Tesamorelin in Human Clinical Trials: Populations, Endpoints and Findings

A trial-by-trial account of the published clinical literature on tesamorelin: the phase 2 and phase 3 trials in people with HIV and abdominal fat accumulation, the hepatic-fat trials, the endpoints each used, what was reported, and what remains unstudied.

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Tesamorelin occupies an unusual position in this field. Most compounds discussed alongside it have no completed phase 3 programme and no approval anywhere. Tesamorelin has both — an approval in the United States for the reduction of excess abdominal adipose tissue in people with HIV and lipodystrophy, granted on the strength of two phase 3 trials that enrolled more than 800 people between them.

That approval is also narrow in a way that is easy to lose. It attaches to one population, one indication and one endpoint. Every trial described below enrolled people with HIV. Every primary endpoint was an imaging measure of adipose tissue or hepatic fat. No trial in this record enrolled a population without HIV, and no trial measured a clinical outcome.

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

The molecule and its target

In vitro research

Tesamorelin is an analogue of growth hormone-releasing hormone — specifically of the 1-44 form — modified to resist the enzymatic degradation that limits the native peptide. Native growth hormone-releasing hormone is cleaved rapidly in human plasma by dipeptidylpeptidase IV and by trypsin-like activity, which was characterised in 1989 [1]. The receptor it acts on, the anterior pituitary growth hormone-releasing hormone receptor, was cloned and expressed in 1993 [2].

The mechanistic position this creates matters for reading the trials. Tesamorelin does not supply growth hormone; it acts upstream, on the pituitary, and the pituitary's own regulatory feedback remains in place. That is the stated pharmacological distinction between a releasing-hormone analogue and exogenous growth hormone, and it is the reason the trials below report insulin-like growth factor-1 as a pharmacodynamic marker rather than as an endpoint in itself.

Analytical methods for detecting synthetic growth hormone-releasing hormone analogues, tesamorelin among them, have been developed and reviewed in the anti-doping literature [9].

The phase 2 amount-ranging 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. 61 people with HIV, increased waist circumference and an increased waist-to-hip ratio, randomised in a double-blind, placebo-controlled trial to placebo or 1 mg or 2 mg of the compound then designated TH9507, administered subcutaneously once daily for 12 weeks [3].

Primary endpoint. Change in abdominal fat, assessed by X-ray densitometry and by cross-sectional computed tomography. Secondary endpoints included insulin-like growth factor-1, metabolic measures, quality of life and safety.

Results as reported. Insulin-like growth factor-1 rose in proportion to the amount administered — 48% at 1 mg and 65% at 2 mg, both P<0.01 against placebo. Trunk fat changed by +0.8%, −4.6% and −9.2% in the placebo, 1 mg and 2 mg groups respectively, with the 2 mg comparison significant at P=0.014. Visceral adipose tissue changed by −5.4%, −3.6% and −15.7%, and this change was not significant against placebo. Subcutaneous fat was preserved and did not change within or between groups. Lean body mass and the ratio of visceral to subcutaneous fat improved significantly in both active groups. Triglycerides and the cholesterol-to-HDL ratio decreased significantly in the 2 mg group. Treatment was generally well tolerated without changes in glucose [3].

Limitations. The measure that became the phase 3 primary endpoint — visceral adipose tissue — did not reach significance in this trial, in 61 participants over 12 weeks. The authors stated the position plainly: longer trials with more participants were needed to determine effects on visceral fat, durability and safety. That is what the phase 3 programme was designed to do.

The phase 3 programme

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 26-week trial. 412 people with HIV — 86% of them men — with abdominal fat accumulation, randomly assigned to a daily subcutaneous injection of 2 mg tesamorelin or placebo for 26 weeks. The primary endpoint was percentage change from baseline in visceral adipose tissue by computed tomography [4, 11].

Visceral adipose tissue decreased by 15.2% on tesamorelin and increased by 5.0% on placebo. Triglycerides decreased by 50 mg/dL and increased by 9 mg/dL respectively; the total-cholesterol-to-HDL ratio decreased by 0.31 and increased by 0.21 (P<0.001 for all three). Insulin-like growth factor-1 increased by 81.0% against a 5.0% decrease on placebo (P<0.001). Adverse events did not differ significantly between groups, though more participants on tesamorelin withdrew because of an adverse event. No significant differences were observed in glycaemic measures [4].

The 12-month trial. 404 people with HIV and excess abdominal fat on antiretroviral therapy, enrolled between January 2007 and October 2008, in a two-phase design. Months 0 to 6 were the primary efficacy phase, randomised 2:1 to tesamorelin 2 mg daily or placebo. At month 6, participants on tesamorelin were re-randomised either to continue or to switch to placebo, while those initially on placebo switched to tesamorelin. Blinding was maintained throughout. The primary endpoint was visceral adipose tissue [5].

Over the six-month efficacy phase, visceral adipose tissue decreased by 10.9% (−21 cm²) on tesamorelin against 0.6% (−1 cm²) on placebo, P<0.0001. Trunk fat (P<0.001), waist circumference (P=0.02) and waist-to-hip ratio (P=0.001) also changed, with no change in limb or abdominal subcutaneous fat. Insulin-like growth factor-1 increased (P<0.001) with no change in glucose parameters. Participant-rated and physician-rated body-image measures improved significantly (both P=0.02). In participants continuing for 12 months, visceral adipose tissue was reduced by approximately 18% (P<0.001). In participants switched from tesamorelin to placebo at month 6, the improvement observed over the first six months was rapidly lost [5].

What the re-randomisation established. Very few trials in this field build a withdrawal phase into the design, and this one did. The finding — that the effect reverses quickly on discontinuation — is a statement about the pharmacology, and it is one of the most useful pieces of information in the entire record. A review of the compound's use in HIV-associated lipodystrophy summarises the programme as a whole [6].

Limitations. Both trials were 26 weeks and 12 months in a single population, with an imaging primary endpoint. Neither counted a cardiovascular event, a hospitalisation or a death, so the clinical significance of the visceral adipose change is inferred rather than measured. The 86% male composition of the first trial limits what it says about women. And the substantial rise in insulin-like growth factor-1 is a pharmacodynamic finding whose long-term implications these trials were not designed or sized to address.

The hepatic-fat 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 6-month trial. 50 antiretroviral-treated men and women with HIV and abdominal fat accumulation, enrolled at a single hospital between January 2011 and September 2013 and randomised to tesamorelin 2 mg (n=28) or placebo (n=22) subcutaneously daily for six months. Coprimary endpoints were changes in visceral adipose tissue and liver fat [7, 12].

48 participants received study drug. Visceral adipose tissue changed by −34 cm² on tesamorelin against +8 cm² on placebo, a treatment effect of −42 cm² (95% CI −71 to −14; P=0.005). Liver fat, measured as lipid-to-water percentage, changed by a median −2.0% against +0.9% (P=0.003), a net treatment effect of −2.9%. Fasting glucose was higher on tesamorelin at two weeks — treatment effect 7 mg/dL (95% CI 1 to 14; P=0.03) — but the difference was not significant at six months or across time points overall [7].

The 12-month trial. 61 people with HIV and a hepatic fat fraction of 5% or more by proton magnetic resonance spectroscopy, enrolled between August 2015 and January 2019 at a hospital and a medical research centre in the United States, randomised 1:1 to tesamorelin 2 mg daily or identical placebo for 12 months, followed by a 6-month open-label phase in which all participants received tesamorelin. The primary endpoint was change in hepatic fat fraction between baseline and 12 months; the primary safety endpoint was glucose [8, 13].

Hepatic fat fraction fell more on tesamorelin than on placebo, with an absolute effect size of −4.1% (95% CI −7.6 to −0.7; p=0.018), a relative reduction of −37% (−67 to −7; p=0.016). After 12 months, 35% of the tesamorelin group and 4% of the placebo group had a hepatic fat fraction below 5% (p=0.0069). Changes in fasting glucose and glycated haemoglobin did not differ between groups at 12 months. More localised injection-site complaints occurred on tesamorelin, none judged serious. The authors' own conclusion is conditional: tesamorelin might be beneficial in this population, and further studies are needed to determine long-term effects on liver histology [8].

The integrase-inhibitor analysis. Because the phase 3 programme predates integrase inhibitors, which are now a mainstay of antiretroviral therapy, a prespecified subset of the 61-participant trial examined participants on integrase-inhibitor regimens: 38 at baseline, of whom 15 on tesamorelin and 16 on placebo completed 12 months. Visceral fat changed by a median −25 cm² against +14 (P=0.001), hepatic fat by −4.2% against −0.5% (P=0.01), and the trunk-to-appendicular fat ratio by −0.1 against 0.0 (P=0.03). Adverse-event frequency, including hyperglycaemia, was similar between groups [10].

Limitations. These are 50- and 61-participant trials with imaging endpoints. The 12-month trial did not measure histology, so nothing in it speaks to inflammation or fibrosis — the authors say so. The integrase-inhibitor analysis rests on 31 completers across two arms and is explicitly described as the first dedicated data in that setting, not as a confirmatory result.

What the evidence base does not establish

Anything outside HIV. Every trial above enrolled people with HIV [3, 4, 5, 7, 8]. The approved indication is defined by that population, and the trials provide no basis for extending the findings to anyone who would not have been enrolled.

Any clinical outcome. Visceral adipose tissue and hepatic fat fraction are imaging measures. No trial in this record counted a myocardial infarction, a hepatic decompensation, a hospitalisation or a death.

Durability beyond the treatment period. The re-randomisation in the 12-month trial answers this directly and unfavourably: the effect was rapidly lost on switching to placebo [5].

Hepatic histology. The 12-month hepatic trial measured fat fraction by spectroscopy and its authors state that further studies are needed to determine long-term effects on histology [8].

Long-term consequences of raised insulin-like growth factor-1. The phase 3 trial reported an 81.0% increase [4]. The trials were sized and timed for adipose-tissue endpoints, not for anything that a sustained elevation of that marker might imply over years.

Comparison against any active agent. Every trial in this record is placebo-controlled. There is no head-to-head trial against growth hormone itself, against any other releasing-hormone analogue, or against any metabolic agent.

All of the research described in this article is research into a pharmaceutical product, conducted under registered protocols, using 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

What is tesamorelin approved for?
Tesamorelin is approved in the United States for the reduction of excess abdominal adipose tissue in people with HIV and lipodystrophy. That is the only approved indication, and the approval rests on the phase 3 programme described in this article [4, 5, 6]. A 2024 analysis describes it as the only approved therapy for abdominal fat accumulation in people with HIV [10].
How large were the tesamorelin phase 3 trials?
412 participants in the first 26-week trial, 86% of them men [4], and 404 participants in a 12-month, two-phase trial conducted between January 2007 and October 2008 [5]. A preceding phase 2 trial enrolled 61 participants over 12 weeks [3].
What was the primary endpoint in the tesamorelin trials?
Visceral adipose tissue measured by computed tomography, in both phase 3 trials [4, 5]. The phase 2 trial used change in abdominal fat by X-ray densitometry and computed tomography [3]. The hepatic trials used liver fat: change in hepatic fat fraction by proton magnetic resonance spectroscopy at 12 months [8], and visceral and liver fat at 6 months [7].
What happens when tesamorelin is stopped in these trials?
The 12-month trial re-randomised participants at month 6, and those switched from tesamorelin to placebo rapidly lost the reduction in visceral adipose tissue observed over the first six months [5]. That is one of the few durability observations in this literature and it is explicit in the publication.
Does tesamorelin affect blood glucose in trials?
The phase 3 trials reported no significant differences in glycaemic measures against placebo [4, 5]. A 50-participant trial found fasting glucose higher in the tesamorelin group at two weeks (treatment effect 7 mg/dL; P=0.03) but not significantly different at six months [7]. A 12-month trial reported no difference in fasting glucose or glycated haemoglobin at 12 months [8].
Has tesamorelin been studied in people without HIV?
Not in the trials described here. Every trial in this article enrolled people with HIV, and the approval, the endpoints and the comparator populations all sit inside that setting [3, 4, 5, 7, 8, 10].
What adverse events were reported in tesamorelin trials?
In the 26-week phase 3 trial adverse events did not differ significantly between groups, though more participants on tesamorelin withdrew because of an adverse event [4]. The 12-month hepatic trial reported more localised injection-site complaints on tesamorelin, none judged serious [8]. Insulin-like growth factor-1 increased substantially — by 81.0% against a 5.0% decrease on placebo in the phase 3 trial [4].

References

  1. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma The Journal of Clinical Investigation; 1989. PMID 2565342 doi:10.1172/JCI114049
  2. Molecular cloning and expression of a human anterior pituitary receptor for growth hormone-releasing hormone Molecular Endocrinology; 1993. PMID 7680413 doi:10.1210/mend.7.1.7680413
  3. A placebo-controlled, dose-ranging study of a growth hormone releasing factor in HIV-infected patients with abdominal fat accumulation AIDS; 2005. PMID 16052083 doi:10.1097/01.aids.0000180099.35146.30
  4. Metabolic effects of a growth hormone-releasing factor in patients with HIV The New England Journal of Medicine; 2007. PMID 18057338 doi:10.1056/NEJMoa072375
  5. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension Journal of Acquired Immune Deficiency Syndromes; 2010. PMID 20101189 doi:10.1097/QAI.0b013e3181cbdaff
  6. Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy Drugs; 2011. PMID 21668043
  7. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial JAMA; 2014. PMID 25038357 doi:10.1001/jama.2014.8334
  8. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial The Lancet HIV; 2019. PMID 31611038 doi:10.1016/S2352-3018(19)30338-8
  9. Advances in the detection of growth hormone releasing hormone synthetic analogs Drug Testing and Analysis; 2021. PMID 34665524 doi:10.1002/dta.3183
  10. Efficacy and safety of tesamorelin in people with HIV on integrase inhibitors AIDS; 2024. PMID 38905488 doi:10.1097/QAD.0000000000003965
  11. TH9507 in Patients With HIV-Associated Lipodystrophy. NCT00123253
  12. Effects of Growth Hormone Releasing Hormone in HIV. NCT01263717
  13. Tesamorelin Effects on Liver Fat and Histology in HIV. NCT02196831

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