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06
Section 06 · 6 compounds

Immune & Inflammatory Modulation

Thymic, antimicrobial and immune-signaling peptides, from large trials to cell studies.

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Immune peptides help the body detect threats and keep its response in proportion. This section covers thymic peptides, host-defense molecules, a tissue-protective EPO derivative and several short Russian bioregulators. Evidence ranges from large international trials to a handful of cell studies.

Each entry opens with an evidence grade, then covers how the compound works, what human, animal and cell studies show, safety, open questions and regulatory status, with numbered references. Grades in this section: A: 1 · B: 3 · D: 1 · E: 1.

B
Evidence grade B · Human RCTsWhat this means

Randomized trials exist in sepsis, hepatitis B and melanoma, and the drug is approved in dozens of countries, but not by the FDA or EMA; the largest and best-run trial was negative[1,5,8].

A natural 28-amino-acid thymus peptide that nudges immune cells into action, approved abroad for hepatitis, but a large 2025 sepsis trial found it did not save lives.

Overview

Thymosin alpha-1 (Tα1) is a small peptide first isolated from the thymus, the gland where T cells mature. A synthetic copy called thymalfasin (brand name Zadaxin) is approved in more than 35 countries, mainly for chronic hepatitis B and C and as an immune booster in other conditions[1]. It has never been approved in the United States or by the European Medicines Agency, and its use for hepatitis has largely been overtaken by modern antiviral drugs[1].

The most important recent evidence comes from sepsis. A small Chinese trial in 2013 hinted at fewer deaths[6], but the much larger, double-blind TESTS trial of 1,106 patients, published in 2025, found no difference in 28-day survival[5]. Older hepatitis and melanoma trials showed modest or borderline signals[8,9].

A coach on the sideline, not a playerTα1 does not kill viruses or bacteria itself. It acts more like a coach shouting instructions to immune cells that are already on the field, telling sentinel cells to sound the alarm and T cells to get organized. If the team is already exhausted or overwhelmed, as in severe sepsis, better coaching may not change the final score.

Mechanism of Action

Tα1 is reported to act as an agonist at Toll-like receptors 9 and 2 on dendritic cells and other myeloid cells, the immune system's early-warning sensors[1]. In laboratory work, it caused dendritic cells exposed to the fungus Aspergillus to mature and produce interleukin-12, a signal that steers T cells toward a Th1 (infection-fighting) response. This ran through the MyD88, p38 MAPK and NF-κB pathways[3]. Reviews describe downstream increases in IL-2, interferons and natural killer and CD8+ T-cell activity, along with lower IL-1β and TNF-α[1].

Tα1 also appears to have a calming side. In human and mouse dendritic cells it switched on indoleamine 2,3-dioxygenase (IDO), an enzyme that breaks down tryptophan and promotes regulatory T cells and IL-10. This effect depended on TLR9 and type I interferon signaling[4]. The authors framed Tα1 as a balancer of inflammation and tolerance rather than a simple stimulant[4]. These mechanisms come mostly from one research network's cell and mouse studies, and how well they translate to sick patients is uncertain.

What the Research Shows

Human studies
  • Phase 3 RCT (TESTS), BMJ 2025 (n=1,106 adults with sepsis, 1,089 analyzed, double-blind): 28-day mortality was 23.4% with Tα1 vs 24.1% with placebo (hazard ratio 0.97, 95% CI 0.76 to 1.24, P=0.82). No difference in adverse events[5].
  • Single-blind RCT (ETASS), Critical Care 2013 (n=361 with severe sepsis): 28-day mortality 26.0% vs 35.0% (P=0.062 unstratified; P=0.049 log-rank). Monocyte HLA-DR, a marker of immune function, rose more with Tα1 at days 3 and 7[6].
  • Meta-analysis of 11 sepsis RCTs, 2025 (n=1,927): pooled 28-day mortality odds ratio 0.73 (95% CI 0.59 to 0.90). Restricted to the five higher-quality trials, the benefit was not significant (OR 0.82, 95% CI 0.65 to 1.03, P=0.09), and the authors judged the total evidence insufficient[7].
  • Meta-analysis of 5 hepatitis B RCTs, 2001 (n=353): no significant viral response at the end of treatment (OR 0.56), but a significant response 12 months after stopping (OR 2.67, 95% CI 1.25 to 5.68). Liver enzymes did not differ[8].
  • RCT in metastatic melanoma, J Clin Oncol 2010 (n=488, five arms, added to chemotherapy): more tumor responses with Tα1 (10 and 12 vs 4 in control), median survival 9.4 vs 6.6 months (HR 0.80, P=0.08, not significant). No added toxicity[9].
Animal studies
  • Mice, invasive aspergillosis after stem cell transplant: Tα1 activated Th1 antifungal immunity, sped recovery of myeloid cells and protected highly susceptible transplanted mice from fungal infection[3].
  • Mice, fungal infection and transplant tolerance models: Tα1-primed dendritic cells both triggered protective immunity and induced tolerance, through an IDO-dependent pathway[4].
Cell & mechanistic
  • Human and mouse dendritic cells: Tα1 increased IDO activity, IL-10 production and generation of regulatory T cells, dependent on TLR9[4].
  • Mouse dendritic cells pulsed with Aspergillus: Tα1 induced maturation and IL-12 production via MyD88-dependent Toll-like receptor signaling[3].
What This Could Mean in Practice

Outside the U.S., Tα1 has decades of use as an immune adjunct, which is reassuring about short-term tolerability[1]. But the best evidence now argues against the hope that it lowers sepsis deaths: the large TESTS trial was clearly neutral[5], and the positive pooled signal came mostly from smaller, lower-quality studies[7]. Hepatitis and cancer findings were modest, older and largely pre-date current treatments[8,9]. Claims that it broadly strengthens immunity in healthy people have not been tested in controlled trials.

Safety & Side Effects
  • Generally well tolerated in trials: the most common effect reported is local irritation or redness at the injection site[1].
  • Large sepsis trial: adverse events 66.4% vs 67.6% and serious adverse events 26.8% vs 29.3% (Tα1 vs placebo), with no significant differences[5].
  • Cancer trial: adding Tα1 to chemotherapy did not increase toxicity[9].
  • Immunogenicity: FDA has stated that compounded Tα1 may pose a significant risk of immune reactions and that safety information is inadequate[2].
  • Caution in immunosuppressed patients: reviews list organ transplant recipients as a group in whom it should be avoided unless benefit outweighs risk, since it stimulates immunity[1].

Open Questions

  • Why the small 2013 sepsis trial looked positive while the large 2025 trial did not; subgroup hints (older or diabetic patients) are unconfirmed[5,7].
  • Sepsis results conflict across trials of different size and quality, and much of the mechanism work comes from a single research network[3,4,7].
  • Whether any benefit exists in conditions where it is marketed informally, such as chronic fatigue or general immune support; no controlled trials address this.
  • Long-term effects of repeated use in people without a diagnosed immune problem.

Regulatory Status

Not FDA-approved; thymalfasin is approved in more than 35 other countries, mainly for hepatitis B and C[1]. FDA previously placed Tα1 in Category 2 (significant safety risk, citing immunogenicity) under its compounding policy; the nomination was later withdrawn, and as of May 2026 it does not appear on FDA's list of bulk substances nominated or under evaluation for 503A compounding[2,10].

Related Compounds

LL-37Vasoactive Intestinal PeptideARA-290
References (10)
  1. Dominari A, Hathaway D 3rd, Pandav K, et al. Thymosin alpha 1: a comprehensive review of the literature. World J Virol. 2020;9(5):67-78. PMID: 33362999
  2. U.S. Food and Drug Administration. Certain bulk drug substances for use in compounding that may present significant safety risks. 2026. fda.gov
  3. Romani L, Bistoni F, Gaziano R, et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through Toll-like receptor signaling. Blood. 2004;103:4232-9. DOI: 10.1182/blood-2003-11-4036
  4. Romani L, Bistoni F, Perruccio K, et al. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood. 2006;108(7):2265-74. PMID: 16741252
  5. Wu J, Pei F, Zhou L, 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. PMID: 39814420
  6. Wu J, Zhou L, Liu J, 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. DOI: 10.1186/cc11932
  7. Gu B, Zhou Y, Nie Y, et al. Efficacy of thymosin α1 for sepsis: a systematic review and meta-analysis of randomized controlled trials. Front Cell Infect Microbiol. 2025;15:1673959. DOI: 10.3389/fcimb.2025.1673959
  8. Chan HL, Tang JL, Tam W, et al. The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis. Aliment Pharmacol Ther. 2001;15(12):1899-905. PMID: 11736720
  9. Maio M, Mackiewicz A, Testori A, et al. Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma. J Clin Oncol. 2010;28(10):1780-7. PMID: 20194853
  10. U.S. Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act. Updated May 2026. fda.gov

Sources last reviewed October 2026.

B
Evidence grade B · Human RCTsWhat this means

Topical LL-37 has been tested in two randomized, placebo-controlled trials in venous leg ulcers, the larger of which missed its main endpoint, and it is not approved anywhere[1,2].

The body's only cathelicidin, a natural germ-killing and wound-signaling peptide, tested as a topical leg-ulcer treatment with mixed results and not approved for any use.

Overview

LL-37 is a 37-amino-acid peptide cut from a larger protein called hCAP-18, the only cathelicidin humans make. Neutrophils, skin cells and the linings of the airways and gut release it when they meet microbes or injury[3]. It punches holes in bacterial membranes, but it also acts as a signal: it recruits immune cells, stimulates new blood vessels and helps skin cells cover a wound[3,5]. Its name comes from its first two amino acids (two leucines) and its length.

The most serious drug development so far has been a topical LL-37 for hard-to-heal venous leg ulcers. A small 2014 trial looked promising[1], but a larger 2021 phase IIb trial found no overall benefit over placebo[2]. LL-37 also has a darker side: it helps drive the inflammation of psoriasis by turning the body's own DNA into an immune alarm signal[4].

A security guard who also calls the repair crewLL-37 behaves like a guard posted at the skin and mucous membranes. It tackles intruders directly by breaking their outer walls, then radios for backup and signals builders to lay new blood vessels. The trouble is that an overeager guard can sound the alarm at the body's own debris, which is part of what goes wrong in psoriasis.

Mechanism of Action

LL-37 is released when proteases cleave the storage protein hCAP-18, which is encoded by the CAMP gene[3]. In membrane-like environments it folds into an amphipathic alpha-helix, with positively charged amino acids on one face and water-repelling ones on the other. The positive face is drawn to the negatively charged surfaces of bacteria; the oily face then inserts into the membrane and disrupts it[3]. This physical mode of killing is one reason antimicrobial peptides draw interest as resistance to conventional antibiotics grows. Activity is weakened by salt and serum, which complicates use inside the body[3].

Beyond killing microbes, LL-37 signals to human cells. It stimulates endothelial cells through formyl peptide receptor-like 1 (FPRL1), triggering their growth and new vessel formation; mice lacking the mouse version of the peptide had fewer blood vessels at wound edges[5]. LL-37 can also bind fragments of the body's own DNA and carry them into plasmacytoid dendritic cells, where they trigger interferon-alpha release through TLR9. This is a recognized driver of psoriasis[4], so the same signaling that may help a wound can also fuel chronic inflammation.

What the Research Shows

Human studies
  • Randomized placebo-controlled trial, 2014 (n=34 with hard-to-heal venous leg ulcers, 4 weeks topical treatment after a placebo run-in): the two lower strengths healed faster than placebo, with roughly a 68% average reduction in ulcer area in the lowest-strength group; the highest strength did not differ from placebo. No safety concerns emerged[1].
  • Phase IIb RCT (HEAL LL-37), 2021 (n=148, mean ulcer size 11.6 cm², median ulcer duration 20.3 months, with compression therapy): no significant improvement in healing versus placebo in the full study population. A post hoc analysis suggested benefit in ulcers of at least 10 cm², which the authors said needs a properly powered confirmatory trial[2].
  • Both trials used topical application to wounds; no controlled human trial of injected LL-37 has been published.
Animal studies
  • Rabbits, hind-limb ischemia: LL-37 increased collateral vessel growth, calf-muscle capillary density and blood flow at 4 weeks versus a scrambled peptide or buffer; group sizes were small (3 to 4)[5].
  • Mice lacking CRAMP (the mouse cathelicidin), skin incisions: fewer new blood vessels at the wound edge 3 days after injury than in normal mice[5].
  • Chick embryo membrane assay: LL-37 increased blood vessel formation; a scrambled control did not[5].
Cell & mechanistic
  • Human endothelial cells: LL-37 increased proliferation through FPRL1, an effect not blocked by serum and not mediated by VEGF[5].
  • Human plasmacytoid dendritic cells: LL-37 bound to self-DNA triggered interferon-alpha production, a mechanism linked to psoriasis[4].
What This Could Mean in Practice

LL-37 is one of the better-studied peptides in this reference, yet the evidence still does not show a clear benefit. The only larger randomized trial found no overall improvement in venous leg ulcer healing, and the positive large-ulcer subgroup was identified after the fact[2]. The earlier positive result came from 34 patients[1]. Its role in psoriasis[4] is a reminder that boosting a natural immune signal can backfire. Evidence for injected or systemic use, or for treating infections in people, is lacking.

Safety & Side Effects
  • Topical use in trials: well tolerated at the strengths tested, with no safety signal in either venous ulcer trial[1,2].
  • Inflammatory disease: LL-37 helps drive psoriasis by turning self-DNA into an interferon alarm signal, so boosting it could plausibly worsen autoimmune skin inflammation[4].
  • Host-cell toxicity: at higher concentrations LL-37 can damage human cells as well as bacteria[3].
  • Injected use: no published human safety data exist. FDA previously placed LL-37 in Category 2 for compounding over safety concerns before the nomination was withdrawn[6].

Open Questions

  • Whether LL-37 truly helps large venous ulcers depends on a confirmatory trial that has not been reported[2].
  • Systemic or injected LL-37 has no human efficacy or safety data, and salt and serum blunt its antimicrobial activity[3].
  • The balance between helpful wound signaling and harmful inflammation in conditions such as psoriasis is not well defined[4].
  • Long-term effects of repeated exposure, including immune reactions, are unstudied.

Regulatory Status

Not approved by FDA or any major regulator. Cathelicidin LL-37 was removed from FDA's Category 2 compounding safety-risk list in April 2026 after its nomination was withdrawn, and FDA's compounding advisory committee is scheduled to consider it before the end of February 2027[6,7]. LL-37 is not specifically named on the WADA Prohibited List.

Related Compounds

Thymosin Alpha-1KPVTB-500
References (7)
  1. Grönberg A, Mahlapuu M, Ståhle M, et al. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22(5):613-21. PMID: 25041740
  2. Mahlapuu M, Sidorowicz A, Mikosinski J, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: a multicentric prospective randomized placebo-controlled clinical trial. Wound Repair Regen. 2021;29(6):938-950. PMID: 34687253
  3. Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006;1758(9):1408-25. DOI: 10.1016/j.bbamem.2006.03.030
  4. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564-9. DOI: 10.1038/nature06116
  5. Koczulla R, von Degenfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003;111(11):1665-72. DOI: 10.1172/JCI17545
  6. U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (content current as of April 22, 2026). fda.gov
  7. McDermott Will & Schulte. Bulk-list bound? PCAC backs majority of peptides in two-day public meeting. July 2026. mcdermottlaw.com

Sources last reviewed October 2026.

A
Evidence grade A · FDA-approvedWhat this means

VIP (as aviptadil, combined with phentolamine) has held a UK marketing authorisation since 2015 for erectile dysfunction[5]; it is not FDA-approved, and other uses rest on small or uncontrolled studies[2,3].

A natural gut and nerve peptide that relaxes blood vessels and calms immune cells, licensed in the UK only as part of an erectile dysfunction injection and otherwise still experimental.

Overview

Vasoactive intestinal peptide (VIP) is a 28-amino-acid messenger made by nerves in the gut, brain, lungs and elsewhere, and by some immune cells[1]. It widens blood vessels, relaxes smooth muscle and dampens inflammation[1,2]. Its drug form is called aviptadil. The only regulatory approval found is in the UK, where aviptadil combined with phentolamine (Invicorp) was licensed in 2015 as an injection for erectile dysfunction[5].

Beyond that, research has explored inhaled VIP for pulmonary hypertension, with an encouraging but uncontrolled eight-patient study[2] and only a modest, short-lived effect from a single inhalation in a later study[3]. Animal research shows striking anti-inflammatory effects in arthritis, colitis and other models[1,4], but these have not been confirmed in controlled human trials.

A dimmer switch for tensionMany body systems run on a balance of tightening and relaxing signals. VIP works like a dimmer switch that turns down tension: blood vessel walls loosen, airways relax, and overexcited immune cells quiet down. The trouble as a drug is that the switch is very short-lived and sits all over the body, so effects are hard to aim.

Mechanism of Action

VIP acts mainly through two receptors, VPAC1 and VPAC2, which are coupled to adenylate cyclase. Activating them switches on the cyclic AMP and cyclic GMP signaling systems inside cells[2]. In blood vessels and smooth muscle this causes relaxation, which explains both its vessel-widening action in the lungs and its use, alongside phentolamine, to produce erections[2,5]. In cultured lung artery muscle cells from patients with pulmonary hypertension, both receptors were markedly increased and VIP slowed cell overgrowth[2].

In the immune system, VIP and its receptors are present on many cell types. VIP reduces production of inflammatory signals such as TNF-α and IL-6 by macrophages and microglia, and has been reported to induce regulatory T cells, which restrain autoimmune attack[1]. Its effects on T-helper subsets are more complex, with some studies showing it can promote Th17 or Th1 responses[1]. VIP is also unstable in blood[2], one reason it has been hard to develop as a systemic drug.

What the Research Shows

Human studies
  • Randomized crossover trial vs alprostadil (VP 007), erectile dysfunction (n=187 in dose-finding phase): good-quality erections in 73% with aviptadil/phentolamine vs 83% with alprostadil, significantly favoring alprostadil. In a second phase (n=107), rates were similar (84% vs 83%), but only patients who responded to both drugs were included. Patients more often preferred aviptadil/phentolamine, which caused less pain[5].
  • Open-label study, pulmonary hypertension, J Clin Invest 2003 (n=8, 12 weeks inhaled): mean pulmonary artery pressure fell from 59 to 46 mmHg, vascular resistance fell about 50%, and six-minute walk distance rose 113 m (all P<0.01). No control group[2].
  • Single-dose open-label study, pulmonary hypertension, Eur Respir J 2008 (n=20): mean pulmonary artery pressure fell only 1.7 mmHg; the authors called the vasodilation modest and short-lived[3].
Animal studies
  • Mice, collagen-induced arthritis: VIP reduced the frequency and severity of arthritis and prevented joint swelling and destruction of cartilage and bone, by damping both inflammatory and autoimmune components[4].
  • Rodent inflammation and autoimmunity models: reviews describe protection in experimental multiple sclerosis (EAE), Crohn's-like colitis, lethal endotoxemia, autoimmune uveitis, pancreatitis and a Parkinson's model[1].
Cell & mechanistic
  • Pulmonary artery smooth muscle cells (pulmonary hypertension patients): VPAC1 about 3-fold and VPAC2 about 8-fold higher than controls; VIP inhibited cell proliferation[2].
  • Macrophages and microglia: VIP inhibited production of TNF-α, IL-6 and chemokines[1].
What This Could Mean in Practice

In the UK, aviptadil is an accepted option as part of a combination injection for erectile dysfunction, with efficacy roughly comparable to, and in one phase somewhat lower than, the standard alternative[5]. For pulmonary hypertension, the promising early result came from just eight patients without a control group and was not matched by a later study[2,3]. Anti-inflammatory and immune-balancing effects are well documented in animals but remain unproven in people[1,4]. Its use for other conditions has not been established by controlled trials.

Safety & Side Effects
  • Combination injection (UK label): about 10% of patients have side effects, most often bruising at the injection site and flushing[5].
  • Flushing: facial flushing was far more common than with alprostadil (17 vs 3 per 100 injections); no priapism was seen in the comparison trial[5].
  • Inhaled use: tolerability was rated very good in 19 of 20 patients and systemic blood pressure did not change significantly in a single-dose study[3].
  • Absent data: no long-term safety data exist for repeated systemic or inhaled VIP outside the licensed combination; because it widens blood vessels, low blood pressure is a theoretical concern.

Open Questions

  • Whether the anti-inflammatory effects seen in arthritis, colitis and multiple sclerosis models translate to patients.
  • Whether inhaled VIP offers any lasting benefit in pulmonary hypertension; the published human data are small and uncontrolled.
  • How to overcome VIP's instability in the body well enough for reliable systemic effects[2].
  • Clinical value in conditions where it is promoted informally, which have not been tested in randomized trials.

Regulatory Status

Not FDA-approved. Aviptadil combined with phentolamine (Invicorp) received a UK marketing authorisation in April 2015 for erectile dysfunction[5]. FDA lists vasoactive intestinal peptide in 503A Category 1 (bulk substances under evaluation for compounding) as of May 2026[6].

Related Compounds

Thymosin Alpha-1KPVARA-290
References (6)
  1. Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. 2013;45(1):25-39. DOI: 10.1007/s00726-011-1184-8
  2. Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339-46. DOI: 10.1172/JCI17500
  3. Leuchte HH, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32(5):1289-94. DOI: 10.1183/09031936.00050008
  4. Delgado M, Abad C, Martinez C, et al. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. 2001;7(5):563-8. DOI: 10.1038/87887
  5. All Wales Therapeutics and Toxicology Centre. AWMSG Secretariat Assessment Report: aviptadil/phentolamine mesilate (Invicorp) 25 micrograms/2 mg solution for injection (reference 3435). 2017. awttc.nhs.wales
  6. U.S. Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act. Updated May 2026. fda.gov

Sources last reviewed October 2026.

B
Evidence grade B · Human RCTsWhat this means

Three small randomized, placebo-controlled trials (22 to 48 patients, about 4 weeks each) have been published in sarcoidosis and type 2 diabetes; it has not been approved anywhere[1,2,3].

A small fragment engineered from the hormone EPO that aims to keep EPO's tissue-protecting effects without raising red blood cell counts, tested in a few small nerve-pain trials.

Overview

ARA-290, also called cibinetide, is an 11-amino-acid peptide modeled on one face of erythropoietin (EPO), the kidney hormone that tells bone marrow to make red blood cells[3]. Besides its blood role, EPO protects stressed tissues. ARA-290 was designed to keep that protective signal while losing the red-cell signal, which carries risks such as thicker blood and clots[3,4].

Human testing has focused on small fiber neuropathy, painful damage to the thinnest nerves, in people with sarcoidosis or type 2 diabetes. Small, short placebo-controlled trials reported improved symptom scores and, in some patients, regrowth of tiny corneal nerves[1,2,3]. No large or long trial has been published, and the drug remains investigational.

Copying one key off a master key ringEPO is like a master key ring that opens two doors: one to the red blood cell factory and one to a repair workshop. ARA-290 is a copy of just the repair-workshop key. The idea is to open the door for tissue protection without also cranking up blood production.

Mechanism of Action

EPO acts on two different receptor setups. The classic one, a pair of EPO receptors, drives red blood cell production. A second complex, made of an EPO receptor paired with the beta common receptor (CD131), is sometimes called the innate repair receptor and is switched on locally by injury, inflammation and metabolic stress[1]. ARA-290 was engineered from the helix B surface of EPO to engage this repair complex without stimulating red blood cell production[1,3]. In mice lacking the beta common receptor, its pain-relieving effect disappeared, supporting that target, as summarized in the diabetes trial report[1].

In animal tissue, activating this pathway has been linked to less inflammation and less cell death. In a rat hemorrhagic shock model, a closely related helix B peptide increased protective Akt and eNOS signaling and reduced NF-κB activation, a master switch for inflammation[5]. The peptide itself is short-lived: in healthy volunteers, the terminal half-life after injection under the skin was about 20 minutes[1]. Its effects are thought to come from triggering longer-lasting repair programs, but this has not been proven in humans.

What the Research Shows

Human studies
  • Pilot RCT in sarcoidosis, Mol Med 2012 (n=22, 4 weeks, intravenous): small fiber neuropathy symptom score improved by 11.5 points vs 2.9 on placebo (P<0.05). Pain and fatigue scores improved similarly in both groups[2].
  • RCT in sarcoidosis, Mol Med 2013 (n=38, 28 days, under the skin): symptom score fell 12.2 points (about 28%) vs 3.8 on placebo (P=0.005). Corneal nerve fiber area rose 14.5% (P=0.022) vs a non-significant 5.3% fall. Six-minute walk improved 18.7 m vs a 15.1 m decline (P=0.049). Pain intensity did not differ between groups[3].
  • Phase 2 RCT in type 2 diabetes, Mol Med 2014 (n=48, 28 days of treatment, 56-day follow-up): HbA1c changed by -0.21% vs +0.21% at day 56 (P=0.002). Neuropathic pain scores improved 4.2 vs 0.74 points (P about 0.03). Corneal nerve density did not change significantly in the whole group, only in a subgroup with the lowest baseline values[1].
Animal studies
  • Rats, heart attack model: a single dose of the helix B peptide after coronary artery ligation reduced infarct size by 50% and cell death in at-risk heart muscle by 80% at 24 hours, comparable to EPO, without stimulating red blood cell production[4].
  • Rats, hemorrhagic shock: reduced injury to kidney, liver, pancreas and muscle and reduced lung inflammation, even when given an hour into resuscitation; it did not restore blood pressure[5].
  • Rodent neuropathic pain and diabetes models: earlier studies reported long-term pain relief in rats, reversal of autonomic nerve degeneration in diabetic mice and benefits in diet-induced insulin resistance, as summarized by the developers[1].
Cell & mechanistic
  • Isolated heart muscle cells: the helix B peptide raised the oxidative-stress threshold needed to trigger mitochondrial collapse by 40%, similar to EPO[4].
What This Could Mean in Practice

For people with painful small fiber neuropathy, ARA-290 is an intriguing but unproven idea. The trials were tiny, lasted about a month and measured symptom scores that also improved on placebo[1,2,3]. Nerve regrowth findings were limited to corneal measurements, and in the diabetes trial only to a subgroup[1,3]. The claim of tissue protection without red blood cell stimulation rests mainly on animal work[4,5]. Whether any benefit lasts, or matters for function over months to years, is unknown.

Safety & Side Effects
  • Short-term tolerability: two sarcoidosis trials reported no safety concerns in clinical or laboratory checks over about 4 weeks[2,3].
  • Serious events: in the diabetes trial, four serious adverse events occurred in the ARA-290 group, two judged possibly drug-related; none occurred on placebo[1].
  • Blood counts and antibodies: no medically significant changes in hematology and no anti-drug antibodies were detected in the 38-patient trial[3].
  • Absent data: no long-term safety, pregnancy or drug-interaction data have been published.

Open Questions

  • Whether the small, short trial results hold up in a larger, longer randomized trial; none has been published.
  • Developer involvement is substantial: several trial authors were employees and shareholders of the company developing the drug[3].
  • Whether EPO's other non-blood risks, such as effects on tumor growth, are truly absent with this fragment.
  • Whether corneal nerve changes translate into meaningful, lasting reductions in pain or disability.

Regulatory Status

Not approved by the FDA or any other major regulator; it remains an investigational drug studied in phase 2 trials[1,3]. Under FDA's 503A compounding program, cibinetide (ARA-290) is listed in Category 3, substances nominated without adequate supporting information, as of May 2026[6].

Related Compounds

Thymosin Alpha-1Vasoactive Intestinal Peptide
References (6)
  1. Brines M, Dunne AN, van Velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2014;20:658-66. DOI: 10.2119/molmed.2014.00215
  2. Heij L, Niesters M, Swartjes M, et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med. 2012;18(11):1430-6. DOI: 10.2119/molmed.2012.00332
  3. Dahan A, Dunne A, Swartjes M, et al. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med. 2013;19:334-45. DOI: 10.2119/molmed.2013.00122
  4. Ahmet I, Tae HJ, Juhaszova M, et al. A small nonerythropoietic helix B surface peptide based upon erythropoietin structure is cardioprotective against ischemic myocardial damage. Mol Med. 2011;17:194-200. DOI: 10.2119/molmed.2010.00235
  5. Patel NS, Nandra KK, Brines M, et al. A nonerythropoietic peptide that mimics the 3D structure of erythropoietin reduces organ injury/dysfunction and inflammation in experimental hemorrhagic shock. Mol Med. 2011;17(9):883-92. DOI: 10.2119/molmed.2011.00053
  6. U.S. Food and Drug Administration. Bulk drug substances nominated for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act. Updated May 2026. fda.gov

Sources last reviewed October 2026.

D
Evidence grade D · Animal onlyWhat this means

Evidence consists of one rat COPD-model study plus cell-culture and test-tube DNA work, all from the developers' network, with no human trials[1,2,3].

A four-amino-acid synthetic peptide aimed at the airways, studied in bronchial cell cultures and one rat lung-damage model, with no published human trials.

Overview

Bronchogen is a synthetic tetrapeptide from Vladimir Khavinson's family of "peptide bioregulators," aimed at the lining of the airways[1,4]. Its sequence is usually given as Ala-Glu-Asp-Leu (AEDL)[3,4], but the developers' own 2014 paper in Lung named it Ala-Asp-Glu-Leu (ADEL), so even the published sequence is inconsistent[1]. It is not Ala-Glu-Asp-Pro, which is cortagen. Almost all research comes from one St. Petersburg network, much of it in Russian journals.

In human bronchial cell cultures, the peptide raised markers of cell renewal and airway-cell identity, especially in aged cultures[1]. In rats with lung damage from 60 days of nitrogen dioxide exposure, a month of Bronchogen was reported to reverse signs of airway remodeling and reduce neutrophil inflammation[2]. No human trials have been published, and no independent replication was found, including in 2025.

Reminding worn cells of their jobThe developers picture Bronchogen as a reminder note for tired airway-lining cells, nudging them back toward making mucus, surfactant and new cells the way younger cells do. In lab dishes and one rat model the note seemed to be read. Whether it reaches or helps human lungs is unknown.

Mechanism of Action

The proposed mechanism is gene regulation. In cultured human bronchial epithelial cells at early, middle and late passages, the peptide increased the proliferation marker Ki67 (3.4-fold in the oldest cultures), raised the survival protein Mcl-1, and lowered p53 by 28 to 38%. It increased expression of airway-identity and function genes including NKX2-1, SCGB1A1, FOXA1, FOXA2, MUC4, MUC5AC and SFTPA1, with FOXA2 up 15.5-fold in young cultures[1]. Several genes did not respond in the oldest cultures, and the text claim of reduced NOS-3 was not clearly supported by the paper's own table[1].

Test-tube studies suggest the peptide binds DNA, most likely at guanine N7 in the major groove, without distorting the double helix. Binding was seen only at very low salt (5 mM) and was weak at body-like salt levels (0.15 M), which raises doubt about whether it happens inside cells[3]. The authors state that in vivo DNA binding is supported but not proven[3]. The developers' 2021 review also reports histone binding in fluorescence assays[4].

What the Research Shows

Human studies
  • No human clinical trials of Bronchogen have been published in peer-reviewed literature, and no human pharmacokinetic or safety data were found.
Animal studies
  • Rats, COPD model from 60-day intermittent nitrogen dioxide exposure: one month of Bronchogen was reported to eliminate goblet-cell excess, squamous changes, lymphocyte infiltration and emphysema features, restore ciliated cells, normalize bronchoalveolar cell counts and cytokines, and raise secretory IgA. Numerical results and group sizes were not available in the abstract[2].
Cell & mechanistic
  • Human bronchial epithelial cells (young, mature and aged passages): Ki67 rose 1.6 to 3.4-fold and p53 fell 28 to 38%, with increased airway-identity gene expression; five samples per group[1].
  • Purified calf DNA: the peptide bound DNA at low salt without changing melting temperature meaningfully (65 vs 62°C)[3].
What This Could Mean in Practice

Bronchogen is an experimental peptide with cell-culture and single-rat-model evidence[1,2]. The findings fit the developers' idea that it supports airway-lining renewal, but nothing shows that it improves breathing, lung function or COPD outcomes in people. The sequence itself is reported inconsistently in the developers' papers[1,3], which complicates any attempt to replicate the work. People with lung disease have tested treatments; this one has not been studied in humans.

Safety & Side Effects
  • No human safety data, adverse-event reports or toxicology studies of Bronchogen have been published in peer-reviewed literature.
  • Raising proliferation and lowering p53 in airway cells, as seen in culture, could in theory be unwelcome in people at risk of lung cancer; no data address this[1].
  • Products sold under this name are unregulated, and because published sequences differ (AEDL vs ADEL), what a product actually contains is uncertain[1,3].
  • Effects in pregnancy, children and people with asthma or cancer are unknown.

Open Questions

  • Which sequence, AEDL or ADEL, was used in each study, and whether they behave the same[1,3].
  • Whether the rat COPD result can be reproduced in another laboratory[2].
  • Whether the peptide reaches the airways intact by any route.
  • Whether DNA binding seen only at very low salt occurs in living cells[3].

Regulatory Status

Not approved by the FDA, the EMA or another major regulator for any use. It was not among the peptides reviewed at the FDA's July 2026 Pharmacy Compounding Advisory Committee meeting, which considered the related Khavinson-group peptide epitalon[5]. Bronchogen is not named individually on the WADA Prohibited List, which separately bars substances not approved for human therapeutic use.

Related Compounds

ChonlutenThymosin Alpha-1Epitalon
References (5)
  1. Khavinson VKh, Tendler SM, Vanyushin BF, et al. Peptide regulation of gene expression and protein synthesis in bronchial epithelium. Lung. 2014;192:781-91. DOI: 10.1007/s00408-014-9620-7
  2. Kuzubova NA, Lebedeva ES, Dvorakovskaya IV, et al. Modulating effect of peptide therapy on the morphofunctional state of bronchial epithelium in rats with obstructive lung pathology. Bull Exp Biol Med. 2015;159(5):685-688. DOI: 10.1007/s10517-015-3047-x
  3. Morozova EA, Lin'kova NS, Khavinson VKh, et al. In vitro interaction of the AEDL peptide with DNA. J Struct Chem. 2017;58(2):420-424. DOI: 10.1134/S0022476617020299
  4. Khavinson VK, Popovich IG, Linkova NS, et al. Peptide regulation of gene expression: a systematic review. Molecules. 2021;26(22):7053. PMID: 34834147
  5. U.S. Food and Drug Administration. FDA Briefing Document: Pharmacy Compounding Advisory Committee meeting, July 23-24, 2026 (epitalon evaluation). 2026. fda.gov

Sources last reviewed October 2026.

E
Evidence grade E · Cell / minimalWhat this means

Peer-reviewed evidence is essentially one cell-culture study; animal and human results appear only in a patent filing, never in a peer-reviewed journal[1,2].

A three-amino-acid synthetic peptide marketed for the lungs, with almost no peer-reviewed research: one immune-cell study and claims that appear only in a patent.

Overview

Chonluten is the synthetic tripeptide Glu-Asp-Gly (EDG), described by the developers as being of bronchial and lung origin[1]. It is part of Vladimir Khavinson's family of short "peptide bioregulators." The same molecule is indexed in the U.S. medical vocabulary as glutamyl-aspartyl-glycine, also called T-34 tripeptide, with an older note that it was found in a neurotoxic dialysate[3]. The developers' own 2021 systematic review of gene-regulating peptides does not discuss EDG at all[4].

The only peer-reviewed study found is a 2022 Italian-Russian collaboration in which EDG and four other bioregulators were tested on human monocyte cells; EDG reduced some inflammatory signals but slightly increased TNF release in resting cells[1]. A U.S. patent describes rat stress experiments and a small human altitude study, but these were never published in a journal[2]. No independent replication was found, including in 2025.

A label without much insideChonluten has a name, a sequence and a target organ on its label, but very little published research inside the box. Most of what is claimed about it comes from the developers' patents and marketing rather than from studies other scientists can read and check.

Mechanism of Action

No mechanism has been established. In THP-1 cells, a human monocyte and macrophage line, EDG was tested alongside epitalon, Vilon, Thymogen and Thymalin. The peptides generally increased cell growth and reduced LPS-triggered release of the inflammatory signals TNF-α and IL-6, and most reduced monocyte sticking to activated blood-vessel cells[1]. EDG stood out in two ways: it caused a slight TNF release in unstimulated monocytes, and it roughly doubled the apoptosis readout compared with the other peptides[1]. The study did not measure gene expression, and the authors said the mechanism remains to be investigated[1].

The patent proposes a stress-protective action, reporting changes in brain and blood levels of noradrenaline, dopamine and serotonin in rats, altered c-Fos activity in a brain stress center, and inhibition of the enzyme that breaks down enkephalins in human serum samples[2]. None of these findings has been published in a peer-reviewed journal. Lung-specific effects, the main marketing claim, have no published support.

What the Research Shows

Human studies
  • Patent filing, not peer-reviewed (80 young men, simulated 5,000 m altitude): treated groups reportedly had less anxiety, higher hypoxia tolerance (80 to 90% vs 60% on placebo) and smaller heart-rate rises. Randomization, blinding and statistics are not described, and the study has not appeared in a journal[2].
  • No peer-reviewed human trials of Chonluten have been published.
Animal studies
  • Rats, mice and guinea pigs, patent data only: changes in brain and serum monoamines in 27 rats, and no reported toxic effects in acute, 90-day and 6-month studies, apart from a temporary rise in white blood cells at 3 months. These data are not peer-reviewed[2].
Cell & mechanistic
  • Human THP-1 monocytes: EDG reduced LPS-induced TNF-α and IL-6 release along with the other peptides, but caused slight TNF release in resting cells and about double the apoptosis readout. Exact values were reported only in figures and supplements[1].
What This Could Mean in Practice

Chonluten has almost no peer-reviewed evidence. One cell study shows mixed effects on immune-cell inflammation, including a slight pro-inflammatory signal on its own[1], and the remaining claims rest on a patent rather than published research[2]. Nothing shows that it supports lung function, treats COPD or protects against stress in people. Any lung-related claims about it are, at present, unsupported.

Safety & Side Effects
  • No peer-reviewed human safety data, adverse-event reports or toxicology studies of Chonluten exist.
  • Patent animal studies reported no toxic effects but a temporary rise in white blood cells; these results were never independently reviewed[2].
  • In cell culture, EDG alone triggered slight TNF release and more apoptosis than related peptides, which deserves study before anyone assumes it is purely anti-inflammatory[1].
  • Products sold under this name are unregulated, so identity, purity and sterility are not assured.

Open Questions

  • Whether EDG has any effect on lung or airway tissue; no published study tested this.
  • Why the developers' own 2021 review of gene-regulating peptides leaves EDG out[4].
  • Whether the patent's animal and human results would hold up in a peer-reviewed study[2].
  • How the molecule behaves in the body, including whether it survives digestion.

Regulatory Status

Not approved by the FDA, the EMA or another major regulator for any use. It was not among the peptides reviewed at the FDA's July 2026 Pharmacy Compounding Advisory Committee meeting, which considered the related Khavinson-group peptide epitalon[5]. Chonluten is not named individually on the WADA Prohibited List, which separately bars substances not approved for human therapeutic use.

Related Compounds

BronchogenThymosin Alpha-1Epitalon
References (5)
  1. Avolio F, Martinotti S, Khavinson VK, et al. Peptides regulating proliferative activity and inflammatory pathways in the monocyte/macrophage THP-1 cell line. Int J Mol Sci. 2022;23(7):3607. DOI: 10.3390/ijms23073607
  2. U.S. Patent and Trademark Office. US Patent 8,071,556: Peptide substance revealing a stress protective effect, pharmaceutical composition on its base, and the method of its application (H-Glu-Asp-Gly-OH). uspto.gov
  3. U.S. National Library of Medicine. MeSH Supplementary Concept C026740: glutamyl-aspartyl-glycine (Glu-Asp-Gly; T-34 tripeptide). meshb.nlm.nih.gov
  4. Khavinson VK, Popovich IG, Linkova NS, et al. Peptide regulation of gene expression: a systematic review. Molecules. 2021;26(22):7053. PMID: 34834147
  5. U.S. Food and Drug Administration. FDA Briefing Document: Pharmacy Compounding Advisory Committee meeting, July 23-24, 2026 (epitalon evaluation). 2026. fda.gov

Sources last reviewed October 2026.

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