An immune-modulating peptide approved in dozens of countries for nearly thirty years, never in the United States or Europe, whose largest trial ever run reported in 2025 and found nothing.

Summary

  • Thymosin alpha-1 is a 28-amino-acid acetylated peptide first isolated from calf thymus in 1977. The synthetic version, thymalfasin, is marketed as Zadaxin.1

  • It is approved in Italy, India, Hong Kong, Singapore and other markets, mainly for chronic hepatitis B and as a vaccine adjuvant in immunocompromised people. It has never been approved by the FDA or the European Medicines Agency.2

  • In the largest trial of the compound, 1,106 adults with sepsis at 22 Chinese centres, 28-day mortality was 23.4 percent on thymosin alpha-1 and 24.1 percent on placebo. The trial found no clear evidence of benefit.3

  • A 508-patient double-blind trial in severe acute pancreatitis found no reduction in infected necrosis.4

  • In hepatitis B, a meta-analysis of seven Chinese trials found combination with entecavir improved response at 24 weeks but not at 48 or 52.5

  • The safety record is long and reassuring: over 4,400 trial participants and an estimated 350,000 people treated post-marketing, with injection-site discomfort the main adverse effect.2

  • In December 2024 the FDA reviewed it for twelve proposed uses, found "a lack of evidence to support the effectiveness" for every one, and its advisory committee voted 4 to 17 against allowing pharmacies to compound it.26

  • Not named on the WADA Prohibited List. Because it holds governmental approval, it does not fall under the S0 catch-all; ONPEPS cannot state a definitive status and athletes should ask their anti-doping organisation.

The Most Common Error About This Compound

Treating "approved in over 30 countries" as evidence that it works. Those approvals were granted, mostly in the 1990s and 2000s, on the basis of small trials against comparators that are no longer standard of care, and the two largest, best-designed trials since, in sepsis and pancreatitis, were negative.34 Approval status and evidence status are different things, and for this compound they have moved in opposite directions.

Identity

What Is Thymosin Alpha-1?

A peptide originally purified from thymosin fraction 5, an extract of calf thymus, by Allan Goldstein's group in 1977, and sequenced as 28 residues with an acetylated N-terminus.1 It is produced in the body as a fragment of a larger protein, prothymosin alpha, and is found in thymus, blood and other tissues. The synthetic copy, thymalfasin, was developed by SciClone Pharmaceuticals and marketed as Zadaxin, typically as 1.6 mg for subcutaneous injection twice weekly.2

It is not related to thymosin beta-4 or TB-500 beyond the name. Those are actin-binding peptides studied for tissue repair; thymosin alpha-1 acts on the immune system through toll-like receptors on dendritic cells and promotes T-cell maturation.7 A seller conflating them is describing two different molecules.

Where Is It Approved?

The FDA's 2024 review, working from the manufacturer's 2014 annual report and national registers, records approvals across the Asia-Pacific, Latin America, Eastern Europe and the Middle East, primarily for hepatitis B and as a vaccine adjuvant, with some countries adding hepatitis C or use as a chemotherapy adjuvant. It confirmed specific listings in Italy, as an adjuvant to influenza vaccination in immunocompromised people; India, for chronic hepatitis B; Hong Kong; and Singapore. The agency added that it was "unable to independently verify these claims of approval" and that it was "unclear whether SciClone Pharmaceuticals remains in business."2

It is not approved in the United States, the European Union, the United Kingdom, Canada or Japan, and is not in the European or Japanese pharmacopoeias.2

Evidence Base

How Much Research Exists?

A great deal, most of it from China and Italy, and most of it old, small, or both. A targeted PubMed search returns 626 records and ClinicalTrials.gov lists 63 studies, the counts on the ONPEPS library index. A 2020 comprehensive review catalogues work in hepatitis B and C, HIV, sepsis, cancer, vaccine adjuvancy and, at the time, COVID-19.7

The FDA read that literature across twelve proposed uses and its verdict was uniform: studies "were inconclusive and limited by small sample sizes and design deficiencies," including retrospective or single-arm designs, control arms receiving outdated or unapproved therapy, lack of randomisation or blinding, and endpoints of unclear clinical relevance. It found "no evidence to suggest that Ta1 monotherapy, or Ta1 with other therapies would provide an advantage over standard of care alone."2

Sepsis

This is where the compound's reputation was made and, in 2025, where it was tested.

A 2013 multicentre trial of 361 patients with severe sepsis in six Chinese hospitals reported 28-day mortality of 26.0 percent on thymosin alpha-1 against 35.0 percent on control, a relative risk of 0.74 with a confidence interval that crossed 1, and improved monocyte HLA-DR, a marker of immune function. It was single-blind.8 That result drove a decade of use in Chinese intensive care and a great deal of marketing elsewhere.

The same group then ran the definitive trial. TESTS randomised 1,106 adults with sepsis at 22 centres between 2016 and 2020 to thymosin alpha-1 or placebo every 12 hours for seven days, double-blind. Twenty-eight-day mortality was 23.4 percent against 24.1 percent, hazard ratio 0.99. No secondary or safety outcome differed. A prespecified subgroup analysis suggested possible harm in patients under 60 and possible benefit in those with diabetes, findings the authors reported as hypothesis-generating. Their conclusion: "no clear evidence to suggest that thymosin α1 decreases 28 day all cause mortality in adults with sepsis."3

This is the pattern that runs through the whole literature: a small, imperfectly blinded trial suggests benefit; a large, properly blinded one does not find it. Anyone citing the 2013 result without the 2025 one is citing half the story, and the half that was superseded.

Pancreatitis

The same design, the same outcome. A double-blind trial of 508 patients with predicted severe acute necrotising pancreatitis, nearly all in intensive care, gave 1.6 mg every 12 hours for a week then daily for a week. Infected pancreatic necrosis developed in 15.7 percent on drug and 18.1 percent on placebo, a difference that was not significant, with no difference in organ failure, bleeding or fistula.4

Hepatitis B

This is the indication most approvals rest on. A 2020 meta-analysis of seven randomised trials, 1,144 patients, all from mainland China, compared entecavir plus thymosin alpha-1 with entecavir alone in HBV-related cirrhosis. The combination produced higher rates of undetectable viral DNA and e-antigen loss at 24 weeks. At 48 and 52 weeks the differences had disappeared, and surface antigen loss did not differ.5

The FDA's review notes that thymosin alpha-1 is not a recommended therapy in current US guidelines for chronic hepatitis B, and that the Asian Pacific guidelines which acknowledge its licensing in some countries do not list it as recommended treatment.2 Modern antivirals suppress the virus without it.

COVID-19

Widely used in China early in the pandemic, and the subject of at least four meta-analyses. A 2023 pooled analysis of eight studies reported lower mortality in treated patients, with a relative risk of 0.59, but no difference in mechanical ventilation or length of stay, heterogeneity of 84 percent, and an effect that depended on sample size, which is the signature of small-study bias.9 The FDA counted the meta-analyses and found three of four concluded no mortality benefit; the underlying studies were mostly retrospective, unblinded and conducted early in the pandemic with concomitant therapies that are no longer used.2

Cancer

The one area with continuing serious investigation. A Phase 2 trial and an expanded-access programme in metastatic melanoma combined thymosin alpha-1 with dacarbazine in the pre-immunotherapy era, and a 2018 long-term follow-up reported markedly longer survival in the 21 patients who subsequently received anti-CTLA-4 antibodies, suggesting a preconditioning effect the authors themselves called hypothesis-generating.10 A Phase 3 trial of 2,500 patients in resected colorectal cancer has been recruiting at Fudan University since 2021, and several Chinese Phase 2 trials combine it with checkpoint inhibitors.11 None has reported.

What Is It Sold For in the United States?

Everything. The FDA found compounded thymosin alpha-1 marketed as an injection and a nasal spray "for use in conditions such as hepatitis B, hepatitis C, HIV, chronic fatigue, inflammation, sepsis, COVID-19, Lyme disease, allergies, cancer, asthma, COPD, and psoriatic arthritis."2 For most of those, no trial exists. For the ones where trials exist, the large ones were negative.

Safety

What Is Known?

More than for almost any other compound in this library, and it is genuinely reassuring. The FDA's conclusion: across most clinical studies, thymosin alpha-1 "has been found to be well-tolerated and not associated with significant AEs attributable to Ta1 when administered in doses in the range of 1-16 mg via the SC ROA for up to 12 months." The commonest reaction is local irritation at the injection site. A search of the FDA's adverse event database through June 2024 found one applicable report, confounded by concurrent interferon.2 The 1,106-patient sepsis trial found no safety outcome that differed from placebo.3

Foreign labels carry warnings and contraindications for children, pregnancy and lactation, autoimmune disease, and deliberately immunosuppressed patients such as transplant recipients, and the Indonesian label notes transient liver enzyme flares in hepatitis B patients.2

What Is Unknown

Whether the compounded product carries that safety record. The FDA's concern was not the molecule but the vial: neither form was "well-characterized" because impurity, aggregate, bioburden and endotoxin data were missing from the nomination; immunogenicity from aggregates in an injectable is a risk it could not assess; and the peptide's limited water solubility left the agency unable to see how the proposed 3 mg/mL injection could be made at all.2 The safety record belongs to Zadaxin. Whether it transfers to a compounded or gray-market product is an open question.

The other unknown is the sepsis subgroup finding of possible harm in adults under 60, which is a single prespecified analysis in one trial and should be treated as such, but which exists.3

Regulatory Status

What Happened in December 2024?

On 4 December 2024 the FDA's Pharmacy Compounding Advisory Committee considered thymosin alpha-1 free base and acetate for the 503A bulks list across twelve uses: hepatitis B, hepatitis C, HIV, COVID-19, depressed vaccine response, melanoma, hepatocellular carcinoma, non-small-cell lung cancer, sepsis, infections after stem cell transplant, COPD, and chronic fatigue syndrome. The FDA's review ran to 158 pages and concluded against inclusion on characterisation, safety-in-compounding and effectiveness grounds.2

The committee voted 4 to 17 against each form. The minutes record that members voting no "agreed there was no compelling evidence demonstrating clinical effectiveness and safety in the uses under review," while those voting yes "commented that this substance should be accessible to patients as an option." Twenty-one members voted, the largest panel of the day, because the twelve indications required specialists in hepatology, oncology, infectious disease and critical care.6

Since September 2023 the compound has sat in the FDA's Category 2 of nominated substances that may present significant safety risks; as of April 2026 it appears among substances nominated but withdrawn, with the original safety text unchanged.12 It was not among the peptides considered in July 2026. No pharmacy in the United States has a lawful basis on which to compound it.

Related ONPEPS Coverage

What Would Change This Page

The 2,500-patient colorectal cancer trial, which is the only adequately powered study of the compound in progress and would settle whether the immunotherapy-era oncology signal is real.11 A properly blinded trial in any of the twelve uses the FDA reviewed. Neither is expected before 2027.

References

  1. Goldstein AL, Low TL, McAdoo M, McClure J, Thurman GB, Rossio J, et al. Thymosin alpha1: isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci U S A. 1977;74(2):725-729. Open access. pubmed.ncbi.nlm.nih.gov/265536

  2. US Food and Drug Administration. Thymosin alpha-1-related bulk drug substances: FDA review for the December 4, 2024 meeting of the Pharmacy Compounding Advisory Committee. Docket FDA-2024-N-4777. Primary source for approval status, the FAERS search, the safety conclusion, the characterisation findings and the effectiveness conclusion. fda.gov

  3. Wu J, Pei F, Zhou L, Li W, Sun R, Li Y, et al. The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial. BMJ. 2025;388:e082583. Open access. pubmed.ncbi.nlm.nih.gov/39814420

  4. Ke L, Zhou J, Mao W, Chen T, Zhu Y, Pan X, et al. Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial. Intensive Care Med. 2022;48(7):899-909. Paywalled. pubmed.ncbi.nlm.nih.gov/35713670

  5. Peng D, Xing HY, Li C, Wang XF, Hou M, Li B, et al. The clinical efficacy and adverse effects of entecavir plus thymosin alpha-1 combination therapy versus entecavir monotherapy in HBV-related cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol. 2020;20(1):348. Open access. pubmed.ncbi.nlm.nih.gov/33076834

  6. US Food and Drug Administration. Final Summary Minutes of the Pharmacy Compounding Advisory Committee Meeting, December 4, 2024. Approved 21 February 2025. fda.gov

  7. Dominari A, Hathaway D III, Pandav K, Matos W, Biswas S, Reddy G, et al. Thymosin alpha 1: a comprehensive review of the literature. World J Virol. 2020;9(5):67-78. Open access. pubmed.ncbi.nlm.nih.gov/33362999

  8. Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit Care. 2013;17(1):R8. Open access. pubmed.ncbi.nlm.nih.gov/23327199

  9. Soeroto AY, Suryadinata H, Yanto TA, Hariyanto TI. The efficacy of thymosin alpha-1 therapy in moderate to critical COVID-19 patients: a systematic review, meta-analysis, and meta-regression. Inflammopharmacology. 2023;31(6):3317-3325. Paywalled. pubmed.ncbi.nlm.nih.gov/37845598

  10. Danielli R, Cisternino F, Giannarelli D, Calabrò L, Camerini R, Savelli V, et al. Long-term follow up of metastatic melanoma patients treated with thymosin alpha-1: investigating immune checkpoints synergy. Expert Opin Biol Ther. 2018;18(sup1):77-83. Paywalled. pubmed.ncbi.nlm.nih.gov/30063847

  11. ClinicalTrials.gov. NCT05086614. Thymosin-alpha 1 for Adjuvant Treatment After Radical Resection of High-risk Stage II and III Colorectal Cancer. Sponsor Fudan University. Phase 3, 2,500 participants estimated, recruiting. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT05086614

  12. 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-alpha 1. Content current as of 22 April 2026. fda.gov

Not Medical Advice

Thymosin alpha-1 is an approved prescription medicine in some countries and an unapproved substance in the United States, the European Union and the United Kingdom. Nothing here substitutes for the label in a jurisdiction where one exists, or for a prescriber. Consult a qualified healthcare provider before acting on anything here.

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