Tesamorelin — HIV-associated lipodystrophy
GHRH analog — FDA-approved for HIV-associated lipodystrophy
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
Snapshot
Class: GHRH analog (synthetic)
Evidence tier: Approved drug
Status: FDA-approved prescription drug (HIV-associated lipodystrophy); Health Canada-approved; EMA marketing authorization withdrawn by sponsor
Best-supported effect: Visceral adipose tissue reduction (~15–18%) in adults with HIV-associated lipodystrophy, established by Phase III RCTs and confirmed at 52 weeks; with human evidence for hepatic fat reduction and exploratory human evidence for cognitive outcomes in people with HIV
Main caveat: Approved indication is narrow and population-specific — dedicated RCTs in healthy aging adults or non-HIV populations do not exist; visceral fat benefit is treatment-dependent and reverses after discontinuation
What this is
Tesamorelin is a synthetic 44-amino-acid analog of human growth hormone-releasing hormone (GHRH), modified at the N-terminus with a trans-3-hexenoyl group. This modification protects the peptide from rapid cleavage by dipeptidyl peptidase IV (DPP-IV), extending its half-life and making once-daily dosing clinically viable. The underlying GHRH sequence was characterized in the 1980s; Theratechnologies (Montreal) developed the stabilizing modification and completed the clinical program.
The FDA approved tesamorelin in November 2010 under the brand name Egrifta, specifically for reducing excess abdominal fat in HIV-infected patients with lipodystrophy — a disfiguring metabolic complication of antiretroviral therapy. It is the only GHRH analog to have cleared full FDA approval; an earlier approval for sermorelin (GHRH fragment 1–29) was withdrawn in 2008.
Tesamorelin works by stimulating pulsatile growth hormone release from the pituitary, driving downstream IGF-1 production and selective visceral adipose tissue mobilization. Its distinctive feature is preserving the body's natural GH feedback mechanisms rather than replacing the hormone directly. The approved evidence base is anchored in the HIV-lipodystrophy population; off-label use in broader metabolic and anti-aging contexts is widespread but is not supported by the approved clinical program.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | Approved (Phase III) | Visceral fat reduction in HIV-associated lipodystrophy — two pivotal RCTs (n=816 pooled); 52-week extension confirms durability of benefit during treatment. Secondary: hepatic fat reduction, lipid improvement, and lean mass preservation in the HIV-lipodystrophy population. Exploratory human RCT evidence for cognitive outcomes and neurocognitive function in people with HIV. No controlled evidence in healthy aging adults or general obesity. |
| Animal | Moderate (preclinical program) | available literature describes a comprehensive preclinical development program; detailed individual animal study data are not individually extracted. |
| In vitro | Not individually extracted | available literature covers receptor binding and mechanistic characterization; individual assay data are not separately extracted in this card. |
| Computational | None identified | No platform prediction or docking data attached. |
| Mechanism | Strong | Well-characterized GHRH receptor agonism; cAMP/PKA pathway; pulsatile GH secretion; downstream IGF-1-mediated lipolysis in visceral adipose tissue. Mechanistic basis is consistent with the approved clinical effect. |
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Reduces visceral adipose tissue in adults with HIV-associated lipodystrophy | Supported | Human Phase III / approved label | High |
| Does not reduce subcutaneous fat — effect is visceral-selective | Supported | Human Phase III / approved label | High |
| Works as a general weight-loss drug or for fat loss in healthy adults | Contradicted / not established | Human label and trials | High |
| Improves cognitive function | Partially supported — human exploratory | Human Phase II (HIV population with neurocognitive impairment) | Low — small controlled trials in specific population; not established in healthy aging adults |
| Reduces hepatic fat (NASH/NAFLD context) | Partially supported — human RCT, HIV population | Human RCTs (HIV-positive patients with hepatic steatosis) | Medium — controlled evidence in HIV population; non-HIV generalization not established |
| Benefit is permanent — visceral fat loss is sustained after stopping | Contradicted | Human Phase III extension | High — discontinuation data show VAT regresses; benefit is treatment-dependent |
| Safe and appropriate for anti-aging use in healthy adults | Not established | Human (no dedicated RCTs in this population) | High — off-label use exists; controlled evidence does not |
| Long-term cardiovascular safety is established | Not established | Human (label limitation) | High — FDA label explicitly states long-term cardiovascular safety is not known; trial window was 26–52 weeks |
Exposure studied
This section reports exposure used in approved labels and human studies. It is not a personalized protocol.
| Context | Population | Exposure studied | Duration | Endpoint | Evidence strength | Limitation |
|---|---|---|---|---|---|---|
| FDA label — Egrifta SV (F1/F4 formulation) | Adults with HIV-associated lipodystrophy | 2 mg subcutaneous once daily | Approved for continuous use; Phase III primary endpoint at 26 weeks, extension to 52 weeks | CT-measured visceral adipose tissue reduction | Approved label / Phase III RCT | Approved indication only; off-label use is not covered by this labeling |
| FDA label — Egrifta WR (F8 formulation, approved March 2025) | Adults with HIV-associated lipodystrophy | 1.28 mg subcutaneous once daily (0.16 mL from 11.6 mg weekly-reconstituted vial) | Continuous; weekly reconstitution | CT-measured visceral adipose tissue reduction | Approved label — bioequivalence demonstrated | Reformulation; daily injection continues; approved indication unchanged |
| Phase III pivotal trials (LIPO-010 and LIPO-011) | HIV-infected adults with abdominal fat accumulation (n=816 pooled) | 2 mg subcutaneous once daily | 26 weeks (main phase) + 26-week extension | CT-measured VAT, trunk fat, lipid profiles | Phase III RCTs | Population-specific; no comparator arm against other metabolic therapies |
| Phase II RCT — cognitive function | Adults with HIV and abdominal obesity / neurocognitive impairment | 2 mg subcutaneous once daily | 20–26 weeks | Executive function composite, verbal memory | Phase II randomized controlled trial | Small; specific HIV population; not established in healthy aging adults |
| RCT — hepatic fat / NAFLD in HIV | HIV-positive patients with hepatic fat accumulation | 2 mg subcutaneous once daily | 6 months | Liver fat by MRS, ALT, fibrosis markers | Randomized controlled trial | HIV population; non-HIV liver disease extrapolation not established |
Safety signals
| Signal | Evidence context | Notes |
|---|---|---|
| Injection-site reactions (erythema, pruritus, pain, induration) | Label / Phase III trials | Reported in 8–13% of trial participants; most common adverse event; rarely led to discontinuation |
| Arthralgia and myalgia (joint and muscle pain) | Label / Phase III trials | Common; dose-related; described as generally mild to moderate and typically diminishing with continued treatment |
| Peripheral edema (fluid retention) | Label / Phase III trials | Related to GH-axis activation; class effect |
| Glucose intolerance and HbA1c elevation | Label / Phase III trials | GH antagonizes insulin action; monitoring of glucose and HbA1c is built into the approved prescribing information |
| IGF-1 elevation above normal range | Label / Phase III trials | Expected pharmacodynamic effect; persistent supraphysiological IGF-1 is a monitoring concern given theoretical cancer-risk implications of chronically elevated IGF-1 |
| Carpal tunnel-like symptoms and paresthesias | Label / trials | Reported; class effect of GH/IGF-1 elevation; generally mild |
| Hypersensitivity reactions (urticaria, rash, anaphylaxis) | Label | Rare; includes serious reactions; contraindicated in known hypersensitivity to tesamorelin or mannitol excipient |
| Long-term cardiovascular outcomes | Label limitation | FDA label explicitly states long-term cardiovascular safety is not known; no dedicated cardiovascular endpoint trial; a mandated 10-year post-marketing cohort study tracking MACE, malignancy, type 2 diabetes, and retinopathy in HIV-lipodystrophy patients is ongoing but has not fully reported |
Label contraindications (per available sources):
- Active malignancy — GH/IGF-1 elevation may accelerate existing tumor proliferation; contraindicated per label
- Disrupted hypothalamic-pituitary axis (hypophysectomy, hypopituitarism, pituitary tumor or surgery, head irradiation, head trauma) — pharmacological effect requires intact somatotroph axis
- Pregnancy — contraindicated per approved label; pharmacologic GH/IGF-1 effects not characterized in reproductive-toxicology studies adequate to support use
- Known hypersensitivity to tesamorelin or mannitol
Interaction signals (per available sources): available literature describes interactions with glucose-regulating agents (insulin, sulfonylureas, GLP-1 receptor agonists) based on GH's counter-regulatory effect on glucose; dose adjustment of antidiabetic agents may be relevant during treatment and is reflected in the prescribing information. available literature also notes that corticosteroids may blunt GH secretion at the pituitary level and attenuate clinical effect. Controlled interaction data beyond these class-level descriptions are not individually extracted.
Regulatory status
| Region / body | Status | Notes |
|---|---|---|
| US (FDA) | Approved prescription drug | Approved November 2010; brand names Egrifta (original), Egrifta SV (2014), Egrifta WR (March 2025). Approved indication: reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Label states: not for weight loss management. Prescription-only; specialty pharmacy distribution. No generic (orphan drug economics). |
| Canada (Health Canada) | Approved prescription drug | Approved under HIV-lipodystrophy indication; same manufacturer |
| EU (EMA) | Marketing authorization withdrawn | EMA initially authorized tesamorelin (Egrifta) in 2014; marketing authorization was subsequently withdrawn by the sponsor. Current EU status requires verification against the current EMA register. |
| WADA | Prohibited at all times | S2 category — Peptide Hormones, Growth Factors, Related Substances and Mimetics; covers GHRH and its analogs; prohibited both in and out of competition. A Therapeutic Use Exemption process exists for athletes with documented medical need; FDA-approved status does not provide automatic exemption. per available sources as of April 2026; current WADA list status should be verified against the current prohibited list. |
| Compounding (US) | Restricted | Per available sources, 503A compounding is restricted; compounding status requires verification against current FDA bulk-substance list and enforcement context — not individually confirmed in this card. |
Clinical trials
Key trials from the available literature bundle. Additional published trials are listed in References.
| Trial / source | Phase | Population | Primary endpoint | Status / result |
|---|---|---|---|---|
| LIPO-010 — Falutz et al. 2007 | Phase III | HIV-infected adults with lipodystrophy (n=412) | CT-measured visceral adipose tissue at 26 weeks | Completed — 15.2% VAT reduction vs 5.0% placebo; basis for FDA approval |
| LIPO-011 pooled analysis — Falutz et al. 2010 | Phase III | HIV-infected adults with lipodystrophy (n=816 pooled) | CT-measured VAT; 52-week extension | Completed — confirmed 15–18% VAT reduction; extension showed sustained benefit during treatment; fat regressed after stopping |
| Stanley et al. 2014 — hepatic fat / NAFLD | Not individually extracted | HIV-positive patients with abdominal fat accumulation and hepatic steatosis (n=50) | Liver fat by MRS, hepatic outcomes | Completed — hepatic fat reduction documented as secondary outcome |
| Stanley et al. 2019 — NAFLD multicentre RCT | Phase II (RCT) | HIV-positive patients with NAFLD | Liver fat | Completed — published in Lancet HIV |
| Fourman et al. 2020 — cognitive function ( per PE source; Annals of Internal Medicine 2020:172) | Randomized controlled trial | Older adults with mild cognitive impairment (non-HIV population per PE source) | Executive function composite | Completed — improvement in executive function scores; effects correlated with IGF-1 increases; exploratory |
| Ances et al. 2024 / 2025 — neurocognitive impairment in people with HIV | Phase II | Virally suppressed people with HIV and abdominal obesity | Neurocognitive impairment endpoints | Completed (2025 publication) — extended tesamorelin evidence beyond visceral fat; specific results not individually extracted |
Last checked: available literature bundle dated April 2026. Total registered trials: not individually enumerated in this card.
Mechanism
Tesamorelin acts as a full agonist at the growth hormone-releasing hormone receptor (GHRH-R) on somatotroph cells in the anterior pituitary gland. Despite the N-terminal trans-3-hexenoyl modification — which sterically protects the peptide from DPP-IV cleavage and extends its plasma half-life to approximately 26–38 minutes after subcutaneous injection — the peptide retains full agonist activity at GHRH-R.
GHRH-R activation triggers the cAMP/PKA signaling cascade, stimulating synthesis and secretion of growth hormone. A key mechanistic feature of tesamorelin versus exogenous GH injection is that GH secretion remains pulsatile: normal negative feedback through somatostatin and IGF-1 remains intact, preventing supraphysiological sustained GH elevation. The resulting rise in circulating GH drives IGF-1 production in the liver, and IGF-1 is the primary downstream mediator of visceral adipose tissue lipolysis. GH receptors are more densely expressed in visceral adipose tissue than in subcutaneous fat, providing a mechanistic basis for the observed selectivity of tesamorelin's fat-mobilizing effect.
Target note: available literature consistently identifies GHRH-R (the growth hormone-releasing hormone receptor) as the primary target. An earlier data import assigned this compound to GHSR (the ghrelin receptor); this is incorrect — tesamorelin acts at GHRH-R, not GHSR. The GHRH-R target is well-characterized and is the basis for FDA approval.
Chemistry
| Field | Value |
|---|---|
| Amino-acid chain | YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL |
| Length | 44 amino acids |
| Topology | Linear |
| Modification | N-terminal trans-3-hexenoyl (trans-3-hexenoic acid) group conjugated to the N-terminal tyrosine residue at position 1 |
| Modification purpose | Steric protection from DPP-IV cleavage; extends half-life; preserves GHRH-R agonist activity |
| Molecular weight | ~5135.8 Da (5135 Da) |
| Molecular formula | C₂₂₁H₃₆₆N₆₈O₆₇S |
| CAS | 901758-09-6 |
| Half-life | ~26–38 minutes (subcutaneous) |
| Sequence confidence | Needs review — two source sections list the sequence as YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL (44 residues); one internal annotation references QQGEESNQE vs QQGESNQE; the sequence above is from the RP source which lists 44 residues, consistent with the stated AA count. Both the PE and RP sections give essentially the same sequence; the QQGE/QQGEE discrepancy is noted in the spec as a known conflict. Verification against a primary chemistry source (Uniprot, DrugBank, or FDA label sequence) is recommended before finalizing. |
| Salt form | Not specified in available literature |
| Origin | Theratechnologies Inc. (Montreal, Canada); developed from endogenous human GHRH(1–44) |
Open questions
- Long-term cardiovascular safety: The FDA label explicitly states that long-term cardiovascular safety is not known. A mandated 10-year post-marketing cohort study tracking MACE, malignancy, type 2 diabetes, and retinopathy in the HIV-lipodystrophy population is ongoing but has not fully reported. Cardiovascular endpoint data are currently limited to metabolic-marker improvements from trial windows of 26–52 weeks.
- Efficacy and safety in healthy aging adults: The dominant off-label use case — body recomposition in men 40+ without HIV — has not been tested in dedicated RCTs. The Baker / Fourman cognitive impairment work is an exception but involved small populations with specific clinical characteristics. Mechanism-based extrapolation from the HIV-lipodystrophy trials to healthy aging adults involves a substantial inference gap.
- Durability of benefit in off-label populations: Regression of visceral fat after discontinuation is well-characterized in the HIV-lipodystrophy population. Whether this pattern holds similarly, more strongly, or differently in non-HIV populations receiving off-label treatment has not been studied.
- Non-HIV NAFLD/NASH hard endpoints: Hepatic fat reduction in HIV-positive patients with steatosis is documented. Whether these effects translate to hard liver endpoints (fibrosis progression, hepatocellular carcinoma incidence) in populations without HIV coinfection has not been established.
- Neurocognitive outcomes: Early Phase II data in people with HIV and abdominal obesity suggest a neurocognitive signal. The mechanistic basis is plausible (IGF-1 promotes neurogenesis and synaptic plasticity), but the evidence remains preliminary and population-specific. Replication in non-HIV populations and in larger trials is needed.
- Sequence verification: Source sections show minor discrepancy in the QQGE/QQGEE region. Verification against a primary chemistry authority (FDA label sequence, DrugBank, Uniprot) is recommended.
- Comparative effectiveness: No controlled data compare tesamorelin against newer GLP-1 receptor agonists or other metabolic therapies for visceral fat reduction in non-HIV populations with general visceral adiposity.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8295246958732605 | boltz-2 |
| ranking score | 0.7991945147514343 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.710 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep04441,
sequence = {YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL},
target = {ghrhr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}