Acthar Gel for Clinicians
Acthar Gel is ACTH (from porcine origin) in a gel form.
Typical starting dose can be 40U twice a week, though 80U is also used if more urgency is at play.
It is preferentially given subcutaneously (though it can also be used intramuscularly).
Dose can be increased to achieve clinical goals. Concomitant use of immunosuppressive medications (methotrexate, azathioprine, or other similar agents is maintained with appropriate monitoring and adverse event management, while attempts should be made to decrease concomitant steroid use.
Maintenance dose should be individualised for each patient.
Efficacy should be evaluated after 3 to 6 months of RCI therapy. Weaning to the lowest efficacious dose RCI should be considered if the patient has stable, well-controlled disease after 6 to 12 months of therapy, and should be performed by decreasing the dosing frequency, and then the dose .
Complete Blood Count, Complete Metabolic Panel and Bone densitometry should be done before initiation of treatment and followed.
Asymptomatic Sarcoidosis is not always treated.
Acute Symptomatic sarcoidosis is treated with steroids, tapered over 3 to 6 months and then if further treatment is needed, the disease would be classified as Chronic.
Chronic sarcoidosis is treated with a combination of steroids and antimetabolites. People with Chronic Sarcoidosis who so not achieve their clinical goals are considered as having Advanced Disease.
Third line therapy may include biologics (see Sarcoidosis Disease State for Clinicians). Acthar Gel may also be considered for the Chronic and Advanced Chronic Disease patients to further clinical goals and decrease steroid use, or for those not tolerant of other treatments.
(Excerpts from Rahaghi et at and Baughman et al. ATS 2017/ please see full prescribing information for further information)
Potential Mechanisms of Action:
Melanocortin System Activation May Affect Multiple Inflammatory Pathways
Targeting all 5 MCRs may have an impact on immune cells and cytokines involved in granulomatous inflammation1-9
- As a melanocortin peptide, Acthar may impact multiple immunomodulatory pathways by binding to MCRs, which are located throughout the body3
- Acthar is believed to work with the body’s immune system to target the cells responsible for granuloma formation3, 10
TARGETING ALL 5 MCRs MAY HAVE AN IMPACT ON IMMUNE CELLS AND CYTOKINES INVOLVED IN GRANULOMATOUS INFLAMMATION1-9*
- Download Your Guide to Acthar, an educational resource for your symptomatic sarcoidosis patients who have been newly prescribed Acthar.
- Download the Acthar Treatment Journal, containing useful sarcoidosis information, tips, tools, and more.
- Download the Access to Acthar Overview, a comprehensive patient support resource for your patients—from prescription through treatment.
- Catania A, Gatti S, Colombo G, Lipton JM. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev. 2004;56(1):1-29.
- Böhm M, Luger TA, Tobin DJ, García-Borrón JC. Melanocortin receptor ligands: new horizons for skin biology and clinical dermatology. J Invest Dermatol. 2006;126(9):1966-1975.
- Data on file: RD-010-00, Mallinckrodt ARD, Inc.
- Data on file: RD-011-00, Mallinckrodt ARD, Inc.
- Catania A, Lonati C, Sordi A, Carlin A, Leonardi P, Gatti S. The melanocortin system in control of inflammation. ScientificWorldJournal. 2010;10:1840-1853.
- Ahmed TJ, Montero-Melendez T, Perretti M, Pitzalis C. Curbing inflammation through endogenous pathways: focus on melanocortin peptides. Int J Inflam. 2013;2013:985815
- Arnason BG, Berkovich R, Catania A, Lisak RP, Zaidi M. Mechanisms of action of adrenocorticotropic hormone and other melanocortins relevant to the clinical management of patients with multiple sclerosis. Mult Scler. 2013;19(2):130-136.
- Rossi S, Maisto R, Gesulado C, et al. Activation of melanocortin receptors MC1 and MC5 attenuates retinal damage in experimental diabetic retinopathy. Mediators Inflamm. 2016;2016:7368389.
- Zhang L, Dong L, Liu X, et al. Alpha-melanocyte-stimulating hormone protects retinal vascular endothelial cells from oxidative stress and apoptosis in a rat model of diabetes. PloS One. 2014;9(4):e93433.
- H.P. Acthar® Gel [package insert]. Hazelwood, MO: Mallinckrodt ARD, Inc; 2017.
- Pranzatelli MR, Tate ED, Hoefgen ER, Swan JA, Colliver JA. Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus-myoclonus syndrome. Cytokine. 2008;44(1):26-32.
- Brod SA, Hood ZM. Ingested (oral) ACTH inhibits EAE. J Neuroimmunol. 2011;232(1-2):131-135.
- Namba K, Kitaichi N, Nishida T, Taylor AW. Induction of regulatory T cells by the immunomodulating cytokines alpha-melanocyte-stimulating hormone and transforming growth factor-beta2. J Leukoc Biol. 2002;72(5):946-952
- Auriemma M, Brzoska T, Klenner L, et al. Alpha-MSH-stimulated tolerogenic dendritic cells induce functional regulatory T cells and ameliorate ongoing skin inflammation. J Invest Dermatol. 2012;132(7):1814-1824.
- Taylor AW, Lee DJ. The alpha-melanocyte stimulating hormone induces conversion of effector T cells into Treg cells. J Transplant. 2011;2011:246856.
- Luger TA, Scholzen TE, Brzoska T, Böhm M. New insights into the function of alpha-MSH and related peptides in the immune system. Ann NY Acad Sci. 2003;994:133-140.
- Taylor AW. The immunomodulating neuropeptide alpha melanocyte-stimulating hormone (alpha-MSH) suppresses LPS-stimulated TLR4 with IRAK-M in macrophages. J Neuroimmunol. 2005;162(1-2):43-50.
- Bhardwaj RS, Schwarz A, Becher E, et al. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J Immunol. 1996;156(7):2517-2521.
- Cannon JG, Tatro JB, Reichlin S, Dinarello CA. Alpha melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1. J Immunol. 1986;137(7):2232-2236.
Acthar Gel is the only other FDA approved treatment aside from prednisone for symptomatic pulmonary sarcoidosis. Large randomized control trials were not available for this condition at the time of FDA approval. At this moment, we rely on smaller studies to further define and understand the place of Acthar Gel in our armamentarium against Sarcoidosis. We will review these studies here:
A prospective, single-blind, pilot study examining the use of Acthar in patients with advanced pulmonary sarcoidosis1
*All patients in both arms were receiving prednisone at baseline.
Patients had the flexibility to reduce their dose by half due to perceived problems with drug treatment.
The efficacy and safety results discussed may not be representative of the overall symptomatic sarcoidosis patient population. Patients may have been on multiple medications. The clinical outcomes for the patients discussed may not be solely attributable to Acthar.
†5 patients stopped the loading schedule at days 7 through 9 due to toxicity.
The prospective study included patients with exposure to the following treatments1:
- Prednisone (n=16)
- Azathioprine (n=4)
- Mycophenolate (n=1)
- Infliximab (n=4)
- Methotrexate (n=8)
- Leflunomide (n=3)
- Hydroxychloroquine (n=8)
- Adalimumab (n=3)
With the exception of prednisone, other therapies are not approved for the treatment of symptomatic sarcoidosis.
Patient Demographics (n=16)1
Of the 16 patients who completed the 24-week study, in addition to lung involvement, most also presented with extrapulmonary disease. There were no subset analyses done by extrapulmonary involvement.1
Significant reductions in steroid dosages and improvements in pulmonary function were associated with Acthar treatment
|Primary||Evaluated prednisone-sparing effect of Acthar|
|Other||Evaluated the effect of Acthar on pulmonary function, chest imaging, and health-related quality-of-life|
Selected Inclusion Criteria
- All patients met American Thoracic Society criteria for diagnosis
- On a stable dose of ≥5 mg prednisone for ≥3 months
- Deterioration of pulmonary disease as defined by a decrease of 5% forced vital capacity (FVC) in the previous year
Selected Exclusion Criteria
- Treatment with anti-TNF antibody (eg, infliximab, adalimumab) in prior 6 months
- Receiving treatment for sarcoidosis-associated pulmonary hypertension
Patients taking Acthar achieved significant reductions in prednisone dose at week 7 that were sustained to week 241
DAILY PREDNISONE DOSE INITIALLY AND AT WEEKS 7 AND 24
- When the effect of Acthar at any dose was analyzed, there was a significant reduction in the prednisone dosage at 7 weeks (P=.0156) and 24 weeks (P=.0078) compared to the initial dosage of prednisone
- At week 7, there was no significant difference in reduction of prednisone dosage for those receiving 80 units of Acthar (median 0 mg, range 0 to -20 mg) vs those receiving 40 units of Acthar (median -2.75 mg, range 0 to -12.5 mg, P >.05)
- There was no significant difference between the prednisone dose at 7 weeks vs 24 weeks, or between the 40- and 80-unit treatment groups
Additional endpoints: Patient-reported outcomes1
Additional endpoints: Patient-reported outcomes1
SUMMARY OF CHANGES IN QUALITY-OF-LIFE MEASURES DURING ACTHAR THERAPY1
†Compared to week 0, P =.0043.
‡Compared to week 0, P =.0084.
§Compared to week 0, P =.0034.
∥Compared to week 0, P =.0067.
¶Compared to week 0, P =.0107.
#Compared to week 0, P =.0067.
- There were significant differences in the KSQ on several domains, including general health status (GHS), general health status lung (GHS lung), and lung
- For all patients, there was a significant improvement (rise) in GHS at weeks 7 and 24 vs week 0. There was no difference in GHS change between the 40- and 80-unit treatment groups
- Neither the SGRQ total nor any of its 3 components changed significantly during the study
- There was a significant fall (less fatigue) in the FAS score at week 24 (P =.0067)
- At week 7, 10 patients had a 4-point or greater drop in their FAS score
- By week 24, 8 patients still had a 4-point or greater drop in their FAS score
94% of patients (16 of 17) were able to remain on Acthar for the full 24 weeks of the study period.1
Additional endpoints: DLCO and SUV
Significant changes in DLCO:1
- In the 14 patients who had their DLCO measured prior to and after 24 weeks of therapy, there was a significant rise in the DLCO percent predicted after 24 weeks (P =.0419)
No change in FVC percent predicted1
- No significant reduction in FVC percent predicted between the 2 dosage groups after 7 weeks of therapy
SUV of highest lung lesion, as measured by FDG-PET scans at week 24, fell from a median 4.0 to 2.9 (P =.0085)1
- There was no correlation between PET scan results and the change in DLCO, FVC percent predicted, or dose of prednisone during the 24 weeks of the study
- There was no significant difference in reduction of prednisone dosage, changes in FVC percent predicted, or the quality-of-life measures of the patients between the 2 dosage groups at week 7
(DLCO=diffusing capacity of the lungs for carbon monoxide. FDG-PET=F-fluorodeoxyglucose positron emission tomography. SUV=standardized update value.)
- 1 withdrew during the initial loading period
- 8 patients complained of one or more of the following: jitteriness (n=6), headache (n=3), edema (n=2), and nausea (n=1)
- 5 stopped loading dose between days 7 and 9 due to toxicity but began the randomized phase
- 1 stopped treatment within 2 weeks because of toxicity in the randomized phase in the 40-U arm
- 7 reduced their dose by half (2 in the 40-U arm and 5 in the 80-U arm, P >.05)
- 8 complained of anxiety and fluid retention on the day of drug administration; many of these occurred during the daily loading doses
- Adverse events associated with Acthar use were collected prospectively for all patients
- No significant differences in reported toxicity, including changes in moodiness, appetite, or bruising
- No significant change in weight during the 24-week study period
- Of the 6 patients who had elevated hemoglobin A1c levels at baseline, none of the values fell into the normal range by the end of 24 weeks
- There were no changes in the patients’ diabetic or hypertensive medications during the course of the study
Retrospective chart review study of patients treated with Acthar gel for symptomatic sarcoidosis1
|CHART REVIEW CRITERIA1||
|DOSING1||80 IU intramuscularly or subcutaneously twice a week|
>10% improvement in FVC
|No clinically significant change in target organ, but reduction in dosage of glucocorticoids||Worsening of target organ when prednisone dosage was reduced and patient had to be maintained on initial or higher dosage of glucocorticoids|
|CNS||>50% reduction in CNS lesion on magnetic resonance imaging|
|Skin||>50% reduction of skin lesions|
|Eyes||>50% reduction in the use of topical glucocorticoids for ocular disease|
Normalization and/or 50% reduction of:
Serum calcium to upper limit of normal
93% of patients treated for ≥3 months had an improved or stable target organ response1
PRIMARY TARGET ORGAN RESPONSE AFTER ≥3 MONTHS OF ACTHAR TREATMENT (n=29)1
*Reduced inflammation, >10% improvement in FVC, >50% reduction in use of topical glucocorticoids, or improvement in other organ abnormalities.
†No clinically significant change in target organ, but reduction in dosage of glucocorticoids.
‡Worsening of target organ when prednisone was reduced and patient had to be maintained on initial or higher dose of glucocorticoids.
IMPROVED OR STABLE RESPONSE BY PRIMARY TARGET ORGAN IN PATIENTS WHO COMPLETED 3 MONTHS OF ACTHAR TREATMENT1
Results are based on a retrospective pilot study of 47 patients with no placebo control and may not be fully representative of outcomes in the overall patient population. Assessment of response was subjective. Most patients were on multiple therapies. The clinical outcomes may not be solely attributable to Acthar.
Reduction of prednisone dose by more than 50% was observed in a majority of patients1
27 of 29 patients treated for ≥3 months were receiving prednisone at initiation of Acthar1
- 8§ improved patients experienced a ≥50% reduction in prednisone dosage
- All 16 stable patients reduced prednisone dosage by ≥50%
- 2 relapsed patients maintained a stable prednisone dose
§Of the 3 remaining patients, 2 were not receiving prednisone at Acthar commencement, and the third maintained a stable dose but discontinued cyclophosphamide.
18 of 47 patients discontinued treatment due to:
- Acthar should never be administered intravenously
- Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar
- Acthar is contraindicated where congenital infections are suspected in infants
- Acthar 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, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction or sensitivity to proteins of porcine origins
Warnings & Precautions
- Cushing’s syndrome and adrenal insufficiency upon withdrawal
- Elevated blood pressure, salt and water retention and hypokalemia
- Masking symptoms of other diseases
- Gastrointestinal perforation and bleeding
- Behavioral and mood disturbances
- Comorbid diseases
- Ophthalmic effects
- Immunogenicity potential
- Use in patients with hypothyroidism or liver cirrhosis
- Negative effects on growth and physical development
- Decrease in bone density
- Use in pregnancy
- Common adverse reactions for Acthar are similar to those of corticosteroids and include fluid retention, alteration in glucose tolerance, elevation in blood pressure, behavioral and mood changes, increased appetite and weight gain
- Specific adverse reactions reported in IS clinical trials in infants and children under 2 years of age included: infection, hypertension, irritability, Cushingoid symptoms, constipation, diarrhea, vomiting, pyrexia, weight gain, increased appetite, decreased appetite, nasal congestion, acne, rash, and cardiac hypertrophy. Convulsions were also reported, but these may actually be occurring because some IS patients progress to other forms of seizures and IS sometimes mask other seizures, which become visible once the clinical spasms from IS resolved