Research Dossier on Tesamorelin

(TH9507; a stabilized 44-amino-acid growth hormone–releasing hormone (GHRH) analog)

(Growth Hormone Secretagogue)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Tesamorelin is a 44–amino-acid peptide analog of human growth hormone–releasing hormone (GHRH(1–44)-NH₂) engineered for greater proteolytic stability and improved pharmacokinetics relative to native GHRH. The analog retains the orthosteric N-terminal pharmacophore necessary for high-affinity binding to the pituitary GHRH receptor, with an N-terminal modification (trans-3-hexenoyl on Tyr¹) and specific residue substitutions that slow dipeptidyl-peptidase and endopeptidase degradation (sequence-level details are cataloged in chemical monographs and FDA primary documents). As a peptide drug, tesamorelin is supplied as a lyophilized powder for subcutaneousadministration after reconstitution.NCBI+1

Molar mass. As a 44-mer amide with an N-acyl group, the calculated molar mass is in the ~5.1–5.2 kDa range (exact value depends on salt/solvent of crystallization; authoritative clinical documents focus on clinical pharmacology rather than exact mass tabulations).FDA Access Data

Discovery history (lab, year, species)

Tesamorelin (TH9507) was developed by Theratechnologies (Montreal) as a stabilized GHRH(1–44) analog. By the mid-2000s it progressed through phase-2/3 for HIV-associated visceral adiposity, culminating in the seminal NEJMreport (2007) of reduced visceral adipose tissue (VAT) in randomized trials and eventual regulatory reviews.New England Journal of Medicine+1

Endogenous vs synthetic origin

• Endogenous: GHRH is a hypothalamic peptide that binds the GHRH receptor on pituitary somatotrophs, driving pulsatile GH release and downstream IGF-1 production.

• Synthetic: Tesamorelin is a synthetic GHRH analog with sequence modifications (including an N-terminal trans-3-hexenoyl moiety on Tyr¹) that confer greater plasma stability and reproducible subcutaneouspharmacology.NCBI

Homologs, analogs, derivatives

• Sermorelin: GHRH(1–29) amide; shorter, less stable in circulation.

• CJC-1295 (DAC:GRF): albumin-binding GHRH analog with prolonged t½ via in-vivo DAC conjugation.

• CJC-1295 without DAC / mod-GRF(1–29): stabilized 29-mer lacking albumin conjugation; shorter t½.

• Other GHRH analogs (e.g., MR-409, MR-502): experimental variants with altered receptor bias/PK. These comparators define a mechanistic landscape but do not share identical clinical evidence with tesamorelin.Analytical Science Journals

Historical Development & Research Trajectory

Key milestones in discovery and study

• Proof-of-concept in HIV lipodystrophy (2007): In a 26-week placebo-controlled trial (n=412), tesamorelinsignificantly reduced VAT and improved trunk fat vs placebo in people living with HIV (PLWH) with central adiposity. Investigational dose used in study: 2 mg subcutaneous once daily.New England Journal of Medicine+1

• Extension and body-composition data (2010–2011): Follow-on randomized extension showed sustained VAT reduction over 52 weeks and re-accumulation after discontinuation; metabolic safety (glucose/IGF-1) and lipidchanges were characterized. Investigational dose used in study: 2 mg SC daily.PubMed+1

• Ectopic fat endpoints (2014): A randomized controlled study in PLWH demonstrated VAT reductions accompanied by liver fat (hepatic steatosis) improvements measured by MRI-PDFF. Investigational dose used in study: 2 mg SC daily.JAMA Network

• Mechanistic PD (2009–2018): Formal clinical pharmacology and LiverTox/monograph summaries established short plasma t½ (tens of minutes), pulsatile GH augmentation, IGF-1 increases, and no direct hepatotoxic profile; glucose effects monitored due to GH physiology.FDA Access Data+1

Paradigm shifts and controversies

1. From GH infusion to GHRH analogs. Rather than administering exogenous GH, tesamorelin amplifies endogenous, pulsatile GH via GHRH-R activation, potentially preserving physiologic signaling and feedback. Whether this confers a safer metabolic profile than GH itself in all subpopulations remains context-dependent.NCBI

2. Visceral vs subcutaneous fat. Trials demonstrated selective VAT reduction with less effect on subcutaneous fat compared with historical GH data, raising interest in ectopic fat biology (e.g., hepatic lipid).JAMA Network

3. Metabolic trade-offs. As with any GH-axis stimulation, careful attention to glucose tolerance (fasting glucose, HbA1c) and IGF-1 elevations is necessary; clinical documents outline monitoring in PLWH, where insulin resistance and NAFLD prevalence are non-trivial.FDA Access Data

Evolution of scientific interest

From HIV-related lipodystrophy toward NAFLD/NASH-adjacent outcomes (liver fat) and neurocognitiveexplorations (GHRH-axis in aging), tesamorelin’s literature spans metabolism, body composition, and brain metaboliceffects in small, controlled settings.JAMA Network+1

Mechanisms of Action

Primary and secondary receptor interactions

Tesamorelin binds to the pituitary GHRH receptor (GHRH-R), a class-B GPCR, promoting Gs–adenylyl cyclase–cAMP–PKA signaling that drives growth hormone (GH) synthesis and pulsatile secretion. GH in turn induces hepatic IGF-1 and mediates lipolysis in adipose tissues, shifts substrate utilization, and influences protein and glucosemetabolism.NCBI

Anabolic vs lipolytic balance. In PLWH with visceral adiposity, the dominant clinically observed effect is VAT reduction, likely via increased lipolysis and fatty-acid oxidation; lean mass may be modestly influenced by the GH/IGF-1 axis, but trials largely focused on adiposity and metabolic endpoints rather than validated hypertrophy measures.New England Journal of Medicine

Intracellular signaling pathways

• Pituitary: GHRH-R → cAMP/PKA → GH gene transcription and exocytosis.

• Liver: GH → JAK2–STAT5 signaling → IGF-1 transcription; IGF-1 has systemic anabolic and metabolic effects.

• Adipose: GH enhances hormone-sensitive lipase activity and lipolysis, preferentially affecting visceral depots in clinical studies of PLWH.PubMed

CNS vs peripheral effects

• Peripheral: Pituitary/liver/adipose actions dominate VAT and lipid endpoints.

• CNS: GHRH-axis manipulation has been studied for cognitive aging and brain metabolism (e.g., ¹H-MRS, FDG-PET) in non-HIV cohorts, but these results are exploratory and not central to tesamorelin’s lipodystrophy literature.JAMA Network

Hormonal, metabolic, immune interactions

• Glucose homeostasis: GH is counter-regulatory to insulin; small increases in fasting glucose/HbA1c have been reported in some settings, necessitating monitoring in PLWH (often with other metabolic risks).FDA Access Data

• IGF-1: Increases in circulating IGF-1 are expected; labeling documents highlight precautions where sustained IGF-1 elevation may be undesirable.FDA Access Data

Evidence grading (A–C)

• A (replicated RCTs/mechanistic consensus): GHRH-R agonism → increased GH pulsatility → VAT reductionwith daily SC tesamorelin in PLWH.New England Journal of Medicine

• B (translational/biomarker-anchored): Liver fat reductions by MRI-PDFF; lipid parameter changes; IGF-1/glucose safety monitoring paradigms.JAMA Network

• C (uncertain/adjacent): Broader use beyond PLWH; long-term cardiometabolic outcomes; neurocognitive benefits via GHRH in aging (adjacent literature).JAMA Network

Pharmacokinetics & Stability

ADME profile (human)

• Absorption: After subcutaneous dosing, bioavailability is low (<4%), consistent with peptide physiology; therapeutic strategy relies on daily SC administration to drive GH pulsatility. Investigational PK from healthy/HIV cohorts.DrugBank

• Distribution: Large apparent Vd (~9–10 L·kg⁻¹) reflecting tissue distribution beyond plasma in both healthy and HIV-infected adults.DrugBank

• Metabolism: Proteolysis to small peptides/amino acids; no formal human metabolism studies have been published, consistent with peptide class.DrugBank

• Elimination half-life: Short—approximately 26–38 minutes after SC administration (healthy vs HIV cohorts), as reported in clinical pharmacology summaries and investigator brochures; nevertheless, the downstream IGF-1response persists well beyond the parent t½.PMC+1

Plasma half-life & degradation pathways

Primary documents (NDA clinical pharmacology review) note that pre-dose/24-h samples sometimes showed assay signal due to matrix interference, reinforcing that true tesamorelin t½ is short and 24-h circulating levels should be negligible with validated methods.FDA Access Data

Stability in vitro & in vivo

As a lyophilized peptide, tesamorelin is stable under labeled conditions; upon reconstitution it is administered promptly. Official labeling distinguishes between original EGRIFTA® and the newer EGRIFTA SV® (different vial strengths/formulation details).FDA Access Data

Storage/reconstitution considerations

Regulatory labeling provides reconstitution specifics, storage temperatures, and handling differences between the 11.6-mg and 2-mg/vial products. (While those materials describe approved medicinal use, here they serve as authoritative physicochemical and PK references.)FDA Access Data+1

Preclinical Evidence

Animal and in-vitro studies

Compared with many peptides, tesamorelin’s preclinical program is relatively standard (receptor binding, cAMP signaling, in-vivo GH pulse augmentation). The clinical program—demonstrating VAT and liver-fat effects—accounts for much of the mechanistic confidence; there is no requirement for receptor over-expression or non-physiologic pathways since GHRH-R is the native target.

Illustrative investigational preclinical features

• Pituitary cAMP and GH pulse enhancement in standard species (details summarized in NDA/IB).

• No genotoxicity signal in conventional in-vitro assays (class expectation); long-term carcinogenicity studies for the analog focus on GH-axis biomonitoring (IGF-1), not on the peptide per se. (Public summaries are limited; clinical monitoring is emphasized.)FDA Access Data

Human Clinical Evidence

Phase 3–style RCTs in PLWH with central adiposity

NEJM 2007 (Falutz et al.) — Metabolic Effects of a GHRH Analog in HIV

• Design: Double-blind, randomized, placebo-controlled; n≈412 PLWH with increased VAT; 26 weeks.

• Intervention: Investigational dose used in study: 2 mg tesamorelin SC once daily vs placebo.

• Primary endpoint: Change in VAT (CT).

• Results: Significantly greater VAT reduction vs placebo; improvements in trunk fat and body image; IGF-1 rose, consistent with mechanism. Safety profile compatible with GH-axis augmentation.New England Journal of Medicine+1

AIDS 2010 / J Clin Endocrinol-style reports — Extension phase to 52 weeks

• Design: Continued tesamorelin vs randomized withdrawal to placebo.

• Findings: Sustained VAT loss at 52 weeks if treatment continued; rebound toward baseline after discontinuation, emphasizing on-treatment effect; IGF-1 elevations persisted while dosing continued; glucose markers required monitoring but were generally manageable in RCTs. Investigational dose used in study: 2 mg SC daily.PubMed+1

JAMA 2014 (Stanley, Grinspoon group) — VAT and Liver Fat

• Design: Randomized, placebo-controlled MRI-PDFF study in PLWH with central adiposity.

• Findings: Tesamorelin decreased VAT and hepatic fat vs placebo; explorations of glucose/insulin homeostasis detailed trade-offs of GH-axis activation in a metabolically diverse HIV population. Investigational dose used in study: 2 mg SC daily.JAMA Network

Meta-analyses / narrative reviews

• Summaries report 15–20% VAT reductions over 6–12 months with tesamorelin, with IGF-1 increase and glucosechanges that are typically small but relevant for high-risk subgroups (e.g., those with pre-existing insulin resistance).Oxford Academic

Pharmacodynamic/physiology studies

Overnight GH secretion increases and IGF-1 elevations have been documented; some analyses indicate no significant deterioration of insulin sensitivity measured by clamp or surrogate indices in selected cohorts, but population heterogeneity in PLWH (antiretrovirals, chronic inflammation) warrants individualized interpretation.Wiley Online Library

Neurocognitive/brain metabolism (adjacent literature)

GHRH in aging: Small randomized trials of GHRH (not necessarily tesamorelin) explored cognitive outcomes and brain spectroscopy in older adults with MCI vs controls, showing metabolic changes and hints of cognitive benefit. These are adjacent to tesamorelin rather than directly on-label studies.JAMA Network

Safety signals/adverse events (trial-level)

• Common AEs: Injection-site reactions, arthralgia, myalgia, peripheral edema, and transient paresthesia; nausea in some participants.

• IGF-1 elevations: Expected pharmacodynamic effect; labeling specifies IGF-1 monitoring and dose adjustments/interruptions if levels exceed thresholds.

• Glucose: Modest increases in fasting glucose/HbA1c in some individuals; trials included glucose monitoring and excluded those with poorly controlled diabetes.

• Malignancy considerations: Because IGF-1 is a growth factor, labeling includes warnings for those with active malignancy or a history thereof—risk–benefit is individualized in clinical practice contexts, though the peptide itself is not directly mitogenic.FDA Access Data

ClinicalTrials.gov examples

• NCT02012556 — phase-1 PK/PD study of tesamorelin (TH9507) formulations and endpoints.ClinicalTrials.gov

• Multiple completed RCTs in PLWH with central adiposity (NEJM 2007; extensions) and MRI-PDFF trials in liver fat have been published as above.New England Journal of Medicine+1

Regulatory note (scientific context only). Medicinal-product labeling identifies tesamorelin as a GHRH analog indicated for the reduction of excess abdominal fat in HIV-infected adults with lipodystrophy; EGRIFTA®/EGRIFTA SV® is the commercial formulation in specific regions. Here, we cite those documents solely for PK/PD and study-design details.FDA Access Data+1

Comparative Context

Related peptides

• Sermorelin (GHRH 1–29-NH₂): shorter, less stable; historically used diagnostically.

• CJC-1295 (with DAC): albumin-binding GHRH analog enabling weekly dosing; mechanistically distinct in PK but similar receptor pathway.

• GH secretagogues (ghrelin mimetics; GHSR agonists): act via ghrelin receptor rather than GHRH-R, often producing single GH pulses with short t½ (e.g., ipamorelin). These comparisons highlight differences in receptor biology, PK, and tolerability.

Advantages (research perspective)

• Physiologic GH augmentation (pulsatile) via GHRH-R rather than exogenous GH exposure.

• Selective VAT reduction demonstrated in RCTs of PLWH, with liver fat improvements in MRI-based trials.

• Known PK/PD: short plasma t½ but sustained IGF-1 response supports daily low-dose SC paradigms.PMC+1

Disadvantages/constraints

• Daily injections are required (short t½).

• IGF-1/glucose monitoring needed because of GH physiology; suitability depends on metabolic profile.

• Generality beyond PLWH lipodystrophy remains Not established in large RCTs.

Research category placement

Tesamorelin is a research-standard GHRH analog for interrogating GH pulsatility, VAT biology, hepatic steatosis, and metabolic endpoints in human and animal systems, and for comparator use against GH or ghrelin-pathway secretagogues.

Research Highlights

• Robust VAT reduction in PLWH with central adiposity across multiple RCTs using 2 mg SC daily (26–52 weeks). Investigational dose used in study.New England Journal of Medicine

• Ectopic fat: MRI-PDFF trial shows hepatic fat reduction concomitant with VAT loss. Investigational dose used in study.JAMA Network

• Mechanistic clarity: GHRH-R agonism → GH pulses → IGF-1 → adipose lipolysis/substrate shifts; short parent t½ (26–38 min) with sustained IGF-1 PD.PMC

• Safety management: Labeling emphasizes IGF-1 and glucose monitoring; injection-site reactions are the most common AEs.FDA Access Data

• Adjacency: GHRH-axis manipulation may modulate brain metabolic markers (¹H-MRS/FDG-PET) in older adults (non-HIV studies; adjacent to tesamorelin).JAMA Network

Conflicting/uncertain areas

• Durability/maintenance of VAT loss after discontinuation: extension trials show re-accumulation off-drug, indicating an on-treatment effect.PubMed

• Long-term outcomes: Hard cardiometabolic endpoints (ASCVD events, liver outcomes) remain not fully definedin PLWH treated chronically with GHRH analogs.

• Broader populations: Efficacy/safety in non-HIV obesity or NAFLD are not established by large RCTs.

Potential Research Applications (no clinical claims; research-use framing)

1. VAT biology & ectopic fat modeling

   • Use tesamorelin to interrogate visceral vs subcutaneous fat responses in mechanistic trials; integrate MRI-PDFF and CT with lipolysis flux (stable isotope tracers) to map adipose–liver crosstalk. Investigational dose paradigms follow RCTs: 2 mg SC daily.JAMA Network

2. Endocrine–metabolic network mapping

   • Quantify GH pulsatility (deconvolution) and IGF-1 trajectories; model impacts on glucose turnover (clamp studies) and hepatic insulin sensitivity in PLWH and controls.Wiley Online Library

3. Comparative receptor pharmacology

   • Systematically compare GHRH-R (tesamorelin) vs GHSR (ghrelin mimetics) on sleep-stage GH pulses, lipid oxidation, appetite, and GI tolerability, using crossover designs with PD biomarker panels.

4. Liver outcomes

   • In research cohorts with HIV-associated NAFLD, pair tesamorelin with omics (lipidomics/proteomics) to identify response signatures predictive of liver fat reduction and fibrosis markers over 48–72 weeks.JAMA Network

5. Brain metabolism (exploratory)

   • Combine tesamorelin with ¹H-MRS/FDG-PET in aging or PLWH to evaluate brain glucose/metabolite shifts associated with GH/IGF-1 axis modulation (adjacent GHRH studies suggest feasibility).JAMA Network

Safety & Toxicology

Preclinical

Standard toxicology packages (summarized in regulatory files) support clinical dosing; as a peptide, tesamorelin is degraded to amino acids/peptides with low potential for classic small-molecule toxicities. No specific genotoxic signals are reported; carcinogenicity concerns are theoretical and relate to IGF-1 physiology rather than any inherent mutagenicity.FDA Access Data

Human (trial-level signals)

• Common AEs: Injection-site reactions (erythema, pruritus), arthralgia, myalgia, paresthesia, edema; typically mild-to-moderate.

• Endocrine/metabolic: IGF-1 elevations (monitor/adjust), glucose shifts (monitor FPG/HbA1c—particularly in insulin-resistant PLWH).

• Hypersensitivity: Labeling notes potential for hypersensitivity/allergic reactions.

• Malignancy risk: Precautionary language due to IGF-1 biology; trials excluded patients with active malignancy.FDA Access Data

Data gaps / monitoring priorities

• Long-term cardiometabolic outcomes (ASCVD events, liver histology) need dedicated follow-up.

• Non-HIV populations: Robust RCTs are lacking; generalization should not be assumed.

Limitations & Controversies

• On-treatment nature: VAT re-accumulation after discontinuation underscores a pharmacologic suppressionrather than permanent remodeling.PubMed

• Glucose vigilance: Given GH physiology, even modest glycemic effects merit attention in high-risk PLWH (ART regimens, aging, NAFLD).

• Translational scope: While liver-fat reductions are encouraging, histologic NASH reversal is Not established; trials used imaging surrogates rather than biopsy endpoints.JAMA Network

Future Directions

• Maintenance strategies: Define dosing intervals and maintenance paradigms that sustain VAT/liver-fat benefits while minimizing AE burden.

• Responder signatures: Use baseline VAT, HOMA-IR, IGF-1 and lipidomic/genomic signatures to predict benefit–risk and personalize treatment in PLWH.

• Long-term outcomes: Prospective studies linking VAT/LF reduction to cardiovascular and hepatic outcomes (fibrosis progression, incident cirrhosis) are needed.

• Comparative trials: Head-to-head studies against other fat-targeting strategies (lifestyle, pharmacologic) to contextualize effect sizes and safety.

• Mechanistic neurocognitive work: Carefully designed studies to test whether GHRH-axis modulation exerts brain metabolic benefits in aging PLWH—a hypothesis extrapolated from non-HIV GHRH studies.JAMA Network

References

1. Falutz J, et al. Metabolic Effects of a Growth Hormone–Releasing Factor in Patients with HIV. N Engl J Med.2007;357:2359–2370. (VAT reduction with tesamorelin.) PMID: 18057338. PubMed+1

2. Stanley TL, et al. Effects of a Growth Hormone–Releasing Factor in HIV Patients With Lipodystrophy. J Clin Endocrinol Metab. 2010;95: (Extension/PD; half-life context). PMCID: PMC3038486. PMC

3. Stanley TL, 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. (VAT & liver fat by MRI-PDFF.) JAMA Network

4. LiverTox (NIH/NCBI). Tesamorelin. (Mechanism, PD, safety overview.) Updated 2018. NCBI

5. FDA Prescribing Information (EGRIFTA/EGRIFTA SV). Full Prescribing Information & Clinical Pharmacology. 2024–2025. (PK, dosing, safety, formulation notes.) FDA Access Data+1

6. FDA NDA Clinical Pharmacology Review (022505). 2009. (Analytical PK commentary; short t½; assay interference note.) FDA Access Data

7. Memdouh S, et al. Detection of GHRH analogs (sermorelin, tesamorelin, CJC-1295) in anti-doping/analytical frameworks. Drug Test Anal. 2021. (Analytical metabolism context.) Analytical Science Journals

8. Ishida J, et al. Growth hormone secretagogues: history, mechanism of action, and clinical utilities. Rev Clin Gerontol. 2020. (GHRH vs ghrelin pathways; insulin sensitivity context.) Wiley Online Library

9. ClinicalTrials.gov — NCT02012556 (Phase-1 PK/PD). (Trial-design reference.) ClinicalTrials.gov

10. Wohl D, et al.; Allas S, Falutz J, et al. Long-term safety/extension. AIDS 2008 & follow-ups. (Sustained effects; metabolic monitoring.) PMC

11. Friedman SD, et al. Brain effects of GHRH in MCI/aging. JAMA Neurol. 2013;70:913–920. (Adjacency to tesamorelin; ¹H-MRS/FDG-PET PD.) JAMA Network

12. Wohl D, Scherzer R, et al. VAT and insulin resistance in FRAM Study. (Background on VAT risk context.) JAIDS2007. (Cited within NEJM/AIDS papers.) NATAP

13. Clinical Infectious Diseases 2012;54:1642–1651. (Review summarizing VAT reductions 15–20% with tesamorelin over 6–12 months.) Oxford Academic

Representative investigational doses cited above:
• NEJM 2007 / RCTs: 2 mg tesamorelin SC once daily for 26 weeks (with 52-week extension). PubMed
• JAMA 2014: 2 mg SC daily for 6 months (VAT and liver fat endpoints). JAMA Network
• PK summaries: t½ ~26–38 min after SC administration in healthy vs HIV cohorts; bioavailability <4%; Vd ≈ 9–10 L·kg⁻¹. PMC+1

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.