Thymopentin (TP-5)

A synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr) reproducing residues 32 to 36 of the thymic hormone thymopoietin, authorized in Italy and produced in China as an immunomodulator but never approved by the FDA after mixed trials in HIV, rheumatoid arthritis and hepatitis B.

Also referenced as: TP5, Timunox, Sintomodulina, Immunox, Timopentina, ORF 15244, NSC 645363

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What is Thymopentin (TP-5)?

Thymopentin is a synthetic linear pentapeptide, arginyl-lysyl-aspartyl-valyl-tyrosine (Arg-Lys-Asp-Val-Tyr), with the molecular formula C30H49N9O9 and a molecular weight of 679.8 Da. It reproduces residues 32 to 36 of thymopoietin, a 49-amino-acid polypeptide of 5,562 Da isolated from bovine thymus and sequenced in 1975 as a T-cell-differentiating thymic hormone (Schlesinger and Goldstein, Cell, 1975;5(4):361–365). In 1979 the same group showed that the free pentapeptide induced murine prothymocytes to differentiate into thymocytes, inhibited differentiative induction of B-lineage cells and reduced autologous rosette-forming cells in the spleens of athymic mice, and proposed it as a readily synthesized therapeutic substitute (Goldstein et al., Science, 1979;204(4399):1309–1310).

Thymopoietin III, a 49-residue homolog isolated from bovine spleen, was sequenced in 1981 (Audhya et al., Biochemistry, 1981;20(21):6195–6200) and later named splenin; it differs from thymopoietin only at position 34, where glutamic acid replaces aspartic acid, so its pentapeptide splenopentin (Arg-Lys-Glu-Val-Tyr) is thymopentin with one conservative substitution. A 1987 report of the human thymopoietin and splenin sequences was retracted by its authors in 1994 (Goldstein et al., Proceedings of the National Academy of Sciences, 1994;91(13):6249), and later cDNA work indicated that the isolated thymopoietins were fragments of larger proteins generated during purification (Singh et al., Immunologic Research, 1998;17(3):345–368).

Thymopentin was marketed in Europe by Cilag as Timunox (Faist et al., Annals of Surgery, 1991;214(3):264–273), and the Immunobiology Research Institute sponsored its US HIV trials under the same brand (NCT00002109). It holds an Italian marketing authorization as Sintomodulina (Italfarmaco) and is produced by multiple manufacturers in China, where it is used as an adjunct in infection, hepatitis, cancer and dialysis settings. It was never approved in the US and circulates as a research-market compound.

How it works

• Active site of thymopoietin with two second-messenger signals. Thymopentin reproduces the activities of the native hormone: in precursor T cells it triggers differentiation through cyclic AMP, while its regulatory actions on mature peripheral T cells are mediated by cyclic GMP, and in animal models it behaves as an “immunonormalizing” agent whether the baseline defect is hyper- or hyporesponsiveness (Goldstein and Audhya, Survey of Immunologic Research, 1985;4 Suppl 1:1–10).
• Seconds of plasma exposure, days of cellular effect. In plasma the pentapeptide is rapidly inactivated by serine protease and aminopeptidase M-like enzymes (Audhya and Goldstein, International Journal of Peptide and Protein Research, 1983;22(2):187–193). The Italian product information gives a plasma half-life of about 30 seconds. A myristic acid-acylated, albumin-binding analog markedly extended stability in human plasma and prolonged activity in immunosuppressed rats (Tan et al., International Immunopharmacology, 2017;47:88–94).
• Shifts the cytokine balance toward interleukin-2. In a mouse model of gut-derived sepsis, thymopentin reduced mortality, lowered interleukin-4 and raised interleukin-2 (Braga et al., Journal of Surgical Research, 1996;62(2):197–200), and in 60 open heart surgery patients thymopentin with indomethacin prevented the postoperative collapse of interleukin-2 synthesis seen in controls (Faist et al., Annals of Surgery, 1991;214(3):264–273).
• Renewed preclinical interest in oncology. In mouse tumor models thymopentin suppressed growth in a strictly T-cell-dependent manner and promoted thymic rejuvenation under immunocompromised conditions (Hossain et al., Biomedicines, 2025;13(10):2494), and an oncolytic adenovirus engineered to express the pentapeptide outperformed the unmodified virus (Kong et al., Communications Medicine, 2026;6(1):265). Neither approach has reached a human trial.

Research status

Rheumatoid arthritis: positive short courses, negative long ones. A double-blind trial randomized 41 patients with active disease to slow intravenous 50 mg injections three times a week for 3 weeks or placebo; thymopentin was superior on tenderness, joint swelling, pain on awakening and disease activity, with a trend toward relapse 4 weeks after stopping (Malaise et al., Lancet, 1985;1(8433):832–836). A German multicenter trial of 119 patients (107 evaluable) on the same regimen reported improvement in five of nine clinical criteria at 3 weeks, benefit subsiding over the following 4 weeks and one systemic allergic reaction (Lemmel et al., Deutsche Medizinische Wochenschrift, 1988;113(5):172–176). A compilation of three trials, including a 6-month double-blind subcutaneous study at three doses and a 3-week high-dose intravenous study, found no statistically significant improvement in any of them (Veys et al., Journal of Rheumatology, 1984;11(4):462–466).

HIV: the largest program, ended without a filing. In a double-blind study of 91 HIV-seropositive patients treated for 24 or 52 weeks, asymptomatic patients on thymopentin had a greater area under the curve for the proportion of CD4+ cells (P = 0.03) but no significant difference in clinical progression, with no benefit in symptomatic patients (Conant et al., AIDS, 1992;6(11):1335–1339). The pivotal trial enrolled 352 zidovudine-treated asymptomatic subjects with 200 to 500 CD4 cells/mm3 for 48 weeks. Because of a significant treatment-by-stratum interaction the two strata were analyzed separately: among 235 subjects with more than 6 months of prior zidovudine, AIDS or death occurred in 2 thymopentin versus 10 placebo recipients (P = 0.024; relative risk 4.9, 95% CI 1.1 to 22.2), whereas among 117 subjects with 6 months or less, 4 events occurred on thymopentin and none on placebo (P = 0.11); CD4 counts, p24 antigen and adverse events did not differ (Goldstein et al., Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 1995;8(3):279–288). A post hoc analysis reported delayed progression concentrated in subjects with the codon 215 resistance mutation, high viral load or low CD4 counts (Merigan et al., AIDS, 1996;10(2):159–165). A phase 3 study of Timunox in patients on nucleoside therapy (NCT00002109) and a 60-patient phase 2 study (NCT00002332) are listed as completed with no results posted, and no new drug application followed.

Chronic hepatitis B and hepatitis B vaccination. Six months of thymopentin in 30 patients with chronic hepatitis B produced HBV-DNA clearance in 13% versus 20% of controls, no HBeAg clearance in treated patients and no HBsAg loss in either group; the authors concluded the regimen was not effective (Fattovich et al., Journal of Hepatology, 1994;21(3):361–366). As a vaccine adjuvant in hemodialysis nonresponders, a 40-patient Italian trial reported seroconversion in 86% of thymopentin recipients versus 36% with repeat vaccine alone (Donati and Gastaldi, Nephron, 1988;50(2):133–136), but a meta-analysis of 11 controlled studies with 272 patients found no significant overall increase in seroresponse (pooled odds ratio of vaccine failure 0.677, 95% CI 0.285 to 1.605), with benefit confined to the higher-dose subgroup (Fabrizi et al., Alimentary Pharmacology and Therapeutics, 2006;23(11):1559–1566). Adding 24 weeks of thymopentin to entecavir plus peginterferon in 45 HBeAg-positive patients did not change mean HBsAg levels between groups (P = 0.112) (Ma et al., Cellular and Molecular Biology, 2019;65(2):75–81).

Atopic dermatitis, surgery and chemotherapy. In a 12-week multicenter trial, 39 patients with severe atopic dermatitis randomized to thymopentin or placebo showed significantly greater improvement on thymopentin with no drug-related adverse events (Stiller et al., Journal of the American Academy of Dermatology, 1994;30(4):597–602). In 206 patients undergoing gastric or colorectal cancer surgery, perioperative thymopentin did not significantly reduce postoperative infection (17.5% versus 24.3%) but prevented the postoperative fall in CD3+ and CD4+ cells in elderly patients (Braga et al., British Journal of Surgery, 1994;81(2):205–208). The Cochrane review of thymic peptides in cancer identified 26 trials with 2,736 patients, only six using synthetic peptides (thymopentin or thymosin alpha-1); it found no effect of thymus extracts on survival, disease-free survival or tumor response, with most trials at moderate risk of bias (Wolf et al., Cochrane Database of Systematic Reviews, 2011;2011(2):CD003993). A meta-analysis of 27 Chinese trials (1,925 patients) of synthetic thymic peptides with chemotherapy for non-small cell lung cancer reported higher 1-year survival (RR 1.43) on moderate to very low quality evidence, with the clearest effects attributed to thymosin alpha-1 (Zeng et al., International Immunopharmacology, 2019;75:105747). A Fudan University phase 3 trial after resection of small hepatocellular carcinoma, started in February 2007 (NCT00460681), has not been updated since October 31, 2007.

Chinese clinical use. The recent literature comes largely from China: a randomized trial of 135 myasthenia gravis patients undergoing extended thymectomy reported higher remission and lower relapse rates with added thymopentin (Liu et al., Zhonghua Yi Xue Za Zhi, 2008;88(33):2335–2338); a 96-patient randomized study in older adults with chronic heart failure reported higher ejection fraction (Xiaojing et al., Anatolian Journal of Cardiology, 2017;17(1):24–30); and a retrospective study of 100 peritoneal dialysis patients associated thymopentin with fewer infections (adjusted HR 0.54, 95% CI 0.30 to 0.95) (Chen et al., BMC Nephrology, 2025;26(1):538). These studies are small or single-center and unreplicated elsewhere.

Safety. Across the Western trials the peptide was well tolerated, with injection-site reactions and one systemic allergic reaction; the Italian product information also notes rare leukocytopenia. Thymopoietin was originally isolated while studying thymic effects on neuromuscular transmission (Singh et al., Immunologic Research, 1998;17(3):345–368), and a 2026 case report described new-onset myasthenia gravis attributed to thymopentin (Zhao et al., Balkan Medical Journal, 2026;43(5):291–293).

Common dosage forms

• Sintomodulina (Italy). Thymopentin solution for injection as a 1 mL ampoule of 50 mg/mL and a 5 mL multidose vial of 10 mg/mL, for intramuscular or subcutaneous injection by a clinician.
• Thymopentin for injection (China). Lyophilized powder in vials from multiple domestic manufacturers, administered in hospitals and clinics.
• Research-market vials. Lyophilized thymopentin sold for laboratory use; oral and long-acting formulations exist only in animal studies.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any FDA-approved thymopentin product and of any active US-directed development program as of November 2026. Italian product information lists Sintomodulina (Italfarmaco), first authorized June 1, 2000, for thymic and other primary immunodeficiencies and as an adjunct in secondary immunodeficiency. The peptide is also produced and used in China, and the US HIV program of the 1990s ended without a filing.
• The evidence is old, small and inconsistent. Positive results came from 3-week intravenous courses in rheumatoid arthritis and from one stratum of one HIV trial, and none was reproduced in a longer or confirmatory study. No adequately powered modern trial exists for any indication.
• A 30-second half-life dictates injection. Plasma peptidases destroy the pentapeptide almost immediately, so every clinical regimen has relied on repeated injection; oral and albumin-binding analogs remain preclinical.
• Tolerability is good but not unremarkable. Allergic reactions, rare leukocytopenia and a reported case of thymopentin-associated myasthenia gravis are the identified signals, and the neuromuscular activity of the parent hormone is a reason for caution in myasthenic disease.
• Naming and relatives. TP-5, Timunox, Sintomodulina and Immunox all denote the same pentapeptide; splenopentin is the single-residue variant from splenin. It is unrelated in sequence to thymosin alpha-1, thymulin and the thymus extract thymalin, although all are sold as thymic immunomodulators.