K4 Elite
K4 Elite
An orally active, selective growth hormone secretagogue receptor 1a (GHS-R1a) agonist and ghrelin mimetic, studied in pituitary GH release, rodent food-intake models and randomized cancer-cachexia trial programs.
Anamorelin (ONO-7643, formerly RC-1291) is a synthetic, orally available small molecule that acts as a ghrelin mimetic at the growth hormone secretagogue receptor 1a. It is not a ribosomally encoded peptide; it is a peptidomimetic built around a trisubstituted scaffold designed for oral exposure [1].
The research interest in it centres on separating the two documented arms of ghrelin receptor signaling - the somatotropic arm at the pituitary and the orexigenic arm in the hypothalamus - in a molecule stable enough for repeated oral administration in animals [1].
It carries regulatory approval in Japan for cancer cachexia in several tumour types, and it is the most extensively trialled selective GHS-R1a agonist in the published record, with two Phase 3 programs and several randomized Phase 2 studies reported [2][3][4].
GHS-R1a is a class A G protein-coupled receptor expressed in the anterior pituitary and in hypothalamic nuclei including the arcuate nucleus. Preclinical characterization reports calcium mobilization in CHO cells expressing rat GHS-R1a and growth hormone release from rat pituitary cells with a reported EC50 near 1.5 nM [1].
Downstream, the published record describes activation of the GH/IGF-1 axis together with NPY/AgRP-linked appetite signaling in the hypothalamus. Structural work on the ghrelin receptor has been used to relate agonist scaffolds to receptor conformation and to the constitutive activity characteristic of this receptor [5].
Preclinical profiling reported by Ono investigators characterized anamorelin hydrochloride in vitro and in rats. In cell assays it induced calcium mobilization in CHO cells expressing rat GHS-R1a and released growth hormone from rat pituitary cells with a reported EC50 of approximately 1.5 nM. In vivo, rats received anamorelin at 3, 10 or 30 mg/kg or control by oral gavage once daily for six days to assess food intake and body weight, with a single administration used to assess the GH response; the report describes dose-dependent GH release in both sham-operated and vagotomized rats and increased food intake across the tested range [1].
ROMANA 1 and ROMANA 2 were randomized, double-blind, placebo-controlled Phase 3 trials conducted at 93 sites in 19 countries in participants with advanced non-small-cell lung cancer and cachexia. Co-primary measures were change in lean body mass and handgrip strength over 12 weeks. Investigators reported an increase in lean body mass relative to placebo and no measured difference in handgrip strength between arms [2].
The ONO-7643-04 randomized, double-blind, placebo-controlled multicentre study enrolled 174 Japanese participants with unresectable stage III/IV non-small-cell lung cancer and cachexia over 12 weeks, with change from baseline in lean body mass by DXA as the primary measure. The reported least-squares mean change in lean body mass was 1.38 +/- 0.18 kg in the active arm versus -0.17 +/- 0.17 kg in the placebo arm [3].
In a lung cancer mouse xenograft model, investigators compared native ghrelin and anamorelin for effects on tumour growth as a mechanistic safety question, since GHS-R1a agonism raises IGF-1 [6].
Combinations examined in the research literature. Descriptive only — not a recommendation to combine compounds.