MK-677 alters GH isoform proportions acutely but stabilizes after repeated dosing
Background
Growth hormone (GH) is not a single molecular entity but a mixture of isoforms — most prominently the 22kDa (22K) form and a 20kDa (20K) variant, along with other non-22K species secreted by the pituitary. The relative proportions of these isoforms may influence biological activity and clinical response. Obesity is associated with blunted GH secretion, making GH secretagogues clinically relevant in this population. MK-677 is an orally active GHSR agonist that stimulates pulsatile GH release, but how it affects the isoform composition of secreted GH — rather than total GH levels — has not been well characterized across chronic dosing.
Study Design
MK-677 25 mg was administered orally once daily for 8 weeks to 12 obese males in an open-label design. GH samples were collected to capture both peak and non-peak total GH concentrations after the initial dose and again at 2 weeks and 8 weeks. The primary endpoints were the proportion of non-22K GH isoforms (expressed as % of total GH) and the proportion of 20K GH in 2-hour samples, assessed using isoform-specific immunoassay methods.
Results
After the initial MK-677 administration, the proportion of non-22K GH isoforms in peak total GH samples was significantly higher than at both 2 weeks (p<0.01) and 8 weeks (p<0.05). However, in non-peak total GH samples from the initial dose, the proportion of non-22K isoforms was similar to that seen in peak samples at weeks 2 and 8, suggesting the acute peak-specific elevation does not persist into trough periods even on day one.
The proportion of 20K GH in 2-hour samples after the initial MK-677 dose was significantly lower than after 2 weeks (p<0.01) and 8 weeks (p<0.05), indicating a relative recovery of the 20K isoform fraction with repeated dosing.
The authors characterized these as moderate changes in non-22K isoform proportion and concluded they are likely of small importance for the clinical response to MK-677 treatment. Isoform distributions appeared to reach a new steady state by the 2-week timepoint, with no indication of progressive further change through 8 weeks.
Key Findings
- Non-22K GH isoform proportion was higher in peak samples after initial dose vs. 2 weeks (p<0.01) and 8 weeks (p<0.05)
- Non-peak non-22K isoform proportion after initial dose was similar to peak proportions at weeks 2 and 8
- 20K GH proportion in 2-h samples was lower after initial dose vs. 2 weeks (p<0.01) and 8 weeks (p<0.05)
- Authors concluded isoform proportion changes are of small clinical importance for MK-677 response
- Study duration: 8 weeks; dose: MK-677 25 mg oral daily; n=12 obese males
Why It Matters
Practitioners and clinicians using MK-677 can be reassured that the isoform composition of secreted GH — while transiently shifted on the first dose — stabilizes within 2 weeks of daily dosing. This means the GH secretory profile at steady state is not dominated by aberrant non-22K isoforms that might behave differently from 22K GH at target tissues. For protocol design, no isoform-driven dose adjustment appears warranted after the initial adaptation period. However, the acute first-dose shift in isoform ratios is a reminder that early measurements of GH isoforms in secretagogue studies may not reflect chronic steady-state biology, which has implications for how early-phase clinical trials interpret GH biomarker data.
TitrateLab articles covering MK-677
Written by TitrateLab, separately from the study summarized above.
mk-677
growth hormone
gh isoforms
20k gh
non-22k gh
obesity
