CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`125390Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`PMR/PMC Development Template-PMR #1-Product Exposure Registry
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`BLA #
`Product Name:
`
`125390
`Myalept (metreleptin)
`
`PMR#1 Description:
`
`A long-term prospective observational study (product exposure registry) of
`patients treated with Myalept (metreleptin), regardless of indication), to
`evaluate serious risks related to the use of Myalept (metreleptin), by
`indication, including: fatal or necrotizing pancreatitis, hepatic adverse events,
`severe hypoglycemia, serious hypersensitivity reactions, serious infections
`resulting in hospitalization or death, new diagnoses of autoimmune disorders
`(for instance, autoimmune hepatitis, glomerulonephritis, lupus erythematosus,
`antiphospholipid antibody syndrome, rheumatoid arthritis), autoimmune
`disease exacerbation, lymphoma, all cancers (excluding non-melanoma skin
`cancer) by cancer type, exposed pregnancies and pregnancy outcomes, and all
`deaths (including causes of death). After agreement with FDA on a targeted
`sample size, the registry will include patients prescribed Myalept
`(metreleptin) and will continue for 10 years from the date of last patient’s
`enrollment, or September 2029, whichever is later.
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`Interim reports
`
`09/30/2014
`09/30/2029
`03/31/2030
`09/31/2015
`09/31/2016
`09/31/2017
`09/31/2018
`09/31/2019
`09/31/2020
`09/31/2021
`09/31/2022
`09/31/2023
`09/31/2024
`09/31/2025
`09/31/2026
`09/31/2027
`09/31/2028
`09/31/2029
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`X Unmet need
`X Life-threatening condition
`X Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 1 of 46
`
`Reference ID: 3459217
`
`

`

`Small subpopulation affected
`Theoretical concern
`Other
`
`Generalized lipodystrophy is a rare disorder characterized by the loss of body fat. As the hormone leptin
`is primarily produced by fat tissue, patients with generalized lipodystrophy are leptin deficient. As a
`consequence of a lack of adequate storage depots for body fat (and resultant ectopic deposition of fat in
`tissues such as muscle and liver), as well as leptin deficiency, patients with generalized lipodystrophy
`often develop life-threatening co-morbidities such as insulin-dependent diabetes mellitus and acute
`pancreatitis from extreme hypertriglyceridemia. Myalept (metreleptin) was granted orphan drug
`designation for the treatment of lipodystrophy. Known and potential safety concerns include serious
`adverse sequelae due to the development of neutralizing antibodies [loss of endogenous leptin activity
`(e.g., severe infections), worsening of metabolic disease, T-cell lymphoma/ other malignancies,
`autoimmune disorders (e.g., autoimmune hepatitis, membranoproliferative glomerulonephritis),
`hypersensitivity reactions, pancreatitis, hepatic adverse events, and hypoglycemia. Given the small
`population affected by this disorder (less than ~1 in a million) and limitations in the conduct of the clinical
`trials, a post-marketing registry is required to generate additional person-years to assess risks related to the
`long-term use of the drug.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`The paucity of long-term safety data on Myalept (metreleptin) remains a concern. Because of the rarity of
`lipodystrophy, the availability of patients and person-years of exposure that contribute to our current
`understanding of the safety of Myalept (metreleptin) is limited. In addition, the obesity development
`program was discontinued. Myalept (metreleptin) pre-clinical and clinical development programs revealed
`known and potential serious risks associated with its use including serious adverse sequelae due to the
`development of neutralizing antibodies [loss of endogenous leptin activity (e.g., severe infections) and loss
`of efficacy (e.g., increases in triglycerides, worsening diabetes mellitus)], autoimmune disorders (e.g.,
`autoimmune hepatitis, membranoproliferative glomerulonephritis), hypersensitivity reactions, pancreatitis,
`hepatic adverse events, and hypoglycemia. The goal of the enhanced pharmacovigilance study is to gather
`additional data to better assess risks related to the long-term use of the drug. The goal of the registry is to
`generate additional person-years of exposure to assess these and other serious risks related to Myalept
`(metreleptin) use. The registry will include a sample of patients prescribed Myalept (metreleptin) and
`continue for 10 years from the date of last patient enrollment.
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`X FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`X Assess a known serious risk related to the use of the drug?
`X Assess signals of serious risk related to the use of the drug?
`X Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`3.
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 2 of 46
`
`Reference ID: 3459217
`
`

`

`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess
`or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`or identify a serious risk
`
`X Study: all other investigations, such as investigations in humans that are not clinical trials as defined
`below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious
`risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation, list here.
`The registry will include a sample of patients prescribed Myalept (metreleptin) and followed for
`10 years to describe the following:
`a. Patient age, sex, and race
`b. Country of treatment
`c. Type of generalized lipodystrophy (congenital or acquired)
`d. History of autoimmune disease
`e. History of pancreatitis
`f. Other medical history
`g. Concomitant medications, including start and stop dates
`h. Use of dietary and vitamin supplements
`i. Metreleptin dose, duration of use, start date, discontinuation date, reasons for
`discontinuation, person-years of exposure
`j. HbA1C
`k. Serum lipid levels
`l. Antibody titer and neutralizing antibodies if applicable
`
`Data to be provided should include incidence rates for the following outcomes of interest:
` Malignancies, including hematologic and solid tumors
`Serious infections resulting in hospitalization or death
`
`Serious hypersensitivity reactions
`
`Fatal, hemorrhagic or necrotizing pancreatitis
`
` Hepatic adverse events including hepatic transaminase elevations with
`and without bilirubin elevations, cirrhosis and hepatic failure
` Autoimmune disorders including autoimmune hepatitis, lupus
`erythematosus, antiphospholipid syndrome, rheumatoid arthritis,
`glomerulonephritis
`Serious /severe hypoglycemic events
`
`
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 3 of 46
`
`Reference ID: 3459217
`
`

`

`Required
`Observational pharmacoepidemiologic study
`X Registry studies
`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Continuation of Question 4
`
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`X Other
`A long-term, prospective, observational study (product exposure registry) of patients treated
`with Myalept (metreleptin), regardless of indication, to evaluate potential serious risks related
`to the use of Myalept (metreleptin), by indication, including: fatal or necrotizing pancreatitis,
`hepatic adverse events, severe hypoglycemia, serious hypersensitivity reactions, serious
`infections resulting in hospitalization or death, new diagnoses of autoimmune disorders (for
`instance, autoimmune hepatitis, glomerulonephritis, lupus erythematosus, antiphospholipid
`antibody syndrome, rheumatoid arthritis), autoimmune disease exacerbation, all cancers
`(excluding non-melanoma skin cancer) by cancer type, exposed pregnancies and pregnancy
`outcomes, and all deaths (including causes of death). After agreement on a targeted sample
`size, the registry will include patients prescribed Myalept (metreleptin) and will continue for 10
`years from the date of the last patient’s enrollment. The sponsor will submit annual updates
`regarding patient enrollment and study progress and interim analyses of study results at 3 and 7
`years.
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`X Does the study/clinical trial meet criteria for PMRs or PMCs?
`X Are the objectives clear from the description of the PMR/PMC?
`X Has the applicant adequately justified the choice of schedule milestone dates?
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 4 of 46
`
`Reference ID: 3459217
`
`

`

`X Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`X This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 5 of 46
`
`Reference ID: 3459217
`
`

`

`PMR/PMC Development Template-PMR #2-Neutralizing antibody ligand binding assay
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`BLA #
`Product Name:
`
`125390
`Myalept (metreleptin)
`
`PMR#2 Description:
`
`To develop, validate, and implement a ligand binding assay to supplement the
`neutralizing bioassay that tests for the presence of neutralizing antibodies in
`serum samples from patients with generalized lipodystrophy.
`
`PMR#2 Schedule Milestones:
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`03/31/2016
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`X Unmet need
`X Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`X Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 6 of 46
`
`Reference ID: 3459217
`
`

`

`Metreleptin is a replacement therapy for treating the complications of generalized lipodystrophy.
`Generalized lipodystrophy is a very rare disease (~1:10,000,000) for which there is no treatment.
`Lipodystrophy patients lack adipose tissue and therefore have dysregulated metabolism; complications
`may include insulin resistance and very high serum triglycerides. This can lead to difficult to control
`diabetes mellitus (often requiring hundreds of units of insulin daily), pancreatitis, and premature death.
`Metreleptin is highly immunogenic. The majority of patients with generalized lipodystrophy evaluated in
`the trials developed anti-metreleptin antibodies (84%). 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;
`however, the incompleteness of the current immunogenicity database precludes understanding of the
`magnitude and persistence of the observed anti-leptin antibody responses. One of the 2 patients was a 19
`year-old female with CGL, who appeared to have loss of metabolic control in association with the
`neutralizing antibodies, and was additionally reported to have multiple hospitalizations for sepsis. The
`second patient, an 18-year-old female with CGL, developed neutralizing antibodies associated with loss of
`efficacy; she also had an adverse event of sepsis, although the temporal relationship with that event is less
`clear. Because of the role that leptin plays in the functioning of the immune system, it is theoretically
`possible that neutralizing antibodies to leptin could have implications for immune functioning (i.e.,
`immunodeficiency), even in patients with very low endogenous leptin. A number of adverse events
`(excessive weight gain, glucose intolerance, diabetes mellitus) associated with the development of
`antibodies with neutralizing activity in patients treated with metreleptin in a development program for the
`treatment of obesity. As (1) this is a rare life threatening disease, (2) the majority of lipodystrophy patients
`did not show clinical sequelae because of neutralizing antibody responses, and (3) distribution of this drug
`will be limited to generalized lipodystrophy patients, this study can be a post-marketing requirement.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`The neutralizing cell based assay lacks sensitivity due to a high degree of matrix interference derived from
`the presence of endogenous serum leptin. Since the only difference between metreleptin and the native
`protein resides in the presence of one additional amino acid residue, cells cannot discriminate between the
`stimulatory dose of metreleptin added to the assay cultures and the amount present in serum. This interferes
`with the detection of samples with low concentration of neutralizing antibodies. A ligand binding assay
`would have reduced matrix interference and increased sensitivity that would allow for identification of
`samples with low levels of neutralizing antibodies that are not detected in the current bioassay.
`
`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`X FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`X Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 7 of 46
`
`Reference ID: 3459217
`
`

`

`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess
`or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`or identify a serious risk
`
`X Study: all other investigations, such as investigations in humans that are not clinical trials as defined
`below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious
`risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation, list here.
`The study will be conducted in generalized lipodystrophy patients enrolled in on-going clinical
`trials, samples collected in previous trials, and a new safety trial proposed in a separate PMR.
`
`Required
`Observational pharmacoepidemiologic study
`Registry studies
`X Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Continuation of Question 4
`
`X Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Stored and banked serum samples from patients that have received metreleptin treatment under
`the clinical development program should also be tested and analyzed together
`Meta-analysis or pooled analysis of previous studies/clinical trials
`X Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 8 of 46
`
`Reference ID: 3459217
`
`

`

`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`X Other
`To develop, validate, and implement a ligand-binding assay, to supplement the neutralizing
`bioassay, that tests for the presence of neutralizing antibodies in serum samples from patients
`with generalized lipodystrophy.
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`X Does the study/clinical trial meet criteria for PMRs or PMCs?
`X Are the objectives clear from the description of the PMR/PMC?
`X Has the applicant adequately justified the choice of schedule milestone dates?
`X Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`X This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 9 of 46
`
`Reference ID: 3459217
`
`

`

`PMR/PMC Development Template-PMR #3 Neutralizing antibody retest-NIH study
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`BLA #
`Product Name:
`
`125390
`Myalept (metreleptin)
`
`PMR #3 Description:
`
`To test all banked clinical samples from pivotal clinical trials NIH
`991265/20010769 and trial FHA101 for the presence of neutralizing
`antibodies against leptin using the ligand binding assay developed and
`validated under PMR#2, and to correlate neutralizing antibodies with clinical
`events.
`
`PMR#1 Schedule Milestones:
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`08/31/2016
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`X Unmet need
`X Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`X Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`Metreleptin is a replacement therapy for treating the complications of generalized lipodystrophy.
`Generalized lipodystrophy is a very rare disease (~1:10,000,000) for which there is no treatment.
`Lipodystrophy patients lack adipose tissue and therefore have dysregulated metabolism; complications
`may include insulin resistance and very high serum triglycerides. This can lead to difficult to control
`diabetes mellitus (often requiring hundreds of units of insulin daily), pancreatitis, and premature death.
`Adipose tissue is the main source of leptin in humans, although other cells such as cells of the immune
`system also produce leptin. The development of neutralizing antibodies was linked to loss of efficacy
`and/or loss of endogenous leptin activity in five patients receiving metreleptin treatment. Three of those
`patients are in the obese population in which metreleptin will be contraindicated. Peak neutralizing
`antibody responses were reported at the time when the following adverse events were observed: severe
`infections, worsening glycemic control, hypertriglyceridemia, and excessive weight gain. As (1) this is a
`rare life threatening disease, (2) the majority of lipodystrophy patients did not show clinical sequelae
`because of neutralizing antibody responses, and (3) distribution of this drug will be limited to generalized
`lipodystrophy patients, this can be a post-marketing requirement.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety
`information.”
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 10 of 46
`
`Reference ID: 3459217
`
`

`

`The bioassay used to determine the presence of anti-leptin antibodies with neutralizing activity in samples
`collected from patients enrolled in pivotal studies NIH 991265/20010769 and FHA 101 lacked sensitivity
`due to a high degree of matrix interference. Thus, there is a concern over underreporting the number
`neutralizing antibody positive patients enrolled under these two studies. Given the concern over loss of
`efficacy to metreleptin treatment and the potential loss of endogenous leptin function, testing of banked
`clinical samples with a ligand binding assay with reduced matrix interference and increased sensitivity
`would allow identification of samples with low levels of neutralizing antibodies that were not detected with
`the current bioassay.
`
`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`X FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`X Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious risk?
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess
`or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA
`is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient
`to assess this known serious risk, or has been established but is nevertheless not sufficient to assess
`or identify a serious risk
`
`XStudy: all other investigations, such as investigations in humans that are not clinical trials as defined
`below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious
`risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines the
`method of assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study
`or trial will be performed in a subpopulation, list here.
`The study will be conducted in banked samples from lipodystrophy patients enrolled in previous
`clinical trials.
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 11 of 46
`
`Reference ID: 3459217
`
`

`

`Required
`Observational pharmacoepidemiologic study
`Registry studies
`X Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Stored and banked serum samples from patients that have received metreleptin treatment under
`the clinical development program should also be tested and analyzed together
`Meta-analysis or pooled analysis of previous studies/clinical trials
`X Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease
`severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`X Other
`To test all banked clinical samples from pivotal clinical studies NIH 991265/20010769 and
`study FHA101 for the presence of neutralizing antibodies against leptin using the ligand
`binding assay developed and validated under PMR #2 described above, and to correlate
`neutralizing antibodies with clinical events.
`
`5.
`
`Is the PMR/PMC clear, feasible, and appropriate?
`X Does the study/clinical trial meet criteria for PMRs or PMCs?
`X Are the objectives clear from the description of the PMR/PMC?
`X Has the applicant adequately justified the choice of schedule milestone dates?
`X Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility,
`and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`X This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 12 of 46
`
`Reference ID: 3459217
`
`

`

`PMR/PMC Development Template-PMR #4 - Immunogenicity clinical study
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`BLA #
`Product Name:
`
`PMR #4 Description:
`
`125390
`Myalept (metreleptin)
`To conduct a study to assess for the immunogenicity of Myalept (metreleptin)
`in a relevant number of patients receiving metreleptin. The study should
`include testing for anti-metreleptin and anti-native human leptin binding
`antibodies at times when antibody responses peak, using a validated assays.
`The presence of neutralizing antibodies should be assessed using a validated
`cell-based assay and a validated ligand-binding assay in samples that are
`confirmed positive for binding antibodies to leptin. All patients with
`suspected loss of metreleptin efficacy (e.g., worsening glycemic control,
`increases in triglycerides) or loss of endogenous leptin activity (e.g., severe
`infections) should be tested for neutralizing activity and followed at least until
`antibody levels revert to baseline. Antibody titers, neutralizing activity, and
`associated clinical events should be characterized over time.
`
`PMR Schedule Milestones:
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`12/31/2014
`12/31/2021
`12/31/2022
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
`X Unmet need
`X Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`X Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`PMR/PMC Development Template
`
`Last Updated 2/23/2014
`
`Page 13 of 46
`
`Reference ID: 3459217
`
`

`

`Metreleptin is a replacement therapy for treating the complications of generalized lipodystrophy.
`Generalized lipdystrophy is a very rare disease (~1:10,000,000) for which there is no treatment.
`Lipodystrophy patients lack adipose tissue and therefore have dysregulated metabolism; complications
`may include insulin resistance and very high serum triglycerides. This can lead to difficult to control
`diabetes mellitus (often requiring hundreds of units of insulin daily), pancreatitis, and premature death.
`Adipose tissue is the main source of leptin in humans, although other cells such as cells of the immune
`system also produce leptin. The development of neutralizing antibodies was linked to loss of efficacy
`and/or loss of endogenous leptin activity in five patients receiving metreleptin treatment. Three of those
`patients are in the obese population in which metreleptin will be contraindicated. Peak neutralizing
`antibody responses were reported at the time when the following adverse events were observed: severe
`infections, worsening glycemic control, hypertriglyceridemia, and excessive weight gain. As (1) this is a
`rare life threatening disease, (2) the majority of lipodystrophy patients did not show clinical sequelae
`because of neutralizing antibody responses, and (3) distribution of this drug will be limited to generalized
`lipodystrophy patients, this can be a post-marketing requirement.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a
`FDAAA