Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Amryt Pharmaceuticals DAC, 45 Mespil Road, Dublin 4, Ireland
Pharmacotherapeutic group: Other alimentary tract and metabolism products, amino acids and derivatives
ATC code: A16AA07
Metreleptin 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 JAK/STAT transduction pathway.
Only the metabolic effects of metreleptin have been studied. No effects on the distribution of subcutaneous fat are expected.
The efficacy and safety of treatment with metreleptin was evaluated in an open-label, single-arm study (Study NIH 991265/20010769) in patients with congenital or acquired generalised LD or familial or acquired partial LD. Patients were eligible for inclusion if they were >6 months old, with a leptin level of <12 ng/mL, and had at least 1 of the following 3 metabolic abnormalities:
The co-primary efficacy endpoints in this study were defined as:
Study NIH 991265/20010769 was conducted over 14 years, with the primary efficacy assessments being made in both generalised LD and partial LD patients after 12 months of treatment. Multiple dosing regimens were explored during the NIH study, which led to the posology recommended in section 4.2.
Concomitant anti-diabetic and lipid-lowering dose regimens were not held constant during the study, but analyses showed no significant difference in efficacy between patients who had no increases or additions to their anti-diabetic or lipid-lowering treatments versus the overall study population.
Of the 66 generalised LD patients enrolled, 45 (68%) had congenital generalised LD and 21 (32%) had acquired generalised LD. Overall, 51 (77%) patients were female, 31 (47%) were Caucasian, 11 (17%) Hispanic, and 16 (24%) Black. The median age at baseline was 15 years (range: 1-68 years), with 45 (68%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was 1.0 ng/mL in males (range: 0.3-3.3 ng/mL) and 1.1 ng/mL in females (range: 0.2-5.3 ng/mL) using the LINCO RIA test method.
The median duration of metreleptin treatment was 4.2 years (range: 3.4 months-13.8 years). The medicinal product was administered subcutaneously either once daily or twice daily (in two equal doses). The weighted average daily dose (i.e., the average dose taking into account duration of treatment at different doses) for the 48 patients with baseline body weight greater than 40 kg was 2.6 mg for males and 5.2 mg for females during the first year of treatment, and 3.7 mg for males and 6.5 mg for females over the entire study period. For the 18 patients with baseline body weight less than or equal to 40 kg, the weighted average daily dose was 2.0 mg for males and 2.3 mg for females in the first year of treatment, and 2.5 mg for males and 3.2 mg for females over the entire study period.
Table 8. Primary outcome results in an open-label, single-arm study (NIH 991265/20010769) in evaluable patients with generalised LD treated with metreleptin at 12 months:
| Parameter | n | Baseline | Change from Baseline at Month 12 |
|---|---|---|---|
| HbA1c (%) | 59 | ||
| Mean (SD) | 8.6 (2.33) | -2.2 (2.15) | |
| P | <0.001 | ||
| Fasting TGs (mmol/L) | 58 | ||
| Mean (SD) | 14.7 (25.6) | -32.1% (71.28) | |
| P | 0.001 |
SD = standard deviation
Among 45 patients with generalised LD who had a baseline HbA1c of 7% or greater and data available at Month 12, the mean (SD) baseline HbA1c was 9.6% (1.63) and the mean reduction in HbA1c at Month 12 was 2.8%. Among 24 patients with generalised LD who had a baseline TG level 5.65 mmol/l or greater and data available at Month 12, the mean (SD) baseline TG level was 31.7 mmol/l (33.68) and the mean percent reduction in triglycerides at Month 12 was 72%.
Among the 39 patients with generalised LD who were receiving insulin at baseline, 16 (41%) were able to discontinue insulin use altogether after starting metreleptin. Most of these patients (13 of 16) were able to stop insulin use within the first year of metreleptin. For the 32 patients with generalised LD who were receiving oral anti-diabetic medicinal products at baseline, 7 (22%) were able to discontinue their use. A total of 8 (24%) of the 34 patients with generalised LD who were receiving lipid-lowering therapies at baseline discontinued their use during metreleptin treatment.
There was evidence of improvement in renal and hepatic function in patients with generalised LD treated with metreleptin. In 24 patients with renal data available, the mean change at Month 12 in protein excretion rate versus baseline (1,675.7 mg/24hr) was -906.1 mg/24 hr. In 43 patients with hepatic data available, the mean changes at Month 12 in alanine aminotransferase, versus baseline (112.5 U/L) was -53.1 U/L, and aspartate aminotransferase versus baseline (75.3 U/L) was -23.8 U/L.
A subgroup of partial LD patients is analysed for whom TG ≥5.65 mmol/l and/or HbA1c ≥6.5% at baseline. Of the 31 partial LD subgroup patients evaluated, 27 (87%) had familial partial LD and 4 (13%) had acquired partial LD. Overall, 30 (97%) patients were female, 26 (84%) were Caucasian, 2 (7%) Hispanic, and 0 Black. The median age at baseline was 38 years (range: 15-64 years), with 5 (16%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was 5.9 ng/mL (1.6-16.9) using the LINCO RIA test method.
The median duration of metreleptin treatment was 2.4 years (range: 6.7 months-14.0 years). The medicinal product was administered subcutaneously either once daily or twice daily (in two equal doses). The weighted average daily dose (i.e., the average dose taking into account duration of treatment at different doses) for all 31 patients with baseline body weight greater than 40 kg was 7.0 mg during the first year of treatment, and 8.4 mg over the entire study period.
Table 9. Primary outcome results in study (NIH 991265/ 20010769) of evaluable patients in the partial LD subgroup treated with metreleptin at 12 months:
| Parameter | n | Baseline | Change from Baseline at Month 12 |
|---|---|---|---|
| HbA1c (%) | 27 | ||
| Mean (SD) | 8.8 (1.91) | -0.9 (1.23) | |
| P | <0.001 | ||
| Fasting Triglycerides (mmol/L) | 27 | ||
| Mean (SD) | 15.7 (26.42) | -37.4% (30.81) | |
| P | <0.001 |
SD = standard deviation
Among 15 patients in the partial LD subgroup who had a baseline TG level 5.65 mmol/L or greater and data available at Month 12, the mean (SD) baseline triglyceride level was 27.6 mmol/L (32.88) and the mean percent reduction in TGs at Month 12 was 53.7%.
Among 18 patients in the partial LD subgroup who had a baseline HbA1c level 8% or greater and data available at Month 12, the mean (SD) baseline HbA1c level was 9.9% (1.59) and the mean reduction in HbA1c at Month 12 was 1.3%.
In the generalised LD group, the number of patients according to age group was as follows: 5 patients <6 years (including a single patient <2 years), 12 patients ≥6 to <12 years and 28 patients aged ≥12 to <18 years; in the partial LD subgroup, there were no patients <12 years of age and 4 patients ≥12 to <18 years.
In the generalised LD group, mean decreases from baseline in HbA1c were noted in all age groups ≥6 years; the mean decreases to Month 12/last observation carried forward LOCF were similar in the two older age groups (-1.1% and -2.6%). Mean change among the 5 patients <6 years of age was 0.2%. These differences across age groups are likely related to differences in mean HbA1c at baseline, which was in the normal range for patients <6 years (5.7%) and lower in patients ≥6 to <12 years (6.4%) compared to the older age group (9.7%). Mean decreases from baseline to Month 12/LOCF in TGs for the generalised LD group were noted in all age groups with larger mean changes observed in the older age group (-42.9%) compared to the younger age groups (-10.5% and -14.1%).
Among the 4 patients in the partial LD subgroup between 12 and 18 years of age, mean change to Month 12/LOCF for HbA1c was -0.7% and for TGs was -55.1%.
The European Medicines Agency has deferred the obligation to submit the results of studies with Myalepta in one or more subsets of the paediatric population in the treatment of lipodystrophy (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
There are limited data on the pharmacokinetics of metreleptin in patients with lipodystrophy and therefore no formal exposure-response analysis has been performed.
Peak serum leptin (endogenous leptin and metreleptin) concentration (Cmax) occurred approximately 4.0 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy adult subjects. In a supportive trial in LD patients, the median Tmax was 4 hours (range: 2 to 6 hours; N = 5) following single-dose administration of metreleptin.
In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution (endogenous leptin and metreleptin) was approximately 4 to 5 times plasma volume; volumes (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.
No formal metabolism studies have been conducted.
Non-clinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/kg metreleptin in healthy adult subjects, the half-life was 3.8 to 4.7 hours. After IV administration, metreleptin clearance was shown to be 79.6 mL/kg/h in healthy volunteers. The clearance of metreleptin appears to be delayed in the presence of ADAs. A higher accumulation is observed with higher ADA levels. Dose adjustments should be made based on clinical response (see section 4.4).
No formal pharmacokinetic studies were conducted in patients with hepatic impairment.
No formal pharmacokinetic studies were conducted in patients with renal impairment. Non-clinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Hence, the pharmacokinetics may be altered in patients with renal impairment.
Specific clinical studies have not been conducted to assess the effect of age, gender, race, or body mass index on the pharmacokinetics of metreleptin in patients with lipodystrophy.
Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity reveal no risks additional to those attributed to an excess of the expected pharmacodynamic responses, such as loss of appetite and body weight.
Two-year carcinogenicity studies in rodents have not been conducted. Metreleptin exhibits no genotoxic potential and no proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to 6 months.
Reproductive toxicity studies conducted in mice have revealed no adverse effects on mating, fertility or embryo-foetal development up to the maximum tested dose, approximately, 15-fold the maximum recommended clinical dose, based on body surface area of a 60 kg patient.
In a pre- and postnatal development study in mice, metreleptin caused prolonged gestation and dystocia at all tested doses, starting at, approximately, a dose identical to the maximum recommended clinical dose, based on body surface area of a 60 kg patient. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. These findings are considered to be related indirectly to metreleptin pharmacology, resulting in nutritional deprivation of treated animals, and also possibly, due to an inhibitory effect on spontaneous and oxytocin-induced contractions, as has been observed in strips of human myometrium exposed to leptin. Decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.
Reproductive toxicity studies have not included toxicokinetics analysis. However, separate studies revealed that exposure of the mouse foetus to metreleptin was low (<1%) after subcutaneous administration of metreleptin to pregnant mice. The AUC exposure of pregnant mice was approximately 2 to 3 times greater than observed in non-pregnant mice after 10 mg/kg subcutaneous administration of metreleptin. A 4 to 5-fold increase in the t1/2 values was also observed in pregnant mice compared to non-pregnant mice. The greater metreleptin exposure and longer t1/2 observed in the pregnant animals may be related to a reduced elimination capacity by binding to soluble leptin receptor found at higher levels in pregnant mice.
No studies with direct administration of metreleptin to juvenile animals have been conducted. However, in published studies, leptin treatment of euleptinaemic prepubertal female mice has led to an earlier onset of puberty.
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