Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macimorelin in Children with Suspected Growth Hormone Deficiency: An Open-Label, Group Comparison, Dose-Escalation Trial

Abstract

Background/Aims: Diagnosis of growth hormone deficiency (GHD) in children requires the use of provocative growth hormone (GH) stimulation tests, which can have limited reliability and are potentially contraindicated in some patients. This is the first paediatric study to test the safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics (PD) of macimorelin, an oral GH secretagogue, approved for diagnosis of adult GHD. Methods: In this open-label, group com-parison, single-dose escalation trial (EudraCT 2018-001988-23), sequential cohorts of patients (C1-C3) received ascending single doses of macimorelin: 0.25 (C1), 0.5 (C2), and 1.0 (C3) mg/kg. Primary endpoints were safety and tolerability, and secondary endpoints were PK/PD. Results: Twenty-four patients aged between 2 and <18 with suspected GHD participated in the study. No macimorelin-related adverse events were reported, and macimorelin was well tolerated.

Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia

“…No macimorelin recipients achieved IGF‐1 efficacy here despite maintained GH secretion. In that study, GH response (30 min post–pre‐anamorelin) averaged over twice that observed here, likely due to the larger dose (~1.0 mg/kg) 14 ; however, macimorelin consistently induced acute GH secretion after single‐dose administration in non‐cancer individuals 9,20–29 . Therefore, GH resistance is an unlikely contributor to the lack of efficacy observed here, evidenced by post‐macimorelin GH ≥ 5.1 ng/mL 39 for all macimorelin recipients.…”

“…Clinical studies using GHS have shown positive effects on appetite, body weight and body composition in healthy volunteers and in patients with cancer cachexia 12–18 and one such drug, anamorelin, has been recently approved for cachexia treatment in Japan 19 . Macimorelin, a novel, orally active GHS with similar GHSR‐1a binding affinity as ghrelin, is well‐tolerated as a single dose in healthy volunteers and individuals at risk for pituitary dysfunction 9,14,20–28 . It received approval from the US Food and Drug Administration (FDA) in 2017 and European Medicines Agency (EMA) in 2019 as a single dose for adult GH deficiency (AGHD) diagnosis 9,22,29 but has not been examined in repeated doses or in the cancer setting.…”

Macimorelin Acetate for the Diagnosis of Childhood-onset Growth Hormone Deficiency

“…12 In the paediatric population, an open-label group comparison, dose-escalation trial was performed to study the safety, tolerability, pharmacokinetics and pharmacodynamics of macimorelin acetate. 13 In this study of 24 children with suspected GHD aged between 2 and 18 years, macimorelin acetate was administered to sequential patient cohorts of eight patients who received ascending single doses of 0.25, 0.5 and 1 mg/kg. Macimorelin provocation testing was performed between 2 standard GH stimulation tests separated by a recovery period of 7-28 days between tests.…”

“…Regarding safety and tolerability, however, there were a total of 158 adverse events and treatment-emergent adverse events combined, although none was caused by macimorelin acetate. 13 As macimorelin acetate is administered orally (although it may still require an infusion centre or a hospital setting and intravenous access for blood draws), based on the safety and tolerability data, the acuity level for macimorelin testing could be lower, with fewer staff members required compared with agents with more serious side effect profiles.…”

“…Regarding safety and tolerability, however, there were a total of 158 adverse events and treatment-emergent adverse events combined, although none was caused by macimorelin acetate. 13 …”