Tabimorelin
(NN703)

Act I: The Peptide Problem

When Pills Seemed Impossible

Why scientists wanted a pill version of peptide drugs

In the 1990s, peptide drugs were revolution changing medicine. Growth hormone-releasing peptides (called GRPs) could tell the body to make more growth hormone. They worked great in the lab. But peptides had a huge problem: they were fragile proteins that your stomach acid destroyed instantly.

Patients with growth hormone deficiency needed injections multiple times per week. Injections are painful, inconvenient, and many people hate needles. Scientists dreamed of a pill that worked like a peptide but survived the journey through your stomach.

Novo Nordisk, a major Danish pharmaceutical company, saw this opportunity. Their scientists realized something brilliant: they didn't need to use a real peptide if they could design a small-molecule chemical that acted exactly like one. The chemical would be tough enough to survive stomach acid, but clever enough to activate the same growth hormone sensors.

This idea would drive a decade of creative chemistry. The goal was simple: take what works in a peptide, strip away everything unnecessary, and rebuild it as a pill. It sounded ambitious, maybe even impossible.

But Novo Nordisk's chemistry team had a secret weapon: a systematic approach. They already made peptide drugs, which meant they understood the blueprint. Now they just needed to translate that blueprint into a new language: small-molecule chemistry.

Act II: Building from GHRP-1

Stripping Away the Extras

From peptide blueprint to chemical redesign

Novo Nordisk's team started with GHRP-1, an early growth hormone-releasing peptide. GHRP-1 worked, but it was complicated—made of six amino acids strung together like beads on a string. The scientists asked: what if we removed the beads we don't need?

Michael Ankersen led the chemistry effort. His team methodically tested which parts of GHRP-1 actually mattered. Each amino acid they removed taught them something. Some parts of the peptide were essential. Other parts were just passengers. They kept the essential parts and threw away the rest.

Next came a brilliant step: they replaced the remaining amino acids with simpler chemical groups. Think of it like simplifying a complex machine by replacing fancy gears with plain blocks, as long as the machine still works. This is the art of medicinal chemistry: keep the function, simplify the structure.

By 1998, the team had created a new compound: tabimorelin, also called NN703. It was a small, simple chemical that looked nothing like the original peptide. Yet it activated the same growth hormone sensor (the ghrelin receptor) and triggered the same response in the body.

Kirsten Raun and B.S. Hansen tested tabimorelin in laboratory experiments. The compound worked. It told pituitary glands to release growth hormone, just like GHRP-1 did. But tabimorelin could be made as a pill, taken by mouth, and survive digestion.

The team had done it. They had successfully translated a peptide into a peptidomimetic. The chemistry was elegant and successful. But success in the lab is only the first test.

Act III: The Human Test

From Lab to Living Bodies

The first clinical trials reveal promise and peril

In the year 2000, Novo Nordisk brought tabimorelin to human testing. M. Zdravkovic and his team ran the first Phase I trial with healthy men. This was the crucial moment: would the pill work in actual people, not just lab dishes?

The trial used escalating doses. Some volunteers got tiny amounts, others got larger doses. The scientists watched carefully for both the good effects and any danger signs. What they found was encouraging: at moderate doses, tabimorelin caused a dose-dependent increase in growth hormone. More drug meant more growth hormone, exactly as predicted.

Even better, tabimorelin avoided a problem that plagued other secretagogues. Some older growth hormone-releasing drugs increased cortisol (a stress hormone) or prolactin (a milk-making hormone) as unwanted side effects. These side effects caused health problems. Tabimorelin, by contrast, was selective—it turned on growth hormone release without activating these other unwanted pathways.

The pill was well-tolerated. Volunteers experienced mild side effects like increased appetite (which makes sense, since ghrelin increases hunger). No serious safety signals appeared. The pharmacokinetics looked good: the pill was absorbed reliably, entered the bloodstream, and produced predictable responses.

By 2001, Novo Nordisk had refined the formulation and run more studies. H. Agersø's team published data on the improved version. The evidence mounted: tabimorelin could work as an oral drug.

The Danish team had achieved something remarkable. They had built a peptidomimetic pill that survived digestion, entered the bloodstream, and caused the desired biological response in humans. The chemistry had translated into medicine.

Yet the excitement would be short-lived. The next test—in patients with actual growth hormone deficiency—would reveal a harsh truth that chemistry alone could not overcome.

Act IV: The Crushing Reality

When 11% Means Failure

Phase II trial reveals tabimorelin cannot help most patients

In 2003, Novo Nordisk ran a Phase II trial that would change everything. Jesper Svensson led a multicenter study with 97 adults who had growth hormone deficiency. These were real patients who suffered from the disease, not healthy volunteers. The trial was double-blind—neither doctors nor patients knew who got tabimorelin and who got placebo. This was the trial that mattered most.

The results were devastating. Success in clinical trials for growth hormone deficiency is usually defined as a peak growth hormone level of at least 5 micrograms per liter during a stimulation test. This threshold separates patients who respond from those who don't.

Out of 97 patients, only 11 responded with growth hormone levels at or above 5 micrograms per liter. That's an 11% response rate. To put it plainly: tabimorelin helped only 1 out of every 9 patients. For 8 out of 9 patients, the pill did nothing useful.

This was not just disappointing—it was a failure that could not be explained away by dosing or timing. The fundamental problem was biological, not chemical. Tabimorelin worked perfectly in healthy volunteers. But in patients whose pituitary glands were damaged or weakened, tabimorelin couldn't generate a strong enough response.

The implication was clear: even if you have perfect chemistry and the pill survives digestion and activates the right sensor, biology has the final say. A drug that only works for 1 in 9 patients cannot be approved for medical use. Doctors need treatments that help most patients, not just a rare few.

Svensson's paper was published under a title that said it all: "A GH secretagogue given as an oral tablet is not effective for the treatment of adult GH deficiency in hypopituitary patients." The conclusion was unambiguous: oral peptidomimetic pills might work in theory, but failed in practice for this disease.

For Novo Nordisk, the dream was crumbling. The chemistry had been brilliant. The pharmacology was sound. But the patient data made the decision inevitable.

Act V: The Second Fatal Flaw

When Chemistry Becomes Poison

Drug interaction problems doom the entire program

Just as the Phase II failure was being absorbed, another problem emerged that made the poor trial results seem almost trivial: tabimorelin was a powerful liver enzyme inhibitor. Specifically, it blocked CYP3A4, one of the most important drug-processing enzymes in the body.

The liver's job is to break down drugs so they don't accumulate to toxic levels. Various liver enzymes do this work. CYP3A4 is responsible for processing about 50% of all prescription drugs. When tabimorelin blocked CYP3A4, it prevented the liver from breaking down other medications.

Nova Nordisk tested tabimorelin with midazolam, a standard test drug for CYP3A4. The results were alarming: tabimorelin increased midazolam exposure by 93%. That means if a patient took tabimorelin plus midazolam, they would have nearly twice as much midazolam in their bloodstream as expected. Too much midazolam causes dangerous side effects.

But the real problem was broader. Tabimorelin didn't just interact with midazolam—it would interact with roughly half of all other medicines patients take. Heart medications, immunosuppressants, cholesterol drugs, cancer medications—all could be affected.

Imagine a patient on tabimorelin for growth hormone deficiency who also needs a heart medication. The tabimorelin blocks the liver from processing the heart drug, causing it to build up to dangerous levels. This wasn't a minor safety concern—it was a deal-breaker.

Pharmaceutical companies cannot approve drugs that dangerously interact with half of all other medications. It would cause more harm than benefit. The regulatory hurdle was insurmountable.

With a 11% efficacy rate and a serious drug-interaction problem, Novo Nordisk had no choice. The entire oral GHS program was discontinued. Tabimorelin would never reach patients. The company eventually explored a follow-up compound, NNC-26-1167, but that never entered clinical trials either.

The dream of a peptidomimetic growth hormone pill had ended. It was an expensive lesson in a hard truth: beautiful chemistry is not enough. Biology must work, and safety must be intact. Tabimorelin had neither.