Thymosin Alpha-1

Also known as: Zadaxin, Thymalfasin, Tα1, TA1

Evidence: Clinical

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Overview

28-residue thymic peptide (thymalfasin, Zadaxin) approved in over 30 countries for hepatitis B and C and as an immune adjuvant, with no US application on file; acts as an immune response modifier.

Thymosin alpha-1 is a 28-residue thymic peptide; its synthetic form, thymalfasin, is sold as Zadaxin. It is approved in more than 30 countries for chronic hepatitis B and C and as an immune adjuvant, with approvals granted market by market from the late 1990s (Tuthill, 2007; Goldstein and Goldstein, 2009). It has no US marketing approval: a Drugs@FDA query for thymalfasin and for Zadaxin returns no application. Randomised trials in hepatitis B gave mixed results, positive in one 98-patient trial (Chien et al., 1998) and null in a 97-patient placebo-controlled phase 3 (Mutchnick et al., 1999). In sepsis, a 361-patient single-blind trial suggested lower 28-day mortality (Wu et al., 2013) but the 1106-patient double-blind phase 3 found none (Wu et al., 2025).

Benefits

Immune support, antiviral, vaccine enhancement, T-cell activation

Dosing reference

Research dose: 1.6 mg subcutaneously twice weekly (the hepatitis B trial regimen and the marketed vial size)
Range: 1600 to 3200 mcg, 2-3x weekly
Reconstitution: 1 mL bacteriostatic water
Common vial sizes: 1.6 mg, 5 mg

Subcutaneous injection. Hepatitis B trials used 1.6 mg twice weekly for 26 to 52 weeks (Chien et al., 1998; Mutchnick et al., 1999). The melanoma trial tested 1.6, 3.2 and 6.4 mg with dacarbazine and interferon alfa (Maio et al., 2010). Sepsis trials dosed much more intensively: 1.6 mg every 12 hours for the first 5 days then daily in ETASS (Wu et al., 2013), and every 12 hours for 7 days in the phase 3 (Wu et al., 2025). The volunteer pharmacokinetic study used 900 mcg/m2, with tmax 1 to 2 hours and no accumulation over 5 days (Rost et al., 1999).

Mechanism

Thymosin alpha-1 is a 28-residue acetylated peptide from the thymosin alpha fraction, used clinically as the synthetic thymalfasin. Published work describes it as an immune response modifier acting on T-cell maturation and function and on dendritic cell maturation, rather than as a receptor agonist with a single defined target (Goldstein and Goldstein, 2009). In the sepsis trials the measured pharmacodynamic endpoint was monocyte HLA-DR expression, which rose at days 3 and 7 relative to control (Wu et al., 2013), and the phase 3 found no difference in any clinical or safety outcome (Wu et al., 2025). Its own developers describe the pleiotropic effect profile as an obstacle to defining the pharmacology (Tuthill, 2007).

Evidence

Clinical: at least one published human trial or an approved drug

Randomised trial in 98 patients with chronic hepatitis B: 1.6 mg subcutaneously twice weekly for 26 weeks gave a higher complete virological response at 18 months than no treatment, with histological improvement and no significant side effects (Chien et al., 1998)
Placebo-controlled phase 3 in 97 HBeAg-positive patients at the same dose for 6 months did not confirm efficacy: 14% versus 4% complete response, not significant (Mutchnick et al., 1999)
Randomised trial in 488 patients with metastatic melanoma tested 1.6, 3.2 and 6.4 mg with dacarbazine and interferon alfa; response rates were higher in the thymalfasin arms than the control arm (Maio et al., 2010)
ETASS, 361 patients with severe sepsis, single-blind: lower 28-day all-cause mortality and higher monocyte HLA-DR expression at days 3 and 7 (Wu et al., 2013)
TESTS, 1106 patients with sepsis, double-blind placebo-controlled phase 3 at 22 Chinese centres: 28-day mortality 23.4% versus 24.1%, hazard ratio 0.99, no secondary or safety outcome differed (Wu et al., 2025)
Human-trial status: approved in over 30 countries for hepatitis B and C and as an immune adjuvant (Tuthill, 2007; Goldstein and Goldstein, 2009), with no US application on file. Subcutaneous pharmacokinetics were characterised in 9 healthy volunteers at 900 mcg/m2 (Rost et al., 1999)

References

Side effects

Injection-site reactions are the commonly reported effect. In the 98-patient hepatitis B trial no significant side effects were observed (Chien et al., 1998), and in the 1106-patient double-blind sepsis trial no safety outcome differed from placebo (Wu et al., 2025), which is the largest controlled safety dataset available. Because it modifies T-cell function, caution is warranted in autoimmune disease and in transplant recipients on immunosuppression; this is a mechanistic concern, not a reported event rate.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Under 3 h (human, subcutaneous; tmax 1 to 2 h, no accumulation over 5 days, n=9; Rost et al., 1999)
Bioavailability: Well absorbed subcutaneously with tmax 1 to 2 h and an apparent distribution volume of 30 to 40 L, consistent with extracellular distribution; absolute bioavailability was not determined and differed between formulations (Rost et al., 1999)
Molecular weight: 3108.27 Da
Sequence: [Ac]SDAAVDTSSEITTKDLKEKKEVVEEAEN