MK-677 (Ibutamoren) in Human Clinical Trials: Populations, Endpoints and Findings

MK-677 has an unusually complete clinical record for a compound sold as a research chemical: multiple randomised trials, including two that enrolled hundreds of patients. This article sets out what each trial measured, what it found, and why the programme stopped.

By Published Updated

MK-677, also written MK-0677 and named ibutamoren mesylate, is unusual among the compounds in this library in two ways. It is not a peptide — it is an orally active small molecule designed to mimic the growth hormone-releasing peptides [1]. And it has a substantial, sponsor-run clinical record: four randomised controlled trials in this article alone, two of which enrolled more than 120 patients and one of which enrolled 563.

That record has a shape worth stating at the outset, because it is consistent across every trial and is rarely described. MK-677 reliably does what it was designed to do at the level of the hormone axis: it raises circulating growth hormone and insulin-like growth factor-1, substantially, in every population studied. What it did not do, in trial after trial, was change the clinical endpoints those trials were built to measure. One trial was stopped early for a safety signal.

This article sets out each trial: population, design, duration, primary endpoint, results as reported, adverse events, limitations. It describes published research and contains no guidance of any kind on handling any material.

What MK-677 is, and what it acts on

In vitro research

MK-677 was described in 1995 as L-163,191: a potent, orally active growth hormone secretagogue designed as a non-peptide mimetic of the growth hormone-releasing peptides [1]. The receptor it acts at — a receptor in pituitary and hypothalamus functioning in growth hormone release — was identified the following year [2]. Its endogenous ligand was not known at the time; ghrelin, an acylated peptide from stomach, was identified as that ligand in 1999 [4].

The order of those discoveries explains a durable confusion. MK-677 was designed as a mimetic of synthetic peptides, was later understood to act at the receptor for a gut hormone, and is now frequently described as a "ghrelin mimetic" — which is accurate about the receptor and misleading about the chemistry. It is a small molecule that happens to engage a peptide hormone's receptor.

Early human pharmacology

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Nine severely growth hormone-deficient men aged 17 to 34, previously treated with growth hormone in childhood, received once-daily oral MK-677 at 10 or 50 mg or placebo for four days across two periods separated by at least 28 days, in a double-blind rising-amount design. Blood was collected every 20 minutes for 24 hours before treatment and at the end of each period [3].

Serum insulin-like growth factor-1 and 24-hour mean growth hormone concentrations increased in all subjects at both amounts. At 10 mg, insulin-like growth factor-1 rose 52 ± 20% and 24-hour mean growth hormone 79 ± 19%; at 50 mg, insulin-like growth factor-1 rose 79 ± 9%. The compound was generally well tolerated with no significant changes in cortisol, prolactin or thyroid hormones [3].

Limitations. Nine men, four days of administration, a crossover and rising-amount design, and a pharmacodynamic endpoint. This establishes that the molecule engages its target when given orally to people. It establishes nothing else, and it was not intended to.

The two-year trial in healthy older adults

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design, duration. 65 healthy adults aged 60 to 81 — men, women receiving hormone replacement therapy, and women not receiving it — in a two-year, double-blind, randomised, placebo-controlled, modified-crossover trial at a university hospital clinical research centre. Administration was oral MK-677 25 mg or placebo once daily [6, 11].

Primary endpoints. Fat-free mass and abdominal visceral fat after one year of treatment. Other endpoints, assessed at baseline and every six months, included body weight, fat mass, insulin sensitivity, lipids, cortisol, bone mineral density, limb composition, isokinetic strength, function and quality of life.

Results as reported. Growth hormone and insulin-like growth factor-1 rose into the range of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group and increased in the MK-677 group — −0.5 kg (95% CI −1.1 to 0.2) against +1.1 kg (0.7 to 1.5), P<0.001 — as did body cell mass reflected by intracellular water (−1.0 kg against +0.8 kg; P=0.021). No significant differences were observed in abdominal visceral fat or total fat mass. The average increase in limb fat was greater on MK-677 (1.1 kg against 0.24 kg; P=0.001). Body weight increased 0.8 kg on placebo and 2.7 kg on MK-677 (P=0.003). Fasting blood glucose rose an average of 0.3 mmol/L (5 mg/dL) on MK-677 (P=0.015) and insulin sensitivity decreased. Low-density lipoprotein cholesterol decreased relative to baseline. The most frequent side effects were an increase in hunger that subsided within a few months, and transient mild lower-limb oedema and myalgia [6].

Limitations. 65 participants across three strata is small for the number of endpoints assessed. One primary endpoint was met and the other was not: fat-free mass changed, abdominal visceral fat did not. Body composition is a surrogate: the trial did not test whether a 1.1 kg change in fat-free mass corresponds to any functional or clinical difference, and the strength and function measures were secondary. The decrease in insulin sensitivity and the rise in fasting glucose are findings in a healthy population over two years and are part of the result, not a footnote to it.

The Alzheimer's disease trial

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Population, design, duration. 563 patients with mild to moderate Alzheimer's disease randomised in a double-blind multicentre trial to MK-677 25 mg or placebo daily for 12 months. 416 completed treatment and assessments at 12 months. The rationale was mechanistic: insulin-like growth factor-1 increases clearance of beta-amyloid from the central nervous system in animals, serum levels of that factor decrease with age and decrease further in Alzheimer's disease, and MK-677 is a potent inducer of its secretion [7, 9].

Efficacy measures. Mean change from baseline at month 12 on four instruments: the Clinician's Interview Based Impression of Change with caregiver input, the cognitive subscale of the Alzheimer's Disease Assessment Scale, the Alzheimer's Disease Cooperative Study Activities of Daily Living scale, and the Clinical Dementia Rating sum of boxes.

Results as reported. Serum insulin-like growth factor-1 increased 60.1% at six weeks and 72.9% at 12 months. In mixed-effects models including treatment, time, randomisation stratum and the treatment-by-time interaction, there were no significant differences between groups on any of the four measures over 12 months [7].

What this trial demonstrates. It is the cleanest illustration in this literature of the difference between target engagement and clinical effect. The mechanism was engaged — measurably, substantially, for a year, in 563 patients — and nothing downstream moved. A mechanistic rationale, an animal model and a confirmed biomarker response were all present, and the trial was still negative.

The hip-fracture trials

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The first trial. 161 hip-fracture patients aged 65 and older, ambulatory before fracture, medically stable after surgery and mentally competent, recruited at 13 medical centres in England, Sweden, Denmark, Belgium, Switzerland, Canada and the United States between 3 and 14 days after surgery. Patients with multiple fractures, severe trauma, diabetes, cancer, uncontrolled hypertension, congestive heart failure or total hip replacement in the involved limb were excluded. Assignment was to six months of daily MK-677 or placebo, with a further six months of follow-up. The measure was change from week 6 to week 26 in a panel of functional performance measures, with the Sickness Impact Profile for Nursing Homes, ability to live independently, and insulin-like growth factor-1 as additional outcomes [5].

Serum insulin-like growth factor-1 increased 84% (95% CI 63 to 107) against 17% (8 to 28) on placebo. There were no significant differences between groups in improvement in functional performance measures or in the overall disability score [5].

The second trial. 123 elderly hip-fracture patients randomised double-blind to MK-0677 25 mg daily (n=62) or placebo (n=61). Primary outcomes were a rank analysis of change in objective functional performance measurements and in blood insulin-like growth factor-1 [8, 10].

At 24 weeks, mean stair-climbing power increased by 12.5 W against placebo (95% CI −10.95 to 35.88; p=0.292 — not significant). Gait speed showed a 0.7-score difference in means (95% CI 0.17 to 1.28; p=0.011). There was no improvement on several other functional performance measures. Fewer falls occurred in the MK-0677 group, and fewer patients had any fall, at p=0.096. Insulin-like growth factor-1 increased by 51.4 ng/mL against placebo (p<0.001). The trial was terminated early because of a safety signal of congestive heart failure in a limited number of patients. The authors' conclusion is explicit: the increase in plasma insulin-like growth factor-1 was not paralleled by improvement in most functional performance measures, and the compound has an unfavourable safety profile in this patient population [8].

Limitations and what they mean. Two randomised trials in the same indication, six years apart, both found target engagement without functional benefit; the second stopped early for a cardiac safety signal. That signal was observed in a frail elderly population after hip fracture and should not be transposed unmodified onto any other group — but neither should it be omitted, and it is routinely omitted.

What the evidence base does not establish

Clinical benefit in any indication. Four randomised controlled trials in three populations produced no significant benefit on the primary clinical endpoints of the Alzheimer's disease trial [7] or the first hip-fracture trial [5], one significant gait measure among several that were not in the second hip-fracture trial [8], and one of two primary endpoints in the healthy-older-adult trial [6].

That body-composition change translates into function. The two-year trial measured a 1.1 kg change in fat-free mass against placebo [6]. The two hip-fracture trials measured function directly, in populations where function was the point, and found little [5, 8].

Metabolic safety over time. Fasting glucose rose and insulin sensitivity decreased over two years in healthy older adults [6]. No trial has followed that further.

Cardiac safety. A trial was terminated early for congestive heart failure in a limited number of patients, and no subsequent trial has been run to characterise that signal [8].

Anything in young or athletic populations. Every trial above enrolled growth hormone-deficient men [3], healthy adults aged 60 to 81 [6], patients with Alzheimer's disease [7], or elderly patients after hip fracture [5, 8]. There is no trial in the population that most discussion of this compound concerns.

Current development. The sponsor-run programme ended with these trials. A 12-participant phase 2 trial in non-alcoholic fatty liver disease is registered as completed [12]. MK-677 is approved nowhere.

All of the research described in this article is research into a pharmaceutical product candidate, conducted under registered protocols, using investigational material manufactured to a regulatory standard and administered under clinical supervision in defined populations. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

Has MK-677 been tested in randomised controlled trials?
Yes, several. A 2-year randomised placebo-controlled trial in 65 healthy older adults [6], a 12-month double-blind trial in 563 patients with mild to moderate Alzheimer's disease [7], a 6-month placebo-controlled trial in 161 patients after hip fracture [5], and a 24-week double-blind trial in 123 patients after hip fracture [8].
Does MK-677 raise insulin-like growth factor-1 in humans?
Consistently, in every trial that measured it. Serum insulin-like growth factor-1 rose 60.1% at six weeks and 72.9% at 12 months in the Alzheimer's disease trial [7], 84% against 17% on placebo in the first hip-fracture trial [5], and by 51.4 ng/mL against placebo in the second [8]. Target engagement is the best-established finding in this literature.
Did MK-677 improve clinical outcomes in those trials?
Largely not. The Alzheimer's disease trial found no significant differences from placebo on any of its four efficacy measures over 12 months [7]. The first hip-fracture trial found no significant differences in functional performance or in its overall disability score [5]. The second found a difference in one gait measure (p=0.011) and no improvement in most other functional measures [8].
What adverse effects were reported in MK-677 trials?
In the 2-year trial in healthy older adults, fasting blood glucose rose by an average of 0.3 mmol/L (P=0.015) and insulin sensitivity decreased; the most frequent side effects were an increase in hunger that subsided, and transient mild lower-limb oedema and myalgia [6]. The second hip-fracture trial was terminated early because of a safety signal of congestive heart failure in a limited number of patients, and its authors state that the compound has an unfavourable safety profile in that population [8].
Is MK-677 approved by the FDA?
No. MK-677 is not approved for any indication in the United States or elsewhere. It was developed through phase 2 and phase 3 trials by a pharmaceutical sponsor and was not carried to approval [7, 8].
Is MK-677 a peptide?
No. It is an orally active non-peptide small molecule designed as a mimetic of growth hormone-releasing peptides [1]. It acts at the growth hormone secretagogue receptor identified in pituitary and hypothalamus [2], the receptor for which ghrelin was later identified as the endogenous ligand [4].
What was the largest MK-677 trial?
The Alzheimer's disease trial, which randomised 563 patients to MK-677 25 mg or placebo daily for 12 months, with 416 completing treatment and assessments [7, 9]. It found no significant treatment differences despite clear evidence of target engagement.
Are MK-677 trials still being run?
Very few. A phase 2 trial of ibutamoren in non-alcoholic fatty liver disease is registered as completed with 12 participants [12]. The large sponsor-run programme ended with the trials described in this article.

References

  1. Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue Proceedings of the National Academy of Sciences of the United States of America; 1995. PMID 7624358 doi:10.1073/pnas.92.15.7001
  2. A receptor in pituitary and hypothalamus that functions in growth hormone release Science; 1996. PMID 8688086 doi:10.1126/science.273.5277.974
  3. Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults The Journal of Clinical Endocrinology and Metabolism; 1997. PMID 9329386 doi:10.1210/jcem.82.10.4297
  4. Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature; 1999. PMID 10604470 doi:10.1038/45230
  5. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture Journal of the American Geriatrics Society; 2004. PMID 15066065 doi:10.1111/j.1532-5415.2004.52156.x
  6. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial Annals of Internal Medicine; 2008. PMID 18981485 doi:10.7326/0003-4819-149-9-200811040-00003
  7. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial Neurology; 2008. PMID 19015485
  8. 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; 2011. PMID 21067829 doi:10.1016/j.archger.2010.10.004
  9. Study of MK0677 for the Treatment of Alzheimer's Disease (0677-030)(COMPLETED). NCT00074529
  10. Treatment of Sarcopenia in Post-Hip Fracture Patients (0677-032). NCT00128115
  11. Effects of an Oral GH Secretagogue (MK-677) on Body Composition and Functional Ability of Older Adults. NCT00474279
  12. The Impact of Ibutamoren on Nonalcoholic Fatty Liver Disease. NCT05364684

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.