Summary Basis of Decision for Myalepta

Clinical Pharmacology

Data from four clinical studies contributed to the characterization of the clinical pharmacology profile of metreleptin (the medicinal ingredient in Myalepta) in healthy subjects and patients with lipodystrophy. No formal clinical pharmacodynamic studies and no pharmacometric analyses (i.e., population pharmacokinetic or exposure-response modelling) of metreleptin were conducted in patients with lipodystrophy.

In healthy subjects, the exposure to metreleptin increased in an approximately dose-proportional fashion following subcutaneous administration at doses ranging from 0.01 mg/kg to 0.3 mg/kg. Both the apparent time to the maximum concentration (t_max) and the apparent half-life of metreleptin were approximately 4.5 hours and were largely independent of dose.

There are very limited pharmacokinetic data in patients with lipodystrophy, derived from Study FHA101, a small, open-label, non-controlled study during which patients received metreleptin according to the proposed dosing regimen. Overall, five metreleptin-naïve patients contributed to the entire pharmacokinetic dataset: 4 adult patients with partial lipodystrophy and 1 pediatric patient with generalized lipodystrophy. The starting daily dose for patients weighing more than 40 kg was 2.5 mg for male patients and 5 mg for female patients. For patients weighing less than or equal to 40 kg, the starting daily dose was 0.06 mg/kg, with no dose adjustment based on sex. In all cases, the dose could be up- or down-titrated based on clinical response (such as inadequate metabolic control and excessive weight loss) or because of tolerability issues. The mean dose-normalized values for the maximum observed concentration (C_max) and area under the concentration-time curve from time zero to 10 hours (AUC_0-10h) were 9.02 ng/mL/kg and 58.55 mg*h/mg/kg, respectively. The median t_max was approximately 4 hours; the half-life of metreleptin could not be calculated because of insufficient sampling times. Due to the low number of patients, no robust conclusions could be drawn on any comparisons of metreleptin exposures between patients with generalized lipodystrophy and patients with partial lipodystrophy or between adult patients and pediatric patients with generalized lipodystrophy. In addition, the pharmacokinetic profiles of metreleptin after 3 months of dosing appeared highly variable, thereby precluding any robust conclusions on consistency of exposure during repeated metreleptin dosing.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Anti-drug antibody testing data were available for 74 (50.0%) of the148 patients enrolled in Study NIH 991265/20010769 (described in the Clinical Efficacy section) and Study FHA101. Of these 74 patients, 65 (87.8%) were ADA positive. The sponsor also provided data from 102 (68.9%) of the 148 patients, whose banked study samples were available to undergo a reanalysis (requested by the United States Food and Drug Administration) with an updated, more sensitive method assessing the presence of neutralizing anti-metreleptin antibodies. Neutralizing antibodies against metreleptin were observed in 98 (96%) of the 102 patients. The incidences of ADAs and neutralizing ADAs were consistent between patients with generalized lipodystrophy and patients with partial lipodystrophy.

Overall, the assessment of the impact of ADAs on the pharmacokinetics of metreleptin was compounded by the small subset of patients with lipodystrophy that contributed pharmacokinetic data, the intersubject variability in the pharmacokinetics of metreleptin, and the fact that high ADA titers (greater than 3,125) interfered with the measurement of plasma metreleptin/leptin concentrations. No robust conclusions could be drawn regarding the impact of the ADAs on the pharmacokinetics, efficacy, and safety of metreleptin. Importantly, a Serious Warnings and Precautions box in the Myalepta Product Monograph specifically addresses the reported occurrence of anti-metreleptin antibodies with neutralizing activity and the potential consequences of their development (inhibition of endogenous leptin action and loss of metreleptin efficacy), and includes a recommendation for testing for neutralizing anti-metreleptin antibodies in patients with severe infections or loss of efficacy during treatment with Myalepta.

For further details, please refer to the Myalepta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Myalepta in patients with lipodystrophy was supported by data derived from a 14-year, open-label, single-arm Study NIH 991265/200107769. The pilot portion (991265) of the study was a short-term (up to 8 months), dose-escalation study, and the long-term portion of the study (20010769) allowed for the rollover of patients from the pilot portion, as well as for direct enrollment of new patients.

Eligibility criteria for patient enrollment evolved and expanded as the study progressed. In general, the study enrolled leptin-deficient patients with congenital or acquired generalized lipodystrophy or familial or acquired partial lipodystrophy who had at least one of the following three metabolic abnormalities: (1) diabetes mellitus, (2) fasting insulin concentration greater than 30 µU/mL, or (3) fasting triglyceride concentration greater than 2.26 mmol/L or postprandially elevated triglyceride concentration greater than 5.65 mmol/L.

Myalepta was administered subcutaneously once daily or twice daily (in two equal doses). Initial starting doses were based on weight and sex, and the dose was subsequently individualized based on clinical response and tolerability. The median daily dose for patients with generalized lipodystrophy was 3.0 mg (range: 1.9 to 6.9 mg) for males and 4.7 mg (range: 0.8 to 19.0 mg) for females, consistent with the higher proportion of adipose tissue and increased rate of leptin production per unit mass of adipose tissue in females compared to males. The median daily dose for patients with partial lipodystrophy was 8.1 mg (range: 4.3 to 15.7 mg).

The co-primary efficacy endpoints were absolute change from baseline in glycated hemoglobin (HbA1c) at Month 12 and relative (percent) change from baseline in fasting serum triglycerides at Month 12.

Sixty-six patients with generalized lipodystrophy were enrolled in the study: 45 with congenital generalized lipodystrophy and 21 with acquired generalized lipodystrophy. Most patients (77%) were female and the median age of the patients at baseline was 15 years (range: 1 to 68 years). The median fasting leptin concentration at baseline was 1.0 ng/mL in males and 1.1 ng/mL in females. The median overall duration of treatment was 4.2 years. At Month 12, the mean change from baseline in HbA1c was -2.2% (95% confidence interval [CI]: -2.7%, -1.6%) and the mean percent change from baseline in fasting serum triglycerides (mmol/L) was -32.1% (95% CI: -51.0%, -13.2%).

Of 41 patients with partial lipodystrophy enrolled in the study, 31 had more severe metabolic disease at baseline (HbA1c greater than 6.5% and/or triglycerides greater than 5.65 mmol/L) and were included in the partial lipodystrophy subgroup (PL Subgroup). The efficacy analyses were based on data derived from this patient subgroup. Of the 31 patients, 27 had familial partial lipodystrophy and 4 had acquired partial lipodystrophy. The majority were female (97%) and the median age of the patients at baseline was 38 years (range: 15 to 64 years). The median fasting leptin concentration at baseline was 5.4 ng/mL in the single male patient and 5.9 ng/mL in the female patients. The median overall duration of treatment was 2.4 years. At Month 12, the mean change from baseline in HbA1c was -0.9% (95% CI: -1.4%, -0.4%) and the mean percent change from baseline in fasting serum triglycerides (mmol/L) was -37.4% (95% CI: -49.6%, -25.2%).

The efficacy evaluation was limited for several reasons, including the study design, retrospective analyses of data, significant missing data, uncontrolled concomitant medication usage, and the rarity of the disease. As a result, only descriptive findings were presented. Overall, clinically meaningful within-patient changes from baseline were observed among patients with generalized lipodystrophy and patients with partial lipodystrophy in the PL Subgroup, thereby supporting a favourable treatment benefit of Myalepta. The heterogeneity in treatment response was greater among the PL Subgroup patients. Therefore, the use of Myalepta in patients with partial lipodystrophy is restricted to second-line therapy for those who continue to have persistent significant metabolic disease despite use of standard treatments.

Indication

The New Drug Submission for Myalepta was filed by the sponsor with the following proposed indication:

Myalepta (metreleptin for injection) is indicated as an adjunct to diet as a replacement therapy to treat the complications of leptin deficiency in lipodystrophy patients:

• with confirmed congenital generalized lipodystrophy (Berardinelli-Seip) syndrome or acquired generalized lipodystrophy (Lawrence syndrome) in adults and children 2 years of age and above.

• with confirmed familial partial lipodystrophy or acquired partial lipodystrophy (Barraquer-Simons syndrome) in adults and children 12 years of age and above for whom standard treatments have failed to achieve adequate metabolic control.

Health Canada revised the proposed indication to further characterize the target subpopulation of patients with partial lipodystrophy. Accordingly, Health Canada approved the following indication:

Myalepta (metreleptin for injection) is indicated as an adjunct to diet as a replacement therapy to treat the complications of leptin deficiency in lipodystrophy patients:

• with confirmed congenital generalized lipodystrophy (Berardinelli-Seip) syndrome or acquired generalized lipodystrophy (Lawrence syndrome) in adults and children 2 years of age and above.

• with confirmed familial partial lipodystrophy or acquired partial lipodystrophy (Barraquer-Simons syndrome) in adults and children 12 years of age and above with persistent significant metabolic disease for whom standard treatments have failed to achieve adequate metabolic control.

For more information, refer to the Myalepta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Myalepta was evaluated in 113 patients with lipodystrophy from the open-label Study NIH 991265/20010769 (described in the Clinical Efficacy section) and a smaller, open-label Study FHA101. Of the 113 patients, 75 had generalized lipodystrophy and 38 patients had partial lipodystrophy with more severe metabolic disease at baseline and were included in the partial lipodystrophy subgroup. The duration of follow-up ranged from 79 days to 14 years.

The most commonly reported adverse events were decreased weight, hypoglycemia, and fatigue.

In patients with generalized lipodystrophy, the most commonly reported serious adverse events (occurring in more than 1 patient) were abdominal pain and pancreatitis (4 patients [5%] each); pneumonia, sepsis, liver disorder (worsening underlying liver disease), cardiac failure, and elevated liver function tests (2 patients [3%] each). In addition, 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.

The most commonly reported serious adverse events in the partial lipodystrophy subgroup were abdominal pain (3 patients [8%]) and cellulitis (2 patients [5%]).

Overall, 7 (6%) of the patients withdrew due to a treatment-emergent adverse event: 6 (8%) of the 75 patients with generalized lipodystrophy and 1 (3%) of the 38 patients in the partial lipodystrophy subgroup. Five (4%) of the patients died during the studies, including 4 of the 6 patients with generalized lipodystrophy who withdrew due to a treatment-emergent adverse event.

Based on the available data, important identified risks associated with the use of Myalepta include hypersensitivity (anaphylaxis, urticaria, and generalized rash), acute pancreatitis associated with abrupt discontinuation of Myalepta, hypoglycemia with concomitant use with insulin and other antidiabetics, and medication errors. Important potential risks include lymphoma, serious and severe infections secondary to the development of neutralizing antibodies, unplanned pregnancy (due to effects on luteinizing hormone), loss of efficacy potentially due to the development of neutralizing antibodies, and progression of pre-existing autoimmune disorder.

The safety concerns associated with the use of Myalepta have been addressed by the inclusion of relevant information in the Myalepta Product Monograph and creation of educational materials for healthcare professionals and patients.

In the Myalepta Product Monograph, a Serious Warnings and Precautions box highlights the reported occurrence of anti-metreleptin antibodies with neutralizing activity and the potential consequences of their development (e.g., inhibition of endogenous leptin action and loss of Myalepta efficacy), alongside a recommendation for testing for neutralizing anti-metreleptin antibodies in patients with severe infections or loss of efficacy during treatment with Myalepta. Furthermore, a serious warning highlights the reported occurrence of T-cell lymphoma in patients with acquired generalized lipodystrophy, and recommends careful consideration of the benefits and risks of treatment with Myalepta in patients with significant hematologic abnormalities and/or acquired lipodystrophy.

Educational materials include a Healthcare Professional Guide, a Specialist Prescriber Guide, a Patient Care Guide, and a Patient Dose Card.

No new safety concerns have been identified in the post-marketing data from other countries where metreleptin has been available for almost 10 years.

There are four ongoing post-marketing safety studies of metreleptin, which were required by the United States Food and Administration and the European Medicines Agency. The studies will further characterize the safety profile of metreleptin in patients with lipodystrophy. Given that lipodystrophy is a rare condition, the results will be globally applicable, and thus, also relevant to the Canadian setting.

For more information, refer to the Myalepta Product Monograph, approved by Health Canada and available through the Drug Product Database.

The non-clinical data submitted support the use of metreleptin (the medicinal ingredient in Myalepta) for the specified indications.

Metreleptin, a recombinant human leptin analog, mimics the physiological effects of leptin by binding to and activating the human leptin receptor, which belongs to the Class I cytokine family of receptors that signals through the Janus kinase / signal transducer and activator of transcription (JAK/STAT) transduction pathway.

In two pivotal repeat-dose toxicity studies of metreleptin in mice and dogs, consistently observed findings were reduced body weight, reduced food consumption, and atrophy of adipose tissue, all of which were considered to be exaggerated pharmacodynamic effects of metreleptin. Mice were administered metreleptin at doses of 0.3, 1, 3, 10, or 30 mg/kg body weight or vehicle (control group) once per day by subcutaneous injection for 3 or 6 months, followed by a 28-day recovery period. The no-observed-adverse-effect level (NOAEL) was determined to be 1 mg/kg/day (corresponding to 0.12- and 0.24-fold the maximum recommended clinical dose, based on body surface area of a patient weighing 20 kg and a patient weighing 60 kg, respectively). The principal toxic effects noted at higher doses were decreased thymus weight and spleen weight, centrilobular hepatocyte degeneration, lymphocytolysis in lymphoid tissues, and gastric mucosal erosions. A subcutaneous abscess involving the preputial glands, with superficial skin ulceration, and osteosarcoma were each observed in one mouse from a low-dose group, while lymphosarcoma was observed in one mouse from a high-dose group; the relationship of these findings to metreleptin is unknown.

Dogs were administered metreleptin at doses of 0.05, 0.15, 0.5, 1.5, or 5 mg/kg body weight or vehicle (control group) once per day by subcutaneous injection for 1, 3, or 6 months, followed by varying recovery periods. A NOAEL could not be established due to adverse effects observed at all doses. The lowest-observed-adverse-effect level (LOAEL) was approximately equal to the maximum recommended clinical dose, based on body surface area of a patient weighing 20 kg and a patient weighing 60 kg. The findings included hemorrhage and inflammation in the gastrointestinal tract, gingival tissues, conjunctiva, and urinary bladder; perivasculitis in the adipose tissue, liver, and kidney; hyperplasia of the lymph nodes; and thyroid hypertrophy/hyperplasia.

Carcinogenicity studies were not conducted with metreleptin. In standard genotoxicity studies, metreleptin did not exhibit genotoxicity.

A fertility study, an embryo-fetal development study, and two pre- and postnatal development studies of metreleptin were conducted in mice. No adverse effects on mating, fertility, or embryo-fetal development were observed at doses ranging between 4- and 7-fold the maximum recommended clinical dose, based on body surface area of a patient weighing 20 kg and a patient weighing 60 kg, respectively.

Metreleptin caused prolonged gestation and dystocia at all tested doses in the two pre- and postnatal development studies in mice; therefore, a NOAEL could not be determined. The LOAEL was approximately equal to the maximum recommended clinical dose, based on body surface area of a patient weighing 60 kg. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Of note, in pregnant mice, the exposure to metreleptin (as measured by the area under the curve) was two to three times greater than that in non-pregnant mice. In addition, the half-life of metreleptin in pregnant mice was four to five times longer compared to that in non-pregnant mice. The higher exposure to metreleptin and its longer half-life observed in pregnant mice may be related to a reduced elimination capacity because of metreleptin binding to soluble leptin receptors, which are found at higher levels in pregnant mice.

Juvenile toxicity studies were not conducted with metreleptin.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Myalepta Product Monograph. In view of the intended use of Myalepta, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Myalepta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Metreleptin, the medicinal ingredient in Myalepta, is a recombinant human leptin analogue that differs from the human leptin sequence by a single additional amino acid, methionine, located at the N-terminal end.

Detailed characterization studies were performed to provide assurance that metreleptin consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Metreleptin is produced in a strain of Escherichia coli that is genetically engineered to express the protein.

The manufacturing process of the drug substance involves bacterial fermentation to express metreleptin as inclusion bodies, isolation of the inclusion bodies by cell disruption and centrifugation, and purification of the target protein. The purified metreleptin is concentrated by ultrafiltration/diafiltration, formulated, filtered, filled into drug substance containers and stored at -20°C.

The drug product manufacturing process consists of thawing of the bulk drug substance, formulation, sterile filtration, aseptic filling into vials and partial stoppering, lyophilization, and sealing. None of the non-medicinal ingredients (excipients) found in the drug product is prohibited by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Controls of critical steps of the drug substance and drug product manufacturing processes were established during manufacturing development and were based on a risk assessment and process characterization. Process validation, conducted at commercial scale, demonstrated that the manufacturing processes are capable of consistently manufacturing drug substance and drug product that meet the predefined specifications and quality attributes.

Control of the Drug Substance and Drug Product

Specifications for the drug substance and drug product were set using compendial guidelines, product and process knowledge, and statistical analyses of release and stability data. The established release and stability specifications for the drug substance and drug product are considered appropriate and in accordance with relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The analytical procedures used in the release and stability testing of the drug substance and drug product were adequately validated according to relevant ICH guidelines. Compendial methods were satisfactorily verified under conditions of use.

A risk assessment for the presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. No risk was identified of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes. Accordingly, no confirmatory testing is required.

Myalepta is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered satisfactory.

The stability data support the proposed shelf life of 60 months at -20 °C for the drug substance (with a short-term storage of 12 months at -65 °C within the 60-month period) and 48 months at 2 °C to 8 °C for the drug product, when protected from light. In addition, after reconstitution of the 11.3 mg multi-use vial of Myalepta with bacteriostatic water for injection, the resulting solution may be stored for up to 3 days at 2 °C to 8 °C, based on simulated in-use (microbial challenge) data.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and an extractables and leachables study.

Facilities and Equipment

Based on the risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. Both manufacturing sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of metreleptin to prevent contamination and maintain microbial control.

The Escherichia coli expression system used does not support the replication of viral adventitious agents. Bacteriophage, bioburden and endotoxin testing procedures are integrated in the control strategy and meet relevant guidelines and requirements.

Most raw materials used in the production process are of non-animal source. Materials of animal origin (Bacto Tryptone, Trypticase Peptone, and glycerin) are compliant with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMA/410/01 rev. 3).

The excipients used in the drug product formulation are not of animal or human origin.