A genuine investigational drug with twenty years of registered trials, three large Phase 3 studies that missed their endpoints, and a name that has been borrowed by a seven-amino-acid fragment sold in its place.

Summary

  • Thymosin beta-4 is a naturally occurring 43-amino-acid protein, the body's main sequesterer of monomeric actin, present in nearly every cell and in wound fluid, and studied for tissue repair since the 1990s.1

  • It is not TB-500. TB-500 is a synthetic seven-residue fragment with 16 indexed papers and no completed human trial. Thymosin beta-4 has 684 indexed papers and 18 registered trials, the counts on the ONPEPS library index. ONPEPS grades them separately.

  • Intravenous doses of up to 1,260 mg daily for 14 days were well tolerated in healthy volunteers, with no dose-limiting toxicity.2

  • Topical thymosin beta-4 eye drops, RGN-259, reached Phase 3 for dry eye. ARISE-2 and ARISE-3, 601 and 700 patients, found no difference from placebo on their primary endpoints.34

  • In neurotrophic keratopathy, a rare corneal condition, a Phase 3 trial of 18 patients found complete healing in 6 of 10 on drug against 1 of 8 on placebo, narrowly missing significance; a second trial of 70 is recruiting.56

  • Phase 2 trials in venous and pressure ulcers completed in 2008 and 2009 with acceptable safety and modest efficacy signals; no Phase 3 followed.7

  • A Chinese recombinant version is in Phase 2 for heart attack, with a 189-patient trial due to start in 2026.8

  • Prohibited in sport under WADA section S2 since 2018, and the substance at the centre of the largest team doping case in Australian history.910

The Most Common Error About This Compound

Assuming the research belongs to the product. Almost every human study of thymosin beta-4 used the full 43-residue protein, applied topically to eyes or wounds or given intravenously in a hospital. What is sold as "thymosin beta-4" by peptide vendors is usually TB-500, the fragment, for subcutaneous injection. The trials do not transfer across the molecule, the route or the indication, and the ONPEPS TB-500 versus thymosin beta-4 article covers the difference in detail.

Identity

What Is Thymosin Beta-4?

A 43-amino-acid peptide encoded by the TMSB4X gene, isolated from calf thymus in 1981 and later found to be the most abundant member of a family of beta-thymosins present in nearly all cells. Its primary function is to bind actin monomers and hold them in reserve; that role in cytoskeletal dynamics is what gives it effects on cell migration, and the migration of keratinocytes and endothelial cells into a wound is the proposed basis of its repair activity. It also has anti-inflammatory and anti-apoptotic actions in animal models.1

The synthetic drug was developed by RegeneRx Biopharmaceuticals, whose scientific founder, Allan Goldstein, discovered the thymosins. Its ophthalmic formulation, RGN-259, is developed by ReGenTree, a joint venture with a Korean partner. A separate recombinant version, NL005, is in development in China.8

How Does It Differ From TB-500?

Thymosin beta-4TB-500
Length43 amino acids7 amino acids, Ac-LKKTETQ
OriginNaturally occurring proteinSynthetic fragment of the actin-binding region
Human trials18 registered, including Phase 3One, recruiting since 2026, no results
Routes studiedTopical, ophthalmic, intravenousNone in humans; sold for subcutaneous injection
ONPEPS gradeBD

Evidence Base

What Did the Safety Studies Show?

Four cohorts of ten healthy volunteers received single intravenous doses of 42, 140, 420 or 1,260 mg or placebo, then the same dose daily for 14 days. Adverse events were infrequent and mild to moderate, with no dose-limiting toxicity and no serious events, and pharmacokinetics were dose-proportional.2 Two Chinese Phase 1 studies of the recombinant version, in 54 and 30 volunteers, completed in 2018 and 2019 without published results.11

Those are large doses given intravenously under observation. They establish that the protein itself is well tolerated in the short term. They do not describe any product a consumer can buy.

Dermal Wounds

Two Phase 2 trials in 2006 to 2009, each of 72 patients, tested topical thymosin beta-4 gel at three concentrations against placebo for up to 84 days: one in venous stasis ulcers at eight European sites, one in pressure ulcers. Both were designed with safety as the primary endpoint and both met it. In venous ulcers the 0.03 percent dose showed a possible acceleration of healing, with complete closure within three months in about a quarter of patients, mainly those with smaller wounds.712 A Phase 2 trial in epidermolysis bullosa was terminated.13 No Phase 3 in any dermal indication has been run in the fifteen years since.

Dry Eye

This is the programme that came closest to approval, and it is the clearest case in the library of promising small trials failing at scale.

A Phase 2 trial in nine patients with severe dry eye, six times daily for 28 days, found a 35 percent reduction in discomfort and a 59 percent reduction in corneal staining against vehicle at day 56.14 A larger Phase 2 in 72 patients followed.15

Then three Phase 3 trials. ARISE-1 enrolled 317 patients in 2015 and 2016. ARISE-2 enrolled 601 with co-primary endpoints of ocular discomfort and corneal staining at day 29; the registered results show a change of 0.07 on RGN-259 against −0.04 on placebo for discomfort, and 0.07 against −0.01 for staining.3 ARISE-3 enrolled 700 in 2019 and 2020 with primary endpoints at day 15; the registered results show inferior corneal staining changed −0.41 on drug and −0.46 on placebo, and discomfort −0.4 on both.4

Neither of the two large trials has been published in a journal. The results are on the registry, and they show a product indistinguishable from vehicle on the outcomes it was designed to change.

Neurotrophic Keratopathy

The programme's remaining hope, and a reasonable one. Neurotrophic keratopathy is a rare condition in which corneal nerve damage leaves epithelial defects that will not heal. In SEER-1, 18 patients with stage 2 or 3 disease received 0.1 percent RGN-259 or placebo. Complete healing at four weeks occurred in 6 of 10 on drug and 1 of 8 on placebo, a difference with p = 0.0656; healed defects on drug did not recur at day 43, the one placebo healing did, and comfort scores improved significantly.5 SEER-2, in 70 patients, has been recruiting since April 2023.6

A trial of 18 people that narrowly misses its primary endpoint is a strong reason to run the next one. It is not an approval, and it is not evidence for anything beyond the eye.

Heart

The cardiac programme rests on animal work in which thymosin beta-4 protected heart muscle after infarction.1 RegeneRx's own Phase 2 in heart attack was withdrawn before enrolling anyone.16 Beijing Northland's recombinant NL005 has completed two Phase 2 trials in acute myocardial infarction, of 62 and 90 patients, with no results posted, and a 189-patient Phase 2 is listed to begin in May 2026.8 Until something is published, the human cardiac evidence is a set of registry entries.

Is There Evidence for Tendon, Muscle or Injury Recovery?

No human evidence at all. The uses that drive the peptide market, tendon repair, muscle injury and athletic recovery, have never been tested in a human trial of thymosin beta-4 by any route. A 2026 review in the American Journal of Sports Medicine assessed thymosin beta-4 and TB-500 together and concluded that both promoted angiogenesis and tissue repair in preclinical models, that human orthopaedic data are lacking, and that both remain banned in sport.17

Safety

What Is Known?

Short-term tolerability is well established for the protein at high intravenous doses and for topical and ophthalmic formulations over weeks to months, with adverse events comparable to placebo in every published trial.275

What Is Unknown

Long-term exposure. The mechanism, promotion of cell migration and new blood vessel growth, is the mechanism tumours use, and thymosin beta-4 is overexpressed in a number of cancers. No trial has run long enough to address that, and the question is unresolved rather than answered either way. For subcutaneous injection of gray-market product, which is how the name is actually used, there is no human safety data of any kind, because no trial has ever given the protein that way.

Sport and Drug Testing

Is Thymosin Beta-4 Prohibited?

Yes. Thymosin beta-4 and its derivatives were added to the WADA Prohibited List for 2018 as named examples of prohibited growth factors under section S2, with TB-500 named as an example of a derivative.9 It was already prohibited before that under the general growth factor language.

The Essendon Case

On 12 January 2016 the Court of Arbitration for Sport upheld a WADA appeal and found that 34 current and former players of the Essendon Football Club had used thymosin beta-4 during the club's 2012 supplements programme, imposing two-year bans that ended in November 2016. It reversed an AFL tribunal that had cleared them.10 The case turned on what had been injected, by whom, and from where, and none of the players could say with certainty. That is the sourcing problem stated as a legal finding.

Regulatory Status

Is It Approved Anywhere?

No. Thymosin beta-4 has no marketing authorisation in any jurisdiction for any indication. It is investigational, which is a real regulatory category with real trials behind it, and one that grants no access outside them.

Can It Be Compounded?

Not in the United States. It is not a component of an approved drug, has no monograph, and is not on the 503A bulks list. The FDA's Category 2 list names the fragment, "thymosin beta-4, fragment (LKKTETQ), also known as TB-500," among substances nominated and withdrawn; the full protein was never nominated.18 In July 2026 the FDA's advisory committee considered TB-500 for wound healing, not thymosin beta-4.19 A pharmacy has no lawful basis on which to compound either.

Related ONPEPS Coverage

What Would Change This Page

SEER-2, due to complete in 2026, would settle whether the neurotrophic keratopathy signal holds in a trial large enough to test it, and a positive result would put thymosin beta-4 on a path to its first approval.6 Publication of the Chinese cardiac trials would create human cardiac evidence where there is currently none. Nothing in either would bear on subcutaneous use for injury.

References

  1. Goldstein AL, Kleinman HK. Advances in the basic and clinical applications of thymosin β4. Expert Opin Biol Ther. 2015;15 Suppl 1:S139-S145. Paywalled. pubmed.ncbi.nlm.nih.gov/26096726

  2. 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. Paywalled. pubmed.ncbi.nlm.nih.gov/20536472

  3. ClinicalTrials.gov. NCT02974907. Assessment of the Safety and Efficacy of RGN-259 Ophthalmic Solutions for Dry Eye Syndrome: ARISE-2. Sponsor ReGenTree, LLC. Phase 3, 601 participants, completed March 2018, results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT02974907

  4. ClinicalTrials.gov. NCT03937882. Assessment of the Safety and Efficacy of RGN-259 Ophthalmic Solutions for Dry Eye Syndrome: ARISE-3. Sponsor ReGenTree, LLC. Phase 3, 700 participants, completed October 2021, results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT03937882

  5. Sosne G, Kleinman HK, Springs C, Gross RH, Sung J, Kang S. 0.1% RGN-259 (thymosin ß4) 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. Open access. pubmed.ncbi.nlm.nih.gov/36613994

  6. ClinicalTrials.gov. NCT05555589. Assessment of the Safety and Efficacy of 0.1% RGN-259 Ophthalmic Solution for the Treatment of NK: SEER-2. Sponsor ReGenTree, LLC. Phase 3, 70 participants estimated, recruiting. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT05555589

  7. Guarnera G, DeRosa A, Camerini R; 8 European sites. The effect of thymosin treatment of venous ulcers. Ann N Y Acad Sci. 2010;1194:207-212. Paywalled. pubmed.ncbi.nlm.nih.gov/20536470

  8. ClinicalTrials.gov. NCT07586865. Recombinant Human Thymosin Beta 4 for Injection (NL005) for Acute Myocardial Infarction. Sponsor Beijing Northland Biotech. Phase 2, 189 participants estimated, not yet recruiting. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT07586865

  9. United States Anti-Doping Agency. 2018 Prohibited List: Summary of Major Changes. Archived advisory. Records that thymosin beta-4 and its derivatives, for example TB-500, were added as examples of prohibited growth factors. usada.org

  10. ABC News (Australia). Essendon supplements saga: players banned for 12 months after WADA appeal upheld by Court of Arbitration for Sport. 12 January 2016. abc.net.au

  11. ClinicalTrials.gov. NCT04555824. A Phase 1a Study of Thymosin Beta 4 in Healthy Volunteers. Sponsor Beijing Northland Biotech. 54 participants, completed June 2018, no results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT04555824

  12. ClinicalTrials.gov. NCT00832091. Study of Thymosin Beta 4 in Patients With Venous Stasis Ulcers. Sponsor RegeneRx Biopharmaceuticals. Phase 2, 72 participants, completed January 2009, results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT00832091

  13. ClinicalTrials.gov. NCT00311766. A Phase 2 Study on Effect of Thymosin Beta 4 on Wound Healing in Patients With Epidermolysis Bullosa. Sponsor RegeneRx Biopharmaceuticals. Terminated. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT00311766

  14. 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. Paywalled. pubmed.ncbi.nlm.nih.gov/25826322

  15. ClinicalTrials.gov. NCT01387347. Safety and Efficacy of Thymosin Beta 4 Ophthalmic Solution in Patients With Dry Eye. Sponsor ReGenTree, LLC. Phase 2, 72 participants, completed December 2011, results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT01387347

  16. ClinicalTrials.gov. NCT01311518. A Study of the Safety and Efficacy of Injectable Thymosin Beta 4 for Treating Acute Myocardial Infarction. Sponsor RegeneRx Biopharmaceuticals. Withdrawn, 0 participants. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT01311518

  17. Mayfield CK, Bolia IK, Feingold CL, Lin EH, Liu JN, Hatch GFR, et al. Injectable peptide therapy: a primer for orthopaedic and sports medicine physicians. Am J Sports Med. 2026;54(1):223-229. Paywalled. pubmed.ncbi.nlm.nih.gov/41476424

  18. US Food and Drug Administration. Category 2 of the Bulk Substances Nominated Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act. Entry for thymosin beta-4 fragment (LKKTETQ). Content current as of 22 April 2026. fda.gov

  19. US Food and Drug Administration. July 23-24, 2026: Meeting of the Pharmacy Compounding Advisory Committee. Docket FDA-2025-N-6895. fda.gov

Not Medical Advice

Thymosin beta-4 is an investigational compound with no marketing authorisation anywhere, no established human dose outside its trials, and a WADA prohibition under section S2. Consult a qualified healthcare provider before acting on anything here.

Evidence counts on the library index retrieved 23 July 2026. Literature, registry and regulatory sources verified 16 September 2026. Re-verify before relying on any regulatory statement here.