Corticotropin (ACTH 1-39)

The full-length 39-amino-acid adrenocorticotropic hormone, marketed in the United States since 1952 as porcine-derived repository corticotropin injection (Acthar Gel, Purified Cortrophin Gel) for infantile spasms, multiple sclerosis relapses, and other inflammatory conditions.

Also referenced as: ACTH, Adrenocorticotropic hormone, Adrenocorticotropin, Corticotrophin, Acthar Gel, Purified Cortrophin Gel, Cortrophin Gel

Also appears in: Immune

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What is Corticotropin (ACTH 1-39)?

Corticotropin is the pharmaceutical name for adrenocorticotropic hormone (ACTH), the 39-amino-acid peptide (Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly…Pro-Leu-Glu-Phe in humans, molecular weight about 4,540 g/mol) that the anterior pituitary cleaves from pro-opiomelanocortin and releases in response to hypothalamic corticotropin-releasing hormone. The porcine hormone, which is what the two US drug products contain, differs from the human sequence at a single residue (leucine in place of serine at position 31). As a drug it exists in one form in the United States: repository corticotropin injection, a porcine pituitary extract suspended in gelatin for slow release after intramuscular or subcutaneous injection, sold as Acthar Gel (approved April 29, 1952) and Purified Cortrophin Gel (approved June 16, 1954, returned to the market by ANI Pharmaceuticals after a supplemental approval on October 29, 2021). It is a prescription specialty-pharmacy product rather than a research-market compound, although synthetic ACTH 1-39 is sold by research vendors as a laboratory reagent for receptor and adrenal cell work, and it should not be confused with cosyntropin, the synthetic 24-residue diagnostic fragment.

How it works

• MC2R steroidogenesis. ACTH is the sole endogenous agonist of the melanocortin-2 receptor on the adrenal zona fasciculata, and MC2R needs the melanocortin-2 receptor accessory protein (MRAP) to reach the cell surface and signal; MRAP loss-of-function mutations cause familial glucocorticoid deficiency type 2, an inherited ACTH resistance (Metherell et al., Nature Genetics, 2005;37(2):166-170). A cryo-EM structure of the ACTH-bound MC2R-Gs-MRAP1 complex shows MRAP1 acting as a “seat belt” that stabilizes the hormone in the binding pocket, with the N-terminal His-Phe-Arg-Trp message and the Lys-Lys-Arg-Arg basic motif (residues 15-18) making the key contacts; Gs coupling raises cAMP, mobilizes cholesterol into mitochondria, and drives cortisol, corticosterone, aldosterone, and weak-androgen output (Luo et al., Cell Research, 2023;33(1):46-54). The Acthar Gel label describes this adrenal stimulation and states that the mechanism of action in infantile spasms is unknown.
• Melanocortin pharmacology beyond cortisol. The same N-terminal sequence that ACTH shares with alpha-MSH (residues 1-13) lets full-length ACTH activate all five melanocortin receptors: MC1R on melanocytes and immune cells, MC3R and MC4R in the brain and on macrophages, and MC5R on exocrine glands. Activation of MC1R and MC3R in particular reduces nuclear translocation of NF-kappaB and lowers a broad set of inflammatory mediators in a glucocorticoid-independent way, which is the basis for the proposal that ACTH and related melanocortins act as anti-inflammatory agents in their own right (Catania et al., Pharmacological Reviews, 2004;56(1):1-29). The MC1R action also explains the skin darkening seen when ACTH is chronically elevated. The Acthar Gel label notes that the product is reported to bind melanocortin receptors but does not claim a clinical effect from that binding.
• A depot of a short-lived hormone. Endogenous ACTH has a plasma half-life of roughly 15 minutes after intravenous administration. The repository products suspend the extract in 15-16% gelatin so that it is absorbed slowly from an intramuscular or subcutaneous site: in 20 healthy volunteers given 80 USP units of Purified Cortrophin Gel intramuscularly, the median time to peak cortisol was 8 hours (range 3-12), and the Acthar Gel label states that its pharmacokinetics have not been adequately characterized.
• Not a single defined molecule. Both US products are described on their labels as complex mixtures of ACTH, ACTH-related peptides, and other porcine pituitary peptides. Acthar Gel’s label identifies its major component as N-25 deamidated porcine ACTH (1-39), a chemically modified form of the hormone; Cortrophin Gel’s names porcine ACTH (1-39) as the active peptide. The two products have not been compared head to head in a clinical trial.

Research status

Infantile spasms. This is the best-supported indication, and the evidence is still small. The pivotal trial randomized 29 infants (median age 6 months) to two weeks of high-dose intramuscular ACTH or oral prednisone, with response requiring both cessation of spasms and elimination of hypsarrhythmia on video-EEG judged by a blinded investigator: 13 of 15 (86.6%) responded to ACTH against 4 of 14 (28.6%) on prednisone (Baram et al., Pediatrics, 1996;97(3):375-379). The United Kingdom Infantile Spasms Study randomized 107 infants at 150 hospitals to vigabatrin or hormonal treatment (oral prednisolone or intramuscular depot tetracosactide, the synthetic 1-24 fragment rather than ACTH 1-39): spasms had stopped on days 13 and 14 in 40 of 55 (73%) on hormonal treatment versus 28 of 52 (54%) on vigabatrin, with adverse events in 55% and 54% of the two arms (Lux et al., Lancet, 2004;364(9447):1773-1778), and at 14 months developmental scores favored hormonal treatment only in infants with no identified cause (Lux et al., Lancet Neurology, 2005;4(11):712-717). A later single-center randomized trial in 97 Sri Lankan infants found that high-dose oral prednisolone outperformed synthetic depot ACTH at the UKISS dose on day-14 spasm cessation (28 of 48 versus 18 of 49) and on electroclinical remission (Wanigasinghe et al., Pediatric Neurology, 2015;53(3):193-199). The FDA granted the infantile spasms indication on October 15, 2010, under NDA 022432, on the basis of the Baram trial and a supportive high-dose versus low-dose study.

Multiple sclerosis relapse. Corticotropin was better than placebo in the 1960s and has been no better than methylprednisolone since. The US multicenter cooperative study that underpins the MS indication compared intramuscular ACTH with placebo in acute exacerbations (Rose et al., Neurology, 1970;20(5):1-59); the current label summarizes that era of trials as showing faster resolution of exacerbations but no effect on ultimate outcome. A double-blind randomized comparison of high-dose intravenous methylprednisolone with intramuscular ACTH in 61 patients found marked improvement in both groups and no difference in rate of recovery or final outcome (Thompson et al., Neurology, 1989;39(7):969-971), and the Cochrane review of corticosteroids or ACTH for acute exacerbations found a short-term protective effect for both, with a non-significant trend favoring methylprednisolone and no data on long-term disability beyond one year (Filippini et al., Cochrane Database of Systematic Reviews, 2000;(4):CD001331).

Rheumatology, lupus, sarcoidosis. The record is mixed and consists mostly of manufacturer-sponsored phase 4 trials. In rheumatoid arthritis active despite a corticosteroid and one or two DMARDs, 259 patients received open-label repository corticotropin for 12 weeks; 163 (62.9%) reached low disease activity (DAS28-ESR below 3.2), and among the 154 responders randomized to continue or switch to placebo for 12 more weeks, 47 (61.0%) on active drug versus 32 (42.1%) on placebo maintained low disease activity (p = 0.019) (Fleischmann et al., Rheumatology and Therapy, 2020;7(2):327-344; NCT02919761). In persistently active systemic lupus erythematosus despite moderate-dose glucocorticoids, 172 patients were randomized to repository corticotropin or placebo for 24 weeks and the primary endpoint failed in the 169-patient modified intention-to-treat population: SRI-4 response at week 16 was 47.6% versus 43.5% (odds ratio 1.2, 95% CI 0.6 to 2.2, p = 0.5762), with post hoc analyses favoring the drug on other instruments (Askanase et al., Rheumatology and Therapy, 2020;7(4):893-908; NCT02953821). A placebo-controlled trial in pulmonary sarcoidosis randomized 55 patients (27 to the drug, 28 to placebo) before the investigators ended it early for low enrollment during the COVID-19 pandemic, precluding statistical analysis; numerical trends favored the drug (Mirsaeidi et al., Pulmonary Therapy, 2023;9(2):237-253; NCT03320070).

Nephrotic syndrome. The evidence is open-label series and one failed placebo-controlled trial. Prospective open-label series reported partial or complete proteinuria remission in some patients with membranous nephropathy and focal segmental glomerulosclerosis, for example 7 of 24 patients (29%) with steroid-resistant or steroid-dependent idiopathic FSGS treated at two US centers, with adverse events in 21 of the 24 (Hogan et al., Clinical Journal of the American Society of Nephrology, 2013;8(12):2072-2081). The sponsor’s randomized, double-blind, placebo-controlled phase 4 trial in treatment-resistant idiopathic membranous nephropathy (CHART, NCT01386554) enrolled 60 participants between August 2011 and November 21, 2016; per the results posted on ClinicalTrials.gov, partial remission at 24 weeks occurred in 5 of 35 on the higher dose, 1 of 4 on the lower dose, and 2 of 21 on placebo, with no complete remissions in any arm. A Columbia University open-label trial in proliferative lupus nephritis was terminated for lack of funding after enrolling 8 patients (NCT02226341).

The evidence base as a whole. A scoping review of 41 studies involving 2,235 participants across the approved indications found that 19 were single-arm or compared only dosing strategies, that the evidence was most robust for infantile spasms and MS, that almost all MS comparisons found corticotropin better than placebo but no different from corticosteroids, that only one small randomized trial in infantile spasms found it superior to corticosteroids, and that placebo-controlled trials in rheumatoid arthritis, ankylosing spondylitis, optic neuritis, lupus, and nephrotic syndrome were generally small and did not consistently show superiority to placebo, while blinded trials showed similar or more adverse effects than with corticosteroids (Tran et al., JAMA Internal Medicine, 2022;182(2):206-217).

Active development as of November 2026. Cerium Pharmaceuticals is recruiting for a two-part phase 3 superiority trial of SNP-ACTH (1-39) Gel against rituximab in an estimated 148 adults with primary membranous nephropathy, with a 24-month complete-response endpoint in the second part and estimated primary completion on April 1, 2027 (NCT05696613, last updated June 25, 2026). Massachusetts General Hospital opened a randomized, double-blind phase 4 trial of two dose levels of Purified Cortrophin Gel in 150 patients with acute gout flares on December 20, 2025 (NCT07346079), and a 20-patient phase 4 pilot of the Acthar Gel SelfJect injector in autoimmune keratitis is recruiting (NCT06964269). No new indication has been approved for either US product since 2010.

Common dosage forms

Repository corticotropin injection is supplied in the United States as a sterile gel at a single strength of 80 USP units/mL. Acthar Gel (Keenova ARD LLC, formerly Mallinckrodt ARD; NDA 008372) comes as a 5 mL multiple-dose vial (400 USP units/5 mL) in 16% gelatin and, since February 29, 2024, as the single-dose prefilled SelfJect injector in two fixed presentations, 40 USP units/0.5 mL and 80 USP units/mL, labeled for subcutaneous use in adults. Purified Cortrophin Gel (ANI Pharmaceuticals; NDA 008975) comes as 1 mL and 5 mL multiple-dose vials (80 USP units/mL and 400 USP units/5 mL) in 15% gelatin and, since February 28, 2025, as single-dose prefilled syringes of 40 USP units/0.5 mL and 80 USP units/mL.

Key considerations

• Regulatory status. The FDA Approved status reflects Acthar Gel (NDA 008372, approved April 29, 1952) and Purified Cortrophin Gel (NDA 008975, approved June 16, 1954), both still marketed, with Acthar’s infantile spasms indication added on October 15, 2010 and its SelfJect injector approved on February 29, 2024. Both original approvals predate modern efficacy standards.
• Corticotropin is not cosyntropin. Cosyntropin (tetracosactide) is a synthetic 24-residue fragment with a diagnostic indication; corticotropin is the full 39-residue hormone in a gelatin depot with therapeutic indications. The infantile spasms evidence is split between the two: the US pivotal trial used repository corticotropin, while UKISS and the Sri Lankan trial used depot tetracosactide, and results from one do not automatically transfer to the other.
• Evidence gap. The gap is widest outside infantile spasms and MS. The approved list rests largely on pre-1962 practice; the only modern placebo-controlled trials in lupus, membranous nephropathy, and sarcoidosis missed their primary endpoints or could not be analyzed, and the rheumatoid arthritis trial tested maintenance after open-label response rather than superiority to a corticosteroid. Whether the melanocortin-receptor effects add anything clinically beyond the cortisol the drug releases has not been demonstrated in humans.
• Safety signals. The labels carry glucocorticoid-excess warnings, porcine-protein hypersensitivity and a congenital-infection contraindication in infants. Antibodies can form after chronic use, and anaphylaxis and angioedema have been reported.
• Naming. Corticotropin (USAN), corticotrophin (older British spelling), adrenocorticotropic hormone, adrenocorticotropin, and ACTH all denote the same 39-residue peptide; “repository corticotropin injection” is the gelatin depot dosage form, not a different molecule. Units are USP units of biological activity rather than milligrams, and the SNP-ACTH (1-39) Gel in phase 3 is a distinct investigational product that should not be read as either approved brand.