Thymosin alpha 1 (thymalfasin): what it is, its regulatory status, and what the trials actually tested

What thymosin alpha 1 is#

Thymosin alpha 1 (often written thymosin α1, Tα1 or Ta1) is a peptide of 28 amino acids whose first residue carries an acetyl group. It was described in 1977 by Allan Goldstein and colleagues, who isolated it from calf thymus. It was one of several polypeptides in a crude thymus extract known as thymosin fraction 5, and the authors described it as a heat-stable, highly acidic molecule and reported its full amino acid sequence.^[1] FDA's 2024 review summarizes the same history: an N-terminally acetylated 28-amino-acid peptide, originally isolated from thymosin fraction 5 of calf thymus in 1977.^[2]

The peptide studied today is not extracted from thymus tissue. It is made by chemical synthesis. The synthetic version is called thymalfasin, and FDA describes it as identical in amino acid sequence to the natural peptide.^[2] The thymosin alpha 1 product page lists the identifiers below alongside the lot records for our vials.

Thymosin alpha 1 sequence and molecular weight#

The sequence, written N-terminus to C-terminus with the acetyl cap, is Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH, or Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN in single-letter code. Nine of the 28 residues are glutamate or aspartate and four are lysine, so acidic side chains predominate, consistent with the original paper's description of a highly acidic molecule.^[1][2] PubChem lists the free base as thymalfasin, CID 16130571, with the same formula.^[3]

The distinction between forms matters when reading a label. FDA's review treats thymosin alpha 1 free base and thymosin alpha 1 acetate as two bulk substances with the same active moiety; the acetate is a salt, so a given weight of acetate powder contains less peptide than the same weight of free base.^[2][4] A lot's Certificate of Analysis should state which form it is.

Thymalfasin (Zadaxin): where it is and is not approved#

Thymalfasin has been marketed under the brand name Zadaxin. A 2020 literature review states that it is approved in more than 35 countries for hepatitis B and C and as an immune enhancer in other conditions, without listing the countries.^[5] FDA's 2024 presentation to its Pharmacy Compounding Advisory Committee is more specific about what it could confirm. It states that thymosin alpha 1 is not approved in the United States, Japan or Europe, with the exception of Italy; that a 2014 report from the manufacturer described approvals in countries in the Asia-Pacific region, Latin America, Eastern Europe and the Middle East; and that FDA was unable to independently verify those approval claims. It also states plainly that FDA has approved no drug products containing thymosin alpha 1.^[2]

In short, thymalfasin is marketed in some countries outside the U.S., and it is not an FDA-approved drug.

Why thymosin alpha 1 has been studied#

The original interest came from the thymus itself. Thymosin fraction 5 was being examined as a source of factors involved in T-cell development, and the 1977 paper described thymosin alpha 1 as one of several peptides in that fraction thought to take part in regulating T-cell differentiation and function.^[1] Later work moved toward specific immune pathways. FDA's review describes the peptide's activity as mediated at least in part by Toll-like receptor 9, and the 2020 review describes it as acting on Toll-like receptors 9 and 2 in myeloid and dendritic cells and as affecting T-cell maturation.^[2][5] These are descriptions of proposed mechanism drawn from laboratory studies; they are not findings about any outcome in people.

Because the peptide was developed as a drug in several countries, it has something most research peptides lack: a body of human clinical trials. That literature is uneven. Many of the trials are small, open-label or run in a single country, and the larger, better-controlled trials have not always confirmed earlier signals.

The clinical trial literature, and what each trial measured#

The trials below are described as research findings: who was enrolled, what was compared and what was measured. None of them establishes a use, and FDA's review concluded that the evidence was insufficient for every indication it examined.^[2]

Chronic hepatitis B: Chien et al., Hepatology, 1998#

This randomized controlled trial, run by investigators at Chang Gung Memorial Hospital in Taiwan, enrolled 98 patients with clinically and pathologically confirmed chronic hepatitis B and compared two thymosin alpha 1 treatment durations with an untreated control group. The primary measure was complete virological response, defined as clearance of serum HBV DNA and HBeAg. At 18 months, the reported response rates were 40.6% in the shorter-course group, 26.5% in the longer-course group and 9.4% in controls; only the shorter-course comparison reached statistical significance (P = .004). Response rates at the end of treatment were similar across all three groups, no responder lost HBsAg, and blinded liver histology scores were reported as better in the treated groups.^[6] The control group received no treatment rather than a placebo.

Hepatitis C#

The hepatitis C literature is mostly combination work. The 2020 review states that thymosin alpha 1 on its own does not appear useful against hepatitis C and summarizes studies in which it was added to interferon-based therapy, an approach that has since been displaced by direct-acting antivirals.^[5] FDA's review concluded that there are insufficient data to establish effectiveness for hepatitis C.^[2]

Vaccine response: Carraro et al., Vaccine, 2012#

This pilot study, registered as a phase 2, randomized, open-label trial sponsored by Sigma-Tau, enrolled adults with end-stage kidney disease on chronic dialysis, a population the authors describe as especially vulnerable to infection.^[7][8] Participants received an adjuvanted H1N1 pandemic influenza vaccine alone or together with thymosin alpha 1 at one of two amounts. The study measured antibody responses by hemagglutination inhibition, microneutralization and single radial hemolysis at intervals up to day 168, with 94 participants in the intention-to-treat analysis. The authors reported higher antibody titers at day 21 in both thymosin groups than with the vaccine alone, a steeper decline by day 42, and no adverse events attributed to the peptide, and they called for larger studies.^[7] FDA's 2024 review found the evidence insufficient to reach any conclusion on thymosin alpha 1 as a vaccine adjuvant.^[2]

Sepsis: the ETASS trial, Critical Care, 2013#

ETASS was a single-blind randomized trial at six teaching hospitals in China that enrolled 361 adults with severe sepsis in intensive care, comparing conventional care with and without thymosin alpha 1. The primary outcome was 28-day all-cause mortality: 26.0% in the thymosin group against 35.0% in controls, a difference the authors described as marginal (log-rank P = 0.049; non-stratified P = 0.062). The trial also measured monocyte HLA-DR expression, an immune marker, which rose more in the thymosin group at days 3 and 7.^[9]

Sepsis: the TESTS trial, BMJ, 2025#

TESTS, led by the same first author as ETASS, was a larger double-blind, placebo-controlled, phase 3 trial at 22 centers in China, enrolling 1,106 adults aged 18 to 85 with sepsis between 2016 and 2020. The primary outcome was again 28-day all-cause mortality. In the modified intention-to-treat analysis of 1,089 participants, mortality was 23.4% with thymosin alpha 1 and 24.1% with placebo (hazard ratio 0.99, P = 0.93), and no secondary or safety outcome differed significantly. Prespecified subgroup analyses suggested possible differences in effect by age and by diabetes status. The authors concluded that there was no clear evidence that thymosin alpha 1 reduces 28-day mortality in adults with sepsis.^[10]

FDA's 2024 review and compounding status#

In December 2024, FDA presented thymosin alpha 1 free base and thymosin alpha 1 acetate to its Pharmacy Compounding Advisory Committee as candidates for the list of bulk substances that pharmacies may compound under section 503A. FDA reviewed twelve proposed uses, including hepatitis B and C, HIV, COVID-19, sepsis, several cancers, infections after stem-cell transplant and vaccine adjuvant use, and concluded for each that the evidence was insufficient to establish effectiveness. It also raised a possible risk of immunogenicity, potentially amplified by aggregation, and a possible risk of causing or worsening graft-versus-host disease in stem-cell transplant recipients. Its overall assessment weighed against adding either form to the 503A list.^[2]

On FDA's page of bulk drug substances that may present significant safety risks in compounding, thymosin alpha 1 appears in the table of substances previously in Category 2 whose nominations were withdrawn by the nominators. The entry notes a possible significant risk of immunogenicity for certain routes, possible complexities with peptide-related impurities, and safety information FDA considered inadequate.^[4]

Thymosin alpha 1 vs thymosin beta 4#

The shared name is historical. Research on thymosins began with thymus extracts such as thymosin fraction 5, and the peptides found in that line of work were grouped as alpha, beta and gamma thymosins largely by their isoelectric point, a measure of charge. They are otherwise unrelated molecules. Thymosin alpha 1 is the acetylated N-terminal segment of a larger protein, prothymosin alpha. Thymosin beta 4 is the founding member of a separate family, the beta-thymosins, which are roughly 40 to 44 residues long.^[11] Its best-described role is inside cells, where it binds and sequesters actin monomers, the building blocks of the cytoskeleton, while thymosin alpha 1 is studied for its effects on immune signaling.^[5]

TB-500 is a short synthetic fragment of thymosin beta 4, not of thymosin alpha 1, so research on one says nothing about the other. The TB-500 product page covers that peptide separately.

What has not been established#

• No thymosin alpha 1 product is FDA-approved, and FDA could not independently verify the approval claims made for other countries.
• FDA's 2024 review found insufficient evidence of effectiveness for every use it examined.
• The largest and best-controlled trial, TESTS, found no mortality difference in sepsis.
• Much of the earlier literature is small, open-label or single-country, and some of it predates current standard treatments.
• Mechanistic statements about Toll-like receptors and T-cell maturation come from laboratory work and reviews, not from trial outcomes.

Reading a thymosin alpha 1 listing and COA#

For a 28-residue peptide, identity and purity cannot be judged from a label. A useful Certificate of Analysis for thymosin alpha 1 names the lot, states whether the material is free base or acetate, reports purity by HPLC with the chromatogram, and confirms identity by mass spectrometry with an observed mass consistent with the expected 3108.3 g/mol average mass (or the 3106.5 Da monoisotopic mass, depending on how the instrument reports it). It should also give the testing laboratory and the date. Truncated or deletion sequences and an incomplete N-terminal acetyl group are the kinds of impurities that a mass spectrum can reveal and that FDA's compounding entry alludes to when it mentions peptide-related impurities.^[4] Our guide to reading a Certificate of Analysis explains each section, HPLC and mass spectrometry explained covers the methods, and the COA library lists every Renuvia lot and its testing status.