Thymosin Alpha-1

The story

1. 1966 Goldstein, Slater and White name the partially purified thymic factors "thymosins" in PNAS; the program begins in Abraham White's lab at Albert Einstein College of Medicine
2. 1972–1974 Thymosin fraction 5 prepared at UTMB Galveston; FDA grants the first IND for a thymic hormone preparation; phase I in children with primary immunodeficiency at UCSF
3. 1977 Goldstein et al. isolate and sequence thymosin alpha-1 — 28 residues, N-terminally acetylated — as the most immunologically active component of fraction 5
4. 1981 The same laboratory sequences thymosin beta-4 (43 residues) from the same extract — shared name, unrelated biology
5. by 2005 ZADAXIN (thymalfasin) approved for sale in "over 30 countries," principally for hepatitis B, with country-specific approvals for HCV, vaccine adjuvant and chemotherapy adjuvant use — the company's own statement (T3-adjacent); FDA restates it and declines to verify it
6. 2005-12-13 / 2006-05-25 Both US phase 3 hepatitis C trials report no statistically significant benefit; SciClone abandons the US hepatitis C route and pivots to melanoma
7. 2010 488-patient randomized melanoma study published in JCO: median OS 9.4 vs 6.6 months, hazard ratio 0.80, P =.08 — not statistically significant
8. 2012 European phase 3 (n=552) in hepatitis C non-responders: SVR 12.7% vs 10.5%, P = 0.407 — primary endpoint missed
9. 2013 ETASS (n=361) reports 28-day mortality 26.0% vs 35.0% in severe sepsis — a marginal result that anchors a decade of Tα1 critical-care use
10. 2020–2022 COVID-19 generates a large, almost entirely observational Tα1 literature, concentrated in China
11. 2024-12-04 FDA Pharmacy Compounding Advisory Committee votes 4–17 against placing Ta1 free base and Ta1 acetate on the 503A Bulks List; FDA's own evaluation weighed against both
12. 2025 TESTS (n=1,106), the largest and only double-blind placebo-controlled phase 3 of Tα1 in sepsis, reports no mortality benefit (23.4% vs 24.1%, HR 0.99, P=0.93)
13. 2026-07 Thymosin alpha-1 is not among the seven peptides considered at FDA's July 2026 PCAC meeting; its 503A question was already answered in December 2024

What it does

• T-cell function
• immune modulation

What the evidence shows

Large, well-designed randomized trials exist and were negative. The three biggest placebo-controlled trials — 1,106 patients in sepsis, 508 in pancreatitis, 552 in hepatitis C — all missed their primary endpoints; positive findings are confined to smaller, single-blind or post-hoc analyses, and lose significance when the evidence is restricted to high-quality or multicentre studies. No trial has ever enrolled a healthy adult. Thymalfasin is a licensed prescription medicine in roughly thirty-plus countries — a count that comes from the manufacturer's own SEC filing, which FDA restates and expressly declines to verify — principally for hepatitis B, with printed labels and prescriber supervision, and none of that is reachable through any lawful US route.

Overall evidence strength: Low certainty

• TESTS (2025) — sepsis — the largest trial ever conducted on this molecule (2025) Randomized controlled trial

  In the only large, properly blinded, placebo-controlled test of thymosin alpha-1 in sepsis, it did not save lives — 23.4% of the thymosin group and 24.1% of the placebo group died within 28 days (hazard ratio 0.99, 95% CI 0.77 to 1.27, P=0.93), and no secondary or safety outcome differed significantly either. That is not evidence the molecule does nothing biologically; it is evidence that in unselected sepsis, at this exposure, it does not change the outcome the trial was designed to change.

  Source PMID 39814420

• ETASS (2013) — severe sepsis — the trial that built the case TESTS then tested (2013) Randomized controlled trial

  Fewer people died in the thymosin group — 26.0% versus 35.0% — but the result sat right on the edge of statistical significance and the confidence interval crossed no effect (relative risk 0.74, 95% CI 0.54 to 1.02). It was a promising signal in a trial that was not fully blinded, which is precisely why a 1,106-patient double-blind trial was then run; that trial did not confirm it.

  Source PMID 23327199

• TRACE (2022) — acute necrotising pancreatitis (2022) Randomized controlled trial

  Infected pancreatic necrosis occurred in 15.7% of the thymosin group and 18.1% of the placebo group — a difference of −2.4% with a confidence interval running from −7.4% to +5.1% and P=0.48, meaning the trial could not distinguish this from chance. Results were similar across all four predefined subgroups, and other major complications did not differ.

  Source PMID 35713670

• Sigma-Tau phase 3 (2012) — chronic hepatitis C non-responders (2012) Randomized controlled trial

  Adding thymosin alpha-1 to standard hepatitis C re-treatment did not clear more virus — sustained virologic response was 12.7% versus 10.5%, P=0.407, in the intention-to-treat population. A per-protocol analysis restricted to the minority who completed all 48 weeks showed 41.0% versus 26.3% (P=0.048), and the authors themselves frame this only as a hypothesis about relapse prevention, concluding that Tα1 "seems to play no role in the primary therapy of the disease."

  Source PMID 22233415

• Metastatic melanoma (2010) — the largest oncology trial (2010)

  Two of the thymosin arms produced more tumour responses than the control arm (10 and 12 responses versus 4), which is what the trial's response-based primary endpoint asked. What it did not show is that people lived longer: median overall survival was 9.4 months with thymosin versus 6.6 months without, hazard ratio 0.80, P =.08 — a difference in the expected direction that did not reach statistical significance, with progression-free survival likewise at P =.06.

  Source PMID 20194853

• The hepatitis B evidence — where the approved indication actually lives

  Thymalfasin's international approvals are principally for hepatitis B, and the supporting evidence is a set of small randomized trials aggregated in meta-analyses rather than a single pivotal trial.

  Source PMID 18078676

• The COVID-19 literature — characterizing the quality, not just the conclusion

  This is the body of work most often cited in wellness marketing, and it is the weakest in the file.

  Source PMID 32442287

• Evidence synthesis — sepsis after TESTS Review / meta-analysis

  The 2025 systematic review is the cleanest statement of where this stands. Across 11 randomized trials and 1,927 patients, Tα1 was associated with reduced 28-day mortality (OR 0.73, 95% CI 0.59–0.90, P=0.003). But the high-quality subgroup (OR 0.82, 95% CI 0.65–1.03, P=0.09) and the multicentre subgroup (OR 0.86, 95% CI 0.68–1.08, P=0.20) both lost significance — that is, the benefit is carried by the smaller and methodologically weaker trials. Heterogeneity-of-treatment-effect analysis on the two large trials flagged possible benefit in patients with cancer (moderate credibility) and diabetes (low credibility) (DOI 10.3389/fcimb.2025.1673959 · PMID 40969554).

  Source PMID 40969554

• The approved product outside the United States — what it covers, and why none of it is a US route

  This subsection exists because thymosin alpha-1 is the one compound in this batch with a genuine, supervised, labelled channel — and that channel is somewhere else. The material below was previously presented as a table of studied ranges. It is presented here instead, as evidence, with the jurisdiction stated, because a US reader must not read a foreign label as something they can act on.

  Source

Who it's for, who should skip

Only under physician supervision. Status is gray_zone — never FDA-approved in the US; ex-US approvals (Zadaxin) don't transfer and sources conflict. Caution in autoimmune conditions (a copy-level caution, not a coded rule).

Running it

No dosing protocol is published for this compound — there is no lawful supervised channel for the use this guide covers. What follows is monitoring, expectations, and safety framing only.

Form

injectable

What to expect

• First days (critical illness) — Immune-parameter shifts are measurable within days: monocyte HLA-DR was assessed on days 0, 3 and 7 in ETASS, with greater improvement reported in the Tα1 arm (Confidence: Trial-documented, single-blind)
• First 1–2 weeks (critical illness) — Complete 7- and 14-day courses were the studied exposures in sepsis and pancreatitis; neither produced a difference in mortality or in the primary complication rate (Confidence: Trial-documented, double-blind)
• 24 weeks (hepatitis B, added to entecavir) — Higher HBV DNA undetectable and HBeAg loss rates than entecavir alone (Confidence: Trial-documented (meta-analysis of 7 RCTs, n=1,144))
• 48–52 weeks (hepatitis B) — The 24-week advantage was not maintained at 48 and 52 weeks (Confidence: Trial-documented)
• 48 weeks (hepatitis C re-treatment) — No improvement in on-treatment virological response or intention-to-treat sustained virologic response (Confidence: Trial-documented, double-blind)
• After stopping (hepatitis B vs interferon) — The characteristic pattern is a delayed response — Tα1 underperformed interferon at 6 months and the odds reversed at longer follow-up (Confidence: Trial-documented (meta-analysis, 4 RCTs, n=199))
• Long term / repeated courses in healthy people — No data of any kind (Confidence: No data)

Response signs

Getting it right

• Monitoring: T-cell subsets and ratios — CD4+ percentage, CD8+, and the CD4+/CD8+ ratio were the immune endpoints in the pancreatitis randomized literature (DOI 10.3389/fimmu.2025.1571456); absolute lymphocyte count was the variable that a post-hoc analysis of TRACE identified as modifying any effect (DOI 10.1016/j.eclinm.2023.101915). mitigate side effect
• Monitoring: Monocyte HLA-DR in critical illness, measured serially on days 0, 3 and 7 in ETASS (DOI 10.1186/cc11932). mitigate side effect
• Monitoring: Disease-specific virology and liver chemistry in hepatitis — HBV DNA, HBeAg, HBsAg and ALT, on the 24-, 48- and 52-week schedules used in the trials (DOI 10.1186/s12876-020-01477-8). mitigate side effect
• Monitoring: Nothing validated for a healthy person. No trial has established a monitoring parameter for immune "optimisation," and none of the markers above has a documented meaning in a person with normal baseline immune function. mitigate side effect
• General safety: The randomized safety record with pharmaceutical-grade product is reassuring on its own terms: no safety outcome differed from placebo across 1,089 sepsis patients, and no significant between-group difference in adverse events across 552 hepatitis C patients (DOI 10.1136/bmj.r1098; DOI 10.1111/j.1365-2893.2011.01524.x). Injection-site reactions were the most commonly reported events in FDA's review (FDA briefing document). mitigate side effect
• General safety: That record does not transfer to non-pharmacopoeial material. FDA found Ta1 free base and acetate "not well-characterized," with no publicly available impurity, aggregate or bacterial-endotoxin data, no USP monograph, and a nominated 3 mg/mL injectable concentration exceeding the substance's water solubility — conditions under which aggregation, and with it immunogenicity risk, becomes more likely (FDA briefing document). (A regulatory formulation record — the strength proposed to FDA — not an administered exposure.) Analytical work on pharmacopoeial thymalfasin found 23 related impurities above 0.1 mg/g, most traceable to the labile C-terminal asparagine (DOI 10.1007/s00216-022-04336-5) — again a composition, not a quantity administered. mitigate side effect
• General safety: Populations where FDA has flagged specific concern: haematopoietic stem-cell transplant recipients, on grounds of possible graft-versus-host disease and engraftment failure (FDA briefing document). mitigate side effect
• General safety: Drug interactions and pregnancy are not characterized in the published trial literature reviewed here. Treat that as an absence of data, not as reassurance. mitigate side effect
• The physician conversation: What condition are we actually treating, and is it one of the indications thymalfasin is approved for anywhere, or one of the twelve uses FDA reviewed and found insufficiently supported? mitigate side effect
• The physician conversation: If it is being suggested for chronic Lyme, mould illness/CIRS, long COVID or chronic fatigue: what randomized evidence exists in that condition specifically? (The answer in the literature reviewed here is none.) mitigate side effect
• The physician conversation: How do the two largest blinded trials — TESTS in sepsis and TRACE in pancreatitis, both null — change your view of what this molecule does? mitigate side effect
• The physician conversation: If I have a diagnosed condition an immunomodulator is relevant to, what are the approved options with better evidence, and how do they compare? mitigate side effect
• The physician conversation: What product would this be, where would it come from, and what characterisation data exists for it — impurities, aggregates, endotoxin? mitigate side effect
• The physician conversation: Do I have any condition — autoimmune disease, transplant, active immunosuppression — that changes the risk calculus? mitigate side effect
• The physician conversation: What would we measure to know whether anything is happening, and what would make us stop? mitigate side effect

Safety

• theoretical caution in autoimmune conditions — shifting immune regulation could destabilize an already-dysregulated system (plausible, not established)

Access & cost

Legally unsettled. Access, where it exists at all, runs through a physician — not a consumer purchase. See the status note above.

A lawful channel exists — it is not a US one, and that distinction is the whole of this section. Thymalfasin is a licensed prescription medicine sold as ZADAXIN and by other manufacturers in a substantial number of countries: SciClone's SEC filing records approval "for sale in over 30 countries internationally, primarily in Asia, the Middle East and Latin America" (SEC 10-K) — a company statement about its own product, T3-adjacent, and the source of the country count used throughout this dossier — and FDA describes approvals in "select Asia-Pacific, Latin American, Eastern European, and Middle Eastern countries," excluding Japan and excluding Europe outside Italy, while noting that it "is unable to independently verify these claims" (FDA briefing document). Where those approvals hold, thymalfasin is bought through the ordinary pharmacy system at whatever price the local market and reimbursement system set. sets out what that channel covers and why none of it reaches a US reader. There is no lawful US channel to price. Thymosin alpha-1 is not FDA-approved, was voted down 4–17 for the 503A Bulks List on 4 December 2024, and appears on FDA's bulk drug substances page only under substances nominated but withdrawn (PCAC minutes; FDA bulks page). No legitimate US prescription, compounding-pharmacy or telehealth price therefore exists to report. On the international price: we could not verify a list or reimbursed price for thymalfasin in any approving country from a non-vendor, non-marketing source, and per the brief no seller is cited for it. That gap is carried forward as anrather than filled with a vendor figure. A gray market for thymosin alpha-1 exists in the United States and is served by compounding-adjacent and offshore supply; the December 2024 advisory committee proceedings, at which businesses in compounded-peptide distribution appeared to argue for 503A listing, are the clearest documented evidence of that commercial ecosystem (PCAC minutes). No INTERNAL subsection appears in this file: we obtained no journalist-reported price figure specific to thymosin alpha-1. That is an absence, not an omission. ---

Questions

Does thymosin alpha-1 actually work?

It depends entirely on what for. For hepatitis B, it is an approved drug in dozens of countries — the count is per the manufacturer's 2005 SEC filing, which FDA restates while saying it cannot independently verify it — and meta-analyses show real virological effects, though the advantage over or alongside standard antivirals is modest and not durable to a year (DOI 10.1186/s12876-020-01477-8). For sepsis and for necrotising pancreatitis, the two largest double-blind placebo-controlled trials were both null (DOI 10.1136/bmj.r1098; DOI 10.1007/s00134-022-06745-7). For general immune support in a healthy adult, there is no trial at all.

Is thymosin alpha-1 FDA approved?

No. It is approved in a number of other countries as thymalfasin/ZADAXIN, but it is not an FDA-approved drug in the United States, and FDA's Pharmacy Compounding Advisory Committee voted 4–17 against making it eligible for compounding under section 503A on 4 December 2024 (PCAC minutes). FDA's bulk-substances page lists it under substances "nominated but withdrawn" (FDA).

Is thymosin alpha-1 safe?

In randomized trials it has been well tolerated: TESTS reported no safety outcome differing between arms across 1,089 patients (DOI 10.1136/bmj.r1098), and the 552-patient hepatitis C trial reported no significant between-group difference in adverse events (DOI 10.1111/j.1365-2893.2011.01524.x). Two caveats belong with that. FDA flags immunogenicity risk for a 28-residue peptide, amplified by aggregation and peptide-related impurities, and specific concern about graft-versus-host disease and engraftment failure in stem-cell-transplant patients (FDA briefing document). And trial safety data describe a pharmaceutical-grade, pharmacopoeially specified product — not a compounded or gray-market one.

Is thymosin alpha-1 the same as TB-500?

No. Both were isolated from the same calf-thymus extract in the 1970s and early 1980s and both carry the word "thymosin," but Tα1 is a 28-residue immunomodulator and TB-500 is a short fragment of the unrelated 43-residue thymosin beta-4. Different sequences, different mechanisms, different trial records, different anti-doping status. See.

How long until thymosin alpha-1 works?

There is no answer for healthy adults because no study has looked. In the populations studied, the timescales are those of the underlying disease: immune markers moved within days in ICU trials, and hepatitis B virological endpoints were measured at 24, 48 and 52 weeks, with the characteristic pattern being a slow, delayed response rather than a fast one (DOI 10.1016/j.antiviral.2007.10.014).

Does it help long COVID, chronic Lyme, or mould illness?

No randomized trial has tested it in any of those conditions, and none of them was among the twelve uses FDA evaluated (FDA briefing document). The acute COVID-19 literature — which is a different question — is retrospective and heterogeneous. The claim is unstudied rather than refuted, and clinic pages making it generally cite nothing (Ducharme clinic page).

Is oral, sublingual, or nasal thymosin alpha-1 as good as the injection?

There is no evidence for any non-injectable route. Every human exposure in the trial record was subcutaneous, and no published human bioavailability study exists for oral, sublingual or intranasal Tα1. Sublingual strips are nevertheless sold with a claimed "bio-availability of up to 92%" (TruHealth). The marketing here clearly outruns the data.

What happens when you stop?

Nothing is documented about cessation in healthy people. In hepatitis B the interesting feature is the opposite of a withdrawal effect — responses continued to accrue after treatment ended, which is why comparisons against interferon look worse at 6 months and better later (DOI 10.1016/j.antiviral.2007.10.014).

Is it banned in sport?

Thymosin alpha-1 is not named on the WADA 2026 Prohibited List, which is not the same as being cleared — for the exact status and the caveats that go with it. ---