other countries and in other languages please see the Amryt Pharma website
MEDICAL INFORMATION ENQUIRIES
Metreleptin Prescribing Information
To report SUSPECTED ADVERSE REACTIONS, contact Amryt Pharmaceuticals DAC at 1-855-303-2347 or FDA at 1-800-FDA-1088 or check our page
Patient Support Materials
COMPREHENSIVE SUPPORT FOR YOUR PATIENTS ON METRELEPTIN: The Amryt Assist support program and its dedicated team provide your patients taking metreleptin helpful support services and resources, including personalized nutrition consultation, education, support, and guidance to help support the care you provide.
Amryt Clinical Educators
Insurance support Contact an Amryt Assist Coordinator to help verify your patients’ insurance coverage and walk you through the prior authorization and appeals process.
Dedicated Amryt Clinical Educators are Registered Dietitians who are ready to help with these services:
Personalized Nutrition Consultations A nutrition program was developed by dietitians with expertise in GL to help support your care with a healthy eating plan specifically for your GL patient.
Access and Affordability
Injection Training, Adherence, and Pharmacy Support
Generalized lipodystrophy (GL) and Metreleptin Education and Support An Amryt Clinical Educator can provide your patient one-on-one education about GL and metreleptin either in-person or virtually. They are here to support your patient for the duration of their treatment to help them stay on track, supporting your treatment plan for them.
Co-pay assistance Help your commercially insured eligible patients obtain 100% coverage of their monthly out-of-pocket costs (up to an annual maximum) for metreleptin regardless of their financial status and whether they are new to metreleptin or already on therapy. There are no income requirements.
Free drug assistance Help your eligible patients access metreleptin for free if they are uninsured or underinsured (e.g., have reached their insurance cap or have insurance that will not cover their metreleptin treatment).
a
c
a,c
ICD-10-CM diagnosis code
Type
E88.1
Code
Lipodistrophy, not elsewhere classfied
Description
Injection training and adherence support Start your patients off right with metreleptin by using a registered nurse to provide in person injection training at no cost. Keep your patients motivated to stay on track with refill reminders and helpful tips for staying on therapy.
Metreleptin fulfillment support Utilize key pharmacy services to fulfill your patient’s prescription such as direct-to-patient medication and supplies shipments, metreleptin refills and replacement, and a 24/7 pharmacist and nurse hotline.
HealthBeacon Amryt has partnered with HealthBeacon to offer metreleptin patients a digital health solution to manage their injections as well as provide a safe and responsible means to dispose of needles/syringes and other medical waste related to metreleptin.
To speak with an Amryt Assist Coordinator, please call 1-855-669-2537, Monday through Friday, 8AM to 8PM ET
a)Applicants with federal and state government insurance such as Medicare, Medicaid, VA/DoD, and TRICARE are not eligible. b) This program is operated by Amryt Pharma, Inc. and can be modified at any time without notice. c) Subject to other eligibility criteria
EFFICACY OF METRELEPTIN TREATMENT IN PARTIAL LIPODYSTROPHY
Month 12 (n=28)
Baseline (n=30)
250
180.6
145.4
Absolute change from baseline -31.8 p = 0.023
10.0
8.1
Absolute change from baseline -1.8 p = 0.023
Change in Fasting Plasma Glucose
Month 12 (n=27)
Baseline (n=29)
% change from baseline -37.4% p < 0.001
1386.6
535.4
45
35
15.7
6.0
Change in Fasting Triglycerides**
8.7
Absolute change from baseline -0.9 p < 0.001
7.9
*Subgroup of PL patients with triglycerides ≥ 5.65 mmol/L ( ≥ 500 mg/dL) and/or HbA1c ≥ 6.5% at baseline
EFFECTS OF METRELEPTIN ON HbA1c, fasting triglycerides and glucose in PARTIAL LIPODYSTROPHY (PL) PATIENTS (PL SubGroup 1*)
1. Oral et al Endocrine 2019; 64(3):500-51 2. Amryt Pharmaceuticals DAC, Data on file
Data generated using a mixed-model repeated measures analysis. HbA1c, glycated haemoglobin PL, partial lipodystrophy
Month 24 (n=6)
Month 36 (n=5)
Overall (n=26)
Month 12 (n=21)
-36.2
-31.7
-13.7
-18.6
Mean % reduction fasting Triglycerides
Overall change versus baseline P=0.004
Overall (n=27)
Overall change versus baseline P<0.001
Month 12 (n=22)
-0.9
-1.3
-1.0
-0.6
In patients who remained on therapy, improvements in glycaemic control and triglyceride levels remained clinically significant overall
PL Patients: Improvement in Metabolic Parameters Over Time in the PL subgroup with HbA1c ≥6.5% and/or TG ≥5.65 mmol/l (≥500 mg/dL) at baseline
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GL, generalized lipodystrophy; HbA1c, glycated haemoglobin; PL, partial lipodystrophy
-33%
-65%
-35%
-96%
-47%
-12%
-14%
-58%
-50%
-98%
-86%
-56%
Disruption to female reproductive system HbAlc (>6.5%) Hypertension Hyperphagia Impaired physical appearance Kidney abnormality Elevated 24-hour protein excretion Liver abnormality Elevated ALT Elevated AST Pancreatitis Triglycerides (>200 mg/dl) Inability to work/attend school
Number of PL Patients with Disease Attribute
% IMPROVING ON METRELEPTIN WITH GL
% IMPROVING ON METRELEPTIN WITH PL
60
70
-57%
-88%
-77%
-100%
-68%
-51%
-91%
-79%
-95%
-90%
Disruption to female reproductive system HbA1c (>6.5%) Hypertension Hyperphagia Impaired physical appearance Kidney abnormality Elevated 24-hour protein excretion Liver abnormality Elevated ALT Elevated AST Pancreatitis Triglycerides (>200 mg/dL) Inability to work/attend school
Number of GL Patients with Disease Attribute
Evidence of attribute at baseline Attribute not improved at 12 months
% of patients with baseline characteristics and % of those improving on metreleptin
EFFECT OF METRELEPTIN ON CHARACTERISTIC SYMPTOMS AND SIGNS IN GENERALIZED AND PARTIAL LIPODYSTROPHY
*analysis excluding data from one non-compliant patient. P-values generated using paired t-tests from evaluable baseline and Month 12 data. HbA1c, glycated haemoglobin; TG, triglycerides
Month 12 (n=15)
Baseline (n=15)
% change from baseline -53.7% p < 0.001
2440.3
799.7
27.6
9.0
Patients with baseline triglycerides ≥ 5.65 mmol/L (≥500 mg/dL)
Change in Fasting Triglycerides*
Month 12 (n=18)
Baseline (n=18)
9.9
Absolute change from baseline -1.3 p = 0.001
Change in HbA1c*
Patients with baseline HbA1c ≥ 8.0%
Effectiveness of metreleptin in PARTIAL LIPODYSTROPHY (PL) patients: patients with HbA1c ≥8.0% or TG ≥5.65 mmol/l (≥500 mg/dL) at baseline
-63
-50
-11
-27
-17
-7
-10
-56
Hyperphagiaᵃ Pancreatitisᵇ Inability to perform work/school work Impaired Physical Appearance HbA1c > 8% Liver abnormality Progression of Organ Damage (fast) Triglycerides > 500mg/dL Disruption to female reproductive functioning (PCOS)ᶜ Triglycerides >200 mg/dL and ≤ 500 mg/dL HbA1c > 6.5% and ≤ 8% Kidney abnormality Heart abnormalityᵈ Progression of Organ Damage (slow)
0.044
0.019
0.015
0.006
0.004
0.003
<0.001
-0.003
-0.007
-0.017
Hyperphagiaᵃ Pancreatitisᵇ Inability to perform work/school work Impaired Physical Appearance HBA1C > 8% Liver abnormality Progression of Organ Damage (fast) Triglycerides > 500mg/dL Disruption to female reproductive functioning (PCOS)ᶜ Triglycerides >200 mg/dL and ≤ 500 mg/dL HbA1c >6.5% and ≤ 8% Kidney abnormality Heart abnormalityᵈ Progression of Organ Damage (slow)
Impact of metreleptin on QUALITY OF LIFE in patients with PARTIAL LIPODYSTROPHY
HbA1c, glycated haemoglobin; PCOS, polycystic ovary syndrome; PL, generalized lipodystrophy; QALY, quality-adjusted life-year 1. Adapted from Cook et al. 2021 Journal of the Endocrine Society; 5:1–16
Data based on 44 PL patients; Data on hyperphagia were collected for 32 PL patients One patient with PL experienced a single episode of pancreatitis while on treatment with metreleptin. Only female patients of reproductive capacity (PL, n=29) were eligible for impairment; all other patients were considered unimpaired. Reproductive capacity was defined as female patients who were postpubescent and premenopausal who had not undergone surgical removal of reproductive organs at the time of starting metreleptin. Prevalence of heart abnormality can only increase as clinical resolution of abnormalities could not be determined with available data.
Treatment with standard of care
After treatment with metreleptin
0.8
0.6
0.4
0.2
Utility
Generalized Lipodystrophy
Partial Lipodystrophy
0.466
0.624
0.779
0.741
Improved by +0.313
Improved by +0.117
This study estimated the Quality of Life (QoL) impact of metreleptin using 2 separate analyses. • In patients with lipodystrophy the study assessed the impact of metreleptin on changes in lipodystrophy disease attributes related to metreleptin. • Separately the impact of these attributes on QoL was assessed using a discrete choice experiment conducted in healthy subjects without lipodystrophy. Quality adjusted life-year gains associated with 12 months of treatment with metreleptin were estimated at 0.313 for patients with generalized lipodystrophy and 0.117 for patients with partial lipodystrophy, reducing the gap in quality of life between untreated lipodystrophy and perfect health by approximately 59%, 31% respectively.
1. Adapted from Cook et al. 2021 Journal of the Endocrine Society; 5:1–16
Analysis based on 68 patients with generalized lipodystrophy and 44 patients with partial lipodystrophy
Quality adjusted life-year gains associated with 12 months of treatment with metreleptin
Note: Modeled results are after adjusting for the following covariates: lipodystrophy diagnosis (GL or PL), birth year, triglyceride levels, elevated HbA1c, having ≥1 episode of pancreatitis, and the presence of observed abnormalities in the heart or kidneys. CI, confidence interval; GL, generalized lipodystrophy; HR, hazard ratio; PL, partial lipodystrophy
1.00
0.75
0.50
0.25
0.00
Survival Probabilty
Time in Years
Metreleptin treatment was associated with a 65% reduction in mortality risk (HR 0.348, 95% CI: 0.134-0.900; P = 0.029).
Treatment Status
Metreleptin - treated
Metreleptin - naïve
In an indirect comparison with matched metreleptin-naïve patients, metreleptin treatment was associated with a reduction in mortality risk (Cox proportional model)
This analysis evaluated 103 metreleptin-treated patients with characteristics matched to 103 metreleptin-naïve patients. The data on metreleptin-treated patient were from medical records of patients enrolled in a studies conducted at the US National Institutes of Health. Metreleptin-naïve data were obtained from a lipodystrophy natural history study. Patients were required to have at least 1 year of follow-up after their date of lipodystrophy diagnosis.
BL
M4
M8
M12
Up to Year 14
Ongoing, open-label assessment
Long-term, open-label, single-arm pivotal study integrated analysis of the pilot study and its long-term extension
Primary endpoints: Change from baseline in HbA1c (month 12), Percent change from baseline in fasting serum TGs at Month 12
• Liver volume: (assessed in 30 patients [GL, n=21; PL, n=9] at baseline and 20 patients [GL, n=12; PL=8] at M12)¹ • Paired liver biopsy: (assessed in 50 patients/ 27 had follow up biopsy)² • 24-hour urine protein: (assessed in 60 patients [GL, n=42; PL, n=18] at baseline and 35 patients [GL, n=24; PL=11] at M12)¹
KEY SECONDARY ENDPOINTS: • Changes over time in HbA1c, triglycerides, and fasting glucose • Responder analyses for patients with elevated levels of HbA1c or triglycerides at baseline ADDITIONAL SECONDARY ENDPOINTS: • Assessment of responders at consecutive visits prior to Month 12 • Evaluation of changes in other parameters known to be abnormal in patients with LD (lipids, FFA, liver function, and liver volume) • Actual change from baseline in ALT and AST at each post-baseline visit through month 12 • Actual change from baseline in liver volume at each post-baseline visit through month 12
Sub-studies
Secondary Endpoints
NIH Studies: Trial Design
1. Amryt Pharmaceuticals DAC, Data on file. 2. Brown et al. Endocrine (2018) 60:479–489 3.Oral et al. Endocrine (2019) 64:500–511
1-3
ALT, alanine aminotransferase; AST, Aspartate transaminase; BL, baseline; FFA, free fatty acid; GL, generalized lipodystrophy; HbA1c; glycated hemoglobin; LD, lipodystrophy; M, month; NIH, National Institute of Health; PL, partial lipodystrophy; TG, triglycerides
SAFETY OF METRELEPTIN IN PATIENTS WITH PL
Weight decrease
Pain in extremity
Fatigue, Alopecia, Constipation
TEAE by preferred term (≥10% incidence)
TEAE leading to study drug discontinuation
Drug-related treatment-emergent SAE
Treatment-emergent SAE
Drug-related severe TEAE
Severe TEAE
Drug-related TEAE
≥1 TEAE
2 (4.9)
3 (7.3)
6 (14.6)
7 (17.1)
1 (2.4)
11 (52.4)
16 (39.0)
8 (19.5)
35 (85.4)
Overall PL population (N=41)
Adverse event, n (%)
2 (6.5)
3 (9.7)
5 (16.1)
6 (19.4)
1 (3.2)
7 (22.6)
13 (41.9)
27 (87.1)
PL subgroup 1 (n=31)
Most common TEAEs in the overall PL patient population (% patients)
Hypoglycaemia
17
83
95
85
Fatigue, Alopecia Pain in extremity Constipation Arthralgia Back pain
93
*Patients with PL and baseline HbA1c ≥ 6.5% and/or TGs ≥ 5.65 mmol/L. NIH, National Institute of Health; PL, partial lipodystrophy; SAE, serious adverse event; TEAE, treatment-emergent adverse event Oral EA, et al. Endocrine (2019) 64:500–511
1. Cook et al. J Clin Endocrinol Metab 2021, Vol. 106, e2953–e2967
