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Mallinckrodt Statement on H.P. Acthar® Gel (Repository Corticotropin Injection) Update

UPDATED June 22, 2017

To address the false and misleading information about Mallinckrodt Pharmaceuticals and its product H.P. Acthar Gel, the company is committed to regularly providing important facts about this critical medicine.

H.P. Acthar Gel makes a significant difference in the lives of very sick patients with unmet medical needs. The U.S. Food and Drug Administration (FDA) reviewed H.P. Acthar Gel’s label in 2010, and determined there was sufficient scientific and clinical evidence to support the 19 indications now in the current label. In most indications, H.P. Acthar Gel is a later line treatment, prescribed by skilled healthcare providers to a small subset of patients who need an alternative treatment option. H.P. Acthar Gel is a first line monotherapy treatment for infantile spasms (IS).

UPDATE: Adverse Event Reports
Mallinckrodt annually provides the FDA with data about adverse events related to its marketed products. As we approach our yearly filing, we are pleased to report that the positive benefit-risk of H.P. Acthar Gel has remained unchanged across all marketed indications and is consistent with previous years.

To derive meaningful conclusions of this topic, adverse event reports for H.P. Acthar Gel need to be considered within the appropriate context.

H.P. Acthar Gel is typically prescribed to patients with very serious medical conditions, often as a third or fourth line of treatment when other treatments have failed. It is well known that many of these patients suffer from diseases in which co-morbidities are high, and often they are on other medications that may be contributing factors.

The frequency of adverse event reports also does not necessarily correlate to an increase in the actual prevalence or relative severity of any particular side effect or event. Each event is reported and counted whether it relates to a relatively minor event such as a headache or a more serious event such as anaphylaxis.

Furthermore, the FDA itself cautions on its website that reporting of a side effect or adverse event occurring while taking a drug doesn’t establish a causal relationship between the adverse event and the medicine.

Over the past years, the number of patients using H.P. Acthar Gel has increased significantly. Critically, however, company-generated H.P. Acthar Gel data on adverse events over the last three calendar years indicates that the number of serious adverse events as a proportion of the number of H.P. Acthar Gel prescriptions (measured by vials sold) has remained very low and consistent with the FDA’s independent analysis.

Body of Evidence
There is clinical evidence to support the effectiveness of H.P. Acthar Gel. For instance, two randomized clinical trials were conducted to support the effectiveness of the drug in obtaining FDA approval as a treatment for infantile spasms, one of which compared H.P. Acthar Gel to prednisone, where 86.7% of patients responded to H.P. Acthar Gel vs. 28.6% that responded to prednisone. The IS clinical trial results appear in Section 14 of the full prescribing information for the drug. A representative sampling of articles citing the clinical experience of the drug follow:

• Baughman, R, Barney, J, O’Hare, L, Lower, E. A retrospective pilot study examining the use of H.P. Acthar Gel in sarcoidosis patients. Respiratory Medicine 110 (2016) 66-72. Link.
• Berkovich R, Agius, M. Mechanisms of action of ACTH in the management of relapsing forms of multiple sclerosis. Ther Adv Neurol Disord. 2014;7(2):83-96. Link.  
• Thompson AJ, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology. 1989;39:969-97. Link. 
• Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. 1970;20(5):1-59. Link.
• Hogan J, Bomback AS, Mehta K, et al. Treatment of idiopathic FSGS with adrenocorticotropic hormone gel. Clin J Am Soc Nephrol. 2013;8(12):2072-2081. Link.
• Bomback AS, Canetta PA, Beck LH, Ayalon R, Radhakrishnan J, Appel GB. Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: A prospective trial. American Journal of Nephrology. 2012;36(1):58-67. Link.

Significant additional evidence exists, including company-sponsored controlled clinical trials, investigator-initiated research conducted in top hospitals and medical centers by some of the country’s preeminent physicians, and health economic and outcomes research data. A bibliography referencing hundreds of studies related to H.P. Acthar Gel can be found on the company’s website, and press releases specific to company-sponsored trials for the product can also be found in the news section of the site. Equally important are the more than 50 years of clinical experience physicians have with the product as a demonstrated therapy for appropriate patients.

Mallinckrodt Investment
As the company has stated consistently, Mallinckrodt’s goal has been - and continues to be – to acquire under-resourced, under-utilized products like H.P. Acthar Gel that are used in areas of high unmet medical need, typically in narrow patient populations, and then invest significantly in those products. The company invests by building an even larger body of evidence to demonstrate which patients can benefit most from the drug and shares that information with physicians and payers to ensure those patients can get access to the product. This strategy has been very successful, and in the roughly 2.5 years it has owned the product, Mallinckrodt has expanded the number of commercial lives under contract from zero to nearly 60%.

Since acquiring H.P. Acthar Gel in 2014, Mallinckrodt has invested more than a quarter of a billion dollars into the drug, including building a larger body of evidence for the drug through clinical trials and health economic outcomes research data; payer engagement; manufacturing modernization; and other medical affairs and research activities. Since adding the drug to its portfolio, Mallinckrodt has initiated six well-designed, company-sponsored randomized, controlled clinical studies, targeting combined enrollment of more than 1,100 patients.
H.P. Acthar Gel Pricing
The current “list price” per vial for the drug is $36,382, not the higher numbers which have appeared in various reports, and Mallinckrodt discounts this list price to both public and private payers. Mallinckrodt takes our responsibility as a pharmaceutical manufacturer very seriously, and our pledge on drug pricing and innovation describes our philosophy around responsible pricing.

H.P. Acthar Gel Dosage
H.P. Acthar Gel is an injectable formulation, and therefore physicians have flexibility in dosing in order to prescribe and administer the amount of drug they believe is needed (based on clinical data and their own experience) to effectively treat their patient’s symptoms. This means that dosing may differ between the conditions it is used to treat and between individual patients.

There is no evidence – and Mallinckrodt has no reason to believe – that the amount of H.P. Acthar Gel prescribed to individual patients by their respective physicians is excessive. There may, however, be some confusion about the difference between dosages (USP units), and vials of H.P. Acthar Gel that could lead to misunderstanding about prescribing behavior by doctors. For reference, dosing information can be found in the FDA-approved prescribing information (label).

MNK-1411
MNK-1411 (formerly Synacthen® Depot) is simply not a “generic competitor to Acthar” – the two products are very different drugs. MNK-1411 is not approved by the FDA for any indications, and has never been commercialized in the United States. H.P. Acthar Gel is biologically derived and amongst its many components includes a 1-39 peptide chain so includes more than simply ACTH, while MNK-1411 is a synthetic 24-peptide chain. Importantly, the company believes the regulatory path for any corticotropin-type new drug application would require FDA approval and, if successful, could take many years.
Reimbursement
Specific to reimbursement, coverage gains among commercial payers has resulted in the overall payer mix for H.P. Acthar Gel between private and public plans becoming – and staying – relatively stable, and Mallinckrodt is seeing volume growth across both publicly and privately insured patients.

Medicare patients represent a slightly higher percentage of overall patients simply because presentation of expanding data sets to healthcare practitioners over time has resulted in increased usage in aging patient populations, particularly in the rheumatology and pulmonology spaces, where Medicare coverage is more likely to be utilized. H.P. Acthar Gel is typically used episodically and acutely with patients, as opposed to a drug that is used regularly or chronically with patients. Additionally, these patients are often on concurrent treatments.

In the commercial reimbursement space, the majority of payers have an established pathway for the use of H.P. Acthar Gel in those patients for whom it is appropriately prescribed - those with conditions covered by the FDA-approved label and for whom the product’s extensive existing data and clinical experience support H.P. Acthar Gel’s use as a proven therapy. The prior-authorization and reimbursement processes used by commercial payers rely on these criteria.

Partners to Help Reach Patients
Mallinckrodt engages with a variety of partners in all parts of the industry value chain to ensure access for appropriate patients who are prescribed H.P. Acthar Gel. The company contracts with the majority of the largest Pharmacy Benefit Managers in the U.S., among them Express Scripts.

As is common practice for self-administered, injectable products that are not stocked at neighborhood pharmacies and require special climate-controlled handling, Mallinckrodt utilizes a network of independent specialty pharmacies to deliver H.P. Acthar Gel to patients who have been prescribed the medicine. Mallinckrodt has individual contracts with each of the independent specialty pharmacies in its network, of which Accredo, a specialty pharmacy owned and operated under the Express Scripts umbrella, is one. The pharmacies Mallinckrodt contracts with are selected based on a number of criteria, including their overall ability to fulfill prescriptions and provide product to patients in a timely manner.

To deliver H.P. Acthar Gel to its network of independent specialty pharmacies who then deliver the medicine to patient’s homes, Mallinckrodt also contracts with Express Scripts’ subsidiary CuraScript SD.

Mallinckrodt also has two other contracts with another separately owned Express Scripts subsidiary, United BioSource Corporation – one to manage order processing for the product, and another to conduct income or means testing for a program under which Mallinckrodt provides free product to low-income, uninsured or underinsured patients who qualify.

Utilization of all these services is a standard industry practice for most specialty pharmaceutical drugs, of which H.P. Acthar Gel is one.

Summary
Mallinckrodt strongly believes in the product’s efficacy in its approved indications and will continue significant investment in H.P. Acthar Gel to ensure those patients who can benefit from the therapy have access to it.

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

• As an orphan monotherapy medication for the treatment of IS in infants and children under 2 years of age.
• Inducing a diuresis or a remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.
• Treatment of acute exacerbations of multiple sclerosis in adults.
• Use during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus.
• Use during an exacerbation or as maintenance therapy in selected cases of systemic dermatomyositis (polymyositis).
• Use as adjunct therapy for short-term administration in psoriatic arthritis; rheumatoid arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis to tide patients over an acute episode or exacerbation.
• Treatment of symptomatic sarcoidosis.
• 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.

For more information about Acthar, please visit www.acthar.com. Please click to see full Prescribing Information and Medication Guide.

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 adrenal (HPA) axis may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Cushing's Syndrome may occur during therapy but generally resolves after therapy is stopped. Monitor patients for signs and symptoms.
• Monitor patients for elevation of blood pressure, salt and water retention, and hypokalemia.
• Acthar often acts by masking symptoms of other diseases/disorders. Monitor patients carefully during and following discontinuation.
• Acthar can cause gastrointestinal (GI) bleeding and gastric ulcer with an increased risk for perforation with certain GI disorders. Monitor for signs of bleeding.
• Acthar may be associated with central nervous system (CNS) effects ranging from euphoria, insomnia, irritability, mood swings, personality changes, depression, and psychosis. Existing conditions may be aggravated.
• Patients with comorbid disease may have that disease worsened. Caution should be used in patients with diabetes and myasthenia gravis.
• Prolonged use of Acthar may produce cataracts, glaucoma and secondary ocular infections.
• Acthar is immunogenic and prolonged use may increase the risk of hypersensitivity reactions.
• There is an enhanced effect in patients with hypothyroidism and those with cirrhosis of liver.
• Long-term use may have negative effects on growth and physical development in children. Monitor pediatric patients.
• Decrease in bone density may occur. Monitor during 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 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.

Please see full Prescribing Information here for additional Important Safety Information.

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.

Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.

CONTACTS

Investor Relations
Coleman N. Lannum, CFA
Senior Vice President, Investor Strategy and IRO
314-654-6649
cole.lannum@mallinckrodt.com

Daniel J. Speciale, CPA
Director, Investor Relations
314-654-3638
daniel.speciale@mallinckrodt.com

Media
Rhonda Sciarra
Senior Communications Manager
908-238-6765
rhonda.sciarra@mallinckrodt.com

Meredith Fischer
Chief Public Affairs Officer
314-654-3318
meredith.fischer@mallinckrodt.com