Thymosin Beta-4

Dosing from the Literature

Published for tendon and gut repair: animal doses only, such as 1 µg placed once in a cut knee ligament in rats (Xu et al., 2013) and 100 µg a day by mouth in mice with colitis (Zhao et al., 2026). Not published: any human dose for a tendon, ligament, muscle or gut injury.

The human doses below come from trials for other uses, given as eye drops, as a gel on wounds or into a vein (ClinicalTrials.gov); the animal doses follow them. The table records each dose as the study gave it.

What It Is

Thymosin β4 (Tβ4) is a protein of 43 amino acids, Ac-SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES, its first amino acid capped with an acetyl group (Low et al., 1981; FDA substance registry). Its mass is 4,963 Da (C212H350N56O78S; PubChem). Its international nonproprietary name, also its US adopted name, is timbetasin (FDA substance registry, UNII 2D5MRE3SSY). The developer’s product codes are RGN-259 for eye drops, RGN-137 for a skin gel and RGN-352 for injection (RegeneRx 10-K, 2023); NL005 is a recombinant version of 44 amino acids made in China (Wang et al., 2021).

A group led by Allan Goldstein isolated it from calf thymus and published its full sequence in 1981, as one of the peptides in an extract called thymosin fraction 5, and described it as a thymic hormone (Low et al., 1981). It is not specific to the thymus: it is present in many rat and mouse tissues, at high levels in macrophages, and in mice born without a thymus (Hannappel et al., 1982). In 1991 it proved identical to Fx, the peptide that holds the bulk of the unpolymerized actin in resting human platelets (Safer et al., 1991). It is found at high levels in almost every cell, and outside cells in blood plasma and wound fluid (Huff et al., 2001); exercise raised its level in human plasma (Gonzalez-Franquesa et al., 2021).

TB-500 is not the same molecule. It is a synthetic seven-amino-acid piece, Ac-LKKTETQ, residues 17–23 of thymosin β4 with an acetyl group added, 889 Da; FDA’s 2026 review states that “thymosin beta-4 and TB-500 are not the same substance” and that several websites use the two names interchangeably (FDA TB-500 review, 2026). The developer’s products use a synthetic copy of the whole natural protein (RegeneRx 10-K, 2023), and the Chinese trials a recombinant one (Wang et al., 2021).

RegeneRx Biopharmaceuticals, a Rockville, Maryland company that Goldstein founded in 1982 and chaired, licensed NIH patent rights on Tβ4 as a tissue-repair factor in 2001, after NIH studies first suggested a role in wound healing (RegeneRx 10-K, 2023). It licensed its programs out: in 2012 to Lee’s Pharmaceutical for China, Hong Kong, Macau and Taiwan, a license assigned to Zhaoke Ophthalmology in 2019, and to GtreeBNT, now HLB Therapeutics, for the rest of Asia; in 2015 RegeneRx and HLB formed ReGenTree to develop the eye drops in the US (RegeneRx 10-K, 2023). In its last annual report RegeneRx said that without immediate new funding it expected to curtail operations, temporarily or permanently, in the second quarter of 2023, and in August 2023 it stopped filing reports with the SEC (RegeneRx 10-K, 2023; RegeneRx, August 2023). In China, Beijing Northland Biotech has tested its recombinant version, NL005, by IV in healthy volunteers (Wang et al., 2021) and registered IV trials of it after heart attack (NCT05485818; NCT05984134; NCT07586865); a 96-patient trial of a recombinant form after heart attack, with three Northland staff among its authors, was published in 2025 (Zhang et al., 2025).

No approval of thymosin β4 by any health authority turned up for this page (see Legal Status). PubMed returns 1,229 records for “thymosin beta4” (October 4, 2026), a search PubMed expands to both spellings; eight published studies gave it alone to people, and two more gave it in mixtures (see Human Data).

Mechanism of Action

Everything below was shown in cells or animals; no trial has tested how it works in people. Goldstein, the protein’s discoverer and RegeneRx’s founder, is an author of the early blood-vessel and skin-wound studies (Malinda et al., 1997; Malinda et al., 1999; RegeneRx 10-K, 2023).

• Actin-monomer buffer (G-actin sequestration) — Purified from human platelets, where it was known as Fx, it bound actin monomers one to one and blocked their assembly into filaments (Safer et al., 1991). A review describes it as the main actin buffer inside cells, holding monomers until the cell needs filaments (Huff et al., 2001).
• Endothelial-cell migration and new vessels (the LKKTETQ stretch) — In Boyden-chamber tests it drew human umbilical-vein endothelial cells four- to sixfold more than medium alone, raised their output of matrix metalloproteinases, and drew cells into implanted gel plugs (Malinda et al., 1997). Its seven-amino-acid actin-binding stretch, LKKTETQ, matched the whole protein in endothelial migration and chick aortic-arch sprouting at about 50 nM, while pieces lacking any part of it were inactive (Philp et al., 2003).
• Cell survival through ILK and Akt — It improved the survival of embryonic and newborn heart-muscle cells in culture, and formed a complex with PINCH and integrin-linked kinase that activated the survival kinase Akt (Bock-Marquette et al., 2004). In mouse and rat heart cells deprived of oxygen and then reoxygenated, a recombinant form activated ErbB2 signaling and reduced programmed cell death, and blocking ErbB2 removed its benefit in mice (Zhang et al., 2025).
• Epicardial progenitor cells (contested) — Mice primed with Tβ4 before a heart attack made new heart-muscle cells from epicardial progenitor cells (Smart et al., 2011). Given after the heart attack instead, it thickened the epicardium and raised capillary density, but epicardial cells did not become heart muscle (Zhou et al., 2012).
• Inflammation signaling (NF-κB) — In human corneal epithelial cells stimulated with TNF-α, it lowered NF-κB activity and p65 phosphorylation and blocked p65 from entering the nucleus (Sosne et al., 2007).
• Ac-SDKP, its first four amino acids — In kidney tissue extracts the enzyme prolyl oligopeptidase released Ac-SDKP from added Tβ4, and in rats a drug blocking the enzyme lowered Ac-SDKP in plasma, heart and kidney; the same paper notes that Ac-SDKP given to hypertensive rats reduced heart and kidney fibrosis (Cavasin et al., 2004).

What the Research Shows

The results below are in animals; the human studies are in the next section. For tendons, ligaments, muscle, bone and the gut, the record is a handful of rodent studies, and the gut studies point in opposite directions (Zhao et al., 2026; Hao et al., 2024; Sun et al., 2025).

• Ligament (rats) — In rats with a cut medial collateral ligament, 1 µg in 100 µL of fibrin sealant placed in the gap gave evenly spaced collagen bundles, thicker collagen fibrils and healing tissue that was stronger in mechanical tests at four weeks (Xu et al., 2013).
• Tendon: no study of the whole protein — No study found for this page gave thymosin β4 itself to an injured tendon (PubMed, October 4, 2026). The one Achilles-repair study gave rats a vendor peptide sold as TB-500, which its authors call synthetic thymosin beta-4, at 60 µg/kg a day into the abdomen; it is covered on the TB-500 page (Biçer et al., 2026).
• Bone (mice) — Mice with a cut fibula given 6 mg/kg into the abdomen had calluses that took 41% more force to break and were about 25% stiffer than those of saline-treated mice (Brady et al., 2014).
• Muscle (mice) — In mdx mice, a model of Duchenne muscular dystrophy, 150 µg into the abdomen twice a week for six months raised the count of regenerating muscle fibers (11.6 against 2.6) but did not improve grip strength, heart function or fibrosis; RegeneRx supplied the peptide (Spurney et al., 2010). Another group found that it did not enhance muscle regeneration in mice (Gonzalez-Franquesa et al., 2021).
• Gut (mice and rats): conflicting — Recombinant Tβ4 given by mouth, 100 µg a day, improved weight recovery, colon length and inflammation in mice with chemically induced colitis, and mice lacking its gene fared worse (Zhao et al., 2026). One group, at the Third People’s Hospital of Chengdu, found the opposite in two studies: Tβ4 injected into the abdomen of mice damaged the intestinal mucus barrier and disrupted tight junctions (Hao et al., 2024), and Tβ4 lowered tight-junction proteins in the gut of mice, while rats lacking the gene resisted stress-induced barrier damage (Sun et al., 2025).
• Skin wounds (rats) — Applied to full-thickness wounds or injected into the abdomen, Tβ4 increased re-epithelialization by 42% over saline at day 4 and by up to 61% at day 7, and treated wounds contracted at least 11% more by day 7 (Malinda et al., 1999).
• Eye (mice) — In mice with alkali-burned corneas, 5 µg in drops twice a day sped re-epithelialization and reduced white-cell infiltration and inflammatory signals (Sosne et al., 2002).
• Heart (mice and pigs) — After coronary artery ligation in mice, it improved early heart-muscle survival and heart function (Bock-Marquette et al., 2004). In pigs, 15 mg infused backward through a heart vein after 55 minutes of blocked blood flow brought infarct size to 37% of the area at risk, against 54% in controls (Hinkel et al., 2008).
• Hair (rats and mice) — It stimulated hair growth in normal rats and mice and increased the migration of hair-follicle stem cells in culture (Philp et al., 2004).
• Tumor cells (mice) — Mouse melanoma cells made to overexpress Tβ4 grew larger tumors (21.7 against 13.3 mm) and about four times more lung nodules (46.7 against 10.9) than control cells (Cha et al., 2003).

Human Data

Published (PubMed, searched October 4, 2026): eight studies that gave thymosin β4 alone to people (two IV safety studies in healthy volunteers, a heart-attack trial, a venous-ulcer trial, three eye-drop trials and a compassionate-use eye series), and two that gave it in mixtures (the last item below). The eye-drop, skin-gel and US IV trials were sponsored by the developer, RegeneRx, its joint venture ReGenTree or HLB’s subsidiary Lenus Therapeutics, except the 9-patient dry-eye study, which an eye practice sponsored (NCT01393132; NCT03578029; RegeneRx 10-K, 2023); Beijing Northland Biotech, which makes NL005, sponsored the Chinese Phase 1 and the registered heart-attack trials (NCT04555824; NCT04555850; NCT05485818; NCT05984134). With results posted on ClinicalTrials.gov but no paper: trials in pressure ulcers, epidermolysis bullosa, corneal wounds after eye surgery and two Phase 3 dry-eye trials. None tested a tendon, ligament, muscle or gut injury (ClinicalTrials.gov and PubMed, searched October 4, 2026).

• IV safety, 40 healthy volunteers (Ruff et al., 2010) — Four groups of 10 got placebo or 42, 140, 420 or 1,260 mg of synthetic Tβ4 into a vein once, and then daily for 14 days. Adverse events were infrequent and mild or moderate, with no dose-limiting toxicity or serious adverse events, and the half-life rose with the dose. The paper’s second author, David Crockford, was RegeneRx’s study director on its gel and eye trials (NCT00311766; NCT00598871), and RegeneRx reported completing its IV Phase 1a and 1b in 2009 with 60 healthy subjects, 20 of them in both parts, more than the paper’s four groups of 10 (RegeneRx 10-K, 2023). RegeneRx’s planned heart-attack Phase 2 never started: FDA put it on clinical hold in March 2011 over the contract manufacturer’s alleged manufacturing violations (RegeneRx 10-K, 2023), and its registration is listed as withdrawn (NCT01311518).
• Recombinant IV, 84 healthy volunteers (Wang et al., 2021) — NL005 was given once at 0.05–25 µg/kg to 44 of 54 volunteers, or daily for 10 days at 0.5, 2.0 or 5.0 µg/kg to 24 of 30, in randomized, double-blind cohorts in China; the rest got placebo. There were no dose-limiting toxicities or serious adverse events, the authors judged adverse events as frequent and as severe as on placebo, and the half-life was 0.5 to 2.08 hours (Wang et al., 2021). Three of the authors were employees of the sponsor (Wang et al., 2021).
• Heart attack, 96 patients (Zhang et al., 2025) — In a randomized, placebo-controlled, double-blind trial of a recombinant form (rhTβ4) in patients with STEMI treated by emergency PCI, infarct size at 90 days did not differ significantly between the drug and placebo groups as a whole. Comparing the 43 treated patients whose first dose came within 8 hours of PCI with the placebo group, the infarcted area was significantly smaller (Zhang et al., 2025). Three of the paper’s authors work at the R&D center of Beijing Northland Biotech (Zhang et al., 2025). Northland’s two Phase 2 registrations of NL005, of 62 and 90 patients, led by the paper’s last author and measuring infarct area at 5 and 90 days, completed in 2021 and 2023 and post no results (NCT05485818; NCT05984134); the paper’s abstract does not say which registration its 96 patients come from (Zhang et al., 2025).
• Venous leg ulcers, 73 patients (Guarnera et al., 2010) — A Phase 2, double-blind, placebo-controlled, dose-escalation trial at eight sites in Italy and Poland (Guarnera et al., 2010) gave a 0.01%, 0.03% or 0.1% gel once a day for up to 84 days (NCT00832091), with compression stockings (Guarnera et al., 2007). The authors judged safety comparable to placebo and write that the 0.03% dose “may have the potential to accelerate wound healing” and that complete healing came within 3 months in about 25% of patients (Guarnera et al., 2010). The registry’s posted results count 12 of 55 on gel and 4 of 17 on placebo healed by day 84, about 22% and 24%, so healing was no more common on gel; the registered main endpoint was safety, and healing a secondary one (NCT00832091). RegeneRx called the trial’s results “both clinically and statistically significant” without naming the measure (RegeneRx 10-K, 2023).
• Pressure ulcers and epidermolysis bullosa: registry results only — In 72 adults with pressure ulcers given a 0.01%, 0.02% or 0.1% gel once a day for up to 84 days, 8 of 54 on gel and 3 of 18 on placebo healed, about 15% and 17% (NCT00382174). RegeneRx reported that among patients who healed, the 0.02% gel took a median 22 days against 57 on placebo, a difference that was not statistically significant (RegeneRx 10-K, 2023). In 30 people with epidermolysis bullosa given gel for up to 56 days, wounds healed in 8 of 22 on gel and 5 of 8 on placebo, about 36% and 63% (p > 0.05); the trial stopped early for lack of patients and expired study drug (NCT00311766). In both trials, as in the venous-ulcer trial, the registered main endpoint was safety and healing a secondary one (NCT00382174; NCT00311766). A second gel trial in epidermolysis bullosa stopped at 4 patients for a “business decision” (NCT03578029). A review co-written by Goldstein and RegeneRx’s David Crockford, the company’s study director on the 2006 trial (NCT00311766), reports that in the ulcer trials, patients who healed did so almost a month sooner (Treadwell et al., 2012).
• Dry eye: one small trial with positive secondary results, then misses — In 9 adults with severe dry eye, 0.1% drops six times a day for 28 days cut ocular discomfort by 35.1% (P = 0.0141) and corneal staining by 59.1% (P = 0.0108) against vehicle at day 56, the time point the abstract singles out (Sosne, Dunn et al., 2015). These were secondary measures: the registered main endpoint was safety, and 6 patients got the drops and 3 the vehicle (NCT01393132). In 72 adults tested in a controlled-adverse-environment chamber, 0.1% drops for 28 days left both main endpoints no different from placebo; discomfort inside the chamber on day 28 was 27% lower (P = 0.0244) (Sosne & Ousler, 2015). By the developer’s account, the Phase 2/3 ARISE-1 (317 patients) and the Phase 3 ARISE-2 (601) and ARISE-3 (700) all missed their main endpoints, ARISE-3 both of its co-primary endpoints, and FDA would not accept a pooled analysis of the three for a license application (RegeneRx 10-K, 2023; NCT02974907; NCT03937882). In ARISE-3’s posted results, inferior corneal staining changed by −0.41 on the drops and −0.46 on placebo, and ocular discomfort by −0.4 in both groups (NCT03937882). None of the three is published in a journal (PubMed, October 4, 2026); HLB Therapeutics says it is preparing another Phase 3, ARISE-4 (Edaily, August 26, 2026).
• Neurotrophic keratopathy (Sosne et al., 2022) — The Phase 3 SEER-1 planned 46 patients and stopped at 18 because recruitment was slow, by the authors’ account (Sosne et al., 2022); the registry gives the reason as a “business decision” (NCT02600429). With 0.1% drops five times a day for 4 weeks, 6 of 10 on the drops and 1 of 8 on placebo healed completely (p = 0.0656), so the main endpoint was missed; two weeks after treatment ended, the difference in healing was significant (p = 0.0359) (Sosne et al., 2022). ReGenTree funded the trial, and its employees designed it with the lead author; three of the six authors work for ReGenTree or its parent company, HLB Therapeutics (Sosne et al., 2022). A 2025 Cochrane review graded this result as low-certainty evidence that the drops may not increase corneal healing (risk ratio 9.00, 95% CI 0.57 to 141.88; Kruoch et al., 2025). Earlier, in nine patients treated on compassionate grounds, the six with geographic defects showed “dramatic healing,” three with punctate defects did not change, and one developed stromal thinning (Dunn et al., 2010). SEER-2, at 50 sites in the US and Europe, finished its last patient visit in August 2026, and HLB Therapeutics plans to report topline results in November 2026 (Edaily, August 26, 2026).
• Corneal wounds after eye surgery, 12 patients (NCT00598871) — Diabetic patients given 0.01% drops or placebo four times a day for 14 days after vitrectomy all healed by day 14, 9 of 9 and 3 of 3; the trial stopped for slow recruitment.
• In mixtures — An open-label, single-arm study injected a scalp formulation of four growth factors, Tβ4 and copper tripeptide-1 into 1,000 people with hair loss every three weeks for eight sessions (Kapoor & Shome, 2018). A retrospective chart review at a US clinic counted 4 knee-pain patients given BPC-157 with “TB4” (Lee & Padgett, 2021). Neither can separate the effect of Tβ4.

The evidence meter on the Thymosin Beta-4 card reads “Animal only”: it counts published human data on thymosin β4 alone for tendon and gut repair, and there is none; the knee-pain chart review gave it with BPC-157 (Lee & Padgett, 2021). The controlled trials above are for eye, skin-ulcer and heart conditions: the eye-drop trials mostly missed their main endpoints (RegeneRx 10-K, 2023; Sosne et al., 2022), the skin gels healed no larger share of patients than placebo (NCT00832091; NCT00382174; NCT00311766), and the heart-attack trial found no significant difference overall (Zhang et al., 2025).

Reconstitution & Storage

No label exists, and no trial document gives reconstitution steps for powder sold outside the trials. The trial products were preservative-free sterile eye drops (NCT05555589), a gel applied once a day (NCT00832091), and IV vials: 0.1 mg vials kept at 2–8 °C (Wang et al., 2021) and, in the planned Phase 2c, a sterile solution of 1.5 mg in 1 mL kept at 2–8 °C (NCT07586865).

• Powder outside the trials — Laboratory suppliers list recombinant thymosin β4, made in bacteria, as freeze-dried powder labelled for research use only (lab-reagent listings read October 4, 2026). Recombinant versions can carry extra amino acids: NL005 has 44 (Wang et al., 2021), and one reagent listing read for this page describes 45 (lab-reagent listings read October 4, 2026).
• Storage — No label sets storage conditions for thymosin β4 outside a trial; the NL005 trial vials were kept at 2–8 °C (Wang et al., 2021; NCT07586865).
• Which molecule a vial holds — Several websites use the names thymosin beta-4 and TB-500 interchangeably (FDA TB-500 review, 2026). The whole protein weighs 4,963 Da (PubChem) and TB-500 889 Da (FDA TB-500 review, 2026), so a measured mass on a lab report tells them apart.

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Side Effects & Risks

• In the IV trials — In four groups of 10 healthy volunteers given placebo or 42–1,260 mg, adverse events were infrequent and mild or moderate, with no serious adverse events (Ruff et al., 2010). With the recombinant form, adverse events were no more frequent than on placebo, 25 of 44 against 7 of 10 after one dose, and none was serious (Wang et al., 2021).
• Eye drops — In ARISE-3, instillation-site pain was reported by 23 of 350 on the drops and 16 of 349 on placebo, and reduced visual acuity by 12 and 7, with no serious adverse events (NCT03937882). In SEER-1, one patient on the drops had a serious adverse event, depression, which the authors list as unrelated (Sosne et al., 2022; NCT02600429).
• Skin gel — In the venous-ulcer trial, serious adverse events affected 3 of 55 on gel and 1 of 17 on placebo (NCT00832091), and the authors judged safety comparable to placebo (Guarnera et al., 2010). In the pressure-ulcer trial, 13 of 53 on gel and 5 of 18 on placebo had serious adverse events (NCT00382174).
• Cancer: a theoretical risk — Tβ4 promoted endothelial-cell migration in lab tests (Malinda et al., 1997), and mouse melanoma cells made to overexpress it formed about four times more lung nodules (Cha et al., 2003). Several trials excluded anyone with a current or past cancer (NCT00311766; NCT00832091; NCT07586865), so they say nothing about that risk. The Chinese Phase 1 measured tumor markers. An abnormal SCC antigen, a tumor marker of epithelial growth that the authors call low in sensitivity and specificity, was recorded in 8 of the 44 people given one dose of the drug, each tested once, on day 14 (3 of 8 at each of the two highest doses), and in none of 10 on placebo (Wang et al., 2021). In the daily-dose part, tested on days 14 and 28, the adverse-event table, which counts events rather than people, lists 4 abnormal SCC results among the 24 on the drug and 2 among the 6 on placebo (Wang et al., 2021). The authors describe a mild, short-lived rise that returned to normal and tracked the drug’s blood levels, relate it to the drug’s effect on epithelial cells, and found no tumor-related adverse events (Wang et al., 2021).
• Antibodies — In the recombinant Phase 1, 1 of 108 single-dose samples and 2 multiple-dose samples tested positive for antibodies to the drug, and all turned negative on follow-up (Wang et al., 2021). The six-month mouse study did not look for antibodies (Spurney et al., 2010).
• The gut lining — In mice, one group found that injected Tβ4 damaged the intestinal mucus barrier (Hao et al., 2024) and that Tβ4 lowered tight-junction proteins in the gut (Sun et al., 2025); whether extra Tβ4 helps or harms the human gut has not been tested.
• What has not been tested — The longest use of thymosin β4 alone was up to 84 days of gel on ulcers (NCT00832091; NCT00382174), and the longest IV course 14 days (Ruff et al., 2010); a scalp-injection mixture containing it was given every three weeks for eight sessions (Kapoor & Shome, 2018). No published animal toxicology study, drug-interaction study or human pregnancy study turned up on PubMed (searched October 4 and 5, 2026); a 2007 review of RegeneRx’s heart program says it presents the program’s toxicology studies, but its abstract gives no results (Crockford, 2007). One mouse study gave Tβ4 from RegeneRx, 6 mg/kg into the abdomen on days 14 and 17 of pregnancy, to three pregnant mice, against three injected with the solution alone; it reported longer pups with more mature organs, and no safety results (Faa et al., 2021).
• WADA — Thymosin β4 is named on WADA’s 2026 Prohibited List: section S2.3, growth factors and growth factor modulators, lists “Thymosin-ß4 and its derivatives e.g. TB-500,” and the class is prohibited at all times, in and out of competition, as non-Specified Substances (World Anti-Doping Agency, 2026).

Bloodwork & Monitoring

No monitoring guidance for thymosin β4 has been published outside the trials. The trials measured these:

• Blood and urine safety tests — Blood chemistry, blood counts, coagulation and urinalysis every week, and plasma Tβ4 at the start and the end, in the venous-ulcer trial (Guarnera et al., 2007).
• Heart and tumor markers, antibodies — Vital signs, ECGs, blood counts, chemistry, markers of heart-muscle injury, coagulation, tumor markers and anti-drug antibodies in the recombinant Phase 1 (Wang et al., 2021).
• Eye safety — Visual acuity, slit-lamp examination, intraocular pressure, corneal sensitivity and dilated fundoscopy in the neurotrophic keratopathy trial (Sosne et al., 2022).
• Infarct size — The 2025 heart-attack trial compared infarcted area at 90 days (Zhang et al., 2025); the planned Phase 2c measures infarct size by cardiac MRI (NCT07586865).
• Which tests fit a given person — A question for a licensed healthcare provider. This page can’t answer it.

Commonly Stacked With

In its trials thymosin β4 was given on top of other treatment, not with another peptide: compression stockings in the venous-ulcer trial (Guarnera et al., 2007) and emergency PCI in the heart-attack trials (Zhang et al., 2025). Two published studies gave it together with a compound on this site; neither was a controlled test of the pair (PubMed and Europe PMC, searched October 4, 2026).

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Legal Status

Related Compounds

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References

1. Low TL, Hu SK, Goldstein AL. Complete amino acid sequence of bovine thymosin beta 4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations. Proc Natl Acad Sci U S A. 1981;78(2):1162-1166. PMID: 6940133. DOI: 10.1073/pnas.78.2.1162.
2. Hannappel E, Xu GJ, Morgan J, Hempstead J, Horecker BL. Thymosin beta 4: a ubiquitous peptide in rat and mouse tissues. Proc Natl Acad Sci U S A. 1982;79(7):2172-2175. PMID: 6954532. DOI: 10.1073/pnas.79.7.2172.
3. Safer D, Elzinga M, Nachmias VT. Thymosin beta 4 and Fx, an actin-sequestering peptide, are indistinguishable. J Biol Chem. 1991;266(7):4029-4032. PMID: 1999398.
4. Huff T, Müller CS, Otto AM, Netzker R, Hannappel E. beta-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol. 2001;33(3):205-220. PMID: 11311852. DOI: 10.1016/s1357-2725(00)00087-x.
5. National Library of Medicine. PubChem: Thymosin Beta 4, CID 45382195, and Timbetasin, CID 16132341 (C212H350N56O78S, 4963 g/mol). pubchem.ncbi.nlm.nih.gov. Read October 4, 2026.
6. FDA. Global Substance Registration System: Timbetasin, UNII 2D5MRE3SSY (INN and USAN name; sequence SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES, 43 amino acids; calculated molecular weight 4,963.0 Da; CAS 77591-33-4). gsrs.ncats.nih.gov. Read October 4, 2026.
7. Gonzalez-Franquesa A, Stocks B, Borg ML, Kuefner M, et al. Discovery of thymosin β4 as a human exerkine and growth factor. Am J Physiol Cell Physiol. 2021;321(5):C770-C778. PMID: 34495765. DOI: 10.1152/ajpcell.00263.2021.
8. FDA. FDA Evaluation of TB-500-Related Bulk Drug Substances (TB-500 (Free Base) and TB-500 acetate). Pharmacy Compounding Advisory Committee briefing document for the meeting of July 23–24, 2026 (memorandum dated May 15, 2026): TB-500 is C38H68N10O14, 889.01 g/mol; “thymosin beta-4 and TB-500 are not the same substance”; no study of TB-500 in humans. fda.gov/media/193349/download. Read October 4, 2026.
9. RegeneRx Biopharmaceuticals, Inc. Annual report (Form 10-K) for the fiscal year ended December 31, 2022, filed April 11, 2023: business (product candidates, clinical status, strategic partnerships, government regulation, intellectual property) and directors. sec.gov/Archives/edgar/data/707511/000141057823000628/rgrx-20221231x10k.htm. Read October 4, 2026.
10. RegeneRx Biopharmaceuticals, Inc. Current report (Form 8-K) filed August 7, 2023 (1-for-100 reverse split approved, Forms 15 to follow) and Form 15 filed August 14, 2023 (termination of registration under section 12(g)). sec.gov, EDGAR filer CIK 707511. Read October 4, 2026.
11. Edaily (English edition). HLB Therapeutics Completes Global Phase 3 Clinical Trial for ‘RGN-259’… Topline Results to Be Announced in November. Reporter Kim Sae-mi, August 26, 2026. en.edaily.co.kr/news/eda202608265430. Read October 4, 2026.
12. Malinda KM, Goldstein AL, Kleinman HK. Thymosin beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J. 1997;11(6):474-481. PMID: 9194528. DOI: 10.1096/fasebj.11.6.9194528.
13. Philp D, Huff T, Gho YS, Hannappel E, Kleinman HK. The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J. 2003;17(14):2103-2105. PMID: 14500546. DOI: 10.1096/fj.03-0121fje.
14. Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004;432(7016):466-472. PMID: 15565145. DOI: 10.1038/nature03000.
15. Zhang Y, Dong Q, Bian X, Qiao Z, et al. Recombinant human thymosin beta 4 improves ischemic cardiac dysfunction in mice and patients with acute ST-segment elevation myocardial infarction after reperfusion. Cardiovasc Res. 2025;121(17):2747-2758. PMID: 41229390. DOI: 10.1093/cvr/cvaf223.
16. Smart N, Bollini S, Dubé KN, Vieira JM, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474(7353):640-644. PMID: 21654746. DOI: 10.1038/nature10188.
17. Zhou B, Honor LB, Ma Q, Oh JH, et al. Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes. J Mol Cell Cardiol. 2012;52(1):43-47. PMID: 21907210. DOI: 10.1016/j.yjmcc.2011.08.020.
18. Sosne G, Qiu P, Christopherson PL, Wheater MK. Thymosin beta 4 suppression of corneal NFkappaB: a potential anti-inflammatory pathway. Exp Eye Res. 2007;84(4):663-669. PMID: 17254567. DOI: 10.1016/j.exer.2006.12.004.
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24. Zhao TR, Hu EB, Wang MW, Zhai YF, et al. Recombinant human Thymosin β4 ameliorates experimental colitis and intestinal fibrosis through suppression of mineralocorticoid receptor signaling. Mol Biomed. 2026;7(1). PMID: 42606759. DOI: 10.1186/s43556-026-00539-9.
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26. Sun YS, Bai XQ, Sun KD, Li J, et al. Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome. World J Gastroenterol. 2025;31(42):111706. PMID: 41278163. DOI: 10.3748/wjg.v31.i42.111706.
27. Malinda KM, Sidhu GS, Mani H, Banaudha K, et al. Thymosin beta4 accelerates wound healing. J Invest Dermatol. 1999;113(3):364-368. PMID: 10469335. DOI: 10.1046/j.1523-1747.1999.00708.x.
28. Sosne G, Szliter EA, Barrett R, Kernacki KA, et al. Thymosin beta 4 promotes corneal wound healing and decreases inflammation in vivo following alkali injury. Exp Eye Res. 2002;74(2):293-299. PMID: 11950239. DOI: 10.1006/exer.2001.1125.
29. Hinkel R, El-Aouni C, Olson T, Horstkotte J, et al. Thymosin beta4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection. Circulation. 2008;117(17):2232-2240. PMID: 18427126. DOI: 10.1161/CIRCULATIONAHA.107.758904.
30. Philp D, Nguyen M, Scheremeta B, St-Surin S, et al. Thymosin beta4 increases hair growth by activation of hair follicle stem cells. FASEB J. 2004;18(2):385-387. PMID: 14657002. DOI: 10.1096/fj.03-0244fje.
31. Cha HJ, Jeong MJ, Kleinman HK. Role of thymosin beta4 in tumor metastasis and angiogenesis. J Natl Cancer Inst. 2003;95(22):1674-1680. PMID: 14625258. DOI: 10.1093/jnci/djg100.
32. Faa G, Piras M, Mancuso L, Coni P, et al. Thymosin beta-4 prenatal administration improves fetal development and halts side effects due to preterm delivery. Eur Rev Med Pharmacol Sci. 2021;25(1):431-437. PMID: 33506933. DOI: 10.26355/eurrev_202101_24411. (Full text read October 5, 2026.)
33. Crockford D. Development of thymosin beta4 for treatment of patients with ischemic heart disease. Ann N Y Acad Sci. 2007;1112:385-395. PMID: 17947592. DOI: 10.1196/annals.1415.051.
34. Ruff D, Crockford D, Girardi G, Zhang Y. A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers. Ann N Y Acad Sci. 2010;1194:223-229. PMID: 20536472. DOI: 10.1111/j.1749-6632.2010.05474.x.
35. Wang X, Liu L, Qi L, Lei C, et al. A first-in-human, randomized, double-blind, single- and multiple-dose, phase I study of recombinant human thymosin β4 in healthy Chinese volunteers. J Cell Mol Med. 2021;25(17):8222-8228. PMID: 34346165. DOI: 10.1111/jcmm.16693. (Full text at PMC8419156, read October 4, 2026.)
36. Guarnera G, De Rosa A, Camerini R. Thymosin beta-4 and venous ulcers: clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on healing. Ann N Y Acad Sci. 2007;1112:407-412. PMID: 17495250. DOI: 10.1196/annals.1415.003.
37. Guarnera G, DeRosa A, Camerini R. The effect of thymosin treatment of venous ulcers. Ann N Y Acad Sci. 2010;1194:207-212. PMID: 20536470. DOI: 10.1111/j.1749-6632.2010.05490.x.
38. Treadwell T, Kleinman HK, Crockford D, Hardy MA, et al. The regenerative peptide thymosin β4 accelerates the rate of dermal healing in preclinical animal models and in patients. Ann N Y Acad Sci. 2012;1270:37-44. PMID: 23050815. DOI: 10.1111/j.1749-6632.2012.06717.x.
39. Dunn SP, Heidemann DG, Chow CY, Crockford D, et al. Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4. Ann N Y Acad Sci. 2010;1194:199-206. PMID: 20536469. DOI: 10.1111/j.1749-6632.2010.05471.x.
40. Sosne G, Dunn SP, Kim C. Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. Cornea. 2015;34(5):491-496. PMID: 25826322. DOI: 10.1097/ICO.0000000000000379.
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48. ClinicalTrials.gov. Registrations of thymosin β4 (RGN-259, RGN-137, RGN-352, NL005): NCT00311766 (Phase 2, epidermolysis bullosa, 30, terminated, results posted), NCT00382174 (Phase 2, pressure ulcers, 72, completed, results posted), NCT00832091 (Phase 2, venous stasis ulcers, 72, completed, results posted), NCT00598871 (Phase 2, corneal wounds after vitrectomy, 12, terminated, results posted), NCT00743769 (Phase 1 IV, withdrawn, never initiated), NCT01311518 (Phase 2 IV in STEMI, withdrawn, never initiated), NCT01393132 (Phase 2, severe dry eye, 9, completed, results posted), NCT01387347 (Phase 2, dry eye, 72, completed, results posted), NCT02597803 (ARISE-1, Phase 2/3, 317, completed, no results posted), NCT02974907 (ARISE-2, Phase 3, 601, completed, results posted), NCT03937882 (ARISE-3, Phase 3, 700, completed, results posted), NCT02600429 (SEER-1, Phase 3, 18, terminated, results posted), NCT05555589 (SEER-2, Phase 3, listed as recruiting, last updated December 23, 2025), NCT03578029 (RGN-137 in epidermolysis bullosa, Phase 2, 4, terminated), NCT04555824 and NCT04555850 (NL005 Phase 1a and 1b, 54 and 30, completed), NCT05485818 (NL005 Phase 2a, 62, completed 2021, no results posted), NCT05984134 (NL005 Phase 2b, 90, completed 2023, no results posted), NCT07586865 (NL005 Phase 2c, 189 planned, not yet recruiting). clinicaltrials.gov, API v2. Read October 4, 2026.
49. FDA. Warning letter MARCS-CMS 718739, January 20, 2026, to a US outsourcing facility: thymosin beta-4 products named as unapproved new drugs and as biological products under section 351 of the Public Health Service Act, not the subject of an approved BLA; biological products subject to licensure “are not eligible for the exemptions for compounded drugs under sections 503A and 503B of the FDCA.” fda.gov, Warning Letters. Read October 4, 2026.
50. FDA. Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application. Guidance for industry, January 2018, section II.C. fda.gov/media/90986/download. Read October 4, 2026.
51. US Code of Federal Regulations. 21 CFR 600.3(h), definition of a biological product; (h)(6): “A protein is any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” ecfr.gov. Read October 4, 2026.
52. US Code of Federal Regulations. 21 CFR 216.23, Bulk drug substances that can be used to compound drug products in accordance with section 503A of the Federal Food, Drug, and Cosmetic Act. ecfr.gov. Read October 4, 2026.
53. FDA. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act (categories 1–3). Updated May 14, 2026. fda.gov/media/94155/download.
54. FDA. Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the Federal Food, Drug, and Cosmetic Act (categories 1–3). Updated March 21, 2025. fda.gov/media/94164/download.
55. FDA. Drugs@FDA through openFDA (api.fda.gov/drug/drugsfda.json): searches for thymosin, thymosin beta 4 and timbetasin, October 4, 2026 (no records). European Medicines Agency. Medicines data table (ema.europa.eu, medicines-output-medicines_json-report, 2,746 records), searched for thymosin and timbetasin, October 4, 2026 (no entry).
56. World Anti-Doping Agency. Prohibited List 2026 (in effect January 1, 2026). S2.3, Growth factors and growth factor modulators: “Thymosin-ß4 and its derivatives e.g. TB-500.” wada-ama.org.
57. Searches of October 4, 2026: PubMed, “thymosin beta4” (1,229 records; PubMed maps it to both spellings), “thymosin beta 4” (1,054), “RGN-259” (6); PubMed, thymosin beta4 with clinical-trial, case-report, compassionate-use and healthy-volunteer terms (eight studies that gave it alone to people), with tendon, ligament, muscle, bone, cartilage and gut terms, with toxicology terms (no toxicology study), and with BPC-157, GHK-Cu, KPV, thymosin alpha 1, VIP and growth hormone (Lee & Padgett, 2021, and Kapoor & Shome, 2018, the only human studies of a combination); Europe PMC, the same eye-trial terms; ClinicalTrials.gov, “thymosin beta 4,” “RGN-259,” “RGN-137,” “RGN-352,” “timbetasin” and “NL005” (19 thymosin β4 registrations; a fictional TB-500 record from the sponsor Hudson Biotech left out); laboratory-supplier listings of recombinant thymosin β4 powder labelled for research use only (suppliers not named). Searches of October 5, 2026: PubMed, thymosin beta4 with pregnancy, prenatal, gestation, fetal and teratogen terms (60 records; one study gave it during pregnancy, in mice, Faa et al., 2021), with toxicology, repeat-dose, genotoxicity, carcinogenicity and drug-interaction terms (45 records; no toxicology or interaction study; the abstract of a 2007 review of RegeneRx’s heart program, Crockford, 2007, says it presents toxicology studies), and thymosin beta4 or TB-500 with purity, counterfeit, adulteration and black-market terms (9 records; no purity analysis of a product sold as thymosin β4).

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