The history of the discovery of Tesamorelin

Tesamorelin is one of the few analogs of the growth hormone-releasing hormone that managed to make the whole journey from the laboratory to a registered drug. Its history is connected not with sport and not with “anti-aging,” but with a specific medical problem of people living with HIV. Our editors tell how this molecule appeared and why it succeeded where other analogs stopped.

The scientific basis: the discovery of GHRH

The history of tesamorelin begins in 1982, when two groups of researchers — R. Guillemin and J. Rivier, W. Vale and M. Thorner — isolated from the pancreatic tumors of patients with acromegaly a peptide that stimulates the secretion of growth hormone (GH). Thus the structure of the growth hormone-releasing hormone (GHRH), or somatoliberin, was deciphered.

Human GHRH consists of 44 amino acids. It was soon found that the first 29 amino acids are sufficient for biological activity, and on the basis of this fragment sermorelin was created. But all the early analogs had a common problem — a very short duration of action due to rapid destruction by blood enzymes.

The main “enemy” of GHRH turned out to be the enzyme dipeptidyl peptidase-4, which cleaves off the first two amino acids from the N-terminus of the molecule. After this the peptide loses its ability to activate the receptor. So to obtain a more stable drug, it was necessary to protect precisely the beginning of the chain.

Different companies chose different strategies. Some replaced individual amino acids with more stable ones, others prolonged circulation through binding to plasma proteins, as in CJC-1295. The Canadian company Theratechnologies took a different path — it modified the full 44-amino-acid molecule.

The chemical idea of tesamorelin

Tesamorelin, which at the development stage had the code TH9507, is the full sequence of human GHRH(1-44), to whose N-terminal tyrosine a trans-3-hexenoic acid residue is attached. This small chemical “cap” protects the molecule from the action of dipeptidyl peptidase-4 without disrupting binding to the GHRH receptor in the pituitary.

Unlike CJC-1295 with DAC, tesamorelin does not bind to albumin and does not act for days. It is prescribed daily, and each injection causes a relatively short-term stimulation of GH secretion. This approach is closer to the physiological pulsatile rhythm and gives the doctor more control.

The choice of the full molecule instead of a fragment also had a practical rationale: the developers sought to preserve the natural interaction with the receptor as much as possible, changing only the vulnerable site. Early studies showed that tesamorelin raises GH and IGF-1, while regulation through somatostatin and feedback is preserved.

The last circumstance is important for safety: since tesamorelin acts through the pituitary, the body retains part of its own “safeguards” that limit excessive GH secretion. This distinguishes secretion stimulators from the direct administration of the recombinant hormone.

The medical problem: lipodystrophy in HIV

In the late 1990s, after the introduction of combination antiretroviral therapy, many people with HIV developed a peculiar redistribution of fat. Fat disappeared from the face and limbs but accumulated in the abdominal cavity — in the form of visceral fat around the internal organs.

Visceral obesity not only changes appearance and affects quality of life but is also associated with insulin resistance, dyslipidemia and increased cardiovascular risk. At the same time diet and physical exercise gave a limited effect precisely with respect to visceral fat in this group.

Doctors noticed that in patients with abdominal fat accumulation GH secretion is reduced. Recombinant GH reduced visceral fat but often caused side effects — fluid retention, joint pain, worsening of glucose tolerance. A logical idea was to stimulate one’s own GH secretion more gently, through GHRH.

It was precisely in this niche that other companies also tried to work, in particular ConjuChem with CJC-1295. But it was Theratechnologies that brought its program to completion.

Phase III studies and registration

In 2007 the results of the first large phase III study (Falutz and colleagues) were published in the New England Journal of Medicine. In a randomized double-blind trial, patients with HIV and excess abdominal fat received tesamorelin or placebo for 26 weeks. The area of visceral fat according to computed tomography in the tesamorelin group decreased by about 15%, whereas in the placebo group it grew somewhat.

An important detail was that subcutaneous fat did not change substantially — the effect was relatively selective for visceral fat. An improvement in some lipid measures was also observed. A second phase III study and a pooled analysis (Falutz and colleagues, JCEM, 2010) confirmed the results.

Data from the extension phase showed that after the drug was discontinued, visceral fat gradually returned to the baseline level. That is, tesamorelin works while it is taken and does not “cure” lipodystrophy forever.

In November 2010 the FDA approved tesamorelin under the trade name Egrifta for reducing excess abdominal fat in patients with HIV and lipodystrophy. The prescribing information contains an important caveat: the effect on cardiovascular outcomes has not been established, and the drug is not intended for weight loss. In the European Union tesamorelin did not obtain registration.

After approval: new forms and new questions

After registration the manufacturer worked on more convenient forms of the drug that require fewer manipulations with reconstitution. In parallel, researchers began to study tesamorelin beyond the initial indication.

• Fatty liver disease.Stanley and colleagues (JAMA, 2014) reported a reduction in liver fat content with tesamorelin in patients with HIV, and a subsequent randomized study (Lancet HIV, 2019) evaluated the effect on non-alcoholic fatty liver disease.
• Cognitive functions.Baker and colleagues (Archives of Neurology, 2012) studied tesamorelin in elderly people with and without mild cognitive impairment and reported certain positive changes in tests.
• Muscle tissue.Individual works analyzed the effect on fatty infiltration of muscles in patients with HIV.

These directions remain investigational: they are not registered indications, and the results require confirmation in larger trials.

As information about the drug spread, tesamorelin also attracted the attention of the sports community. WADA directly prohibits it in class S2 as an analog of GHRH, and use outside the indications without medical supervision carries the risks described in the prescribing information.

Editorial conclusions

Tesamorelin is the result of the consistent development of the GHRH idea: from the discovery of the hormone in 1982 to the chemical protection of the full molecule from enzymatic destruction.

Its success is explained by a clear clinical goal: the drug was developed for a specific problem — visceral obesity in HIV lipodystrophy — and the effect was proven in large randomized studies.

At the same time the history of tesamorelin also shows the limitations: the effect disappears after discontinuation, the indication is narrow, and the drug did not obtain European registration.

We also recommend reading “The history of the discovery of CJC-1295,” “Tesamorelin and carbohydrate metabolism” and “Myths about Tesamorelin.”

References

1. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5889):276–278.
2. Guillemin R, Brazeau P, Böhlen P, et al. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585–587.
3. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357(23):2359–2370.
4. Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. J Clin Endocrinol Metab. 2010;95(9):4291–4304.
5. Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014;312(4):380–389.
6. Baker LD, Barsness SM, Borson S, et al. Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol. 2012;69(11):1420–1429.
7. EGRIFTA (tesamorelin for injection). Prescribing information. Theratechnologies Inc.; U.S. Food and Drug Administration.