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Mallinckrodt Statement on October 20, 2017, Neurology Today Journal Article

October 20, 2017

An article entitled, “Debate: ACTH or Prednisolone for Infantile Spasms?” appeared on the website of Neurology Today on October 20, 2017, discussing a paper written by researchers in Sri Lanka comparing synthetic adrenocorticotropic hormone (ACTH) – not H.P. Acthar® Gel (repository corticotropin injection) – and prednisolone in management of infantile spasms (IS). Again, to be clear the referenced study is not about H.P. Acthar Gel®.

H.P. Acthar Gel in the Treatment of Infantile Spasms
In a controlled study comparing H.P. Acthar Gel (repository corticotropin injection) to prednisone in the treatment of IS, data demonstrated that 86.7% of IS patients responded to H.P. Acthar Gel vs. 28.6% that responded to prednisone. H.P. Acthar Gel is an approved, first-line treatment in the U.S. for IS.

H.P. Acthar Gel is a complex organic formulation containing the 39 amino acid ACTH peptide. The clinical evidence provided to the U.S. Food and Drug Administration (FDA) to gain approval of the drug in IS patients included two randomized controlled clinical trials demonstrating effectiveness of the drug as a treatment for IS, including the one noted above. The IS clinical trial results appear in Section 14 of the full prescribing information for H.P. Acthar Gel.

By contrast, the compound used in the study by Wanigasinghe and others is a synthetic form of truncated 24 amino acid ACTH, which is not H.P. Acthar Gel, not FDA-approved and not marketed in the U.S.

The Wanigasinghe study authors acknowledge in the manuscript that these are two different products, and they note the clinical responses of patients with IS to these two therapies are unlikely to be the same, due to differences in the active ingredients, the formulations and the dosing regimens studied.

Mallinckrodt also notes the following:

• The latest set of guidelines on the treatment of IS published by the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society (Go et al, 2012) states: “There is insufficient evidence to determine whether other forms of corticosteroids are as effective as adrenocorticotropic hormone (ACTH) for short-term treatment of infantile spasms.”
• The U.S. Consensus Report published by the Infantile Spasms Working Group (Pellock et al, 2010) published recommendations including a statement that: “Effective treatment for IS should produce both cessation of spasms and resolution of hypsarrhythmia on EEG and is an ‘‘all-or-none’’ response.” This was not the criteria for response in the Wanigasinghe et al. study.
• Most recently, a multicenter study, including 22 U.S. centers and 230 infants with IS, conducted by the Pediatric Epilepsy Research Consortium (Knupp et al, 2016), demonstrated clinical superiority of H.P. Acthar Gel over both Vigabatrin and high-dose corticosteroids, with the greatest difference achieved at the high-dose treatment regimen for H.P. Acthar Gel, as recommended in the H.P. Acthar Gel prescribing information.

To be clear, there is only one H.P. Acthar Gel (corticotropin repository injection). Other products referenced are other formulations of corticotropin products, not versions of Acthar. H.P. Acthar Gel is a naturally derived mixture of organic components – including an extraction from porcine pituitary glands – and is a unique medicine and much more than just ACTH. It contains a complex combination of peptide components.

Mallinckrodt has made a public pledge to price its products responsibly, and in a way that reflects the value they offer patients, providers and the U.S. healthcare system as a whole, and this is true for H.P. Acthar Gel. Mallinckrodt has made only modest adjustments to the price of the drug since acquiring it in 2014. Mallinckrodt discounts this list price to both public and private payers. The company’s pledge on drug pricing and innovation describes its philosophy around responsible pricing.

About H.P. Acthar Gel (repository corticotropin injection)
Indications
H.P. Acthar Gel is an injectable drug approved by the FDA for the treatment of 19 indications. Of these, today the majority of Acthar use is in these indications:

• Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus
• Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age
• The treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown H.P. Acthar Gel 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
• Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus
• Treatment during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis)
• The treatment of symptomatic sarcoidosis
• Adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
• Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis, iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis, anterior segment inflammation

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 origins

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-axis (HPA) 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, and 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 mask 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 parents and caregivers of IS patients, please also see Medication Guide.

ABOUT MALLINCKRODT
Mallinckrodt is a global business that develops, manufactures, markets and distributes specialty pharmaceutical products and therapies. Areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; and analgesics and hemostasis products. The company's core strengths include the acquisition and management of highly regulated raw materials and specialized chemistry, formulation and manufacturing capabilities. The company's Specialty Brands segment includes branded medicines and its Specialty Generics segment includes specialty generic drugs, active pharmaceutical ingredients and external manufacturing. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

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