Repository Corticotropin Injection (ACTHAR GEL) for Autoimmune and Inflammatory Diseases: Limited Use

First approved by the Food and Drug Administration (FDA) in 1952, repository corticotropin injection (ACTH, ACTHAR GEL, PURIFIED CORTROPHIN GEL) is a long-acting and expensive medication for the treatment of more than a dozen autoimmune and inflammatory diseases, such as exacerbations of multiple sclerosis in adults. Few randomized controlled trials, however, support the clinical benefit of repository corticotropin (hereafter referred to as corticotropin) for most FDA-approved indications. Corticotropin usually performs no better than glucocorticoids, such as prednisone (RAYOS and generics) and prednisolone (OMNIPRED, ORAPRED ODT, PEDIAPRED, PRED FORTE, PRED MILD, PRELONE and generics), for most of the same indications. Nonetheless, clinicians frequently prescribe corticotropin, which is heavily marketed. From August 2013 to December 2022, Acthar Gel ranked 14th among the top 25 drugs related to industry payments to U.S. physicians, with total payments exceeding $50 million.[1]

Public Citizen’s Health Research Group has classified corticotropin as a Limited Use drug; it should rarely be prescribed.

Corticotropin is administered under the skin (subcutaneous) or into the muscle (intramuscular). It is available in multidose vials and in single-dose, prefilled self-injector devices for subcutaneous injections.

The approved conditions for corticotropin treatment include those affecting the brain (for example, infantile spasms — a form of epilepsy — in infants and children under two years of age), the brain and nervous system (multiple sclerosis), joints and connective tissue (rheumatoid arthritis and systemic lupus erythematosus), skin (erythema multiforme), eyes (iritis and uveitis), lungs (sarcoidosis) and kidneys (edematous state).[2]

Corticotropin is a mixture of adrenocorticotropic hormone analogues or smaller molecules harvested from pig pituitary glands.[3] This mixture is formulated with gelatin to create a viscous injectable substance that is released from the muscle or skin over a prolonged period. Although its mechanism of action is not fully understood, corticotropin is believed to increase the adrenal glands’ secretion of the stress hormone cortisol and other natural steroids[4] and to lower the proliferation and activity of various cells (B-cells, T-cells and macrophages) involved in the immune response.

Regulatory history and indications

The first approval of corticotropin in 1952 for many indications preceded amendments to the Food, Drug, and Cosmetic Act of 1962; there were no efficacy standards for these early indications. By the 1970s, the prescribing information for corticotropin included 52 indications.[5] In 1979 the FDA approved corticotropin for exacerbations of multiple sclerosis in adults.

In the 1980s the drug was largely replaced by glucocorticoid treatments (especially prednisone) for many conditions. In the 1990s shortages of corticotropin occurred, in part because of purification challenges, and the rights to the medication were sold by Aventis to Questcor. In 2010, Questcor obtained FDA approval for corticotropin as a treatment for infantile spasms, and the company agreed to remove 33 of the 52 indications from the label.

In 2014 Mallinckrodt Pharmaceuticals bought the rights to corticotropin from Questcor and then “focused on modernizing the manufacturing [of the drug] and…further [evaluating] safety and efficacy.”

In 2021 the drug’s prescribing information was changed to distinguish corticotropin’s adverse-reaction profile from that of glucocorticoids. At present, the commonly reported adverse reactions for Acthar Gel, according to the prescribing information, include “injection site reaction, asthenic [weakness] conditions (including fatigue, malaise, asthenia and lethargy), fluid retention (including peripheral swelling, insomnia, headache and blood glucose increase[s]).” Infections, convulsions, high blood pressure, irritability and pyrexia (fever) occur in at least 5% of infants treated with the drug.

Escalating price, payments to doctors

The price per 400-unit vial (five to 10 doses) of corticotropin has skyrocketed in recent years. In 2001, it was $36; by 2021 it was $39,864, a more than 1,000-fold increase.[6]

In 2017, a study in JAMA Internal Medicine reviewed Medicare Part D spending on corticotropin from 2011 to 2015. Over this five-year period, the Medicare beneficiary cost per year increased from $57,980 to $162,371, and the number of Medicare beneficiaries prescribed corticotropin increased from 853 to 3,014.[7] Importantly, 203 rheumatologists, neurologists and nephrologists accounted for 42% of all Medicare spending on the drug. These frequent prescribers were only 0.4% to 2.1% of all prescribers within the specialties, according to the report.

In 2018 a follow-up study in JAMA Network Open found that among 235 nephrologists, neurologists and rheumatologists who wrote at least 10 prescriptions for corticotropin in 2015, 207 (88%) received at least one corticotropin-related payment from Mallinckrodt; more than 20% of these frequent prescribers received payments in excess of $10,000.[8] The researchers found that every $10,000 in payments was associated with a 79% increase (approximately $53,000) in Medicare spending on corticotropin. The payments were for such items as meals, education materials and fees for speaking and consulting. The study concluded: “Financial conflicts of interest may be driving use of corticotropin in the Medicare program.”

Comparative effectiveness and safety data

In 2022 a review article in JAMA Internal Medicine characterized the clinical evidence supporting corticotropin for FDA-approved indications. The Table below summarizes randomized clinical trials used to evaluate the safety and effectiveness of the drug.[9] Only single-blinded (patient blinded) or double-blinded (patient and prescriber blinded) trials with a glucocorticoid or placebo treatment arm are included.

Randomized Controlled Trials of Corticotropin†

†Trials discussed in the 2022 JAMA Internal Medicine review article
*Year of publication
**Number of patients studied
***Positive means corticotropin was superior; negative means comparator was superior.

The researchers found that most trials were dated, small, often unblinded with regard to investigator knowledge of group assignment, and typically showed that corticotropin was no more effective than glucocorticoids; in the largest study, it was no better than placebo. Specifically, most of the randomized controlled trials found that corticotropin “was not superior to corticosteroids for treating relapses of [multiple sclerosis] or infantile spasms.”[10]

Based on expert opinion, the physician’s reference UpToDate characterizes corticotropin as a first-line option for infantile spasms but as a secondary option for other indications because of the limited evidence of effectiveness.[11] UpToDate also cautions clinicians to advise patients to gradually taper off their maximum dose of corticotropin to avoid adrenal insufficiency (symptoms include fatigue, nausea, dizziness, weight loss, dehydration and muscle aches)[12] and to be aware of numerous interactions with other medications. For example, corticotropin can weaken the safety and effectiveness of many common vaccines.

What You Can Do

If your clinician prescribes corticotropin instead of a glucocorticoid, discuss whether this drug is a better choice than one of the many less expensive and usually equally effective alternatives. Consider tactfully asking your clinician if they have any financial conflicts of interest related to corticotropin. The Open Payments database (https://openpaymentsdata.cms.gov/), maintained by the Centers for Medicare & Medicaid Services, provides information about the financial relations that doctors and other health care providers have with drug and medical-device companies.
 

References

[1] Sayed A, Ross JS, Mandrola J, et al. Industry payments to US physicians by specialty and product type. JAMA. 2024;331(15):1325-1327.

[2] Mallinckrodt. Label: repository corticotropin injection (ACHTAR GEL). February 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/008372s074lbl.pdf. Accessed May 30, 2024.

[3] Kaplan J, Askanase A, Chu D, et al. Acthar® Gel treatment for patients with autoimmune and inflammatory diseases: an historical perspective and characterization of clinical evidence. Clin Drug Investig. 2023;43(10):739-761.

[4] Tran KA, Harrod C, Bourdette DN, et al. Characterization of the clinical evidence xupporting repository corticotropin injection for FDA-approved indications: a scoping review. JAMA Intern Med. 2022;182(2):206-217.

[5] Kaplan J, Askanase A, Chu D, et al. Acthar® Gel treatment for patients with autoimmune and inflammatory diseases: an historical perspective and characterization of clinical evidence. Clin Drug Investig. 2023;43(10):739-761.

[6] Tran KA, Harrod C, Bourdette DN, et al. Characterization of the clinical evidence xupporting repository corticotropin injection for FDA-approved indications: a scoping review. JAMA Intern Med. 2022;182(2):206-217.

[7] Hartung DM, Johnston K, Van Leuven S, et al. Trends and characteristics of US Medicare Spending on Repository Corticotropin. JAMA Intern Med. 2017;177(11):1680-1682.

[8] Hartung DM, Johnston K, Cohen DM, et al. Industry payments to physician specialists who prescribe repository corticotropin. JAMA Netw Open. 2018;1(2):e180482.

[9] Tran KA, Harrod C, Bourdette DN, et al. Characterization of the clinical evidence xupporting repository corticotropin injection for FDA-approved indications: a scoping review. JAMA Intern Med. 2022;182(2):206-217.

[10] Ibid.

[11] Corticotropin injection gel: drug information. UpToDate. May 2024.

[12] Johns Hopkins Medicine. Adrenal Insufficiency (Addison’s Disease). Undated. https://www.hopkinsmedicine.org/health/conditions-and-diseases/underactive-adrenal-glands--addisons-disease. Accessed May 30, 2024.