Tesamorelin: A Peptide Approved for One Narrow Use

Most peptides discussed online have no approval anywhere. Tesamorelin is an exception, and a useful one to study, because its approval is so specific: one population, one measured change, and a label that spells out what it is not for.

What it is

Growth hormone releasing factor, also called growth hormone releasing hormone, is a peptide made in the hypothalamus. It acts on cells in the pituitary gland, the somatotrophs, which respond by making growth hormone and releasing it in pulses. Growth hormone then acts on many tissues, including cartilage, bone, muscle, liver and fat cells, and some of its effects are carried by a second messenger, insulin-like growth factor 1 (IGF-1), made in the liver and elsewhere.

Tesamorelin is a synthetic version of that releasing factor. According to its US prescribing information, it contains the full 44 amino acid sequence of human growth hormone releasing factor, with one addition: a hexenoyl group, a six-carbon chain with a double bond at position 3, attached to the tyrosine at the start of the chain. It is supplied as an acetate salt, and its molecular weight as the free base is 5,135.9 Da. In laboratory tests it binds to and activates the human receptor with a potency similar to the natural hormone.

Because it works through the body's own pathway, tesamorelin raises growth hormone and IGF-1 rather than supplying growth hormone directly. That is why IGF-1 appears in the label's warnings, discussed below: the effects of keeping it raised for long periods are not known.

The problem it was developed for

Many people living with HIV who take antiretroviral therapy accumulate fat inside the abdomen, around the organs, known as visceral adipose tissue. It is part of a condition called lipodystrophy, and visceral fat of this kind is associated with increased cardiovascular risk. Before 2010 there was no approved treatment for it in the United States.

The pivotal trial

In 2007 the New England Journal of Medicine published a randomised, double-blind trial of 412 people with HIV and excess abdominal fat, 86 percent of them men. They received tesamorelin or placebo as a daily injection for 26 weeks. The primary outcome was the percentage change in visceral fat measured by computed tomography, a direct measurement rather than a waist circumference or a body weight.

Visceral fat fell by 15.2 percent on tesamorelin and rose by 5.0 percent on placebo. Several blood lipid measures moved in the same direction, and IGF-1 rose substantially, as expected from the way the compound works.

Adverse events overall did not differ significantly between the groups, but more people on tesamorelin withdrew because of an adverse event. All of the differences above were statistically significant, with P values below 0.001, except the glucose measures.

The approval, and its limits

On 10 November 2010, tesamorelin was approved by the FDA under the brand name Egrifta. The approval rested on two phase 3 trials with a 26-week main phase and a 26-week extension, which together enrolled 816 people with HIV and excess abdominal fat. The current US label is for a newer formulation, Egrifta WR.

The current label indicates tesamorelin for one purpose: reducing excess abdominal fat in adults with HIV who have lipodystrophy. It then lists its limits explicitly:

• its long-term cardiovascular safety has not been established
• prescribers should weigh whether to continue in people whose visceral fat has not decreased
• it is not indicated for weight loss management, because its effect on body weight is neutral
• there are no data showing that it improves adherence to antiretroviral therapy

This is what an approval looks like in practice. It does not say that tesamorelin is a good idea for anyone who wants less abdominal fat. It says that in one defined group, measured one specific way, the benefit was judged to outweigh the risks.

A later research question: liver fat

Researchers later asked whether tesamorelin affects non-alcoholic fatty liver disease, a substantial cause of illness in people with HIV for which there were no proven medicines in that population. A randomised, double-blind trial published in 2019 enrolled 61 people with a liver fat fraction of 5 percent or more, measured by magnetic resonance spectroscopy, and gave tesamorelin or placebo for 12 months.

Liver fat fraction fell by 4.1 percentage points more on tesamorelin than on placebo, with a 95 percent confidence interval of 0.7 to 7.6, a relative reduction of 37 percent from the starting level. After 12 months, 35 percent of the tesamorelin group had a liver fat fraction below 5 percent, compared with 4 percent on placebo. Fasting glucose and HbA1c did not differ between the groups. The tesamorelin group had more local injection site complaints, none judged serious.

The authors concluded that tesamorelin might be beneficial in this group and that further studies are needed on its long-term effects on liver tissue. The trial was small, and fatty liver disease is not among the approved uses on the label.

Safety: what the label warns about

The warnings and precautions on the current label follow from how the compound works:

• Tumours. Any existing cancer should be inactive, with treatment complete, before starting. Treatment should stop if there is any sign of recurrence.
• Raised IGF-1. Tesamorelin increases IGF-1, a growth factor, and the effects of prolonged elevation are unknown. IGF-1 should be monitored, and stopping considered if it stays high.
• Fluid retention. This can show up as swelling, joint pain and carpal tunnel syndrome.
• Glucose. Glucose intolerance or diabetes may develop, so glucose should be checked before and during treatment.
• Allergic reactions. Hypersensitivity reactions occurred in clinical trials.
• Injection site reactions. Listed among the important adverse reactions.
• Critical illness. Stopping should be considered in people who become acutely critically ill, because of increased mortality in that setting.

The adverse reactions reported in more than 5 percent of people were joint pain, redness and itching at the injection site, pain in the arms or legs, swelling in the limbs, and muscle pain.

What the approval does not cover

Tesamorelin's approval covers one medicine for one use. It does not extend to other peptides that also act on the growth hormone pathway. CJC-1295 and ipamorelin, for example, are different molecules, neither is approved, and the FDA's list of bulk substances that may present significant safety risks includes concerns about both, among them the risk of immune reactions and impurities.

It also does not extend to other products sold under the name tesamorelin. The trial results and the safety profile above describe the medicine as manufactured for the approval and used under medical supervision.