MK-677 (Ibutamoren Mesylate /
L-163,191)

The Discovery

The Needle Problem

Why peptides couldn't become pills

In the 1970s and 1980s, scientists discovered something amazing: small peptides could trick your pituitary gland into releasing growth hormone. GHRP-6 and other growth hormone releasing peptides worked brilliantly as injections. But there was a huge problem. These peptides had a half-life of about 20 minutes. Your stomach acid destroyed them. Your intestines couldn't absorb them. Patients hated needles. Every pharmaceutical company wanted the same thing: turn these amazing peptides into a pill. If you could do that, you could sell it to millions of people instead of just cancer patients and people with severe hormone deficiencies.

Cyril Bowers at Tulane University had proven the concept worked. His GHRP-6 peptide showed that activating a specific sensor in your brain could turn on the growth hormone pump. The sensor was called GHS-R, the ghrelin sensor. It sat on cells in your pituitary gland. When activated, it released growth hormone in natural pulses, just like your body does when you sleep or exercise hard. Peptides activated this sensor brilliantly. But pills made from peptides just didn't work. They fell apart in your stomach like paper in water.

Merck Research Laboratories in Rahway, New Jersey saw the opportunity. If they could build a non-peptide molecule that did the same job, they could sell it worldwide as an easy-to-take pill. They could revolutionize growth hormone treatment. No more needles. No more injections every six hours. Just one pill a day. In the mid-1990s, Merck's medicinal chemistry team set out to solve this problem. They knew peptides worked, but they needed something else. Something completely different. Something that could survive your stomach and reach your bloodstream intact.

The challenge was enormous. How do you copy what a peptide does without using a peptide? Peptides are chains of amino acids. They fit into the GHS-R sensor like a key in a lock. You can't just shrink down a peptide and make it smaller. It would stop working. You need to build something completely new that fits into the same lock, but in a different way. You need a 'privileged structure.' This was the breakthrough concept that would change everything.

The Breakthrough

The Spiroindoline Solution

How Merck's chemists built a fake peptide

Roy Smith and his team at Merck started by studying GHRP-6 and other peptides under microscopes. They wanted to understand exactly what shape and electrical charge made these molecules stick to the GHS-R sensor. This is called reverse pharmacology. You start with something that works, take it apart mentally, and figure out which features matter.

They discovered that GHRP-6 had a specific three-dimensional shape that fit into GHS-R like a key. But peptides are long chains. Smith's insight was radical: what if you could build just the important part of that shape, the part that actually touches the sensor, using a totally different arrangement of atoms? You wouldn't need amino acids at all. You could use carbon chains, rings, and sulfur atoms arranged in a novel pattern. This novel pattern was called a 'privileged structure' because it was privileged — it had been shaped by nature or evolved chemistry to hit certain biological targets really well.

Smith's team started with a lead compound called benzolactam L-163,429. It was active but not good enough for a pill. It had poor absorption. Then they designed the spiroindoline sulfonamide scaffold. This was a fancy way of saying they created a three-ringed structure that included sulfur and nitrogen atoms. The spiral of atoms in the middle (the 'spiro') part created exactly the right shape to fit into GHS-R.

MK-677 was born from this design. It wasn't a peptide. It was a small organic molecule with the molecular formula C27H36N4O5S. It weighed 528.7 Daltons, about the size of a small sugar molecule. When tested in laboratory cells, MK-677 activated GHS-R just as well as GHRP-6. But it had advantages that would change medicine: it survived stomach acid. Your intestines could absorb it. It lasted five hours in your body instead of 20 minutes. You could take it once a day as a pill.

The real shock came in animal studies. When researchers gave MK-677 to rats and mice, their growth hormone levels shot up for hours. When they gave it to healthy volunteers, their growth hormone levels climbed to the same heights as young athletes. The dream had come true. A pill that worked like an injectable peptide.

The Trials

The Promise Years

When MK-677 seemed to solve everything

By 1997, Merck was ready to test MK-677 in humans. The early results were stunning. Michael Thorner and his team at the University of Virginia ran studies showing that MK-677 increased growth hormone secretion in both normal adults and in people with growth hormone deficiencies. The hormone levels climbed to match healthy young people. Even more exciting, MK-677 also increased IGF-1, the insulin-like growth factor that carries the growth hormone signal throughout your body.

In 1997, Copinschi and colleagues published results showing something unexpected: MK-677 improved sleep quality. People taking MK-677 spent more time in deep sleep and REM sleep, the stages where your body repairs itself. This made sense because growth hormone naturally increases during sleep. MK-677 was enhancing your natural sleep-GH connection.

The next year brought more good news. Murphy and colleagues at Merck tested MK-677 in obese young males. The compound increased bone turnover markers. Your bones are constantly breaking down and rebuilding themselves. These markers measure how fast that happens. Higher turnover suggested MK-677 might help build stronger bones. This opened the door to treating osteoporosis, a disease where bones become brittle.

Even more impressive was a 1998 study showing that MK-677 reversed diet-induced muscle wasting. When people eat too few calories, their bodies burn muscle for energy. This is called catabolism. MK-677 preserved muscle even during calorie restriction. People taking it kept more lean muscle mass than those on placebo. Growth hormone was doing exactly what it should do — preserve and build muscle.

By 1999, Murphy's team had tested MK-677 in elderly adults and found it increased bone formation markers. The elderly population was perfect for MK-677. As people age, they lose bone mass and muscle mass. They lose growth hormone naturally. MK-677 seemed to reverse the clock. Researchers were convinced they had found something revolutionary. A pill that would help the elderly stay strong, improve their bone health, enhance their sleep, and even boost their metabolism.

Then came the landmark 2008 study that would define MK-677's true promise and limitations. Nass and colleagues published results from a two-year trial in 65 healthy older adults aged 60 to 81 taking 25 mg daily. MK-677 increased growth hormone and IGF-1 to levels seen in healthy young adults. Fat-free mass increased by 1.1 kilograms versus a loss of 0.5 kilograms in the placebo group. It worked. The numbers were real. But something was missing.

The Crisis

The Betrayal of Numbers

Why raising hormones doesn't save lives

The 2008 Nass trial had a secret hidden in its footnotes. Yes, MK-677 increased lean muscle mass by 1.1 kilograms compared to placebo. That sounds good. But the elderly people taking MK-677 didn't get any stronger. They couldn't walk further. They didn't feel better. Their quality of life didn't improve. Their muscle strength didn't increase. This was the dark truth: you can raise growth hormone to youthful levels and still not improve what matters — what people can actually do.

There was something else in those trial results that alarmed doctors. Fasting blood glucose increased by about 5 mg/dL in the MK-677 group. Insulin sensitivity declined. This meant your cells weren't responding to insulin as well. These are early warning signs of diabetes. For elderly patients already at risk for type 2 diabetes, this was concerning. A pill that helped your bones but increased your diabetes risk wasn't a fair trade.

MK-677 also increased appetite. This made sense — it was hitting the ghrelin sensor, which controls hunger. For young people trying to gain muscle, more appetite was useful. But for elderly people trying to maintain their weight, increased hunger could lead to overeating and weight gain. Other side effects included water retention and edema (swelling in the feet and legs). Patients complained of muscle pain and joint discomfort.

In 2008, another major trial brought crushing disappointment. Sevigny and colleagues tested MK-677 in patients with Alzheimer's disease. If raising growth hormone could improve brain function and muscle mass, why not test it in patients losing both due to dementia? The trial failed completely. MK-677 did not slow the progression of Alzheimer's disease. It did not improve cognitive function. It did not help patients maintain brain health. The hormone boost simply didn't translate to the brain improvements that researchers had hoped for.

Merck had already walked away from MK-677 in 1999. The company had decided the benefits didn't justify the risks and side effects. But the compound didn't disappear. It escaped into a different world. Bodybuilders discovered MK-677. Biohackers read the trial data. The underground market exploded. Online forums discussed dosing protocols. People ordered MK-677 from overseas suppliers in unlabeled vials. WADA, the World Anti-Doping Agency, banned MK-677 in competitive sports — both during competitions and outside competitions. The FDA started warning about adulterated dietary supplements containing hidden ibutamoren. Counterfeit products flooded the market.

A compound designed in Merck's pristine laboratories, tested with scientific rigor, was now being sold in unlabeled bottles on the internet. Nobody knew the purity. Nobody knew the dosage. The long-term consequences were unknown. Cancer risk was a concern — elevated IGF-1 can promote tumor growth in some people. Merck's failed dream had become a biohacking experiment with unknown endpoints.

The Legacy

Second Act in Children's Medicine

When the right drug meets the right patients

The story of MK-677 should have ended in 1999 when Merck abandoned it. But Michael Thorner, the endocrinologist who had led clinical development at Merck, saw something others missed. Merck had been testing MK-677 in the wrong patients. They tested it in elderly adults, trying to reverse aging. They tested it in obese young men, trying to improve body composition. But they never found the population where MK-677's benefits were truly transformative.

Thorner acquired the rights to MK-677 from Merck and formed Ammonett Pharma (later renamed Lumos Pharma). His insight was elegant: if you want to help someone grow, don't test a growth hormone releaser in adults. Test it in children who actually need to grow. Children with growth hormone deficiency can't grow normally. Their bones are short. Their future is limited. They need injections of synthetic growth hormone, shots several times per week for years and years.

But what if you could use MK-677 instead? A pill. Once daily. Activating their natural pituitary gland to release their own growth hormone. This was fundamentally different from the elderly trials. A child who gains 1.1 kilograms of lean mass has actually grown. A child who is slightly hungrier has room to eat more and gain the calories needed for growth. A small increase in blood glucose is far less concerning in a child on short-term treatment than in an elderly diabetic patient.

Lumos Pharma developed a 'Predictive Enrichment Marker' (PEM). This was a test that identified which children would respond best to MK-677 before they entered the trial. This enriched the study population with responders, increasing the chances of seeing real benefit. The company rebranded MK-677 as LUM-201 and launched Phase 2 trials called OraGrowtH210 and OraGrowtH212.

The results vindicated Thorner's insight. MK-677 increased growth in children with growth hormone deficiency. The children grew taller. Their growth velocity improved. Both Phase 2 trials met all primary and secondary endpoints. The FDA granted Orphan Drug Designation — a special status for drugs treating rare diseases. This meant faster approval pathways and extended market exclusivity if the drug succeeded.

MK-677 had finally found its purpose. Not as an anti-aging tool. Not as a bodybuilding supplement. But as a once-daily pill for children who couldn't grow on their own. Over 1,300 patients have been studied across adult and pediatric trials. The compound that Merck abandoned in 1999 was being reborn in 2020s for a new generation of patients. A 25-year journey from Rahway, New Jersey to a children's hospital where it might finally change lives. The drug was the same. The disease was different. And that made all the difference.