What Has Published Research Reported About Tesamorelin?

What is tesamorelin?

Tesamorelin is a synthetic analog of human growth hormone-releasing factor (GRF), the hypothalamic hormone more often called GHRH. The FDA prescribing information for EGRIFTA SV describes it as the 44 amino acid sequence of human GRF with a hexenoyl moiety, a C6 chain with a double bond at position 3, attached to the tyrosine residue at the N-terminal part of the molecule (source 4). The same label gives the molecular formula of the free base as C221H366N72O67S and its molecular weight as 5135.9 daltons, with the drug substance supplied as an acetate salt (source 4).

In the early literature the compound appears under its development code, TH9507. A 2007 nonclinical paper by Ferdinandi and colleagues described TH9507 as a human GRF analogue carrying a trans-3-hexenoyl group at tyrosine 1 (source 3), and the 2010 pooled analysis of the phase 3 trials still carried the code in its title (source 6). The Steadfast Research Group blog has already profiled two analogs built on a shorter 29-residue GHRH fragment, sermorelin and CJC-1295. Tesamorelin differs from both because it keeps every one of the native hormone's 44 residues. This profile covers the published literature only and is written for researchers reading that record.

Where does the 44-residue sequence come from?

The sequence tesamorelin is built on was first reported in 1982. Guillemin, Brazeau, Böhlen, Esch, Ling and Wehrenberg described in Science a 44 amino acid peptide with growth hormone-releasing activity isolated from a human pancreatic tumor that had caused acromegaly (source 1). A synthetic replicate showed full biological activity in vitro and in vivo, and the authors reported that the tumor peptide was identical in biological activity to the hypothalamic releasing factor that had not yet been characterized (source 1).

The full-length peptide is the parent molecule for tesamorelin, according to its label (source 4). The key structural facts are summarized below, each attributed to the source that reported it.

Why was a hexenoyl group added to the N-terminus?

The modification answers a problem documented in the late 1980s. In 1989, Frohman, Downs, Heimer and Felix reported in the Journal of Clinical Investigation that native GHRH(1-44)-NH2 incubated in plasma was rapidly cleaved between residues 2 and 3 (source 2). Diprotin A, a competitive inhibitor of dipeptidylpeptidase IV (DPP IV), blocked that conversion, and a D-amino acid at position 1 or 2 also stopped hydrolysis at that site, a pattern the authors described as characteristic of DPP IV. They also identified trypsin-like cleavage sites and concluded that GHRH degradation in plasma occurred primarily through DPP IV (source 2).

Tesamorelin takes a different route from the D-amino acid substitutions tested in that paper. Instead of changing a residue, it caps the N-terminal amino group of tyrosine 1 with a six-carbon acyl chain (sources 3 and 4). In the 2007 nonclinical paper, the trans-3-hexenoyl group was described as making TH9507 resistant to dipeptidyl aminopeptidase IV. Compared with the unmodified hormone, the analogue was degraded more slowly in rat, dog and human plasma and showed prolonged plasma elimination in vivo (source 3).

Dipeptidylpeptidase IV (DPP IV)

A plasma enzyme that removes two-residue units from the N-terminus of susceptible peptides. A 1989 study identified it as the main enzyme degrading GHRH in plasma (source 2).

Visceral adipose tissue (VAT)

Abdominal fat inside the body cavity, reported separately from subcutaneous fat. The phase 3 trials measured it as a cross-sectional area on computed tomography (CT) scans (sources 5 and 6).

IGF-I

Insulin-like growth factor I. It was a measured outcome in the preclinical and clinical studies cited here (sources 3, 7 and 8).

Euglycemic hyperinsulinemic clamp

A laboratory method that holds blood glucose steady while insulin is infused, used to estimate insulin-stimulated glucose uptake. It was a secondary measure in the 2011 pulsatility study (source 7).

What did preclinical studies of TH9507 report?

The main nonclinical record is the 2007 paper in Basic & Clinical Pharmacology & Toxicology (source 3). In pigs, rats and dogs, repeated daily intravenous or subcutaneous administration was followed by marked increases in plasma growth hormone and IGF-1. In subchronic studies lasting up to 4 months in rats and dogs, the authors reported a significant increase in body weight gain that did not scale with the amount given (source 3).

The species did not respond identically. The authors reported a stronger anabolic effect in dogs, along with more pronounced adverse effects after repeated subcutaneous administration, which the authors reported as reversible (source 3). In dogs, the apparent elimination half-life of TH9507 ranged from 21 to 45 minutes (source 3). Because all of these figures come from one sponsor-authored paper, they describe the compound's behavior in those specific models rather than a general property.

How did tesamorelin change growth hormone secretion patterns in clinical research?

A question raised by any GHRH analog is whether it alters the natural pulsatile pattern of growth hormone release. Stanley, Chen, Branch, Makimura and Grinspoon addressed it in a small study published in 2011 in the Journal of Clinical Endocrinology & Metabolism (source 7). Thirteen healthy men received tesamorelin for 2 weeks, with assessments at baseline, after the 2-week administration period and again after a 2-week withdrawal period.

The primary outcome was mean overnight growth hormone, measured by frequent overnight blood sampling. The investigators reported increases in mean overnight growth hormone, in growth hormone pulse area and in basal growth hormone secretion, and IGF-I rose significantly (source 7). Peripheral insulin-stimulated glucose uptake, measured with a euglycemic hyperinsulinemic clamp, was reported to be preserved despite the rise in IGF-I. The authors concluded that short-term administration augmented both basal and pulsatile growth hormone secretion (source 7).

What did the phase 3 trials measure?

The first phase 3 trial was published by Falutz and colleagues in the New England Journal of Medicine in 2007 (source 5). It randomly assigned 412 adults with HIV and abdominal fat accumulation, 86 percent of them men, to tesamorelin or placebo for 26 weeks. The primary endpoint was the percent change from baseline in visceral adipose tissue, measured by CT. The investigators reported that VAT decreased by 27.8 square centimeters in the tesamorelin group and increased by 5.1 square centimeters in the placebo group, and that glycemic measures did not differ significantly between groups (source 5).

A second phase 3 trial followed, and in 2010 Falutz, Mamputu, Potvin and colleagues published a pooled analysis of both studies (source 6). The pooled data covered 806 participants, 543 assigned to tesamorelin and 263 to placebo. At week 26 the authors reported a placebo-adjusted difference of minus 15.4 percent in VAT (P < 0.001), corresponding to mean changes of minus 24 square centimeters with tesamorelin and plus 2 square centimeters with placebo (source 6).

What did later studies examine?

Later work extended the measurements beyond the original HIV population. Makimura and colleagues reported in 2012 a randomized, double-blind, placebo-controlled study of 60 adults with abdominal obesity and reduced growth hormone secretion, followed for 12 months (source 8). The authors reported a placebo-adjusted VAT difference of minus 35 square centimeters (P = 0.003), a placebo-adjusted IGF-I difference of 92 micrograms per liter (P < 0.0001), no significant effect on abdominal subcutaneous fat, and no changes in fasting glucose, 2-hour glucose or glycated hemoglobin (source 8).

In 2014, Stanley, Feldpausch, Oh and colleagues published a randomized trial in JAMA that added liver fat as a co-primary endpoint (source 9). Fifty men and women with HIV who were receiving antiretroviral medication and abdominal fat accumulation were assigned to tesamorelin (28) or placebo (22) for 6 months. The investigators reported a mean VAT change of minus 34 square centimeters with tesamorelin against plus 8 square centimeters with placebo, a placebo-adjusted difference of minus 42 square centimeters (P = .005). The median change in the liver lipid to water percentage was minus 2.0 percent with tesamorelin against plus 0.9 percent with placebo (P = .003) (source 9). The 6-month results table listed 43 participants, 23 and 20 in the two arms.

What is tesamorelin's regulatory status?

Tesamorelin is an approved prescription drug in the United States, which separates it from most compounds profiled on this blog. Its prescribing information lists an initial US approval in 2010 under new drug application 22-505, and the labeled indication concerns excess abdominal fat in adults with HIV and lipodystrophy (source 4). The current label covers the product marketed as EGRIFTA SV (source 4).

That approval covers a specific manufactured product evaluated in specific clinical populations. It does not extend to research-grade material produced outside the approved application, and nothing in the approval history changes the research-use-only status of laboratory material.

What remains unresolved in the tesamorelin literature?

The record is uneven in ways researchers should note. The nonclinical pharmacology, including the DPP IV resistance and the dog half-life range, rests largely on a single 2007 paper from the developing company (source 3). The clinical evidence comes mainly from adults with HIV and abdominal fat accumulation (sources 5, 6 and 9), with one 12-month study in adults with abdominal obesity and reduced growth hormone secretion (source 8). The pulsatility data come from 13 healthy men over 2 weeks (source 7), which is too small and too short to describe longer-term changes.

The 2014 liver fat trial was also small, with 50 participants randomized and 43 listed in the 6-month results (source 9). Studies in other populations and longer follow-up periods are outside the sources reviewed here.

For laboratories, the practical point is analytical. Tesamorelin, native GHRH and the shorter GRF(1-29) analogs differ by defined lengths and modifications, and tesamorelin's free-base molecular weight of 5135.9 daltons (source 4) is far above that of a 29-residue fragment. Confirming the expected mass by mass spectrometry and checking purity by HPLC are the routine ways to tell them apart. Steadfast Research Group supplies tesamorelin as a lyophilized research material with a batch-matched Certificate of Analysis on its tesamorelin research page.