Repository Corticotropin Injection (Acthar Gel and Purified Cortrophin Gel)

Number: 0762

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Brand Selection for Medically Necessary Indications for Commercial Medical Plans

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Acthar Gel and Purified Cortrophin Gel are more costly to Aetna than conventional therapies (e.g., corticosteroids, immunosuppressive agents) for multiple sclerosis, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, respiratory diseases and edematous states. There is a lack of reliable evidence that Acthar Gel and Purified Cortrophin Gel are superior to the lower cost conventional therapies (e.g., corticosteroids, immunosuppressive agents) for these indications. Therefore, Aetna considers Acthar Gel and Purified Cortrophin Gel as not medically necessary for these indications outlined below:

Multiple Sclerosis

Treatment of acute exacerbations of multiple sclerosis in adults
Rheumatic Disorders

As adjunctive therapy for short-term administration (to tide the member over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis
Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis)
Dermatologic Diseases

Severe erythema multiforme, Stevens-Johnson syndrome, severe psoriasis
Allergic States

Atopic dermatitis, serum sickness
Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic conjunctivitis, keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation
Respiratory Diseases

Symptomatic sarcoidosis
Edematous State

To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

Policy

Scope of Policy

This Clinical Policy Bulletin addresses repository corticotropin injection (Acthar Gel and Purified Cortrophin Gel) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of repository corticotropin injection (Acthar Gel or Purified Cortrophin Gel) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Acthar Gel or Purified Cortrophin Gel, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Criteria for Initial Approval
Aetna considers repository corticotropin injection (Acthar Gel only) medically necessary for treatment of infantile spasms in members who are less than 2 years of age.

Aetna considers all other indications as experimental, investigational, unproven, or not medically necessary.
Continuation of Therapy
Aetna considers the continuation of repository corticotropin injection (Acthar Gel only) therapy as medically necessary for infantile spasms when the member has shown substantial clinical benefit from therapy.

Dosage and Administration

Repository corticotropin injection is available as Acthar Gel and Purified Cortrophin Gel. Below includes dosing recommendations for use of Acthar Gel for treatment of infantile spasms, which is an FDA-approved indication. Purified Cortrophin Gel is not FDA-approved for infantile spasms.

Infantile Spasms

Recommended Dosage for Infantile Spasms in Infants and Children Under 2 Years of Age:

Acthar Gel is typically dosed based on body surface area (BSA). To calculate BSA, see Body Surface Area Calculation.
In the treatment of infantile spasms, Acthar Gel must be administered intramuscularly using the Acthar gel vial. Note: Acthar Gel single-dose pre-filled SelfJect injector is not to be used for the treatment of infantile spasms.
The recommended regimen is a daily dose of 150 U/m² (divided into twice-daily intramuscular injections of 75 U/m²) administered over a 2-week period. Dosing with Acthar Gel should then be gradually tapered over a 2-week period to avoid adrenal insufficiency. The following is one suggested tapering schedule: 30 U/m² in the morning for 3 days; 15 U/m² in the morning for three days; 10 U/m² in the morning for 3 days; and 10 U/m² every other morning for 6 days.

Note: The labeling of Acthar gel states that, although drug dependence does not occur, sudden withdrawal of repository corticotropin gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication.

Note: For dosing recommendations for other indications listed in the FDA product labeling which Aetna considers not medically necessary, see Appendix. These dosing recommendations are provided in situations where Aetna's policy does not apply.

Source: Mallinckrodt Pharmaceuticals, 2024

Not Medically Necessary

Aetna considers repository corticotropin injection not medically necessary for diagnostic testing of adrenocortical function because it has not been shown to be superior to cosyntropin for this purpose.

Experimental, Investigational, or Unproven

Aetna considers repository corticotropin injection (Purified Cortrophin Gel) experimental, investigational, or unproven for infantile spasms, as Purified Cortrophin Gel is not FDA-approved, nor has a compendial use, for this indication.

Aetna considers use of Acthar Gel in combination with Purified Cortrophin Gel as experimental, investigational, or unproven because the safety and efficacy for combination use has not been established.

Aetna considers repository corticotropin injection experimental, investigational, or unproven for all other indications, including the following (not an all-inclusive list), because its effectiveness for these indications has not been established:

Amyotrophic lateral sclerosis
Dry eye disease
Focal segmental glomerulosclerosis,
Neurosarcoidosis
Non-infectious retinal vasculitis
Ocular mucous membrane pemphigoid
Ocular sarcoidosis

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0801	Injection, corticotropin (acthar gel), up to 40 units
J0802	Injection, corticotropin (ani), up to 40 units
ICD-10 codes covered if selection criteria are met:
G40.821 - G40.824	Epileptic spasms [West's syndrome] [Acthar gel only]
ICD-10 codes not covered for indications listed in the CPB :
A15.0 - A15.9	Respiratory tuberculosis [when used concurrently with antituberculous chemotherapy]
A17.0	Tuberculous meningitis [with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy]
B02.39	Other herpes zoster eye disease [dermatitis of eyelid; severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
B75	Trichinellosis [with neurologic or myocardial involvement]
C81.00 - C96.9	Malignant neoplasm of lymphatic and hematopoietic tissue [for palliative management of leukemias and lymphomas in adults, acute leukemia of childhood]
D59.0 - D59.9	Acquired hemolytic anemias
D61.01	Constitutional (pure) red cell aplasia
D61.89	Other specified aplastic anemias and other bone marrow failure syndromes [erythroblastopenia] [RBC anemia]
D69.59	Other secondary thrombocytopenia [in adults]
D86.0 - D86.9	Sarcoidosis [symptomatic] [pulmonary sarcoidosis, neurosarcoidosis] [ocular sarcoidosis]
E06.1	Subacute thyroiditis [nonsuppurative]
E83.52	Hypercalcemia [with cancer]
G12.21	Amyotrophic lateral sclerosis
G35	Multiple sclerosis [acute exacerbations]
H04.121 - H04.129	Dry eye syndrome
H10.001 - H10.44	Conjunctivitis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
H16.001 - H16.9	Keratitis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
H20.00 - H20.9	Iridocyclitis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
H30.001 - H30.93	Chorioretinal inflammations [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
H35.061	Retinal vasculitis, right eye
H35.062	Retinal vasculitis, left eye
H35.063	Retinal vasculitis, bilateral
H35.069	Retinal vasculitis, unspecified eye
H44.11 - H44.19	Other endophthalmitis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa] [including panuveitis and posterior uveitis]
H44.131 - H44.139	Sympathetic uveitis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
H46.00 - H46.9	Optic neuritis [severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa]
I00 - I02.9	Acute rheumatic fever [during an exacerbation or as maintenance therapy in selected cases]
J30.1 - J30.9	Allergic rhinitis [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
J45.20 - J45.998	Asthma [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
J63.2	Berylliosis
J68.0	Bronchitis and pneumonitis due to chemicals, gases, fumes and vapors [aspiration pneumonitis]
J69.0 - J69.8	Pneumonitis due to inhalation of food or vomit [aspiration pneumonitis]
J82	Pulmonary eosinophilia, not elsewhere classified [Loffler's syndrome not manageable by other means]
K29.60 - K29.61	Other gastritis [allergic gastritis] [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
K50.00 - K50.919	Crohn's disease[regional enteritis] [to tide the patient over a critical period of the disease]
K51.00 - K51.919	Ulcerative colitis [to tide the patient over a critical period of the disease]
K52.21 - K52.29	Allergic and dietary gastroenteritis and colitis
L10.0 - L10.9	Pemphigus
L12.1	Cicatricial pemphigoid [ocular mucous membrane pemphigoid]
L13.0	Dermatitis herpetiformis
L21.8 - L21.9	Seborrheic dermatosis [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
L24.0 - L24.9	Irritant contact dermatitis [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
L27.0 - L27.9	Dermatitis due to substances taken internally [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
L40.0 - L40.9	Psoriasis [severe]
L50.0 - L50.9	Urticaria [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
L51.0 - L51.9	Erythema multiforme
M05.00 - M14.89	Inflammatory polyarthropathies [as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) including selected cases of juvenile rheumatoid arthritis]
M10.00 - M10.09	Idiopathic gout [acute]
M15.0 - M19.93	Osteoarthritis [synovitis of] [as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation)]
M32.0 - M32.9	Systemic lupus erythematosus (SLE) [during an exacerbation or as maintenance therapy in selected cases]
M33.0 - M33.9	Dermatopolymyositis
M45.0 - M45.9	Ankylosing spondylitis
M75.00 - M77.9	Shoulder lesions [acute and subacute bursitis] [acute nonspecific tenosynovitis]
N04.0 - N04.9	Nephrotic syndrome
N26.9	Renal sclerosis, unspecified [focal segmental glomerulosclerosis]
T50.905+	Adverse effect of unspecified drugs, medicaments and biological sustances [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
T78.3xx+	Angioneurotic edema [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
T78.40x+	Allergy, unspecified [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
T80.51x+ - T80.59x+	Anaphylactic reaction due to serum [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]
T80.61x+ - T80.69x+	Other serum reaction [severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment]

Background

U.S. Food and Drug Administration (FDA)-Approved Indications for Acthar Gel

As monotherapy for the treatment of infantile spasms in infants and children under 2 years of age
Treatment of exacerbations of multiple sclerosis in adults
Acthar Gel may be used for the following disorders and diseases: rheumatic; collagen; dermatologic; allergic states; ophthalmic; respiratory; and edematous state.

U.S. Food and Drug Administration (FDA)-Approved Indications for Purified Cortrophin Gel

Rheumatic Disorders

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis; ankylosing spondylitis; acute gouty arthritis
Collagen Diseases

During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis)
Dermatologic Diseases

Severe erythema multiforme (Stevens-Johnson syndrome), severe psoriasis
Allergic States

Atopic dermatitis, serum sickness
Ophthalmic Diseases

Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic conjunctivitis, keratitis, iritis and iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation
Respiratory Diseases

Symptomatic sarcoidosis
Edematous States

To include a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus
Nervous system

Acute exacerbation of multiple sclerosis.

Repository corticotropin injection is available as Acthar Gel (Mallinckrodt Pharmaceuticals, Inc), formerly known as H.P. Acthar Gel (Questcor Pharmaceuticals), and Purified Cortrophin Gel (ANI Pharmaceuticals, Inc).

Acthar Gel and Purified Cortrophin Gel are highly purified sterile preparations of the adrenocorticotropic hormone (ACTH) available in 16% gelatin (for Acthar Gel) or 15% gelatin (for Purified Cortrophin Gel) to provide a prolonged release after intramuscular or subcutaneous injection. Repository corticotropin injection is a natural product derived from a porcine source of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances. The release of ACTH is modulated by the nervous system via the corticotropin regulatory hormone released from the hypothalamus and by a negative corticosteroid feedback mechanism. Elevated plasma cortisol levels suppress ACTH release.

Repository corticotropin injection was originally approved by the U.S. Food and Drug Administration (FDA) in 1952 for a broad range of corticosteroid-responsive conditions including rheumatic, collagen, dermatologic, allergic states, ophthalmic, respiratory and edematous states. Current labeled indications include multiple sclerosis, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmologic diseases, respiratory diseases, and edematous states. In addition, the FDA approved the use of repository corticotropin injection (Acthar Gel only) for treatment of infantile spasms in infants and children under 2 years of age. In August 2021, the U.S. FDA approved Purified Cortrophin Gel for basically the same indications as Acthar Gel except for the infantile spasms indication.

There are a lack of clinical studies comparing the effectiveness of ACTH gel to corticosteroids in corticosteroid-responsive conditions. In addition, there is no reliable evidence of the effectiveness of ACTH gel in persons who have failed to respond to corticosteroids. Also, because of uncertainties in the effect of ACTH gel on the magnitude of endogenous cortisol production, ACTH gel has the potential for inducing significant adverse effects.

Repository corticotropin should be used in the lowest dose for the shortest period of time to accomplish the therapeutic goal. Adverse effects with ACTH are potentially life-threatening problems that include depression of the immune system and modified response to infection leading to overwhelming sepsis. Minor side effects include behavioral changes especially irritability, changes in appetite, weight gain and alteration in sleep patterns.

Repository corticotropin has the potential for inducing significant adverse effects that are not reversible. Chronic administration of more the 40 units daily may be associated with uncontrollable adverse effects (ANI Pharmaceuticals, 2022).

Adrenocorticotropic hormone has historically been a natural product derived from a bovine or porcine source administered as an intramuscular or subcutaneous injection. However, in the United Kingdom, with the existing concerns surrounding bovine spongiform encephalopathy, ACTH was withdrawn from the market. Tetracosactide is a synthetic alternative to ACTH and displays the same physiological properties as ACTH. In Europe and Japan synthetic ACTH is usually available, while in the United States natural ACTH derivatives are normally used. Acthar Gel and Purified Cortrohin Gel are of porcine origin.

Repository corticotropin is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, hypertension, or sensitivity to proteins of porcine origin. It is also contraindicated in the treatment of primary adrenal insufficiency, hypercortisolism, or any condition associated with these disorders.

Infantile Spasms (West Syndrome)

Repository corticotropin injection has been used as a treatment for West syndrome (also known as infantile spasms), a rare disorder that includes a peculiar type of epileptic seizure and an electroencephalogram (EEG) finding called "hypsarrhythmia". Onset usually occurs within the first year of life and peaks at 3 to 5 months. It is sometimes associated with cerebral palsy or Down's syndrome, but little is known about the exact pathophysiology of the condition. While the seizures generally resolve by the age of 3 years, the long-term prognosis is poor. Psychomotor delay is severe in approximately 70 % of the cases and many will develop other forms of severe epilepsy. Few studies have evaluated the long-term outcome of West syndrome, but it is generally agreed that earlier control might improve prognosis (Hancock and Osborne, 2002).

Individuals diagnosed with infantile spasm are typically treated with a variety of agents; however, treatment has proven to be problematic since it is generally refractory to conventional anti-epileptic drugs. Academy of Neurology and the Child Neurology Society (2004) on the treatment of infantile spasms, repository corticotropin is effective for the short‐term treatment of infantile spasms and the resolution of hypsarrhythmia. While there is some evidence that supports the effectiveness of ACTH for the short-term treatment of infantile spasms and in resolution of hypsarrhythmia, the optimum treatment for infantile spasms has yet to be established.

The FDA has approved H.P. Acthar Gel for treatment of infantile spasms in infants and children under 2 years of age (FDA, 2010). An FDA committee (2010) concluded that there was substantial evidence of effectiveness for Acthar Gel as a treatment for infantile spasms. This conclusion was based upon evidence from 1 randomized controlled trial (RCT) with confirmatory evidence. The committee agreed that effectiveness has been shown in the cessation of spasms and amelioration of the EEG, but not in the prevention of other seizure types, improvement in long-term developmental outcomes, or any other outcomes. According to the product labeling, the recommended regimen is a daily dose of 150 U/m2 (divided into twice-daily intra-muscular injections of 75 U/m2) administered over a 2-week period. Dosing with H.P. Acthar Gel should then be gradually tapered over a 2-week period to avoid adrenal insufficiency.

In a retrospective, multi-center study, researchers from Japan reviewed the medical records of 138 patients with West syndrome who were treated with low dose synthetic ACTH. The authors noted that at the end of ACTH therapy, excellent effect on seizures was noted in 106 (76 %) patients, good effect in 23 (17 %), and poor effect in 9 (7 %). Initial effects on EEG were excellent in 53 (38 %) patients, good in 76 (55 %), and poor in 9 (7 %). As for seizure prognosis at the time of follow-up, 51 of 99 (52 %) patients were seizure-free, whereas 48 (48 %) patients had seizures. Mental outcome was normal in 6 of 98 (6 %) patients, mild mental retardation in 16 (16 %), moderate mental retardation in 26 (27 %), and severe mental retardation in 50 (51 %). The initial effects of ACTH on seizures and long-term outcome were not dose dependent (daily dosage 0.005 to 0.032 mg/kg, 0.2 to 1.28 IU/kg; total dosage 0.1 to 0.87 mg/kg, 4 to 34.8 IU/kg). The severity of adverse effects correlated with total dosage of ACTH, and the severity of brain volume loss due to ACTH correlated well with the daily dosage and total dosage of ACTH. The authors concluded that low-dose synthetic ACTH therapy is as effective for the treatment of West syndrome as higher doses (Ito et al, 2002).

A Cochrane review on the treatment of infantile spasms (2002) compared the effects of single drugs used to treat infantile spasms in terms of long-term psychomotor development, subsequent epilepsy, control of the spasms and adverse effects. A total of 14 RCTs with a total of 667 participants were included in the review and 9 different drugs were evaluated (vigabatrin, ACTH (7 different treatment regimens and different preparations), prednisone, hydrocortisone, nitrazepam, sodium valproate, sulthiame, methysergide and alpha-methylparatyrosine). The review reported that overall, the methodology of the studies was poor due to ethical dilemmas such as giving placebo injections to children. Findings from 2 small studies showed ACTH to be more efficacious than low-dose prednisone (2 mg/kg). One study suggested that hormonal treatments (prednisolone or tetracosactide) might improve long-term developmental outcome compared with vigabatrin in patients who are not found to have an underlying cause for their infantile spasms. One small study found vigabatrin to be more efficacious than hydrocortisone in stopping infantile spasms due to tuberous sclerosis. Few studies considered psychomotor development or subsequent seizure rates as outcomes and none had long-term follow-up; few side effects or deaths were reported. A clear statement on the optimum treatment for infantile spasms could not be made, however, the reviewers stated that

hormonal treatment (i.e., ACTH, tetracosactide or high dose prednisolone) will resolve spasms faster than vigabatrin in more infants (but this may or may not translate into better long term outcome),
if prednisone or vigabatrin are used, then high dosage is recommended,
vigabatrin may be the treatment of choice in tuberous sclerosis but more research is required, and
resolution of the EEG may be important but this has not been proven.

The authors concluded that further trials with larger numbers of participants and longer follow-up are needed.

This is consistent with Riikonen's review (2005) on best treatment practices of infantile spasms in Finland. Riikonen stated that hormonal treatment is the most effective therapy in the short-term treatment of infantile spasms. One study found large doses of prednisolone to be as effective as corticotrophin. Vigabatrin is the treatment of choice for infants with tuberous sclerosis. An earlier review by Riikonen (2004) reported that in an open, randomized, prospective study, the efficacy and relapse rates of ACTH and vigabatrin treatment did not differ significantly and that the high response rates in tuberous sclerosis complex were similar. Both drugs had severe side effects. In the long-term follow-up of 20 to 35 years, 1/3 of the patients died, the intellectual outcome of the remaining patients was normal or slightly subnormal, and 1/4 to 1/3 of the patients were seizure-free. Riikonen stated that ACTH should be the first choice for treatment of infantile spasms since the side effects of ACTH, unlike those of vigabatrin, are well- known, treatable, and reversible; however, the author concluded that an open, prospective study to compare the efficacy, relapse rate, and long-term outcome of treatment with ACTH and vigabatrin is urgently needed.

The American Academy of Neurology and Child Neurology Society (Mackay et al, 2004) reviewed 159 articles to determine the current practice parameter on the medical treatment of infantile spasms. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. The practice parameter concluded that

ACTH is probably an effective agent in the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment,
vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis,
there is insufficient evidence to recommend oral corticosteroids,
there is insufficient evidence to recommend any other treatment of infantile spasms, and
there is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis.

Kivity et al (2004) evaluated the long-term cognitive and seizure outcomes of patients (n = 37) with cryptogenic infantile spasms treated within 1 month of onset with high-dose synthetic ACTH. The patients received a standardized treatment regimen of high-dose tetracosactide depot, 1 mg IM every 48 hrs for 2 weeks, with a subsequent 8- to 10-week slow taper and followed by oral prednisone, 10 mg/day for a month, with a subsequent slow taper for 5 months or until the infant reached the age of 1 year, whichever came later. Seizure outcomes were followed up prospectively. Cognitive outcomes were determined after 6 to 21 years and analyzed in relation to treatment lag and pre-treatment regression. Twenty-two infants were treated within 1 month of onset of infantile spasms, and 15 after 1 to 6.5 months. Normal cognitive outcome was found in all 22 (100 %) patients of the early-treatment group, and in 40 % of the late-treatment group. Normal cognitive outcome was found in all 25 (100 %) patients who had no or only mild mental deterioration at presentation, including 4 in the late-treatment group but in only 3 of the 12 patients who had had marked or severe deterioration before treatment. The authors reported that while early treatment of cryptogenic infantile spasms with a high-dose ACTH protocol is associated with favorable long-term cognitive outcomes, further studies are needed on the optimal treatment regimen for this disorder.

In 2009, the U.S. FDA approved another drug, the oral medication, Sabril (Vigabatrin) as monotherapy for pediatric patients 1 month to 2 years of age with infantile spasms for whom the potential benefits outweigh the potential risks of vision loss. There are no other FDA approved drugs in the United States at this time for infantile spasms.

The United Kingdom Infantile Spasms Study (UKISS), a multi-center randomized trial, compared hormonal treatment with vigabatrin on developmental and epilepsy outcome to age 14 months. Infants were randomly assigned hormonal treatment (n = 55) or vigabatrin (n = 52) and were followed-up until clinical assessment at 12 to 14 months of age. Neurodevelopment was assessed with the Vineland adaptive behavior scales (VABS) at 14 months of age on an intention-to-treat basis. Of 107 infants enrolled, 5 died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment was similar in each treatment group and mean VABS score did not differ significantly. In infants with no identified underlying etiology, the mean VABS score was higher in those allocated hormonal treatment than in those allocated vigabatrin. Results indicated that hormonal treatment controls spasms better than does vigabatrin initially, but not at 12 to 14 months of age. The authors concluded that better initial control of spasms by hormonal treatment in those with no identified underlying etiology may lead to improved developmental outcome (Lux et al, 2005).

Cohen‐Sadan (2009) reported on a long‐term follow‐up of children with West syndrome treated with ACTH or vigabatrin. The medical records of 28 normal MRI West syndrome cases were reviewed for seizure development and cognitive outcome in relation to treatment type and timing. The authors concluded that for West syndrome "ACTH and vigabatrin appear to be equally effective in the short term if treatment is administered within one month of symptom onset. On long‐term follow‐up, early ACTH treatment appeared to yield a better outcome than early vigabatrin or late ACTH treatment in terms of both cognition and seizure development."

The consensus opinion from 39 U.S. physicians specializing in pediatric epilepsy reported that as initial therapy for infantile spasms caused by tuberous sclerosis, vigabatrin and ACTH were considered first-line treatments; however, vigabatrin was considered the treatment of choice. As initial therapy for infantile spasms that are symptomatic in etiology, ACTH and topiramate were considered first-line treatments, however, ACTH was considered the treatment of choice (Wheless et al, 2005). The consensus opinion from 42 European physicians specializing in pediatric epilepsy reported that as initial therapy for infantile spasms caused by tuberous sclerosis, viagabatrin was considered the treatment of choice. As initial therapy for infantile spasms that are symptomatic in etiology, vigabatrin was also considered the treatment of choice, with ACTH and prednisone other first-line options (Wheless et al, 2007).

Collagen Diseases

Levine (2012) reported on a retrospective review of 3 patients with dermatomyositis and 2 patients with polymyositis who were treated with ACTH gel and who experienced a disease exacerbation and either failed or were unable to tolerate the side effects of previous therapy with steroids, intravenous immunoglobulins, and steroid-sparing drugs. Patients received ACTH gel subcutaneous injections of 80 U (1 ml) twice-weekly (4 patients) or once-weekly (1 patient) over the course of 12 weeks for short-term treatment of symptom exacerbations. Manual muscle testing using the Medical Research Council scale was assessed at baseline and at 3 months. The investigator reported that improvement was seen in all patients, including improved muscle strength, decreased pain, and resolution of skin involvement. The investigator stated that all patients tolerated the treatment well, and no significant side effects occurred. The author concluded that these anecdotal reports would suggest consideration of ACTH gel as a therapeutic option, and that further investigation is warranted.

An UpToDate review on "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults" (Miller and Rudnicki, 2014) states that "Case reports have suggested that corticotropin gel, a form of adrenocorticotropic hormone, may be beneficial in patients with exacerbations of DM or PM despite ongoing therapy with other immunosuppressive agents. Additional evidence is required to ascertain the short- and long-term benefits and risks of this agent compared with other therapies for inflammatory myopathies before its use in routine clinical practice can be recommended".

Patel and colleagues (2016) stated that idiopathic inflammatory myopathies are a group of systemic autoimmune diseases that involve inflammation of skeletal muscle. The 2 most common forms are dermatomyositis and polymyositis, the former of which entails a skin component. There are few approved therapeutics available for treatment of this group of diseases and the first-line therapy is usually corticosteroid treatment. Considering that a large proportion of patients do not respond to or cannot tolerate corticosteroids, additional treatments are needed. There are second-line therapies available, but many patients are also refractory to those options. H.P. Acthar Gel (repository corticotropin injection [RCI]) is a melanocortin peptide that can induce steroid-dependent effects and steroid-independent effects. These researchers presented a series of cases that involved the use of RCI in the management of dermatomyositis and polymyositis; RCI treatments resulted in improvement in 3 of 4 patients, despite failure with previous therapies. The use of RCI did not exacerbate any co-morbidity and no significant changes in blood pressure, weight, or glycemic control were observed. The authors concluded that these findings were encouraging and suggested that RCTs applying RCI to dermatomyositis and polymyositis are needed.

In an open-label, clinical trial, Aggarwal and colleagues (2018) evaluated the safety, efficacy, tolerability and steroid-sparing effect of RCI in refractory adult polymyositis (PM) and dermatomyositis (DM). Adults with refractory PM and DM were enrolled by 2 centers. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or greater than or equal to 1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and greater than 2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm visual analog scale (VAS) score of greater than or equal to 3 cm and at least 3 other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice-weekly for 24 weeks. The primary end-point was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end-points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR); 10 of the 11 enrolled subjects (6 DM, 4 PM) completed the study; 7 of 10 met the primary end-point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) versus 2.3 (3.2); p < 0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by greater than 10 % and the physician global by greater than 40 %; RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of hemoglobin A1c or Cushingoid features. The authors concluded that treatment with RCI was effective in 70 % of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. This was an open-label study with small sample size (n = 10); these preliminary findings need to be validated in well-designed studies.

Saygin and colleagues (2020) noted that idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness; and RCI has been approved by the FDA for use in IIM, however, literature is limited. In a prospective, open-label study, these investigators reported longitudinal follow-up of patients with refractory IIM who treated with RCI. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. A total of 2 patients were lost to follow-up after finalization of the trial, and the remaining 8 patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, 4 of 8 patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, 3 required an increase in prednisone; 1 patient was re-started on RCI at 5.5 months, but had minimal improvement after 3 months; 4 patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. The authors concluded that this was the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. These researchers believed that the findings of this study provided the basis for the development of future randomized RCI trials in IIM.

Systemic Lupus Erythematosus

Decker et al (2014) stated that Acthar is a highly purified repository gel preparation of ACTH1-39, a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. These researchers evaluated the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, placebo gel (placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, greater than or equal to 20 % body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immuno-phenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. The authors concluded that these data suggested that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This was the first pre-clinical evidence demonstrating Acthar's potential immunomodulatory activity and efficacy in a murine model of SLE.

In a single-site, open-label trial, Fiechtner and Montroy (2014) evaluated the effectiveness of Acthar gel for reducing active SLE severity among patients receiving underlying conventional maintenance therapies. A total of 10 women (mean age of 49 yrs, disease duration of 7 yrs, Systemic Lupus Erythematosus Disease Activity Index-2000 [SLEDAI-2 K] = 10) currently on maintenance self-administered ACTH(1-39) gel 1 ml (80 U/ml) for 7 to 15 days and were assessed weekly for 28 days. Outcome measures included Physician and Patient Global Assessments, SLEDAI-2 K, Lupus Quality of Life scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, erythrocyte sedimentation rate, and C-reactive protein. Student's t-test compared data obtained at days 7, 14, and 28 with those from baseline. The primary end-point of SLEDAI-2 K improvement was reached at all observation times (p < 0.05) and statistically significant improvements were observed for most other parameters. No treatment-related serious or unexpected adverse events were observed. The authors concluded that these findings revealed that among SLE patients in need of therapeutic alternatives, ACTH(1-39) gel may provide significant disease activity reduction. These preliminary findings from a small, uncontrolled trial need to be validated by well-designed studies.

In post-hoc analyses, Furie and associates (2017) evaluated the safety and effectiveness of RCI in patients with persistently active SLE over 52 weeks. Patients were initially randomized to 40 U daily or 80 U every other day RCI (n = 26) or placebo (n = 12) for the 8-week double-blind period. Completers entered the open-label extension (OLE; n = 33) receiving 16, 40 or 80 U RCI 1 to 3 times/week and were followed through week 52. Outcomes included proportion of responders based on a novel index (resolution of joint or skin activity using hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) without any worsening British Isles Lupus Assessment Group (BILAG) scores in other organ systems) or revised novel index (using SLE Responder Index (SRI) definition of BILAG worsening (1A or 2B)), proportion of responders by SRI and changes in total hSLEDAI and BILAG scores; AEs and laboratory values were assessed. At week 52, 12.0 % (3/25) RCI/RCI patients and 36.4 % (4/11) placebo/RCI patients were responders using the novel index. The revised novel responder index demonstrated response rates of 48.0 % (12/25) and 54.5 % (6/11) in the RCI/RCI and placebo/RCI groups, respectively. Proportions of SRI responders were 40.0 % (10/25) and 54.5 % (6/11). In the RCI/RCI group, total hSLEDAI and BILAG scores declined from 10.0 and 15.7 at week 0 to 3.5 and 4.6 at week 52, respectively. Reductions in the placebo/RCI group on switching were observed (mean hSLEDAI: 9.1 to 3.3; BILAG: 13.5 to 2.6). Other disease activity end-points also improved in both groups. No new safety signals were observed during the OLE. The authors concluded that RCI demonstrated durable effectiveness in patients with persistently active SLE despite moderate-dose corticosteroid therapy; switching from placebo resulted in reduced disease activity during the OLE. They stated that these data provided the foundation for evaluation of RCI in a robustly powered study.

The authors stated that the drawbacks of this study included the small sample size (n = 26 for the RCI group) and the lack of inferential statistical analyses, meaning that conclusions regarding clinical improvement with long-term RCI must be viewed with caution. These researchers noted that further evaluation of RCI in a well-powered clinical trial in SLE is underway.

Askanase et al (2021) carried out post-hoc analyses of biomarker results from a multi-center, randomized, double-blind, placebo-controlled study of RCI in patients with persistently active SLE despite treatment with moderate-dose glucocorticoids. Adults with active SLE and moderate-to-severe rash and/or arthritis were enrolled in the primary study. Patients had active SLE despite treatment with stable glucocorticoids, antimalarials, and non-steroidal anti-inflammatory drugs (NSAIDs) and/or immunosuppressants. Subjects were randomly assigned to 80 U of RCI or placebo subcutaneously every other day for 4 weeks and then twice-weekly through week 24. Blood samples were analyzed for serum cytokines and complement proteins using enzyme-linked immunosorbent or Luminex assays and for circulating leukocytes using flow cytometry. Biomarker levels were reported as percentages of the baseline and were further evaluated in subgroups stratified by baseline SLE Disease Activity Index-2000 (SLEDAI-2K) scores (less than 10 versus 10 or higher), baseline anti-double-stranded DNA levels (less than 15 IU/ml versus 15 IU/ml or higher), and BILAG-based Combined Lupus Assessment (BICLA) responses at week 20 and 24. RCI treatment resulted in reduced levels of B cell-activating factor and interleukin-6 (IL-6) cytokines in all subgroups compared with placebo. RCI treatment also resulted in lower levels of CD19+ B cells and CD19+IgD-CD27-CD95+ atypically activated memory B cells than did placebo in the higher baseline disease activity subgroups and in BICLA non-responders. Furthermore, RCI treatment resulted in greater increases in complement component (C)3 and C4 levels than did placebo in the higher baseline disease activity subgroups and in BICLA responders. The authors concluded that RCI may reduce inflammation through B cell immunomodulation in patients with persistently active SLE, especially in those with higher disease activity. Moreover, these researchers stated that pre-clinical evidence in-vitro, in murine models of SLE, and in studies with healthy volunteers has reported immunomodulatory effects of RCI on B cells; they stated that additional clinical studies are needed to examine the direct immunomodulatory effects of RCI in patients with SLE. In particular, further investigation in a randomized clinical trial in which disease activity subgroups have been determined a priori is warranted.

Dry Eye Disease

Toyos et al (2022) stated that there is a substantial unmet need for effective therapies in the treatment of patients with refractory dry eye disease (DED). In an open-label, pilot study, these investigators examined the safety and effectiveness of RCI in patients with DED, most of whom did not experience adequate response to standard-of-care (SOC) therapies. Adults with moderate or severe acute DED received 80 U of subcutaneous RCI twice-weekly for 12 weeks. Primary effectiveness outcomes were improvements in corneal fluorescein staining of superficial punctate keratitis (SPK) lesions and Symptom Assessment in Dry Eye (SANDE) scores. Secondary outcomes included changes in tear production (Schirmer's test), conjunctival lissamine green staining, erythema, intra-ocular pressure (IOP), and best corrected visual acuity (BCVA); and AEs were assessed continuously throughout the study. A total of 15 subjects received at least 1 dose of RCI, and 12 subjects completed the study. Compared to baseline (day 1), significantly fewer fluorescein-stained SPK lesions were detected on day 14 (p = 0.0250) and day 84 (p = 0.0240) after RCI treatment. Mean SANDE scores progressively declined from 62.0 at baseline to 46.9 on day 84. Erythema (p = 0.0046), conjunctival lissamine green staining of SPK lesions (p = 0.0317), and IOP (p = 0.0052) were all significantly improved after 12 weeks of RCI therapy. Schirmer's test scores and BCVA showed no significant changes throughout the study. No ocular AEs or deaths occurred, and no new safety signals were identified for RCI. The authors concluded that the findings of this open-label pilot study suggested that RCI may be a safe and effective treatment for moderate and severe DED. Moreover, these researchers stated that these findings provided a foundation for a much larger placebo-controlled clinical trial to further examine the overall safety and effectiveness of RCI in the treatment of DED.

Multiple Sclerosis

Thompson et al (1989) reported on a randomized, double-blind, controlled clinical study comparing the efficacy of intravenous methylprednisolone to intramuscular ACTH gel in the treatment of acute relapse in 61 patients with multiple sclerosis. Subjects randomized to methylprednisolone received 1 gram IV methylprednisolone daily for 3 days and 14 days of intramuscular placebo, and subjects randomized to ACTH gel received IV placebo daily for 3 days and at the same time a reducing course of intramuscular ACTH over 14 days, consisting of 80 units for 7 days, 40 units for 4 days, and 20 units for 3 days. Of the 61 subjects, 5 failed to complete the study, 2 on ACTH and 3 on methylprednisolone. The authors reported that there was a marked improvement in both groups over the course of the study, but no differences between groups in either the rate of recovery or final outcome in acute relapse. The authors noted that side effects in the methylprednisolone group were less frequent than in the ACTH group. The authors stated that giving a 3-day course of intravenous treatment rather than 14 days of intramuscular injections "has obvious advantages in terms of both patient comfort and medical resources."

Simsarian et al (2011) performed a small, prospective, randomized pilot study to examine the efficacy and safety of, and patient satisfaction with, a short (5-day) self-administered Acthar dosing protocol for exacerbations of multiple sclerosis, and to compare the subcutaneous and intramuscular routes of administration. Patients for this study were recruited from an outpatient treatment clinic. Each patient self-administered natural Acthar gel 80 U/day by subcutaneous or intramuscular injection for 5 consecutive days and was evaluated at baseline and on days 7 and 14. Patient feedback was collected using the Patient Global Impression of Change (PGI-C, the primary efficacy measure), a patient global visual analog scale, the Expanded Disability Status Scale, a timed walk, the Nine-hole Peg Test, and the Clinical Global Impression of Change. Of the 20 enrolled patients (mean age 39.5 years), 19 completed the study. On day 14, 61.1 % of patients (11 of 18 with day 14 scores) were treatment responders, and rated their condition as "very much improved" or "much improved" on the PGI-C. The intramuscular group had numerically more responders, but there was no significant difference in the proportion of responders between the intramuscular and subcutaneous groups at day 14 (p = 0.3). The intramuscular route of injection was associated with more injection site pain than the subcutaneous route. The authors concluded that a shorter 5-day course of intramuscular or subcutaneous ACTH gel may improve symptoms associated with acute exacerbations of multiple sclerosis. The authors noted that larger studies with standard of care controls are needed to confirm whether this shorter course of intramuscular or subcutaneous Acthar gel is effective and could potentially be substituted for the standard 14-day treatment.

Cusick et al (2015) examined the effects of Acthar in an animal model of relapsing-remitting multiple sclerosis (RRMS), using SJL/J mice sensitized with myelin peptide. All animal studies were reviewed and approved by the University of Utah Institutional Animal Care and Use Committee and conducted in accordance with the guidelines prepared by the Committee on Care and Use of Laboratory Animals, Institute of Laboratory Animals Resources, National Research Council. Mice injected with Acthar to treat the second attack had a significantly lower mean clinical score during relapse and a significantly reduced cumulative disease burden compared to placebo gel-treated mice. Furthermore, Acthar treatment ameliorated inflammation/demyelination in the spinal cord and markedly suppressed ex-vivo myelin peptide-induced CD4(+) T cell proliferation.

Nephrotic Syndrome and Glomerular Diseases

Bomback et al (2011) reported on a retrospective case series of 21 patients with nephrotic syndrome treated with ACTH gel, including 11 patients with idiopathic membranous nephropathy, 4 patients with membranoproliferative glomerulonephritis, 1 patient with focal glomerulosclerosis, 1 patient with minimal change disease, 1 patient with IgA nephropathy, 1 patient with class V systemic lupus erythematosis glomerulonephritis, 1 patient with monoclonal diffuse proliferative glomerulonephritis, and 1 patient with unbiopsied nephrotic syndrome. Given the small number of patients and the observational nature of this study, no formal statistical analyses were performed. Four patients achieved complete remission, and 7 patients achieved partial remission. Five patients reported steroid-like adverse effects. The authors stated that results of the study should be interpreted cautiously due to its limitations, including its retrospective nature, lack of randomization, lack of comparison or control group, and short duration of follow-up. The authors stated that this retrospective data analysis suggests that further studies are warranted to evaluate ACTH gel in the treatment of nephrotic syndrome.

Bomback et al (2012) conducted an open-label prospective study of ACTH gel in resistant glomerular diseases. Fifteen subjects with resistant glomerular diseases were treated with ACTH gel, including 5 subjects with idiopathic membranous nephropathy, 2 subjects with minimal change disease, 3 subjects with focal segmental glomerulosclerosis, and 5 subjects with IGA nephropathy. Subjects were treated with ACTH gel for 24 weeks, dosed at 40 units twice-weekly subcutaneously for 2 weeks, then 80 units twice weekly subcutaneously afterward. Given the small number of subjects and the pilot design of the study, no formal statistical analysis of results was performed. As a group, the 5 subjects with membranous nephropathy went from a pre-ACTH median proteinuria of 3.80 mg/g to a post-ACTH median proteinuria of 3.79 mg/g. Two of the 5 subjects with membranous nephropathy achieved partial remission over the 6-month course of ACTH therapy. As a group, the 5 subjects with minimal change disease or focal segmental glomerulo-sclerosis (FSGS) went from a pre-ACTH median proteinuria of 1.96 mg/g to a post-ACTH median proteinuria of 1.93 mg/g. One subject with minimal change disease and one subject with FSGS achieved partial remission of proteinuria during ACTH therapy. As a group, the 5 subjects with IgA nephropathy went from a pre-ACTH median proteinuria of 1.59 mg/g to a post-ACTH median proteinuria of 0.85 mg/g. Three subjects with IgA nephropathy showed significant reductions in proteinuria to remission levels during the treatment period. Three subjects discontinued therapy early due to adverse events. Two subjects with diet-controlled diabetes had worsened glycemic control prompting initiation of oral hypoglycemic therapy. One subject complained of weight gain, Cushingoid faces, increased blood pressure, and worsening kidney function; the subject had experienced similar side effects with prednisone in the past. The authors stated that the data from this study are limited by the small subject sample, the lack of control group, and the relatively short-term follow-up. The authors stated that these data support further investigations of ACTH for patients with resistant glomerular diseases.

Noting that the data on using Acthar gel to treat idiopathic focal segmental glomerulosclerosis (FSGS) are limited, Hogan et al (2013) reported on 24 patients with nephrotic syndrome from idiopathic FSGS who were treated with ACTH gel at 2 academic medical centers between 2009 and 2012, either as part of investigator-initiated pilot studies (n = 16) or by prescription for treatment-resistant FSGS (n = 8). The primary outcome was remission of proteinuria. The median dose of ACTH was 80 units injected subcutaneously twice-weekly. Treatment durations were not uniform. Twenty-two patients had received immunosuppression (mean, 2.2 medications) before ACTH therapy. Six patients had steroid-dependent and 15 had steroid-resistant FSGS. At the time of ACTH initiation, the median serum creatinine (interquartile range) was 2.0 (1.1 to 2.7) mg/dl, estimated glomerular filtration rate (GFR) was 36 (28 to 78) ml/min per 1.73 m(2), and urine protein-to-creatinine ratio was 4,595 (2,200 to 8,020) mg/g. At the end of ACTH therapy, 7 of 24 patients (29 %) experienced remission (n = 2 complete remissions, n = 5 partial remissions). All remitters had steroid-resistant (n = 5) or steroid-dependent (n = 2) FSGS. Two responders relapsed during the follow-up period (mean ± SD, 70 ± 31 weeks). Adverse events occurred in 21 of 24 patients, including 1 episode of new-onset diabetes that resolved after stopping ACTH and 2 episodes of AKI.

Tumlin et al (2013) reported on an open-label pilot trial of Acthar gel in patients with advanced diabetic nephropathy. A total of 23 patients with diabetic nephropathy were randomized to daily subcutaneous (SQ) injections of 16 or 32 units of Acthar gel for 6 months. The primary end-point was the percentage of patients achieving a complete remission (less than 300 mg/24 hours) within 6 months. Exploratory end-points included the percentage of partial (50 % reduction) remissions, changes in Cr, and urinary cytokine markers. After 6 months of Acthar gel therapy, 8 of 14 (57 %) patients achieved a complete (n = 1) or partial (n = 7) remission. In the low-dose ACTH gel group (16 units), urinary protein fell from 6,709 + 953 to 2,224 + 489 mg/24 hrs (p < 0.001). In contrast, 2 of 6 patients in the 32-unit group achieved partial remission, but aggregate proteinuria (5,324 + 751 to 5,154 + 853 mg/24 hours) did not change. Urinary VEGF increased from 388 to 1,346 pg/mg urinary creatinine (p < 0.02) in the low-dose group but remained unchanged in the high-dose group.

Available evidence regarding the effectiveness of Acthar gel for the treatment of focal segmental glomerulosclerosis (FSGS) consists of uncontrolled case series involving small numbers of subjects and short-term follow-up (Bomback et al, 2011; Bomback et al, 2012; Hogan et al, 2013). It is unclear from these reports whether overlapping patients were included in these studies, as all 3 studies involved an investigator group from Bomback et al (2011 and 2012 studies by Bomback et al; and the 2013 study by Hogan in which Bomback was a co-author).

In a pilot study, Hladunewich et al (2014) hypothesized that Acthar gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy. A total of 20 patients received a subcutaneous dose of 40 or 80 IU twice- weekly. Changes in proteinuria, albumin, cholesterol profile, estimated GFR and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety. Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated GFR (77 ± 30 ml/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (p < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A greater than 50 % decrease in proteinuria was noted in 65 % of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients. The authors concluded that the Acthar^® gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.

Madan (2015) stated that FSGS causes scarring or sclerosis of glomeruli that act as tiny filters in the kidneys, damage to which results in diminished ability to properly filter blood, resulting in the urinary loss of plasma proteins and subsequent proteinuria. These researchers presented the case of a 60-year old white female (with a history of intermittent proteinuria) who was referred by her primary care physician for renal dysfunction. Biopsy confirmed FSGS and she was treated with an angiotensin-converting enzyme inhibitor. She also had rheumatoid arthritis (RA) but no active synovitis and was maintained on prednisone 5 mg/day. She also complained of worsening vision in her right eye and was diagnosed with optic neuritis (ON). She remained stable for about 8 months when examination indicated FSGS relapse, and she reported painful RA flares. She was treated with Acthar gel (40 mg bi-weekly) for 6 months, after which proteinuria and urine protein-to-creatinine ratio decreased to about 50 %. Her ON improved, and she reported that she had fewer RA flares and pain improved by 50 %. This case of confirmed FSGS showed an improved response to treatment with Acthar Gel for FSGS with concomitant RA and ON. The authors concluded that this referral case was relevant to primary care practitioners who treat disorders that may be responsive to corticosteroid therapy. The anti-proteinuric effects and ancillary improvement in RA and ON symptoms during treatment with Acthar Gel were not entirely explained by its steroidogenic actions. ACTH is a bioactive peptide that, together with α-melanocyte-stimulating hormone, exhibits biologic efficacy by modulating pro-inflammatory cytokines and subsequent leukocyte extravasation and may have autocrine/paracrine effects in joints. While Acthar Gel was primarily administered in this case to treat proteinuria, it also showed ancillary benefits in patients with concomitant inflammatory disease states. Well-designed studies are needed to ascertain the effectiveness of Acthar gel for the treatment of FSGS, optic neuritis, and rheumatoid arthritis.

Maroz and colleagues (2018) stated that fibrillary glomerulo-nephritis (FGN) is a rare idiopathic condition linked to malignancy, autoimmune disorders, monoclonal gammopathies and hepatitis C virus. It usually has a poor prognosis, resulting in progression to end-stage renal disease (ESRD) within a few years, given the lack of standardized treatment; RCIs are approved for use in a variety of nephrotic syndromes, but are not routinely considered for treatment of FGN. These researchers presented a case in which a patient with FGN began treatment with RCI 3 months after diagnosis. The patient has attained partial remission with complete resolution of nephrotic syndrome and stabilization of renal function. The authors concluded that few observational reports have demonstrated variable outcomes with use of RCI in patients with FGN. The findings of this case supported the consideration of trying this agent as a first-line therapy in patients with advanced disease in the hope of avoiding side effects of other immunosuppressive or cytotoxic agents. They stated that further studies are needed to establish a sustainable and reproducible response to therapy.

Hayes and colleagues (2020) stated that focal segmental glomerulosclerosis (FSGS) causes renal fibrosis and may lead to kidney failure. FSGS and its common complication, proteinuria, are challenging to treat. Corticosteroids are ineffective in many patients with FSGS, and alternative treatments often yield suboptimal responses. Repository corticotropin injection (RCI; Acthar gel) and other pituitary peptides, may have beneficial effects on idiopathic FSGS via melanocortin receptor activation. These researchers described 2 studies in a pre-clinical (female Sprague-Dawley rats) puromycin aminonucleoside FSGS model that examined the effect of RCI on renal function and morphology: an 8-week comparison of a single RCI dose with methylprednisolone (n = 27), and a 12-week chronic RCI dose range study (n = 34). Primary outcomes were proteinuria and renal pathology improvements for measures of renal fibrosis, tubular damage, glomerular injury, and total kidney injury score. Impact of RCI treatment was also determined by evaluating urinary biomarkers for renal injury, podocyte expression of podoplanin (a biomarker for injury), podocyte effacement by electron microscopy, and histological staining for fibrosis biomarkers. Compared with saline treatment, RCI 30 IU/kg significantly reduced proteinuria, with a 38 % reduction in peak mean urine protein levels on day 28 in the 8-week model, and RCI 10 IU/kg, 30 IU/kg, and 60 IU/kg reduced peak mean urine protein in the 12-week model by 18 %, 47 %, and 44 %, respectively. RCI also showed significant dose-dependent improvements in fibrosis, interstitial inflammation, tubular injury, and glomerular changes. Total kidney injury score (calculated from histopathological evaluations) demonstrated statistically significant improvements with RCI 30 IU/kg in the 8-week study and RCI 60 IU/kg in the 12-week study. RCI treatment improved levels of urinary biomarkers of kidney injury (KIM-1 and OPN), expression of podoplanin, and podocyte morphology. RCI also reduced levels of desmin and fibrosis-associated collagen deposition staining. Methylprednisolone did not improve renal function or pathology in this model. The authors concluded that these findings provided evidence supporting the improvement of FSGS with RCI, which was superior to corticosteroid treatment in this experimental model. To the authors' knowledge, this was the 1st evidence that a drug for the treatment of FSGS supported podocyte recovery after repeated injury in this experimental model.

The authors stated that this study had several drawbacks. First, although a steroid treatment condition was included in the 8-week PAN group to model traditional steroid treatment, the 12-week PAN model did not include an MP group for comparison and was designed as a dose-response study for RCI. Second, the 2 studies also showed slight differences in baseline age and weight. Third, kidney function was evaluated by proteinuria; additional measures such as blood urea nitrogen, serum creatinine, and urinary albumin were not included.

Filippone et al (2016) noted that ACTH is being increasingly studied for treatment of various glomerulopathies, most notably membranous nephropathy. Less data are available regarding its use in idiopathic nephrotic syndrome (INS) secondary to minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). These investigators reported their experience with H.P. Acthar gel (repository corticotropin injection) as 1st-line or subsequent therapy in patients with INS. Data were taken from 3 patients with MCD and 10 patients with FSGS from around the U.S., who were treated with Acthar gel as initial or subsequent therapy. Treatment was solely at the discretion of the primary nephrologist without a specific protocol. A CR was defined as final urine protein-to-creatinine ratio less than 500 mg/g and a PR as 50 % decrease without rise of serum creatinine. Side effects and tolerability were noted. All 3 patients with MCD received Acthar gel as 2nd-line or later immunosuppressive (IS) therapy and all responded (1 CR and 2 PRs); 2 of the 10 patients with FSGS received Acthar gel as 1st-line IS therapy, while the other 8 had failed multiple agents; 4 of the 10 patients with FSGS had responses, including 2 CRs and 2 PRs. The 3 patients with MCD tolerated therapy well without side effects; 5 patients with FSGS tolerated therapy well, while 5 had various steroid-like side effects, resulting in therapy discontinuation in 2 patients. The authors concluded that Acthar gel is a viable alternative IS agent for treatment of INS in patients intolerant or resistant to conventional therapy. Furthermore, these researchers stated that more data are needed to better define its appropriate place; randomized controlled trials (RCTs) using Acthar gel will determine appropriate patients, regimens, and durations of therapy in terms of safety and effectiveness.

The authors stated that this study had several drawbacks, especially the small sample size. It was a retrospective case series collected from various nephrology practices. Biopsies were not reviewed centrally, and the histologic subtype of FSGS was not available in some cases. There was no specific protocol for either initial IS therapy or for the use of Acthar gel (dose or duration), and concomitant therapy was variable. Follow-up was relatively short and also variable in length.

In a retrospective, multi-center, case-series study, Madan et al (2016) examined the effectiveness of Acthar gel in patients with varied-etiology NS. This trial included adult patients with NS (n = 44) treated with Acthar gel at 6 clinical practices. NS etiologies included idiopathic FSGS (n = 15), idiopathic membranous nephropathy (iMN; n = 11), IgA nephropathy (IgAN; n = 5), diabetic nephropathy (DN; n = 4), SLE class V membranous lupus nephritis (MLN; n = 2), MCD (n = 2), membranoproliferative glomerulonephritis (MPGN; n = 1), fibrillary glomerulonephritis (FGN; n = 1), and unbiopsied NS (n = 3). Proteinuria response was assessed as % reduction from baseline and %of patients meeting CR (final proteinuria of less than 500 mg/d), PR (greater than or equal to 50 % reduction in proteinuria from baseline and final proteinuria 500 to 3,500 mg/d), clinical response (greater than or equal to 30 % reduction in proteinuria from baseline that did not meet criteria for CR or PR), and no response (failed to meet remission or clinical response criteria) following Acthar gel therapy. Safety and tolerability were examined using adverse event (AE) frequency reported by patients or treating nephrologists and frequency of early discontinuation of treatment due to AEs. A total of 68.2 % (30/44) of patients had received prior NS treatment with immunosuppressive or cytotoxic therapies; 37 patients completed Acthar gel treatment; 7 patients (15.9 %) had early termination due to AEs, including weight gain (n = 2), hypertension (n = 2), edema (n = 1), fatigue (n = 1), seizures (n = 1) and for reasons not stated (n = 2). Proteinuria reduction of greater than or equal to 30 % was shown in 81.1 % (30/37) of patients and 62.2 % (23/37) showed greater than or equal to 50 % proteinuria reduction. Proteinuria responses were greatest in MCD (n = 2/2 CR), MLN (n = 2/2 PR), MPGN (n = 1/1 PR), FSGS (n = 12/15 [80.0 %] PR or clinical response), and iMN (n = 8/11 [72.7 %] CR, PR, or clinical response). The authors concluded that Acthar gel may meet an important treatment need in patients with treatment-resistant NS in response to 1st-line therapies, patients unable to tolerate 1st-line therapies, and in patients with advanced disease. These researchers stated that future research is needed to determine whether patients who show a proteinuria clinical response without remission benefit from longer-term treatment and show continued clinical improvement. They noted that further research using prospective, controlled trials with longer-duration treatment and follow-up assessments to examine different Acthar gel regimens and cumulative dose effects in varied-etiology NS is needed.

Prasad et al (2018) noted that synthetic ACTH has been demonstrated to be effective in patients with membranous nephropathy, MCD and some histological subtypes of FSGS. Its clinical impact in patients with IgA nephropathy is currently unclear. These researchers described the clinical use of ACTH in patients with IgA nephropathy; 3 female patients (24 to 44 years of age) with overt proteinuria received intra-muscular (IM) ACTH for varying time periods (8 to 14 months). Pre-treatment urine protein varied from 2.9 g/d to 4.3 g/d. The authors concluded that there was CR in 1 patient on ACTH monotherapy and in the other 2 when prescribed as a steroid-sparing agent in combination with cyclophosphamide. All 3 had resolution in proteinuria to less than 1 g/d and maintained their glomerular filtration rate (GFR) to baseline values. There were no reported side effects at a once-weekly dose. The authors concluded that this study showed that ACTH was an effective agent that was well-tolerated with minimal side effects and can be used as an alternative to prednisone in patients with IgA nephropathy. This was a small (n = 3) study; and subjects did not have nephrotic syndrome.

In a randomized trial, Wang and associates (2018) evaluated the safety and efficacy of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome. Subjects aged 2 to 20 years with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the U.S. and randomized 1:1 to ACTH (repository corticotropin injection [RCI]) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice-weekly for 6 months, followed by 40 U/1.73 m2 administered twice-weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Subjects in the control group were offered cross-over to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects. The trial was stopped at a pre-planned interim analysis after enrollment of 31 subjects because of a lack of discernible treatment efficacy; 14 out of 15 (93 %) subjects in the ACTH-arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range [IQR], 9 to 32), compared with 15 out of 16 (94 %) subjects and at a median of 21 days (IQR, 14 to 51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio [OR], 0.93; 95 % CI: 0.05 to 16.40; p > 0.99) or time to first relapse (hazard ratio [HR], 1.03; 95 % CI: 0.50 to 2.15; p = 0.93); 13 out of 16 subjects in the control group crossed-over to ACTH treatment; 3 out of 28 subjects completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the 3 subjects. Most side effects were mild and similar to side effects of corticosteroids. The authors concluded that ACTH at 80 U/1.73 m2 administered twice-weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.

Hartung and colleagues (2019) noted that despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for RCI (rACTH) (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. These investigators tested this assertion by examining the quality and provenance of the evidence likely to emerge in the foreseeable future. They identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. A total of 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (i.e., another form of immunosuppression). The authors concluded that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications.

It is also interesting to note that most nephrologists, neurologists, and rheumatologists who frequently prescribe corticotropin received corticotropin-related payments from Mallinckrodt. Hartung and associates (2018) noted that despite great expense and little evidence supporting use over corticosteroids, prescriptions for repository corticotropin have increased markedly. Aggressive sales tactics and payments from the manufacturer may influence prescribing behavior for this expensive medication. These investigators characterized industry payments to physician specialists who prescribe corticotropin in the Medicare program. This study was a cross-sectional analysis of Centers for Medicare & Medicaid Services (CMS) 2015 Part D prescribing data linked to 2015 Open Payments data. Nephrologists, neurologists, and rheumatologists with more than 10 corticotropin prescriptions (frequent prescribers) in 2015 were included. Main outcome measures included frequency, category, and magnitude of corticotropin-related payments from Mallinckrodt, as well as corticotropin prescriptions and expenditures for Medicare beneficiaries. Of the 235 included physicians, 65 were nephrologists; 59, neurologists; and 111, rheumatologists. A majority of frequent corticotropin prescribers (207 [88 %]) received corticotropin-related payments from Mallinckrodt. The median (range) total payment for 2015 was $189 ($11 to $138,321), with the highest payments ranging from $56,549 to $138,321 across the specialties. More than 20 % of frequent prescribers received more than $10,000 and the top quartile of recipients received a median (range) of $33,190 ($9,934 to $138,321) in total payments per prescriber. Payments for compensation for services other than consulting contributed the most to the total amount. Mallinckrodt payments were positively associated with greater Medicare spending on corticotropin (β = 1.079; 95 % CI: 1.044 to 1.115; p < 0.001), with every $10,000 in payments associated with a 7.9 % increase (approximately $53,000) in Medicare spending on corticotropin. There was no association between corticotropin-related payments and spending on prescriptions for synthetic corticosteroids. The authors concluded that these findings suggested that financial conflicts of interest may be driving use of corticotropin in the Medicare program.

Rice and colleagues (2021) compared patient characteristics and measurable healthcare resource utilization (HCRU) between nephrotic syndrome (NS) patients who received a prescription for RCI and then were either approved or denied treatment by their insurers. This study was a retrospective analysis of adults with NS from January 2015 to December 2018; it was performed using a de-identified open-source claims database. Patients were included in the study if they had greater than or equal to 1diagnosis associated with NS, were age 18+, and had medical claims activity at some point in the year preceding ("baseline") and year following ("follow up") their first approved or denied RCI prescription. Baseline characteristics were reported with p-values indicating the significance of characteristics between cohorts. To assess outcomes, approved and denied patients were matched (1:1) using propensity-matching to account for underlying differences. A total of 1,232 patients met inclusion criteria for the study. At baseline, approved patients were older than denied patients (mean age of 53.9 versus 48.4 years) and had higher rates of co-morbidities. A greater proportion of approved patients required inpatient admissions (34.1 % versus 28.0 %) and "high" doses of corticosteroids (CS) (26.2 % versus 20.7 %) at baseline. Matched outcomes showed directionally more denied patients with inpatient admissions compared to approved (64 versus 52) and a greater utilization of deep vein thrombosis (DVT) ultrasound (12.2 % versus 6.6 %) and dialysis (10.5 % versus 6.1 %). Matched, denied patients had directionally greater CS use during follow-up both in the number of patients receiving CS (104 versus 95) and the average annualized daily dose (4.1 mg versus 3.4 mg). The authors concluded that patients denied access to RCI treatment had directionally higher HCRU compared to matched, approved counterparts; therefore, the findings of this study may aid providers and payers in evaluating scenarios where RCI may be beneficial and improve quality of care for NS patients.

The authors stated that this study had several drawbacks. First, while the data were uniquely rich on a number of dimensions, given the rareness of NS overall, the sample size was limited after implementing the full set of analytic criteria and matching methodology. As a result, most outcomes did not reach conventional levels of statistical significance, and future research should examine, where possible, if these observed trends hold with larger sample sizes. Second, because certain clinical information was unavailable in the data, measures of disease severity could be evaluated by proxy only. Notably, the data did not contain laboratory values for clinical tests; thus, clinical measures of severity were evaluated based on treatment and resource use relying on ICD 9/10 diagnosis codes and CPT codes associated with a particular claim. Furthermore, because the Symphony IDV is an open source claims database, aggregating claims for patients from a variety of different data streams, it was possible that not all patient claims were captured in the data. Third, while a proportion of patients in the approved cohort had their claims for RCI denied before finally being approved, the data did not indicate a reason for claim denials. Therefore, the study could not explain the underlying dynamics that influenced denial and approval patterns for patients. These investigators interpreted these dynamics as the influence of different formulary structures and prior authorization requirements among payers as well as physician prescribing behaviors. A more detailed examination of the factors that led to approval (or denial) of RCI claims for NS patients could be the focus of future research. Finally, the data reflected results from a variety of payer types. While this added to the richness of the data, the convenience sample from which the data were based may not be reflective of or generalizable to any particular payer, depending on the characteristics of their enrolled population.

Neurodegenerative Diseases

Arrat et al (2015) noted that amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex etiology and pathology that makes the development of new therapies difficult. ACTH has neurotrophic and myotrophic effects but has not been tested in an ALS mouse model. The G93A-SOD1 mouse model of ALS was used to test the ability of this drug to delay ALS-like symptoms. These researchers showed that within a specific dose range, ACTH significantly postponed the disease onset and paralysis in the mouse model. The authors found that ACTH significantly reduced the levels of soluble SOD1 in the spinal cord and CNS tissues of G93A-SOD1 treated mice as well as cultured fibroblasts.

Non-Infectious Keratitis

Wirta et al (2022) stated that non-infectious keratitis is a painful corneal inflammation treated with topical cyclosporine and other immunosuppressants. Additional therapeutic options are needed for keratitis that does not improve with standard therapies. In an open-label, multi-center, phase-IV clinical trial, these researchers examined the safety and effectiveness of RCI for the treatment of refractory severe non-infectious keratitis. Patients were 18 years of age or older with persistent severe keratitis despite treatment with topical immunosuppressants. Patients received 80 U of RCI subcutaneously twice-weekly for 12 weeks followed by a 4-week taper. Assessments included all domains of the Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire, Ocular Discomfort and 4-Symptom Questionnaire, and VAS. Corneal fluorescein and conjunctival lissamine green staining, Conjunctival Redness Scale, Schirmer's test, VA, slit lamp examination, and IOP were also examined. Safety was evaluated via treatment-related AEs. Analyses were carried out using the modified intent-to-treat (mITT) population (patients who received 1 dose or more of RCI and contributed any post-baseline effectiveness data). In the mITT population (n = 35), 50.0 % (95 % confidence interval [CI]: 33.2 % to 66.8 %) of patients experienced clinically important improvements in the symptom bother domain of the IDEEL Questionnaire at week 12 of RCI therapy. All domains of the IDEEL and the Ocular Discomfort and 4-Symptom Questionnaire showed improvements at week 12 of RCI treatment. The most pronounced improvements in the VAS at week 12 were for eye dryness and eye discomfort. Corneal staining, conjunctival staining, conjunctival redness, and tear production showed early improvements that were sustained through week 12. No new safety signals for RCI were identified. The authors concluded that RCI was safe and effective for refractory severe non-infectious keratitis that has not improved with other approved therapies.

These researchers stated that the findings of this study added to the body of literature for a condition that is still being examined extensively. They noted that drawbacks of this study included a relatively small sample size (n = 35), a short treatment period of 12 weeks, and a lack of a placebo comparator. However, because the patients were not permitted to receive standard therapies such as cyclosporine, lifitegrast, and corticosteroids during the study period, the observed improvements in the symptoms of keratitis were likely the result of RCI treatment. Moreover, these investigators stated that although the open-label study design was appropriate for this target population of patients with severe refractory keratitis, the safety and effectiveness of this treatment warrant further investigation in a randomized, placebo-controlled trial.

Non-Infectious Retinal Vasculitis

Anesi and colleagues (2023) examined if subcutaneous RCI (Acthar gel) could be an effective potential therapeutic agent for non-infectious retinal vasculitis. Patients with active retinal vasculitis were followed with serial ultra-wide-field fluorescein angiograms and treated with 80 units of subcutaneous repository corticotropin injection twice-weekly. Primary outcome of greater than or equal to 50 % improvement in response level (RL) for retinal vasculitis and percent improvement in retinal vasculitis severity scoring (RVSS) by more than one quartile (greater than or equal to 25 %) at week 12 was met in 15 and 16 of the 30 total eyes, respectively, including 1 eye with severe retinal vasculitis in each group. Complete resolution of retinal vasculitis was observed in 7 eyes with a mean time of 17.1 weeks. Intra-ocular pressure (IOP) elevation requiring therapy and cataract progression were noted in 2 and 3 eyes, respectively; 1 patient stopped medication due to side effects (injection site reaction). The authors concluded that repository corticotropin injection was well-tolerated overall; it may be an effective therapeutic agent in the treatment of non-infectious retinal vasculitis. Moreover, these researchers stated that these findings should be validated with further well-designed studies with larger sample sizes.

The authors stated that this study had several drawbacks, which include its open-label status, a limited study period of only 24 weeks, the lack of a control population, varied etiology and severity of disease, concomitant use of other immunomodulatory medications, as well as the use of subjects either on or off these other forms of therapy. Participants of this study represented a variable group of disease processes that had retinal vasculitis, as might be expected in a condition or population being studied where the number of patients is few. Criticism could be made to this point of the validity of any conclusions brought forth in this study, however, with the etiology of these processes being at least agreeably non-infectious in nature, these investigators expected that these data contain merit in the way of an observed response of a non-infectious inflammatory process to a single given therapy. Lastly, although this trial was carried out with funding provided by “Mallinckrodt Pharmaceuticals, Bedminster, NJ”, the authors were solely responsible for protocol development, initiation of patient recruitment, administration of study protocol, as well as manuscript production.

Ocular Mucous Membrane Pemphigoid

Sharon and colleagues (2022) reported the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by RCI. Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and de-identified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. This study included 15 patients (10 women and 5 men; 36 to 95 years of age) with a mean follow-up of 4.5 years . Most of the patients (80 %) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60 %) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range of 3 to 54 months). Foster stage did not change in any of the 15 patients at the last follow-up; 9 patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well-controlled. No serious AEs because of RCI were observed during the follow-up in any treated patient. The authors concluded that RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP; treatment with RCI appeared to be safe and well-tolerated. These preliminary findings from a small study (n = 15) need to be validated by well-designed studies.

Optic Neuritis

Bryan and Sergott (2019) noted that current treatments following an episode of ON have limited success protecting the retinal nerves and restoring visual function. In an open-label, single-armed study, these researchers examined the effectiveness of RCI following the onset of ON. A total of 24 adults were treated with RCI within 2 weeks of symptom onset; 7 examinations over 400 days measured low- and high-contrast visual acuity (LCVA and HCVA) and spectral domain optical coherence tomography (SD-OCT) of the retinal structures. Differences between and among affected and contralateral eyes were assessed using linear mixed models. HCVA improved in the affected eye over the study (36.2 letters to 52.5), and LCVA improved in both the affected eye (1.8 letters to 6.8) and the contralateral eye (8.3 letters to 11.7). These functional improvements occurred concurrent to a thinning in the papillo-macular bundle and the ganglion cell, inner plexiform, and retinal nerve fiber layers (RNFLs), while the inner nuclear, outer plexiform, outer nuclear, and photoreceptor layers thickened. The authors concluded that the eyes affected by the ON and treated with RCI improved in both LCVA and HCVA, and unexpectedly LCVA improved in the contralateral eye as well. This functional improvement was mirrored by structural changes in the retina. Moreover, these researchers stated that is the findings of this study laid the groundwork for future studies to examine potential neuro-protective and neuro-restorative effects of RCI.

Brown (2016) stated that although numerous therapeutic options are available for patients with psoriatic arthritis (PsA), a need for effective and tolerable treatments remains for patients with refractory disease who have failed previous therapies and continue to experience tender and/or swollen joints, pain, and disease activity. Repository corticotropin injection is believed to produce steroidogenic, steroid-independent, anti-inflammatory, and immunomodulatory effects in patients with rheumatic disorders, such as PsA. Limited literature exists on the use of RCI in patients with refractory PsA. In a case-series study, this investigator provided information on the clinical features of patients with refractory PsA and their response to RCI. A total of 9 patients treated with RCI for refractory PsA were retrospectively identified and included in the case series. All 9 patients experienced at least transient improvements in their active skin and joint disease. In some patients, it was necessary to titrate the RCI to an appropriate dose; RCI was used in some patients to bridge with another PsA therapy, such as apremilast or certolizumab; RCI was well-tolerated, but discontinued in 3 patients due to pre-existing conditions (hypertension and hyperglycemia). The author concluded that RCI may be a safe and effective option for patients with refractory PsA who failed therapy with multiple previous treatments. These preliminary findings need to be validated by well-designed studies.

Rheumatic Disorders

Thorpe (1969) reported on the use of ACTH in 6 patients with temporal arteritis/polymyalgia rheumatica syndrome. Patients were treated over a period of 2 to 6 months. Although no standardized objective clinical outcome measures were reported, the author reported that "all patients responded well to the regimen" and that 2 of the 6 patients remained on steroid therapy. The author stated that 3 patients had fluid retention requiring diuretic therapy, 2 patients had dyspepsia. One patient developed a febrile urinary tract infection and died. The author stated that a long-term study is warranted.

Philbin et al (2017) stated that repository corticotropin injection (RCI; H.P. Acthar gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged-release porcine preparation of ACTH analog that is FDA-approved for treatment of 19 autoimmune and inflammatory disorders. The diverse physiological actions of RCI at the melanocortin receptors (MCRs) affect processes involved in inflammation, pigmentation, steroidogenesis, and immunomodulation. Although RCI has been approved to treat inflammatory and autoimmune diseases for more than 60 years, recent progress in understanding both MCRs and the effects of RCI in modulating immune responses has led to increased interest in RCI as a therapeutic choice. These investigators summarized key clinical and economic data on RCI treatment of 7 disorders: infantile spasms (IS), multiple sclerosis (MS) relapses, proteinuria in nephrotic syndrome, rheumatoid arthritis (RA), dermatomyositis/polymyositis (DM/PM), SLE, and symptomatic sarcoidosis based on published literature and product information. Key studies of clinical efficacy and healthcare utilization and cost from 1956 to 2016 were summarized. The evidence supports the efficacy of RCI across the 7 indications. RCI was effective as a 1st-line therapy for IS. For the other 6 conditions, RCI may improve clinical outcomes during exacerbations or when the condition is resistant to conventional treatments. Use of RCI was associated with reduced use of biologics, corticosteroids, and disease-modifying anti-rheumatic drugs. Initiation of RCI therapy in patients with IS, MS, RA, SLE, or DM/PM has been associated with lower post-therapy healthcare utilization and medical costs, including decreases in hospitalizations, hospital length of stay (LOS), out-patient visits, and emergency department (ED) visits. The authors concluded that the evidence suggested that RCI may improve inflammatory and autoimmune disease control and patient quality of life (QOL), particularly in complex patients, and yielded healthcare cost savings that demonstrated the medicine's value.

In an open-label, interventional, single-group study, Gillis and colleagues (2017) examined the safety and efficacy of using RCI injection as an adjunctive therapy in patients with RA refractory to at least 3 therapeutics with different mechanisms of action. Patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie-Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. A total of 8 patients were enrolled and consisted of 7 women and 1 man with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 (DAS28) and the physician and patient VAS scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in DAS28, physician and patient VAS, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. The authors concluded that while larger clinical trials are needed to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggested that RCI could be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggested that RCI has an alternative mode of action, compared to other available anti-rheumatic drugs.

The authors stated that this study had several drawbacks. The trial size was small (n = 8). Treatment of a larger population of patients with refractory RA may provide further insight into effective treatment and dosing strategies. Additionally, this was an open-label trial and physicians and patients were aware of the status of RCI administration. As such, sampling bias could not be completely excluded. Furthermore, patients were on different medications at the time of intervention with RCI and no wash-out periods or standardization of concomitant medications was undertaken. However, administration of multiple classes of treatments, such as a disease-modifying anti-rheumatic drug (DMARD) and a biologic, is common in patients with inadequate response to methotrexate monotherapy. This was also a single-group study and no cohort exists that was not receiving RCI in order to make a direct comparison.

Fischer and Rapoport (2018) noted that although synthetic and biologic disease-modifying anti-rheumatic drugs are available, many patients with RA have a difficult-to-control disease and need other treatment options. Repository corticotropin injection may alleviate symptoms and exacerbations in patients with refractory disease. A total of 9 patients with refractory RA were included in this study. Patients were maintained on their baseline therapies with a minimum of 7.5 mg prednisone daily; RCI was given daily at 40 U for 7 days. Patients who had an adequate disease response were given 40 U twice weekly through Week 12. For patients who had inadequate disease response, the dose was increased to 80 U daily for 7 days, followed by 80 U twice weekly through week 12. The primary end-point was greater than 1.2 point reduction in the DAS28 using C-reactive protein (DAS28-CRP) at week 12. Secondary end-points were improvements in Health Assessment Questionnaire-Disease Index and Functional Assessment of Chronic Illness Therapy scores; 6 of the 9 patients met the primary end-point. The average change in DAS28-CRP from baseline to week 12 was numerically greater with 40 U than with 80 U RCI. Functional Assessment of Chronic Illness Therapy and Health Assessment Questionnaire-Disease Index improved as early as week 1, and the improvements remained throughout treatment. The authors concluded that there was no association between cortisol levels and low-dose RCI response. No serious AEs occurred; RCI produced a clinically meaningful reduction in markers of disease activity, improved health-related QOL, and a favorable safety profile. They stated that the response rate to RCI was substantial and showed promise in this difficult-to-treat population. Moreover, they stated that further placebo-controlled studies in patients not receiving prednisone are needed to fully understand the mechanisms of RCI.

To better understand the practice patterns and outcomes of RCI in patients with RA, SLE, or DM/PM, Ho-Mahler and colleagues (2020) performed a retrospective medical record analysis. Participating providers selected de-identified medical records of patients meeting the inclusion criteria (age of greater than or equal to 18 years; physician-reported diagnosis of RA, SLE, or DM/PM; initiation of treatment with RCI between January 1, 2011 and February 15, 2016; greater than or equal to 3 in-office visits with same site/provider). Collected data spanned 12 months before and after the first prescription date for RCI. Analyses included patient demographics and clinical history, RCI treatment patterns, and physician's impression of change. Data from 54 patients with RA, 30 patients with SLE, and 8 patients with DM/PM were analyzed. The most frequently reported reasons for initiating RCI were lack of efficacy with prior treatment, acute exacerbation of disease, and use as add-on to ongoing therapy. The most common initial RCI dosing, 80 U twice-weekly, was used for 84 % of patients with RA, 75 % with SLE, and 86 % with DM/PM. The mean duration of treatment was 4.8, 6.5, and 6.8 months for RA, SLE, and DM/PM, respectively. Among the 57 patients with data on physician's impression of change with RCI, 78.1 % of patients with RA, 94.7 % with SLE, and 66.7 % with DM/PM had a rating of "improved", and the mean time to best impression of change was 3.4, 4.3, and 3.4 months for RA, SLE, and DM/PM, respectively. The authors concluded that the findings from this study described the real-world patient profile, use patterns, and outcomes of patients who used RCI for the treatment of RA, SLE, and DM/PM. These data could inform appropriate use of RCI as well as the clinical expectations when using this medication. Moreover, these researchers stated that larger clinical trials are ongoing to add to the body of evidence.

The authors stated that this study was limited by its retrospective design and the small sample size yielded by their recruitment efforts. Another limitation was its reliance on patient medical records, which had missing data, as noted in the analyses, and may have had other unaccounted for errors and omissions (such as care received at other clinics). Reliance on medical records also made it difficult to evaluate disease activity, which was not routinely recorded in the medical records or recorded with the appropriate timing to allow evaluation of clinical response to therapy. These investigators stated that future research should consider this limitation and adjust the study design to accommodate. These researchers implemented quality control measures to minimize the occurrence of data entry errors during medical record abstraction. The study used physician’s impression of change as a descriptive end-point, a subjective measure that relied on an individual clinician’s own standards of improvement. Physician's impression of change was not available for 38 % of the records evaluated. In addition, the retrospective non-comparative study design did not allow these researchers to determine if patients were responding to other therapies. Therefore, these findings were exploratory and should be interpreted with these limitations in mind.

In a randomized controlled withdrawal trial, Fleischmann and associates (2020) examined the safety and efficacy of RCI in subjects with active RA despite treatment with a corticosteroid and 1 or 2 DMARDs. All subjects received open-label RCI (80 U) twice-weekly for 12 weeks (part 1); only those with low disease activity [LDA; i.e., DAS28 joint count and erythrocyte sedimentation rate (DAS28-ESR) of less than 3.2] were randomly assigned to receive either RCI (80 U) or placebo twice-weekly during the 12-week double-blind period (part 2). The primary efficacy end-point was the proportion of subjects who achieved LDA at week 12; and secondary efficacy end-points included proportions of subjects who maintained LDA during weeks 12 through 24 and achieved Clinical Disease Activity Index (CDAI) of less than or equal to 10 at weeks 12 and 24. Safety was evaluated via AE reports. Of the 259 enrolled subjects, 235 completed part 1; 154 subjects (n = 77 each for RCI and placebo) entered part 2, and 127 (RCI, n = 71; placebo, n = 56) completed. At week 12, 163 subjects (62.9 %) achieved LDA and 169 (65.3 %) achieved CDAI of less than or equal to 10 (both p < 0.0001). At week 24, 47 (61.0 %) RCI-treated and 32 (42.1 %) placebo-treated subjects maintained LDA (p = 0.019); 66 (85.7 %) RCI-treated and 50 (65.8 %) placebo-treated subjects maintained CDAI of less than or equal to 10 (p = 0.004). No unexpected safety signals were observed. The authors concluded that RCI was effective and generally safe in patients with active RA despite corticosteroid/DMARD therapy. By week 12, more than 60 % of patients achieved LDA, which was maintained with 12 additional weeks of treatment. Most patients who achieved LDA maintained it for 3 months after RCI discontinuation. Moreover, these researchers stated that future studies with additional treatment arms wherein tapering of glucocorticoids and/or DMARD adjustments are allowed may be needed.

The authors stated that this study had several drawbacks. Although these investigators used a study design that has previously been employed successfully, the primary end-point was measured in the open-label period, during which all subjects knew that they were being treated with RCI. The response observed for this end-point in this population with recalcitrant disease was higher than expected, which could, in part, be a result of the study design (i.e., a placebo effect). However, it would be unusual for a placebo effect to manifest after 8 weeks, as it was in this study. Furthermore, the vast majority (80 %) of subjects were of Hispanic or Latino ethnicity, which may limited extrapolation of the results to the general population. It should also be noted that patients with other rheumatic autoimmune diseases, clinically significant infections, or malignancies were excluded from the study. Caution should be exercised in extrapolating the study’s safety results to such populations. Also, bone density testing was not performed in this study, however, it would be reasonable to examine in future studies, considering the association between glucocorticoid therapy and the development of osteoporosis. Finally, subjects in this study had highly active RA despite treatment with DMARDs and glucocorticoids, and changes in these baseline therapies were not allowed during the study in order to properly examine the rescue effects of RCI. Current guidelines from ACR and EULAR recommend that glucocorticoids be used at the lowest possible dose and tapered as soon as possible.

Sarcoidosis

Chopra and colleagues (2019) stated that RCI has regulatory approval for many indications, including symptomatic sarcoidosis. This large case-series study of patients with advanced symptomatic sarcoidosis treated with RCI described patient characteristics, RCI utilization patterns, concomitant therapies, and physicians' assessments of treatment response. This trial included patients greater than or equal to 18 years of age and with symptomatic sarcoidosis who were treated with RCI in the previous 36 months, and had completed a course of RCI or received RCI for greater than or equal to 6 months at the time of data collection. The study included 302 patients (mean age of 51 years; 52 %, women) with a mean 4.8 years since initial diagnosis of sarcoidosis. Most patients (76 %) had extra-pulmonary involvement, primarily in the skin (28 %), joints (25 %), heart (22 %), and eyes (22 %); 34 % had multiple (greater than or equal to 2) organ involvement. The mean duration of RCI treatment was 32.5 weeks, with 61.6 % of patients continuing RCI therapy for greater than or equal to 6 months. The RCI utilization pattern indicated an individualized approach to therapy, with a higher starting dose associated with a shorter duration of therapy compared with a lower starting dose. The percentage of patients who used corticosteroids decreased from 61.3 % during the 3 months before initiation of RCI to 12.9 % 3 months following RCI therapy; the mean daily dose of corticosteroid decreased from 18.2 mg to 9.9 mg. The proportion of patients given less than 10 mg/day of prednisone increased from 21 % before RCI use to 47 % 3 months after RCI use. According to physicians' assessments of change in patients' health status following RCI therapy, overall status improved in 95 % of patients, overall symptoms in 73 %, lung function in 38 %, and inflammation in 33 %. The authors concluded that these findings suggested that RCI is a viable therapeutic option for patients with advanced symptomatic sarcoidosis and provided insights on patient characteristics and practice patterns to help clinicians determine appropriate use.

The authors stated that this study was limited by its reliance on data retrospectively collected via a survey of respondents who had access to patient medical records, which might have had errors and omissions. These investigators tried to minimize the impact of potential missing data by focusing on patients’ clinical aspects and physicians’ assessments, the types of information that are usually readily available in medical records or best known to the respondents who submitted data for this study. The study did not quantify patients’ outcomes such as diagnostic measurements and safety end-points. Furthermore, because of its inherent retrospective design, there may be a risk of bias, resulting in over-estimation of the effectiveness of RCI based on physicians’ assessments. Because this was an exploratory and hypothesis-generating study, these researchers did not make any comparisons between RCI and a control group or other treatments, which may also result in bias. It is important to note the following: RCI is indicated for symptomatic sarcoidosis; RCI is included in treatment guidelines from the Foundation for Sarcoidosis Research; and a randomized, phase-IV, double-blind, placebo-controlled clinical trial is ongoing to examine the safety and efficacy of Acthar gel in patients with pulmonary sarcoidosis. Another limitation was the use of the physicians’ assessments of improvement in a patient’s health status as a key descriptive end-point to evaluate RCI therapy. This subjective end-point relied on each individual physician’s interpretation of each patient’s medical record and the physician’s standards for assessing improvement. These researchers did not collect data on test results or other objective measures that physicians might have used to make their determinations. The retrospective and non-comparative study design did not allow the authors to discern whether patients were responding to known concomitant treatments or to therapies not known to the physician or not recorded in the medical records. The use of physicians’ assessment may have under-estimated the use of biologics in these patients; however, this could not be fully ascertained from the present study.

Neurosarcoidosis

Baughman and colleagues (2015) stated that Acthar was reported as effective for the treatment of pulmonary sarcoidosis in the 1950s. Use of drug waned due to cost and toxicity compared to prednisone. Recent interest has re-emerged as an alternative to high dose oral glucocorticoids. In a pilot study, chart review was performed on all advanced sarcoidosis patients seen at 2 centers who received at least 1 dose of Acthar gel therapy with at least 6 months of post-treatment follow-up. In all cases prior sarcoidosis therapy and indications for use along with clinical outcome were noted. All patients initially received 80 IU intramuscular or subcutaneous administration twice weekly. A total of 47 patients were treated with Acthar gel therapy during the study period, and 18 (37 %) discontinued drug within 6 months due to cost (4 patients), death (2 patients), or drug toxicity (11 patients), or non-compliance (1 patient). Of the remaining 29 patients, 11 experienced objective improvement in 1 or more affected organs. All but 2patients noted disease improvement or oral glucocorticoid reduction; 21 patients were treated for more than 6 months (median of 274 days); 19 patients were on prednisone at time of starting Acthar gel: 17 had their prednisone dosage reduced by more than 50 % and 1 patient discontinued cyclophosphamide therapy. The authors concluded that in this group of advanced sarcoidosis patients, Acthar gel treatment for at least 3 months was associated with objective improvement in 1/3 of patients; 1/3 of patients were unable to take at least a 3-month of treatment.

The main drawback of this study was its retrospective design with no placebo control. Other drawbacks included the lack of one specific end-point for treatment success; it was unclear whether the use of Acthar gel led to an overall reduction in glucocorticoid effect; and there were no standard criteria for initiation of Acthar gel as new therapy. The authors stated that "The role of Acthar gel in the treatment of sarcoidosis remains uncertain and needs further study. Additional studies on duration of effect after completing therapy and its impact on long-term endocrine outcomes such as lipid profiles and glucose metabolism are desperately needed".

Ocular Sarcoidosis

In a retrospective, chart review, Oh and colleagues (2021) examined the use and side effect profile of subcutaneous RCI in ocular sarcoidosis. Among 6 identified patients on RCI therapy, 4 had uveitis, 1 had optic neuritis and 1 had uveitis and optic neuritis secondary to sarcoidosis. The average follow-up was 43.5 months. RCI therapy was continuous in 4 patients (average of 7.7 months) and intermittent in 2 patients (24 and 12 months); 5 of the 6 patients continued with local and/or systemic corticosteroids for ocular inflammation control while on RCI therapy; 2/3 of patients experienced AEs including hyper-pigmentation, alopecia, and severe hypertension. RCI therapy was discontinued in 5 of the 6 patients due to continued inflammation and AEs (4 patients) and loss of follow-up (1 patient). The authors concluded that in this small cohort, the majority of patients failed to achieve adequate steroid-sparing ocular inflammation control and experienced side effects while on RCI therapy. These researchers stated that additional studies are needed to elucidate the role of RCI in ocular inflammation.

Pulmonary Sarcoidosis

Baughman et al (2016) stated that Acthar was reported as effective for the treatment of pulmonary sarcoidosis in the 1950s. Use of drug waned due to cost and toxicity compared to prednisone. Recent interest has re-emerged as an alternative to high-dose oral glucocorticoids. In a pilot study, these researchers carried out chart review on all advanced sarcoidosis patients seen at 2 centers who received at least 1 dose of Acthar gel therapy with at least 6 months of post-treatment follow-up. In all cases prior sarcoidosis therapy and indications for use along with clinical outcome were noted. All patients initially received 80 IU intra-muscular or subcutaneous administration twice-weekly. A total of 47 patients were treated with Acthar gel therapy during the study period, and 18 (37 %) discontinued drug within 6 months due to cost (4 patients), death (2 patients), or drug toxicity (11 patients), or non-compliance (1 patient). Of the remaining 29 patients, 11 experienced objective improvement in 1 or more affected organs. All but 2 patients noted disease improvement or oral glucocorticoid reduction; 21 patients were treated for more than 6 months (median of 274 days); 19 patients were on prednisone at time of starting Acthar gel: 17 had their prednisone dosage reduced by more than 50 % and 1 patient discontinued cyclophosphamide therapy. The authors concluded that in this group of advanced sarcoidosis patients, Acthar gel treatment for at least 3 months was associated with objective improvement in 1/3 of patients; 1/3 of patients were unable to take at least a 3 months of treatment. Moreover, these researchers stated that the role of Acthar gel in the treatment of sarcoidosis remains uncertain and needs further study. They stated that additional studies on duration of effect after completing therapy and its impact on long-term endocrine outcomes such as lipid profiles and glucose metabolism are desperately needed.

Baughman and colleagues (2017) stated that the dose of RCI and need for a loading dose in sarcoidosis patients receiving chronic corticosteroids are unclear. These researchers performed a single-blind, prospective study, comparing 2 doses of RCI in sarcoidosis. Chronic pulmonary sarcoidosis patients receiving prednisone therapy with deterioration by 5 % in forced vital capacity (FVC) in the previous year were studied; RCI was administered subcutaneously at a loading dose of 80 units RCI for 10 days. Patients were randomized at day 14 to receive either 40- or 80-unit RCI twice-weekly. The dose of prednisone was modified by the clinician who was blinded to the patient's dosage of RCI. A total of 16 patients completed the full 24 weeks of the study. At week 24, there was a decrease in the dose of prednisone, and improvements in diffusion of lung of carbon monoxide (DLCO), King's Sarcoidosis Questionnaire health status and fatigue score. There was no significant change in FVC % predicted. For the PET scan, there was a significant fall in the standard uptake value (SUV) of the lung lesions. Only 3/8 patients remained on 80 units RCI for full 24 weeks. There was no significant difference in the response to therapy for those treated with 40- versus 80-unit RCI. The authors concluded that repository corticotropin treatment was prednisone-sparing and associated with significant improvement in DLCO, PET scan, and patient-reported outcome measures. A dose of 40-unit RCI twice-weekly was as effective as 80-unit RCI and was better tolerated.

This study had several drawbacks. Many patients did not complete the proposed 10-day loading dose due to adverse events (AEs) reported by the patients. While discontinuation of loading dose was part of the protocol, the high number of patients who did not complete all 10 days made it difficult to identify if there was any benefit from taking a loading dose. The impression was that the loading dose added no benefit but enhanced toxicity. For the maintenance phase of the study, the protocol was designed to allow patients halve their dosage of RCI. By 24 weeks, only 2 patients were receiving 80 units RCI. Thus, these researchers could not analyze the effect of 80-unit RCI on steroid sparing or lung function at week 24. However, they had sufficient number of patients to compare 40 versus 80 units at 7 weeks. Since there was no significant difference at 7 weeks, these investigators chose to analyze the effect of any dose of RCI on steroid sparing, lung function, or quality of life (QOL). For the group, there were significant changes in some of these parameters. The study was designed to examine the effect of RCI on toxicity and prednisone sparing. Since there was no placebo group, the authors could not be sure that reduction in prednisone dose was not due to effect of repeat study visits and effort to reduce prednisone. The reduction of prednisone dose may have also been due to stimulation of glucocorticoid release. The small number of patients (n = 16) limited the ability to comment on the effect of RCI on pulmonary function. Also the study was a single-blind study. The authors noted that "The positive results of this study may help in identifying which patients may benefit from RCI. In addition, the study may prove useful information for designing future trials comparing RCI to placebo".

James and Baughman (2018) noted that treatment of sarcoidosis recommendations are often based on clinical experience and expert opinion. However, there are an increasing number of studies which are providing evidence to support decisions regarding treatment. Several studies have identified factors associated with increased risk for organ failure or death ("danger"). There have been several studies focused on the role of treatment to improve QOL for the patient. Sarcoidosis treatment often follows a progression, based on response. Corticosteroids remain the initial treatment of choice for most patients; second-line therapy includes cytotoxic agents. Immuno-suppressives such as methotrexate, azathioprine, leflunomide, and mycophenolate have all been reported as effective in sarcoidosis. Biologics and other agents are third-line therapy. The monoclonal antibodies directed against tumor necrosis factor (TNF) have been shown to be particularly effective for advanced disease. Infliximab has been the most studied drug in this class. Newer treatments, including repository corticotropin injection and rituximab have been reported as effective in some cases.

Furthermore, an UpToDate review on "Treatment of pulmonary sarcoidosis: Disease refractory to glucocorticoid therapy" (King, 2018) does not mention repository corticotropin as a therapeutic option.

Uveitis

In a retrospective, medical record review of U.S. patients, Nelson and colleagues (2019) described patient characteristics, treatment patterns, and physicians' assessments of patients with uveitis treated with RCI. Eligible patients had a diagnosis of uveitis, received RCI in the past 12 months, and had completed or were receiving RCI treatment at the time of data collection. Baseline characteristics and after-treatment clinical data were descriptively reported. The study included 91 patients (mean age of 41 years, 62 % women, and mean time since diagnosis of 3.98 years). Most patients had moderate (n = 48, 53 %) to severe (n = 21, 23 %) visual impairment, and none was blind before RCI therapy. Patients used an average of 2.5 medications before RCI. Initial RCI dosing regimens, dose adjustments, and treatment durations were different for each patient. Concomitant medication use and dosages were reduced during RCI; 76 patients (84 %) improved, 15 patients (16 %) stayed the same, and none worsened; 86 % of patients had improvements in vision. The authors concluded that physicians individualized RCI therapy among patients who suffered uveitis for several years and when previous therapies were inadequate. Most patients improved after initiating RCI, most commonly in vision. They stated that this descriptive study has identified several areas of future research. A detailed quantification of concomitant medications and reduction in their use as well as identification of the reasons behind the treatment patterns observed would further advance the knowledge on the use of RCI for the treatment of uveitis. Studies to quantify the clinical response and evaluate real-world safety of RCI in patients with uveitis would also be valuable.

The authors stated that this study has several limitations. These investigators relied on retrospective collection of data from medical records, which may be incomplete. However, the data collection focused on the clinical aspects of each case, based on data available in the medical record. The study's objective was to describe the characteristics of patients who were prescribed RCI; thus, the study scope did not include quantification of the patients' outcomes, such as diagnostic measurements or safety endpoints. Another drawback was that physician assessment of a patient's improvement following therapy may be subjective, and physicians may have varying definitions of improvement. Although physicians may have used objective measures, such as diagnostic tests, to inform their assessments, these researchers did not collect those data. Finally, as an observational study, the physicians' assessments reported in this study might be related to therapies not documented in the medical records. Furthermore, these investigators noted that this study did not capture information on adverse reactions in this group of patients with uveitis, who were receiving RCI and a variety of other concomitant medications, including corticosteroids. Published safety results of RCI in patients with uveitis were limited to 2 cases, both of whom were also receiving other concomitant therapies, including corticosteroids. There were no AEs reported in either patient after 6 weeks and 6 months of RCI treatment, respectively, including no local ocular or dermal injection site events. Potential common adverse reactions to RCI include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite, and weight gain. These side effects were similar to those known to occur with the corticosteroid class of uveitis treatments.

Appendix

FDA-Approved Dosing Recommendations for Acthar Gel and Purified Cortrophin Gel

Note: These dosing recommendations are provided in situations where Aetna's policy does not apply. Dosing recommendations for these indications are provided for plans that cover all FDA-approved indications for drugs, including those indications that Aetna considers experimental and investigational or not medically necessary. Please check benefit plan descriptions.

Acthar Gel

Recommended dosage regimen for the treatment of acute exacerbations in adults with multiple sclerosis:
- The recommended dose is daily intramuscular or subcutaneous doses of 80-120 units for 2 to 3 weeks for acute exacerbations. Dosage should be individualized according to the medical condition of each patient. Frequency and dose of the drug should be determined by considering the severity of the disease and the initial response of the patient.
- Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication.
Recommended dosage regimen for other indications for adults and children over 2 years of age:
- Dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease and the initial response of the patient. The usual dose of Acthar Gel is 40 to 80 units given intramuscularly or subcutaneously every 24 to 72 hours.
- Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication.

Source: Mallinckrodt Pharmaceuticals, 2024

Purified Cortrophin Gel

Standard tests for verification of adrenal responsiveness to corticotropin may utilize as much as 80 units as a single injection or one or more injections of a lesser dosage. Verification tests should be performed prior to treatment with corticotropins. The test should utilize the route(s) of administration proposed for treatment. Following verification dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease, plasma and urine corticosteroid levels and the initial response of the patient. Only gradual change in dosage schedules should be attempted, after full drug effects have become apparent.
In the treatment of acute exacerbations of multiple sclerosis daily intramuscular doses of 80-120 units for 2-3 weeks.
The chronic administration of more than 40 units daily may be associated with uncontrollable adverse effects.
When reduction in dosage is indicated this should be accomplished gradually by either reducing the amount of each injection, or administering injections at longer intervals, or by a combination of both of the above. During reduction of dosage, careful consideration should be given to the disease being treated, the general medical condition of the patient and the duration over which corticotropin was administered.
This product may be administered subcutaneously or intramuscularly.

Source: ANI Pharmaceuticals, 2023

References

The above policy is based on the following references:

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Last Review 10/16/2024

Effective: 08/08/2008

Next Review: 07/24/2025
Review History
Definitions

Repository Corticotropin Injection (Acthar Gel and Purified Cortrophin Gel)

Table Of Contents

Brand Selection for Medically Necessary Indications for Commercial Medical Plans

Multiple Sclerosis

Rheumatic Disorders

Collagen Diseases

Dermatologic Diseases

Allergic States

Ophthalmic Diseases

Respiratory Diseases

Edematous State

Policy

Scope of Policy

Criteria for Initial Approval

Continuation of Therapy

Dosage and Administration

Infantile Spasms

Not Medically Necessary

Experimental, Investigational, or Unproven

CPT Codes / HCPCS Codes / ICD-10 Codes

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB :

Background

U.S. Food and Drug Administration (FDA)-Approved Indications for Acthar Gel

U.S. Food and Drug Administration (FDA)-Approved Indications for Purified Cortrophin Gel

Rheumatic Disorders

Collagen Diseases

Dermatologic Diseases

Allergic States

Ophthalmic Diseases

Respiratory Diseases

Edematous States

Nervous system

Infantile Spasms (West Syndrome)

Collagen Diseases

Systemic Lupus Erythematosus

Dry Eye Disease

Multiple Sclerosis

Nephrotic Syndrome and Glomerular Diseases

Neurodegenerative Diseases

Non-Infectious Keratitis

Non-Infectious Retinal Vasculitis

Ocular Mucous Membrane Pemphigoid

Optic Neuritis

Rheumatic Disorders

Sarcoidosis

Neurosarcoidosis

Ocular Sarcoidosis

Pulmonary Sarcoidosis

Uveitis

Appendix

FDA-Approved Dosing Recommendations for Acthar Gel and Purified Cortrophin Gel

Acthar Gel

Purified Cortrophin Gel

References

Policy History

Additional Information