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Article

Acthar Downloads

• 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.

Full Prescribing Information/Package Insert

References:

1. 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.
2. 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.
3. Data on file: RD-010-00, Mallinckrodt ARD, Inc.
4. Data on file: RD-011-00, Mallinckrodt ARD, Inc.
5. Catania A, Lonati C, Sordi A, Carlin A, Leonardi P, Gatti S. The melanocortin system in control of inflammation. ScientificWorldJournal. 2010;10:1840-1853.
6. Ahmed TJ, Montero-Melendez T, Perretti M, Pitzalis C. Curbing inflammation through endogenous pathways: focus on melanocortin peptides. Int J Inflam. 2013;2013:985815
7. 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.
8. 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.
9. 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.
10. H.P. Acthar® Gel [package insert]. Hazelwood, MO: Mallinckrodt ARD, Inc; 2017.
11. 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.
12. Brod SA, Hood ZM. Ingested (oral) ACTH inhibits EAE. J Neuroimmunol. 2011;232(1-2):131-135.
13. 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
14. 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.
15. Taylor AW, Lee DJ. The alpha-melanocyte stimulating hormone induces conversion of effector T cells into Treg cells. J Transplant. 2011;2011:246856.
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17. 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.
18. 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.
19. 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.

Efficacy Studies

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:

Baughman (2017)
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.

Study limitations

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.

Study Flow¹

†5 patients stopped the loading schedule at days 7 through 9 due to toxicity.

Patient Characteristics

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

Extrapulmonary Involvement
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

Results:
Significant reductions in steroid dosages and improvements in pulmonary function were associated with Acthar treatment

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

*Median (range).
†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.)

Safety findings¹

• 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

Baughman (2016)
Retrospective chart review study of patients treated with Acthar gel for symptomatic sarcoidosis¹

Study Design

Study Results

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

Study Limitations¹

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.

Safety Findings¹

18 of 47 patients discontinued treatment due to:

Contraindications

• 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

• Infections
• Cushing’s syndrome and adrenal insufficiency upon withdrawal
• Elevated blood pressure, salt and water retention and hypokalemia
• Vaccination
• 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

Adverse Reactions

• 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