MACRILEN Granule for solution Ref.[10309] Active ingredients: Macimorelin

GH stimulation

Maximum GH levels are observed between 30 to 90 minutes after administration of MACRILEN.

Cardiac electrophysiology

The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg) (4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 msec (11.4 msec) at 4 h post-dose, which occurred after the mean maximum macimorelin plasma concentration (0.5 h). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, and 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively). All three dose levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown [see Warnings and Precautions (5.1)].

The mean plasma macimorelin concentrations are similar between patients with AGHD and healthy subjects for 1.5 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight.

Absorption

The maximum plasma macimorelin concentrations (C_max) were observed between 0.5 hour and 1.5 hours following oral administration of 0.5 mg macimorelin/kg body weight to patients with AGHD under fasting for at least 8 hours. A liquid meal decreased the macimorelin C_max and AUC by 55% and 49%, respectively.

Elimination

An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin.

Macimorelin was eliminated with a mean terminal half-life (T_1/2) of 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects.

Carcinogenesis

Long-term carcinogenesis studies in rodents have not been conducted.

Mutagenesis

Macimorelin did not cause mutations in bacteria under assay conditions with or without metabolic activation. There were also no mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation.

Impairment of Fertility

No studies have been conducted to assess the effect of macimorelin on fertility.

The diagnostic efficacy of the MACRILEN test was established in a randomized, open-label, single-dose, cross-over study. The objective of the study was to compare the level of agreement between MACRILEN test results and insulin tolerance test (ITT) results in adult patients with different pre-test probability of growth hormone deficiency and healthy control subjects. The four groups of individuals evaluated were:

• Group A: Adults with a high likelihood of growth hormone deficiency (GHD)
  • Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or
  • Three or more pituitary hormone deficiencies and low IGF-1, or
  • Childhood onset GHD with structural lesions and low IGF-1.
• Group B: Adults with an intermediate likelihood of GHD
  • Eligible subjects not qualifying for either high or low likelihood.
• Group C: Adults with a low likelihood of GHD
  • One risk factor for GHD only, such as history of distant traumatic brain injury or one pituitary hormone deficiency only with otherwise normal pituitary function, or
  • Isolated idiopathic childhood onset GHD without additional pituitary deficits.
• Group D: Healthy adult controls
  • Healthy subjects matching Group A subjects by sex, age ± 5 years, body mass index (BMI ± 2 kg/m²), and estrogen status (females only).

For both the ITT and the MACRILEN test, serum concentrations of growth hormone were measured at 30, 45, 60, and 90 minutes after drug administration. The test was considered positive (i.e., growth hormone deficiency diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut point value of 2.8 ng/mL for the MACRILEN test or 5.1 ng/mL for the ITT.

The level of negative and positive agreement between the results of the ITT and the MACRILEN test was used to evaluate the performance of the MACRILEN test. In the study, the ITT is used as the benchmark (i.e., a negative ITT indicates absence of disease and a positive ITT indicates presence of disease). Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative MACRILEN test. With a high level of negative agreement, the MACRILEN test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive MACRILEN test. With a high level of positive agreement, the MACRILEN test will not wrongly diagnose an individual with GHD per the ITT as not having GHD. The agreement measures are defined mathematically below (see Table 2).

Table 2. Definition of Agreement between ITT and MACRILEN:

Results

One hundred and fifty-seven subjects underwent at least one of the two tests in this study, 59% were male, 41% female, and 86% of white origin. The median age was 41 years (range: 18-66 years) and body mass index 27.5 kg/m² (range: 16-40 kg/m²). The study relied on a cross-over design and each participant was to undergo the two diagnostic tests and serve as his or her own control. Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C, and 25 (18%) in Group D. One out of 154 MACRILEN tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved.

Two-by-two tables presenting the pre-specified primary analysis results for the ITT and MACRILEN test are shown below for all subjects (Groups A, B, C, and D combined) and for each group separately (see Table 3). The estimates for negative and positive agreement between MACRILEN and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between MACRILEN and the ITT in subjects with intermediate or low risk (Groups B and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints).

Table 3. Diagnostic Outcomes for MACRILEN and the ITT in all Subjects (Groups A, B, C, and D) and in Each Group Separately:

Repeatability was tested in a subset of 34 subjects who underwent two MACRILEN tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%).