Repository Corticotropin Injection (H.P. Acthar Gel)

Number: 0762

Aetna considers repository corticotropin (H.P. Acthar® Gel) medically necessary for West syndrome (infantile spasms)

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

Aetna considers repository corticotropin not medically necessary for corticosteroid-responsive conditions because it has not been proven to be more effective than corticosteroids for these indications.

Aetna considers repository corticotropin experimental and investigational 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
• Dermatopolymyositis
• Multiple sclerosis
• Optic neuritis
• Nephrotic syndrome (including focal segmental glomerulo-sclerosis, idiopathic membranous nephropathy, IgA nephropathy, membrano-proliferative glomerulo-nephritis, and monoclonal diffuse proliferative glomerulo-nephritis)
• Rheumatoid arthritis
• Systemic lupus erythematosus

Note: The labeling of H.P 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 (see Appendix).

Repository corticotropin injection (H.P. Acthar® Gel) (Questcor Pharmaceuticals, Union City, CA) is a highly purified sterile preparation of the adrenocorticotropic hormone (ACTH) in 16% gelatin to provide a prolonged release after intramuscular or subcutaneous injection. Repository corticotropin injection is a natural product derived from a bovine or 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 for treatment of infantile spasms in infants and children under 2 years of age. 

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.

Adrenocorticotropic hormone is a natural product derived from a bovine or porcine source and is administered as an intramuscular or subcutaneous injection.  However, in the United Kingdom, with the existing concerns surrounding bovine spongiform encephalopathy, ACTH has been 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. 

Repository corticotropin is contraindicated in patients with scleroderma, osteoporosis, systemic funcal 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.

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 twic- 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 grouip, 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.

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."

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.

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.

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.

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.

Noting that the data on using Acthar gel to treat idiopathic 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.

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 (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 regimes 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 (i) 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), (ii) if prednisone or vigabatrin are used, then high dosage is recommended, (iii) vigabatrin may be the treatment of choice in tuberous sclerosis but more research is required, and (iv) 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 (i) 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, (ii) vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis, (iii) there is insufficient evidence to recommend oral corticosteroids, (iv) there is insufficient evidence to recommend any other treatment of infantile spasms, and (v) 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).

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”.

Available evidence regarding the effectiveness of Acthar gel for the treatment of 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.

Furthermore, an UpToDate review on “Treatment and prognosis of IgA nephropathy” (Cattran and Appel, 2014) does not mention the use of repository corticotropin/Acthar as a therapeutic option.

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.

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.

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.

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.

Appendix

Repository corticotropin injection is available as H.P. Acthar Gel in 5 ml multi‐dose vial containing 80 USP units per mL.

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

H.P. Acthar Gel is typically dosed based on body surface area (BSA) for infantile spasms. To calculate body surface area (BSA), see http://www-users.med.cornell.edu/~spon/picu/calc/bsacalc.htm.

In the treatment of infantile spasms, H.P. Acthar Gel must be administered intramuscularly.  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 H.P. 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 mornining for 3 days; and 10 U/m2 every other morning for 6 days.

Recommended Dosing Regimen for Acute Exacerbations of Multiple Sclerosis*

Note: Aetna considers H.P. Acthar Gel experimental and investigational for multiple sclerosis.  These dosing recommendations are provided in situations where Aetna's policy does not apply.

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 H.P. 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 Dosing Regimen for Other Indications for Adults and Children Over Two Years of Age*

Note: Aetna considers H.P. Acthar Gel experimental and investigational for corticosteroid-responsive conditions.  These dosing recommendations are provided in situations where Aetna's policy does not apply.

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 H.P. 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 H.P. 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: Questcor Pharmaceuticals, Inc. H.P. Acthar Gel (repository corticotropin injection) Injection, Gel for Intramuscular | Subcutaneous Use. Initial U.S. Approval: 1952. Prescribing Information. PL065/Rev.03 No. 1350. PM-554-01. Hayward, CA: Questcor; issued June 2011.

Recommended Dosing for Diagnostic Testing of Adrenocortical Function:*

The recommended dose is up to 80 units subcutaneously or intramuscularly.

*Note: 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.  Please check benefit plan descriptions.

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