Also Known As: Thymosin beta-4, Thymosin β-4, Tβ4, TB4, Timbetasin, Fequesetide, TMSB4X protein, Ac-LKKTETQ, RGN-259, RGN-352, RGN-137
TB-500 is a deliberately ambiguous label: in peer-reviewed and patent literature, "TB-500" denotes the synthetic, N-acetylated heptapeptide Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln (Ac-LKKTETQ, residues 17–23 of full-length Thymosin β-4, CAS 885340-08-9, MW ~889 Da, proposed INN "fequesetide"). In research-chemical and veterinary commerce, "TB-500" is routinely sold as a synonym for full-length 43-amino-acid Thymosin β-4 (timbetasin, CAS 77591-33-4, MW ~4921 Da, UniProt P62328, encoded by the X-linked gene TMSB4X) — and it is this full-length form that has been studied in the human clinical programmes RGN-259 (topical ophthalmic), RGN-352 (intravenous) and RGN-137 (topical dermal). The two molecules are chemically distinct and are NOT interchangeable; any editorial statement must specify which form is intended. Thymosin β-4 is the major intracellular G-actin-sequestering peptide in mammalian cells; it binds globular actin 1:1, regulates the unpolymerised actin pool, and modulates cell migration, angiogenesis, and tissue repair. Studies report, in preclinical rodent cardiac models, infarct size reduction and epicardial-progenitor mobilisation (Bock-Marquette 2004 Nature; Smart 2007 Nature) as well as wound-healing activity partly mediated by the N-terminal cleavage product AcSDKP. Human clinical evidence is mixed: the RGN-259 ARISE programme (Phase 2/3 NCT02597803, Phase 3 NCT02974907) did not meet pre-specified co-primary endpoints in dry-eye disease, although secondary endpoints on central / inferior corneal staining reached significance; the Phase 3 neurotrophic-keratopathy trial (NCT02600429, Sosne 2022) showed a trend toward complete epithelial-defect healing at day 28 (P=0.0656) and significance by day 43 (P=0.0359). The RGN-352 IV cardiac programme (NCT01311518) was withdrawn before enrollment in 2011 after the FDA placed it on clinical hold for contract-manufacturer cGMP non-compliance; the RGN-137 epidermolysis-bullosa programme (NCT03578029) was terminated for business reasons. There is NO marketing approval from FDA, EMA, MHRA, PMDA or NMPA for any indication. The World Anti-Doping Agency lists both Thymosin β-4 and TB-500 explicitly under Class S2 (peptide hormones, growth factors and related substances and mimetics) of the 2026 Prohibited List — prohibited at all times, in- and out-of-competition. Thymosin β-4 (TB-500) is genetically and mechanistically unrelated to Thymosin α1 (Tα1, Zadaxin): different gene (TMSB4X vs PTMA), different chromosome (X vs 2), different protein family (β-thymosin vs pro-/parathymosin), different mechanism (G-actin sequestration vs TLR2/TLR9 immune agonism).
Thymosin β-4 is the major intracellular G-actin-sequestering peptide in mammalian cells; it binds monomeric actin in a 1:1 stoichiometry through the central LKKTETQ motif (the same heptapeptide that is sold in commerce as the "TB-500" 7-mer) and thereby regulates the unpolymerised actin pool, cell migration, angiogenesis and tissue repair.
Thymosin β-4 is a 43-residue, intrinsically disordered peptide encoded by the X-linked gene TMSB4X; it is the most abundant member of the β-thymosin family and the principal G-actin buffer in eukaryotic cells. The central LKKTETQ motif (residues 17–23) — exactly the heptapeptide marketed in commerce as "TB-500" — mediates direct 1:1 binding to monomeric actin (structural basis PDB 1T44, Irobi et al. EMBO J 2004). Beyond actin sequestration, Tβ4 displays "moonlighting" pro-repair activity in preclinical models: in murine cardiac models it activates integrin-linked kinase, promotes cardiomyocyte survival and migration after coronary-artery ligation, and mobilises adult epicardial progenitor cells to drive coronary neovascularisation (Bock-Marquette 2004 Nature; Smart 2007 Nature). It is also processed in vivo to the tetrapeptide AcSDKP, which contributes anti-fibrotic and angiogenic effects independently of actin binding. **Critical disambiguation**: Thymosin β-4 is NOT pharmacologically related to Thymosin α1 — Tα1 is a 28-residue fragment of pro-thymosin α (gene PTMA, chromosome 2), belongs to the pro-/parathymosin family, and acts via TLR2/TLR9 stimulation of antigen-presenting cells (Zadaxin, immune modulator). The two molecules share only the historical "thymosin" naming derived from the 1960s–1970s thymic-extract fractionation work of Goldstein and colleagues; they have different genes, sequences, structures and mechanisms. Mechanism statements here are intentionally hedged — studies report, proposed pathways, inferred from preclinical data — and never framed as established human pharmacology.
The evidence base consists of preclinical rodent actin-binding studies, a murine cardiac-repair literature (Bock-Marquette 2004 Nature; Smart 2007 Nature), completed Phase 2/3 ophthalmic programmes with mixed primary endpoints (RGN-259 ARISE-1/2; Phase 3 NK NCT02600429) and a withdrawn IV cardiac programme (RGN-352 NCT01311518). An adequately powered randomised trial in the leading indication (cardiac repair in humans) has never been completed; the Beijing Northland Phase 2 programme (NCT05984134) has not published its primary outcomes in a peer-reviewed venue.
Studies report that systemic Tβ4 administered after coronary-artery ligation in mice reduced infarct scar size and improved left-ventricular function; the proposed mechanism is ILK activation and Akt-mediated pro-survival signalling.
— Bock-Marquette et al., Nature 2004;432:466–472 (PMID 15565145)
Studies report that Tβ4 mobilised quiescent adult epicardial progenitor cells and triggered a coronary neovascularisation programme in adult mice — a reactivation of the developmental coronary-vasculogenesis programme.
— Smart et al., Nature 2007;445:177–182 (PMID 17108969)
Studies report that, in a randomised placebo-controlled Phase II trial conducted under controlled adverse environment conditions, 0.1% Tβ4 ophthalmic solution did not meet its pre-specified co-primary endpoints (inferior corneal staining P=0.2586; ocular discomfort P=0.2210). Secondary endpoints reached significance: central corneal staining (P=0.0075), superior corneal staining (P=0.0210), 27% smaller increase in CAE-induced ocular discomfort (P=0.0244). Adverse events: 5.6% in the Tβ4 arm vs 13.9% placebo; no SAEs.
— Sosne & Ousler, Clin Ophthalmol 2015;9:877–884 (PMID 26056426)
Studies report that RGN-259 0.1% vs vehicle achieved complete epithelial-defect healing at day 28 in 60% vs 12.5% of patients (trend P=0.0656) and reached statistical significance by day 43 (P=0.0359); Mackie-stage improvement P=0.0467. 16 adverse events across 7 subjects, 1 treatment-related, no treatment-related SAEs.
— Sosne et al., Int J Mol Sci 2022;24(1):554 (PMC9820614)
Studies report that the ARISE-1 / ARISE-2 programme (RGN-259 0.1% ophthalmic, NCT02597803, NCT02974907; ReGenTree LLC) did not meet its pre-specified co-primary endpoints; pooled secondary signals (central and inferior corneal fluorescein staining at week 2) reached significance. Safety was described as well tolerated.
— Nature Sci Rep 2018, s41598-018-28861-5; ClinicalTrials.gov NCT02974907
Observed in research settings
Across completed RegeneRx / ReGenTree / Sosne et al. trials, Tβ4 has been described as well tolerated at the doses studied, with adverse-event rates similar to or lower than placebo / vehicle. Long-term controlled human safety data are largely absent — observed in research settings. The synthetic 7-residue fragment Ac-LKKTETQ has no peer-reviewed human safety dataset; animal/veterinary use (especially in horses) and human research-chemical use are unregulated; safety profile in humans is "not publicly disclosed".
Low TLK, Hu SK, Goldstein AL Complete amino acid sequence of bovine thymosin β4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations Proc Natl Acad Sci USA 1981;78(2):1162–1166. 1981 .
Low TLK, Goldstein AL Chemical characterization of thymosin β4 J Biol Chem 1982;257(2):1000–1006. 1982 .
Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair Nature 2004;432(7016):466–472. 2004 .
Smart N, Risebro CA, Melville AAD, Moses K, Schwartz RJ, Chien KR, Riley PR Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization Nature 2007;445(7124):177–182. 2007 .
Irobi E, Aguda AH, Larsson M, Guerin C, Yin HL, Burtnick LD, Blanchoin L, Robinson RC Structural basis of actin sequestration by thymosin-β4: implications for WH2 proteins EMBO J 2004;23(18):3599–3608 (PDB 1T44). 2004 .
Sosne G, Ousler GW Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model Clin Ophthalmol 2015;9:877–884. 2015 .
Sosne G, Dunn SP, Kim C 0.1% RGN-259 (Thymosin β4) ophthalmic solution promotes healing and improves comfort in neurotrophic keratopathy patients in a randomized, placebo-controlled, double-masked Phase III clinical trial Int J Mol Sci 2022;24(1):554. 2022 .
World Anti-Doping Agency The 2026 Prohibited List — International Standard. Section S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics): Thymosin β-4 and TB-500 explicitly named WADA 2026 Prohibited List. 2026 .
Thymic peptide hormone analogue / immune modulator (slug: immune-other; pleiotropic TLR2/TLR9-mediated effect rather than a classical single-receptor agonist)
Synthetic 28-amino-acid N-acetylated thymic peptide (thymalfasin / Zadaxin); pleiotropic TLR2/TLR9-mediated immune modulator — approved as Zadaxin in 35+ countries (Italy, China, Vietnam, Mexico and others) for chronic hepatitis B and as a vaccine adjuvant in immunocompromised populations, but NOT FDA-approved in the United States — only orphan-drug designations exist there.
View DetailsSynthetic cytoprotective pentadecapeptide (tissue-repair / healing research compound)
Synthetic 15-amino-acid pentadecapeptide (PL-14736) derived from a fragment of a 60-aa protein in human gastric juice. Proposed cytoprotective and angiogenic activity is largely inferred from preclinical rodent and in-vitro data; not approved by any regulator and intended for research use only.
View DetailsGHRH(1-29) Receptor Agonist (Growth-Hormone Secretagogue, GRF Class)
Synthetic GHRH(1-29) amide (Geref); the shortest fragment of human growth-hormone-releasing hormone that retains full biological activity — historically FDA-approved for pediatric GH deficiency and voluntarily withdrawn from the US market in 2008 for commercial reasons.
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