THE 30-SECOND OVERVIEW
At a glance
MK-677 is one of the few compounds in the research-peptide catalogue that is not a peptide, and one of the very few with a clinical trial record that runs to hundreds of participants and years of exposure. Searches for its trials often land on secondary summaries, or on queries about indications it was never studied for. This is the primary record: each trial, its design, and what it reported, drawn from the published abstracts.
One note on scope first. There is no published trial of MK-677 in non-alcoholic steatohepatitis. Queries pairing ibutamoren with NASH circulate, but the indexed literature contains no such study. What exists is below.
The compound
MK-677, ibutamoren mesylate, MK-0677 and latterly LUM-201 are the same molecule: a spiroindoline small-molecule agonist of the ghrelin receptor GHS-R1a, developed by Merck as an orally active growth hormone secretagogue (Ghigo et al., 1998). We stock it as a 25mg per mL oral liquid and as 15mg tablets, for research use only.
1996 to 1997: dose-ranging and the pulse
Chapman and colleagues (1996) enrolled 32 healthy adults aged 64 to 81 and gave placebo or 2, 10 or 25mg once daily for periods of 14 and 28 days, sampling blood every 20 minutes for 24 hours. At 25mg, mean 24-hour growth hormone rose 97 percent, and IGF-1 rose from 141 to 265 micrograms per litre by four weeks, into the young-adult range. The increase came from taller pulses and higher troughs, not more pulses. Fasting glucose rose from 5.4 to 6.8 millimoles per litre. Cortisol did not change; prolactin rose 23 percent within the normal range.
Copinschi and colleagues (1996) ran a three-period crossover in nine young men, placebo against 5 and 25mg at bedtime for seven days. The amount of growth hormone secreted was similar in all conditions, but pulse frequency rose through additional low-amplitude pulses, IGF-1 rose dose-dependently, and 24-hour cortisol was unchanged apart from a shift in the timing of its nadir and morning rise.
The same group's 1997 sleep study gave young adults 5 and 25mg and older adults 2 and 25mg at bedtime. In the young, 25mg increased stage IV sleep by about 50 percent and REM by more than 20 percent; in adults aged 65 to 71, REM rose nearly 50 percent and REM latency fell.
1998 to 1999: catabolism, obesity and bone
Murphy and colleagues (1998) restricted eight healthy volunteers to 18 kilocalories per kilogram per day for two 14-day periods, adding 25mg of MK-677 or placebo for the last seven days of each. Nitrogen balance in the second week was positive on MK-677, 0.31 grams per day, against a loss of 1.48 grams per day on placebo.
Svensson and colleagues (1998) treated 24 obese men with 25mg daily or placebo for eight weeks. IGF-1 rose about 40 percent, fat-free mass rose, total and visceral fat did not change, basal metabolic rate rose at two weeks but not at eight, and an oral glucose tolerance test was impaired at both time points while fasting glucose and insulin were unchanged. Companion papers from the same cohort reported increased markers of bone formation and resorption, altered lipoproteins with no change in lipoprotein(a), and a transient rise in leptin.
Murphy and colleagues (1999) pooled 187 elderly adults across three placebo-controlled studies of two to nine weeks. Doses of 10 and 25mg raised the bone resorption marker NTx by 10 and 17 percent at two weeks; nine weeks of treatment in functionally impaired subjects raised osteocalcin by 29 percent and bone-specific alkaline phosphatase by 10 percent, with IGF-1 up 55 to 94 percent. A later 12-month study in postmenopausal osteoporotic women examined MK-677 alone and combined with alendronate (Murphy et al., 2001).
2001: children
Codner and colleagues (2001) gave 18 prepubertal children with growth hormone deficiency 0.2 or 0.8mg per kilogram per day for seven to eight days. The higher amount raised peak growth hormone, IGF-1 and IGFBP-3, with no change in prolactin, glucose, thyroid hormones, cortisol or insulin.
2004 and 2010: hip fracture
Bach and colleagues (2004) randomised 161 patients aged 65 and over, ambulatory before their fracture, to six months of daily MK-677 or placebo across 13 centres in seven countries. IGF-1 rose 84 percent against 17 percent on placebo. Functional performance measures and the Sickness Impact Profile did not differ significantly between groups.
Adunsky and colleagues (2010) ran a phase IIb study of 123 hip-fracture patients at 25mg a day for 24 weeks. IGF-1 rose 51.4 nanograms per mL against placebo. Gait speed improved; stair-climbing power and most other functional measures did not. The trial was stopped early over a congestive heart failure signal in a small number of patients, and the authors described the safety profile as unfavourable in that population.
2008: two years in healthy older adults
Nass and colleagues (2008) ran the longest MK-677 trial published: 65 healthy adults aged 60 to 81, 25mg once daily or placebo, in a two-year modified-crossover design with endpoints every six months. Growth hormone and IGF-1 rose to young-adult levels. Fat-free mass rose 1.1kg against a 0.5kg decline on placebo, and body cell mass rose with it. Visceral fat did not change; limb fat rose more on MK-677. Body weight rose 2.7kg against 0.8kg. Fasting glucose rose 0.3 millimoles per litre and insulin sensitivity fell. Cortisol rose 47 nanomoles per litre. LDL cholesterol fell. Bone density changed in a pattern consistent with increased remodelling. The most frequent side effects were an appetite increase that subsided over a few months and transient mild lower-limb oedema and muscle pain. Strength and function did not change, and the authors noted the study was underpowered for functional endpoints.
2008: Alzheimer's disease
Sevigny and colleagues (2008) randomised 563 patients with mild to moderate Alzheimer's disease to 25mg daily or placebo for 12 months, on the hypothesis that IGF-1 increases amyloid clearance. IGF-1 rose 60 percent at six weeks and 73 percent at 12 months. None of the four clinical measures differed between groups. The authors' conclusion was direct: target engagement, no effect on progression.
2018: haemodialysis
Campbell and colleagues (2018) ran a three-month randomised crossover in 26 haemodialysis patients with protein-energy wasting. IGF-1 was 1.76-fold higher after MK-677, a 65 percent greater increase than placebo, with no serious adverse effects attributed to the drug. The authors called for longer studies of lean mass and function.
2021 to 2022: paediatric growth hormone deficiency as LUM-201
Lumos Pharma revived the molecule as LUM-201 for children with growth hormone deficiency. Bright and colleagues (2021) analysed a completed randomised, placebo-controlled trial of 68 treatment-naive prepubertal children and identified two markers, baseline IGF-1 above 30 nanograms per mL and a peak growth hormone response of at least 5 nanograms per mL to a single LUM-201 dose, that predicted six-month growth response. A 2022 paper reported that a single dose of LUM-201 produced a median peak growth hormone of 15.0 nanograms per mL against 5.5 for standard diagnostic stimuli. The programme is ongoing and is the only current clinical development of the compound.
What the record shows
Read together, the trials agree on the pharmacology and disagree on the outcome. Twenty-five milligrams once daily raised growth hormone and IGF-1 in every population studied, from healthy young men to dialysis patients, and did so by lifting the existing pulsatile rhythm rather than replacing it. Where body composition was measured, fat-free mass rose. Where clinical function or cognition was measured, it generally did not move, and the metabolic costs, higher fasting glucose, impaired glucose tolerance, reduced insulin sensitivity and one cardiac safety signal, appeared repeatedly. Our MK-677 dosage research article covers the dosing side of the same record, and MK-677 side effects: what the trials recorded the adverse findings.
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References
1. Chapman, I. M., Bach, M. A., Van Cauter, E., et al. (1996). Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. Journal of Clinical Endocrinology and Metabolism, 81(12), 4249-4257.
2. Copinschi, G., Van Onderbergen, A., L'Hermite-Balériaux, M., et al. (1996). Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men. Journal of Clinical Endocrinology and Metabolism, 81(8), 2776-2782.
3. Copinschi, G., Leproult, R., Van Onderbergen, A., et al. (1997). Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology, 66(4), 278-286.
4. Ghigo, E., Arvat, E., & Camanni, F. (1998). Orally active growth hormone secretagogues: state of the art and clinical perspectives. Annals of Medicine, 30(2), 159-168.
5. Murphy, M. G., Plunkett, L. M., Gertz, B. J., et al. (1998). MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. Journal of Clinical Endocrinology and Metabolism, 83(2), 320-325.
6. Svensson, J., Lönn, L., Jansson, J. O., et al. (1998). Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. Journal of Clinical Endocrinology and Metabolism, 83(2), 362-369.
7. Murphy, M. G., Bach, M. A., Plotkin, D., et al. (1999). Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. Journal of Bone and Mineral Research, 14(7), 1182-1188.
8. Murphy, M. G., Weiss, S., McClung, M., et al. (2001). Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. Journal of Clinical Endocrinology and Metabolism, 86(3), 1116-1125.
9. Codner, E., Cassorla, F., Tiulpakov, A. N., et al. (2001). Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children. Clinical Pharmacology and Therapeutics, 70(1), 91-98.
10. Bach, M. A., Rockwood, K., Zetterberg, C., et al. (2004). The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. Journal of the American Geriatrics Society, 52(4), 516-523.
11. Nass, R., Pezzoli, S. S., Oliveri, M. C., et al. (2008). Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Annals of Internal Medicine, 149(9), 601-611.
12. Sevigny, J. J., Ryan, J. M., van Dyck, C. H., et al. (2008). Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology, 71(21), 1702-1708.
13. Adunsky, A., Chandler, J., Heyden, N., et al. (2011). MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Archives of Gerontology and Geriatrics, 53(2), 183-189.
14. Campbell, G. A., Patrie, J. T., Gaylinn, B. D., Thorner, M. O., & Bolton, W. K. (2018). Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study. Nephrology Dialysis Transplantation, 33(3), 523-530.
15. Bright, G. M., Do, M. T., McKew, J. C., Blum, W. F., & Thorner, M. O. (2021). Development of a predictive enrichment marker for the oral GH secretagogue LUM-201 in pediatric growth hormone deficiency. Journal of the Endocrine Society, 5(6), bvab030.
16. Bright, G. M., & Thorner, M. O. (2022). A GH secretagogue receptor agonist (LUM-201) elicits greater GH responses than standard GH secretagogues in subjects of a pediatric GH deficiency trial. Hormone Research in Paediatrics, 95(1), 76-81.
