Metreleptin (1) – Myalepta®

• Clinical trials
  • The NIH 991265 trial is a dose-escalation study designed to determine the safety and efficacy of short-term (up to 8 months) leptin replacement.
  • The FHA101 study is an open-label, single-arm metreleptin study for the treatment of patients aged ≥ 5 years with confirmed lipodystrophy and diabetes mellitus and/or hypertriglyceridaemia (triglyceride levels > 200 mg/dl).

a) Adults and children aged 2 years and over with confirmed congenital generalised lipodystrophy (Berardinelli–Seip syndrome) or acquired generalised lipodystrophy (Lawrence syndrome)

• mortality
  • In the NIH 991265 / 20010769 study, three patients with generalised lipodystrophy died.
  • In the FHA101 study, one death occurred in a patient with generalised lipodystrophy.
  • No data are available for the endpoint category of mortality that would allow the derivation of an additional benefit.
• Morbidity – Actual change in HbA1c
  • In the NIH 991265 / 20010769 study, shows a statistically significant difference in the change in HbA1c for the GL population between the start of the study and month 12 (mean difference -2.2; 95% CI [–2.7; –1.6]; p < 0.001).
  • In the FHA101 study, however, there was no statistically significant change in HbA1c between the start of the study and month 12.
• Morbidity – Percentage change in triglycerides
  • With regard to the percentage change in triglycerides, a statistically significant difference was observed for the GL population in the NIH 991265 / 20010769 study between the start of the study and month 12 (mean difference –32.1; 95% CI [–51.0; –13.2]; p = 0.001).
  • In the FHA101 study, however, there were no statistically significant changes in triglyceride levels between the start of the study and month 12.
• quality of life
  • No data on quality of life were collected in either study.
• Side effects
  • In the NIH 991265 / 20010769, 89.4% of patients in the GL population experienced at least one adverse event, 34.8% of patients experienced serious adverse events, and 7.6% of patients discontinued treatment due to adverse events.
  • In the FHA101 study, only one patient in the GL population discontinued the study treatment due to adverse events. 66.7% of patients experienced a serious adverse event and 77.8% of patients experienced at least one adverse event.
  • No data are available for the endpoint category ‘side effects’ that would allow the derivation of an additional benefit.
• Overall assessment
  • The data presented for the endpoint categories of mortality and side effects cannot be used to infer any additional benefit.
  • In the endpoint category ‘morbidity’, the study NIH 991265 / 20010769, for patients with generalised lipodystrophy, a statistically significant difference was observed between the start of the study and month 12 in the change in HbA1c and triglycerides.
  • Due to considerable uncertainties regarding the relevance of clinical laboratory parameters to patient-relevant endpoints, limited data availability and the highly heterogeneous clinical picture, the results for the aforementioned morbidity endpoints do not allow for quantification of the extent of the additional benefit of metreleptin.
  • Overall, a non-quantifiable additional benefit of metreleptin is identified.

b) Adults and children aged 12 years and over with confirmed familial or acquired partial lipodystrophy (Barraquer-Simons syndrome), in whom standard treatments have failed to achieve adequate metabolic control

• mortality
  • In both the NIH 991265 / 20010769 study and the FHA101 study, one patient with partial lipodystrophy died in each case.
  • No data are available for the mortality endpoint category that would allow the derivation of an additional benefit.
• Morbidity – Actual change in HbA1c
  • In the NIH 991265 / 20010769 study, a statistically significant difference in the change in HbA1c was observed for the PL population between the start of the study and month 12 (mean difference -0.6; 95% CI [–1.0; –0.2]; p = 0.005).
  • In the FHA101 study, however, no statistically significant change in HbA1c was observed between the start of the study and month 12.
• Morbidity – Percentage change in triglycerides
  • In the PL population, there were no statistically significant changes in triglyceride levels between the start of the study and month 12 in either the NIH 991265 / 20010769 study or the FHA101 study.
• quality of life
  • No data on quality of life were collected in either study.
• Side effects
  • In the PL population, 85.4% of patients (NIH 991265 / 20010769) and 84.4% of patients (FHA101), respectively, experienced at least one adverse event.
  • 24.4% and 31.3% of PL patients experienced a serious adverse event, and between (NIH 991265 / 20010769) to three (FHA101) study participants discontinued treatment with metreleptin due to adverse events.
  • No data are available for the endpoint category ‘side effects’ that would allow the derivation of any additional benefit.
• Overall assessment
  • The data presented for the endpoint categories of mortality and side effects cannot be used to infer any additional benefit.
  • In the endpoint category of morbidity, the NIH 991265 / 20010769 study in patients with partial lipodystrophy showed a statistically significant difference in the change in HbA1c between the start of the study and month 12.
  • By contrast, no statistically significant differences were observed in the change in blood triglyceride levels.
  • Due to considerable uncertainties regarding the relevance of clinical laboratory parameters to patient-relevant endpoints, limited data availability and the highly heterogeneous clinical picture, the results for the aforementioned morbidity endpoints do not allow for a quantification of the extent of the additional benefit of metreleptin.
  • Overall, a non-quantifiable additional benefit of metreleptin is identified.

Courtesy translation only, please refer to the German original.