Important Safety InformationPrescribing InformationRequest InfoReferral Formfor patients

CORTISOL INDUCTION, IMMUNE CELL MODULATION, AND REMYELINATION

While the exact mechanism of action of Acthar Gel is not fully understood, further investigation is being conducted.
This information is based on nonclinical and pharmacodynamic data, and the relationship to clinical benefit is unknown.

Cortisol induction

High cortisol levels can lead to immunosuppression.1,2

In pharmacodynamic studies, Acthar Gel engaged melanocortin receptors expressed on the adrenal cortex resulting in the secretion of cortisol at levels slightly above normal endogenous range, which is thought to produce an indirect anti-inflammatory effect.3,4

Free cortisol response after single dose of Acthar Gel

STUDY DESIGN, SAFETY FINDINGS, AND STUDY LIMITATIONS3

An open-label, single-center, randomized, multiple-dose, parallel-group study to compare the PD and safety of intermittent doses of Acthar Gel to daily oral MP in healthy subjects. Subjects between 18 and 50 years old were randomized to receive Acthar Gel 40 or 80 U SC 2x/week for 15 days (n=12/group) or 16 mg of oral MP given once daily for 15 days (n=12), followed by a tapering regimen of 8 mg daily for 2 days, then 4 mg daily for 2 days. The most frequently reported TEAEs that occurred in 2 or more subjects were (in decreasing order of frequency): injection site hemorrhage, headache, injection site erythema, injection site pruritus, insomnia, acne, infrequent bowel movements, and injection site pain. All TEAEs experienced during this study were considered mild in severity. As this was a healthy-subject, open-label study with no placebo control, the clinical relevance of differences in tolerability is unknown and remains to be investigated for patient populations.

Direct cell modulation

Independent of cortisol release, Acthar Gel has shown a direct effect on immune cell modulation5-8

In an in vitro study using human monocyte-derived macrophages (MDMs), Acthar Gel inhibited the production of pro-inflammatory cytokines IL-6 and TNF-α, indicating a potential anti-inflammatory effect independent of cortisol release.5,6

Acthar Gel direct effects on macrophage cell modulation

In an in vitro study using human B cells, Acthar Gel reduced B-cell proliferation and IgG production.7,8

Acthar Gel direct effects on B-cell modulation

MACROPHAGES STUDY DESIGN5,6

An in vitro study to explore the direct effects of Acthar Gel on human macrophages, focusing on induction of pro-inflammatory mediators following LPS stimulation. CD14+ monocytes were selected from human PBMCs. Monocytes were then treated with M-CSF to generate MDMs. MDMs were stimulated with LPS and incubated for a minimum of 24 hours with Acthar Gel (1:11 dilution of 80 U/mL stock) or placebo (vehicle). Highest dose tested is presented in graph. Cytokines were measured by ELISA.

B CELLS STUDY DESIGN7,8

The effects of Acthar Gel on human B-lymphocyte function in vitro were evaluated using highly purified B-cell populations cultured in the absence of glucocorticoids and stimulated by recombinant IL-4 and CD40L as specific B-cell activating signals. IgG was measured in supernatants from healthy human peripheral B cells cultured for 6 days. Percentage of cells that divided and IgG production were assessed under basal conditions (unstimulated), stimulated with IL-4/CD40L alone (vehicle), or stimulated with IL-4/CD40L plus a 1:22 dilution of 80 U/mL stock of Acthar Gel. Data presented were adapted from several independent studies, and the highest doses tested are shown in the graph.

Remyelination

In vitro data using an MCR agonist and in vivo data using Acthar Gel suggest that remyelination may result due to enhanced oligodendrocyte survival, differentiation, and proliferation and/or effect on reducing inflammation.9-11

Acthar Gel effect on remyelination

REMYELINATION STUDY DESIGN9

C57BL/6 mice were fed 0.3% cuprizone co-administered with rapamycin for 12 weeks to induce demyelination and inhibit spontaneous remyelination, respectively. After 12 weeks of cuprizone treatment (disease), mice showed severe demyelination of both white and gray matter. Mice were treated for another 6 weeks with Acthar Gel. Remyelination was analyzed in gray matter (hippocampus) via quantification of PLP and in white matter (corpus callosum) via PPD staining.*

*Higher doses of Acthar Gel showed a reduction in remyelination.

VIDEO

Principal Research Pharmacologist Dale Wright, PhD, explains the potential MOA of Acthar Gel

Principal Research Pharmacologist Dale Wright, PhD, explains the potential MOA of Acthar Gel

CD14=cluster of differentiation 14; CD40L=CD40 ligand; ELISA=enzyme-linked immunosorbent assay; IgG=immunoglobulin G; IL-4=interleukin 4; IL-6=interleukin 6; LPS=lipopolysaccharide; M-CSF=macrophage colony-stimulating factor; MP=methylprednisolone; PBMC=peripheral blood mononuclear cell; PD=pharmacodynamic; PLP=proteolipid protein; PPD=p-Phenylenediamine; SC=subcutaneous; TEAE=treatment-emergent adverse event; TNF-α=tumor necrosis factor alpha.

Indication

Acthar® Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

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Important Safety Information

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 origin

Indication

Acthar® Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

Warnings and Precautions
  • The adverse effects of Acthar are related primarily to its steroidogenic effects
  • Acthar may increase susceptibility to new infection or reactivation of latent infections
  • Suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
  • Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
  • Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium, and potassium levels may need to be monitored
  • Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
  • Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
  • Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression to psychosis. Existing conditions may be aggravated
  • Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
  • Prolonged use of Acthar may produce cataracts, glaucoma, and secondary ocular infections. Monitor for signs and symptoms
  • Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
  • There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
  • Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
  • Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
  • Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
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 masks other seizures, which become visible once the clinical spasms from IS resolve

Other adverse events reported are included in the full Prescribing Information.

Please see full Prescribing Information for additional Important Safety Information.

References: 1. Van Laethem F, Baus E, Smyth LA, et al. Glucocorticoids attenuate T cell receptor signaling. J Exp Med. 2001;193(7):803-814. 2. Choi J, Fauce SR, Effros RB. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008;22(4):600-605. 3. Data on file: REF-MNK14314065. Mallinckrodt ARD LLC. 4. Coolens JL, Van Baelen H, Heyns W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem. 1987;26(2):197-202. 5. Healy LM, Jang JH, Lin YH, Rao V, Antel JP, Wright D. Melanocortin receptor mediated anti-inflammatory effect of repository corticotropin injection on human monocyte-derived macrophages [ECTRIMS-ACTRIMS abstract EP1481]. Mult Scler J. 2017;23(suppl 3):777. 6. Healy LM, Lin YH, Jang JH, Rao V, Antel JP, Wright D. Melanocortin receptor mediated anti-inflammatory effect of repository corticotropin injection on human monocyte-derived macrophages. Poster presented at: 7th Joint ECTRIMS-ACTRIMS Meeting; October 25-28, 2017; Paris, France. Poster EP1481. 7. Olsen NJ, Decker DA, Higgins P, et al. Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. Arthritis Res Ther. 2015;17:300. doi:10.1186/s13075-015-0823-y. 8. Data on file: REF-QSP01-RHEU-002. Mallinckrodt ARD LLC. 9. Wright D, Fitch R. Repository corticotropin injection (H.P. Acthar Gel) enhances remyelination after cuprizone-induced demyelination [CMSC abstract NDM04]. Int J MS Care. 2019;21(suppl 1):61-62. 10. Benjamins JA, Nedelkoska L, Lisak RP. Melanocortin receptor subtypes are expressed on cells in the oligodendroglial lineage and signal ACTH protection. J Neurosci Res. 2018;96(3):427-435. 11. Benjamins JA, Nedelkoska L, Lisak RP. Adrenocorticotropin hormone 1-39 promotes proliferation and differentiation of oligodendroglial progenitor cells and protects from excitotoxic and inflammation-related damage. J Neurosci Res. 2014;92(10):1243-1251.

Indication

Acthar® Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

View Full

Important Safety Information

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 origin

Indication

Acthar® Gel (repository corticotropin injection) is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

Warnings and Precautions
  • The adverse effects of Acthar are related primarily to its steroidogenic effects
  • Acthar may increase susceptibility to new infection or reactivation of latent infections
  • Suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. During recovery of the adrenal gland patients should be protected from the stress (e.g. trauma or surgery) by the use of corticosteroids. Monitor patients for effects of HPA suppression after stopping treatment
  • Cushing’s syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms
  • Acthar can cause elevation of blood pressure, salt and water retention, and hypokalemia. Blood pressure, sodium, and potassium levels may need to be monitored
  • Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and for a period following discontinuation of therapy
  • Acthar can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Monitor for signs of bleeding
  • Acthar may be associated with central nervous system effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, and severe depression to psychosis. Existing conditions may be aggravated
  • Patients with comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar in patients with diabetes and myasthenia gravis
  • Prolonged use of Acthar may produce cataracts, glaucoma, and secondary ocular infections. Monitor for signs and symptoms
  • Acthar is immunogenic and prolonged administration of Acthar may increase the risk of hypersensitivity reactions. Neutralizing antibodies with chronic administration may lead to loss of endogenous ACTH activity
  • There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver
  • Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients
  • Decrease in bone density may occur. Bone density should be monitored for patients on long-term therapy
  • Pregnancy Class C: Acthar has been shown to have an embryocidal effect and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
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 masks other seizures, which become visible once the clinical spasms from IS resolve

Other adverse events reported are included in the full Prescribing Information.

Please see full Prescribing Information for additional Important Safety Information.

References: 1. Van Laethem F, Baus E, Smyth LA, et al. Glucocorticoids attenuate T cell receptor signaling. J Exp Med. 2001;193(7):803-814. 2. Choi J, Fauce SR, Effros RB. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008;22(4):600-605. 3. Data on file: REF-MNK14314065. Mallinckrodt ARD LLC. 4. Coolens JL, Van Baelen H, Heyns W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem. 1987;26(2):197-202. 5. Healy LM, Jang JH, Lin YH, Rao V, Antel JP, Wright D. Melanocortin receptor mediated anti-inflammatory effect of repository corticotropin injection on human monocyte-derived macrophages [ECTRIMS-ACTRIMS abstract EP1481]. Mult Scler J. 2017;23(suppl 3):777. 6. Healy LM, Lin YH, Jang JH, Rao V, Antel JP, Wright D. Melanocortin receptor mediated anti-inflammatory effect of repository corticotropin injection on human monocyte-derived macrophages. Poster presented at: 7th Joint ECTRIMS-ACTRIMS Meeting; October 25-28, 2017; Paris, France. Poster EP1481. 7. Olsen NJ, Decker DA, Higgins P, et al. Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. Arthritis Res Ther. 2015;17:300. doi:10.1186/s13075-015-0823-y. 8. Data on file: REF-QSP01-RHEU-002. Mallinckrodt ARD LLC. 9. Wright D, Fitch R. Repository corticotropin injection (H.P. Acthar Gel) enhances remyelination after cuprizone-induced demyelination [CMSC abstract NDM04]. Int J MS Care. 2019;21(suppl 1):61-62. 10. Benjamins JA, Nedelkoska L, Lisak RP. Melanocortin receptor subtypes are expressed on cells in the oligodendroglial lineage and signal ACTH protection. J Neurosci Res. 2018;96(3):427-435. 11. Benjamins JA, Nedelkoska L, Lisak RP. Adrenocorticotropin hormone 1-39 promotes proliferation and differentiation of oligodendroglial progenitor cells and protects from excitotoxic and inflammation-related damage. J Neurosci Res. 2014;92(10):1243-1251.

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