GHRH(1-44) Receptor Agonist (Growth-Hormone Secretagogue, GRF Class)

Tesamorelin

Also Known As: TH9507, Egrifta, Egrifta SV, Egrifta WR

Tesamorelin is a synthetic 44-amino-acid peptide built on the native human growth-hormone-releasing hormone (GHRH/GRF(1-44)) sequence with a (3E)-hex-3-enoyl group conjugated to the α-amino of Tyr¹. This N-terminal acyl modification blocks dipeptidyl-peptidase-IV cleavage and extends plasma half-life enough for the peptide to engage the pituitary GHRH receptor (GHRHR) on somatotrophs and stimulate the body’s own pulsatile release of growth hormone. Tesamorelin is the active ingredient in Egrifta® (FDA approval 2010), Egrifta SV® (2019), and the current Egrifta WR® (25 March 2025) for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. The European Union has no marketing authorisation — Ferrer Internacional withdrew its application on 21 June 2012 after the CHMP raised concerns about long-term cardiovascular safety.

Identity & Chemistry

Two-dimensional skeletal structural formula of tesamorelin showing the 44-residue GHRH(1-44) peptide backbone with a trans-3-hexenoyl acyl group conjugated to the α-amino group of the N-terminal tyrosine and a C-terminal leucinamide.
Image credit: Vaccinationist, via Wikimedia Commons · Public Domain
Amino Acid Sequence
(trans-3-hexenoyl)-Y-A-D-A-I-F-T-N-S-Y-R-K-V-L-G-Q-L-S-A-R-K-L-L-Q-D-I-M-S-R-Q-Q-G-E-S-N-Q-E-R-G-A-R-A-R-L-NH₂
Molecular Formula
C₂₂₁H₃₆₆N₇₂O₆₇S
Molecular Weight
5135.86 Da
CAS Number
218949-48-5
PubChem CID
16137828
DrugBank ID
DB08869
IUPAC Name
L-Leucinamide, N-((3E)-1-oxo-3-hexenyl)-L-tyrosyl-L-alanyl-L-α-aspartyl-L-alanyl-L-isoleucyl-L-phenylalanyl-L-threonyl-L-asparaginyl-L-seryl-L-tyrosyl-L-arginyl-L-lysyl-L-valyl-L-leucyl-glycyl-L-glutaminyl-L-leucyl-L-seryl-L-alanyl-L-arginyl-L-lysyl-L-leucyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-isoleucyl-L-methionyl-L-seryl-L-arginyl-L-glutaminyl-L-glutaminyl-glycyl-L-α-glutamyl-L-seryl-L-asparaginyl-L-glutaminyl-L-α-glutamyl-L-arginyl-glycyl-L-alanyl-L-arginyl-L-alanyl-L-arginyl-L-leucinamide
Solubility
Lyophilised tesamorelin acetate is reconstituted in sterile water for injection; Egrifta WR vials supply 11.6 mg of tesamorelin per single-patient-use vial (seven daily 1.28 mg doses delivered as 0.16 mL). The peptide is freely water-soluble at therapeutic concentrations; quantitative aqueous solubility (mg/mL) is not publicly disclosed by the sponsor.
Storage
Egrifta SV (F4): refrigerate at 2–8 °C prior to reconstitution. Egrifta WR (F8): store at controlled room temperature 20–25 °C before and after reconstitution; reconstituted vial stable for seven days at room temperature. Research-grade lyophilised peptide: store sealed at −20 °C protected from light; reconstituted aliquots at 2–8 °C for short-term use or −20 °C for longer-term storage. Avoid freeze-thaw cycles.

Mechanism of Action

Tesamorelin is a DPP-IV-resistant GHRH(1-44) analogue that selectively activates the pituitary GHRH receptor (GHRHR) on somatotrophs, stimulating pulsatile, physiologic release of endogenous growth hormone with a downstream rise in hepatic IGF-1.

Tesamorelin (TH9507) was engineered by Theratechnologies from the full 44-residue hypothalamic peptide GRF(1-44) as an N-terminally acylated analogue: a (3E)-hex-3-enoic acid (trans-3-hexenoic acid) is conjugated to the α-amino group of Tyr¹. This modification sterically blocks dipeptidyl peptidase-IV (DPP-IV/CD26) — the protease principally responsible for the rapid (~7 min) plasma inactivation of native GHRH at the Tyr¹–Ala² bond — and confers a measurable plasma half-life of roughly 26–38 minutes after subcutaneous administration with absolute bioavailability ≤4% (FDA clinical pharmacology review NDA 22-505). Because tesamorelin acts through the endogenous somatotroph machinery rather than supplying exogenous recombinant human growth hormone (rhGH/somatropin), the resulting GH release is pulsatile and remains under negative feedback by IGF-1, somatostatin, and free fatty acids — preserving physiologic GH dynamics and largely avoiding the supraphysiologic IGF-1 excursions that complicated earlier rhGH-based regimens for HIV-associated lipodystrophy. In Phase III HIV-lipodystrophy trials, daily 2 mg subcutaneous tesamorelin produced a selective ~15–18% reduction in visceral adipose tissue (VAT) at 26 weeks without significantly altering subcutaneous adipose tissue or limb fat, with concurrent normalisation of mean IGF-1 toward the upper-normal physiologic range (~+81% from baseline) and improvements in triglycerides and the total-cholesterol-to-HDL ratio. Effects are reversible upon discontinuation, consistent with the short pharmacokinetic half-life and the requirement for ongoing GHRHR stimulation.

Molecular Targets

  • GHRH receptor (GHRHR; UniProt Q02643) — class B G-protein-coupled receptor on anterior pituitary somatotrophs; sole high-affinity target of tesamorelin
  • Growth-hormone axis (pituitary → liver) — secondary increase in endogenous GH and downstream IGF-1
  • No meaningful agonism at the ghrelin / GHS-R1a receptor (mechanistically distinct from GHRP-class secretagogues such as ipamorelin or GHRP-2/-6)

Signaling Pathways

  • GHRHR → Gαs → adenylyl cyclase → ↑ cAMP → PKA → CREB phosphorylation → upregulation of GH (GH1) gene transcription and exocytotic GH release from secretory granules
  • Secondary phospholipase-C / IP₃ / DAG arm modulates Ca²⁺ influx and somatotroph proliferation
  • GH → hepatic GH receptor → JAK2/STAT5b → IGF-1 transcription
  • IGF-1 mediates lipolysis in visceral adipose tissue and anabolic effects on lean mass under physiologic negative feedback by IGF-1, somatostatin, and free fatty acids

Research Applications

Tesamorelin has been evaluated in two pivotal Phase III RCTs in HIV-associated lipodystrophy (Falutz 2007 NEJM, Falutz 2010 JCEM) and in independent academic Phase II studies of hepatic steatosis (Stanley 2014 JAMA, Stanley 2019 Lancet HIV) and cognition (Baker 2012 Arch Neurol).

HIV-associated lipodystrophy / VAT reduction (pivotal Phase III RCT; n = 412)

Phase III

Studies report that daily 2 mg subcutaneous tesamorelin for 26 weeks reduced VAT by −15.2% versus +5.0% with placebo (P < 0.001), with concurrent triglyceride reduction of 50 mg/dL and IGF-1 elevation of +81.0%. Subcutaneous and limb fat were not meaningfully changed.

— Falutz et al., N Engl J Med 2007;357(23):2359–2370

Pooled Phase III analysis with 26-week safety extension (n = 806)

Phase III

Studies report a VAT change of −24 ± 41 cm² with tesamorelin versus +2 ± 35 cm² with placebo (treatment effect ≈ −15.4%), maintained through 52 weeks, with no clinically meaningful change in fasting glucose and improvements in trunk fat, waist circumference, lipid profile, and patient-reported body image.

— Falutz et al., J Clin Endocrinol Metab 2010;95(9):4291–4304

NAFLD in HIV — VAT and hepatic-fat reduction (single-centre Phase II RCT, ¹H-MRS-quantified; n = 50)

Phase II

Studies report that over 6 months tesamorelin reduced VAT by −34 cm² versus +8 cm² with placebo (P = 0.005) and lowered hepatic fat fraction by −2.0% versus +0.9% (net effect −2.9%; P = 0.003), with a modest HbA1c rise in the active arm.

— Stanley et al., JAMA 2014;312(4):380–389

NAFLD/NASH in HIV — biopsy-confirmed liver effects (multicentre Phase II RCT, NCT02196831; n = 61)

Phase II

Studies report that at 12 months tesamorelin reduced absolute hepatic fat fraction by −4.1% (~−37% relative); 35% of tesamorelin recipients achieved resolution of steatosis (HFF < 5%) versus 4% on placebo (P = 0.0069). Fibrosis progression was 10.5% versus 37.5% with placebo (P = 0.044).

— Stanley et al., Lancet HIV 2019;6(12):e821–e830

Cognitive function in MCI and healthy older adults (Phase II RCT, SMART trial, n = 137)

Phase II

Studies report that 1 mg/day tesamorelin for 20 weeks increased serum IGF-1 by +117% (within physiologic range), reduced percent body fat by −7.4%, and produced a favourable effect on global cognition with the strongest signal on executive function.

— Baker et al., Arch Neurol 2012;69(11):1420–1429

Clinical Status

Regulatory Status
Approved in the United States (FDA): Egrifta (F1, 10 November 2010), Egrifta SV (F4, 2019), and current Egrifta WR (F8, 25 March 2025) for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Approved in Canada (Theratechnologies’ home market). Not authorised in the European Union — the marketing authorisation application was withdrawn on 21 June 2012 by Ferrer Internacional after the CHMP raised concerns about long-term cardiovascular safety.
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Highest Trial Phase
Approved (Phase IV / post-marketing) in the U.S. and Canada; not authorised in the EU
Sponsor
Theratechnologies Inc. (Montreal, Canada)

Key Clinical Trials

  • TH9507 in Patients With HIV-Associated Lipodystrophy (pivotal Phase III; basis of Falutz et al. NEJM 2007)
    Phase 3
    NCT00123253
  • TH9507 in Patients With HIV-Associated Lipodystrophy (second pivotal Phase III; basis of pooled Falutz 2010 JCEM analysis)
    Phase 3
    NCT00435136
  • TH9507 Extension Study in Patients With HIV-Associated Lipodystrophy (long-term safety extension)
    Phase 3
    NCT00608023
  • Tesamorelin Effects on Liver Fat and Histology in HIV (Mass General; basis of Stanley et al. Lancet HIV 2019)
    Phase 2
    NCT02196831
  • Diabetic Retinopathy in HIV Subjects Treated With EGRIFTA® (FDA-mandated post-marketing safety study)
    Phase 4
    NCT01591902
  • SMART: Somatotrophics, Memory, and Aging Research Trial (cognitive endpoints in MCI and healthy older adults; basis of Baker et al. Arch Neurol 2012)
    Phase 2
    NCT00257712

Safety Profile

Observed in research settings

Across HIV-lipodystrophy Phase III trials and post-marketing experience, tesamorelin was generally well tolerated in research settings, with the most frequent events being injection-site reactions, arthralgia, and IGF-1 elevation. Clinically meaningful concerns relate to glucose intolerance, fluid retention, sustained IGF-1 elevation with theoretical malignancy implications, and hypersensitivity reactions.

Adverse Events Reported in Studies

  • Arthralgia
  • Injection-site reactions (erythema, pruritus, haemorrhage, irritation, pain, swelling)
  • Pain in extremity
  • Peripheral oedema
  • Myalgia
  • Paraesthesia / hypoaesthesia
  • Hyperglycaemia and modest HbA1c elevation
  • Headache, nausea
  • Asymptomatic IGF-1 elevation (some patients exceeding the upper limit of normal)

Serious Adverse Events

  • Theoretical neoplasm risk from GH and IGF-1 stimulation — contraindicated in active malignancy and in patients with disrupted hypothalamic-pituitary axis (hypophysectomy, hypopituitarism, pituitary tumour, pituitary surgery, head irradiation, head trauma)
  • Glucose intolerance and diabetes mellitus — periodic monitoring of fasting glucose and HbA1c recommended
  • Fluid retention (peripheral oedema, carpal-tunnel-like symptoms)
  • Hypersensitivity / acute systemic allergic reactions, including urticaria and anaphylaxis-like reactions (post-marketing)
  • Pregnancy (FDA Pregnancy Category X — contraindicated)
  • Long-term cardiovascular safety has not been established (explicitly retained in the FDA Egrifta WR label)

References

  1. 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. 2007 .

    DOI: 10.1056/NEJMoa072375 PMID: 18057338 View Source

  2. Falutz J, Mamputu J-C, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in HIV-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. 2010 .

    DOI: 10.1210/jc.2010-0490 PMID: 20554713 View Source

  3. Falutz J, Potvin D, Mamputu J-C, et al. 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. J Acquir Immune Defic Syndr 2010;53(3):311–322. 2010 .

    DOI: 10.1097/QAI.0b013e3181cbdaff PMID: 20101189 View Source

  4. 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. 2014 .

    DOI: 10.1001/jama.2014.8334 PMID: 25038354 View Source

  5. Stanley TL, Fourman LT, Feldpausch MN, et al. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. Lancet HIV 2019;6(12):e821–e830. 2019 .

    DOI: 10.1016/S2352-3018(19)30338-8 PMID: 31611038 View Source

  6. Stanley TL, Falutz J, Marsolais C, et al. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis 2012;54(11):1642–1651. 2012 .

    DOI: 10.1093/cid/cis251 PMID: 22495074 View Source

  7. 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. 2012 .

    DOI: 10.1001/archneurol.2012.1970 PMID: 22869065 View Source

  8. U.S. Food and Drug Administration EGRIFTA WR (tesamorelin for injection) — Highlights of Prescribing Information (2025 revision). FDA Drug Label, application 022505. 2025 .

    View Source

  9. Theratechnologies Inc. Theratechnologies Receives FDA Approval for EGRIFTA WR™ (Tesamorelin F8) to Treat Excess Visceral Abdominal Fat in Adults with HIV and Lipodystrophy. Press release. 2025 .

    View Source

  10. European Medicines Agency Ferrer Internacional, S.A. withdraws its marketing authorisation application for Egrifta (tesamorelin). EMA press release / Q&A. 2012 .

    View Source

Frequently Asked Questions

What is tesamorelin?
Tesamorelin (development code TH9507) is a synthetic 44-amino-acid analogue of human growth-hormone-releasing hormone (GHRH/GRF(1-44)) with a trans-3-hexenoyl group conjugated to its N-terminal tyrosine. The acyl modification blocks DPP-IV cleavage and extends in-vivo activity, allowing the peptide to bind the pituitary GHRH receptor (GHRHR) and stimulate the body’s own pulsatile release of growth hormone. It is the active ingredient in Egrifta, Egrifta SV, and the current Egrifta WR formulations marketed by Theratechnologies for HIV-associated lipodystrophy.
How does tesamorelin differ from recombinant human growth hormone (rhGH)?
rhGH (somatropin) supplies exogenous GH directly, producing sustained, supraphysiologic GH and IGF-1 levels that do not respect normal pulsatile feedback. Tesamorelin instead acts upstream at the pituitary GHRH receptor, so somatotrophs release endogenous GH in a pulsatile, physiologically regulated pattern that remains under negative feedback by IGF-1 and somatostatin. In HIV-lipodystrophy trials this translated to selective visceral-fat reduction with a more favourable glucose-tolerance profile than was reported with earlier high-dose rhGH regimens.
Is tesamorelin approved by regulators?
Yes, in the United States. The original Egrifta formulation was approved by the FDA on 10 November 2010 for the reduction of excess abdominal fat in HIV-infected adults with lipodystrophy. The reduced-volume Egrifta SV (F4) followed in 2019, and the current Egrifta WR (F8) — daily injection with weekly vial reconstitution — was approved on 25 March 2025. Tesamorelin is not authorised in the European Union; the marketing authorisation application was withdrawn by Ferrer Internacional in June 2012 after the CHMP raised concerns about long-term cardiovascular safety.
What is the molecular structure of tesamorelin?
Tesamorelin is a single linear 44-amino-acid peptide — sequence-identical to native human GHRH(1-44)-NH₂ — with a (3E)-hex-3-enoic acid acyl group conjugated to the α-amino group of Tyr¹ and a leucinamide at the C-terminus. Its molecular formula (free base) is C₂₂₁H₃₆₆N₇₂O₆₇S and its average molecular weight is 5135.86 Da (CAS 218949-48-5; PubChem CID 16137828).
What VAT (visceral adipose tissue) reduction has been observed in tesamorelin trials?
In the pivotal Phase III NEJM trial (Falutz 2007), daily 2 mg tesamorelin for 26 weeks produced a −15.2% reduction in VAT versus a +5.0% increase with placebo (P < 0.001). The pooled Phase III analysis (Falutz 2010 JCEM, n = 806) reported a treatment effect of approximately −15.4% (−24 cm² absolute), maintained through 52 weeks. The Mass General Phase II (Stanley 2014 JAMA) reported an absolute VAT reduction of −34 cm² at 6 months. Effects are largely reversed within months of discontinuation.
What are the main side effects observed in tesamorelin studies?
Across Phase III HIV-lipodystrophy trials and post-marketing experience the most frequently reported adverse events have been injection-site reactions, arthralgia, pain in extremity, peripheral oedema, myalgia, paraesthesia, headache, and asymptomatic IGF-1 elevation. Less common but clinically meaningful events include hyperglycaemia / glucose intolerance, fluid retention, and hypersensitivity (including anaphylaxis-like) reactions. The label contraindicates use in patients with active malignancy, disrupted hypothalamic-pituitary axis, or pregnancy, and notes that long-term cardiovascular safety has not been established.

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