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

Feb. 21, 2017

Recently, several articles have appeared that draw a number  of erroneous conclusions about Mallinckrodt Pharmaceuticals and its product  H.P. Acthar Gel based on misinformation and a variety of distorted and  conflated facts. Mallinckrodt disagrees with these views and offers the  following basic, but important facts about this critical medicine.

Body of Evidence
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 the label in 2010, and determined there in fact  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). The effectiveness of the drug as  an IS treatment is supported by two randomized clinical trials, one of which compared H.P. Acthar Gel to prednisone, and is reflected in the IS clinical trial results that appear in Section 14 of the full prescribing information for the drug. A representative sampling of articles citing the clinical experience of  H.P. Acthar Gel follow referencing treatment of patients for multiple sclerosis  relapse and to induce a remission of proteinuria in nephrotic syndrome: 

 
• 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.

Substantial 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 (HEOR) 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%.

In that same period, Mallinckrodt has initiated three company-sponsored  Phase 4 clinical trials for H.P. Acthar Gel (rheumatoid arthritis, systemic  lupus erythematosus and focal segmental glomerulosclerosis). The company also announced  a Phase 2 proof-of-concept trial to study the efficacy of the drug in amyotrophic  lateral sclerosis, often called Lou Gehrig’s disease, for which there are very  few effective treatment options available at present. All told, more than 800  patients will be enrolled in these company-sponsored, randomized controlled  clinical trials to study H.P. Acthar Gel. Multiple sclerosis studies are also  underway or nearing initiation, with studies for other indications under  consideration.

These investments, plus manufacturing modernization, investing  in safety stocks to ensure maximal product supply, other medical affairs and  research activities, and HEOR studies bring the total investment in H.P. Acthar  Gel to more than a quarter of a billion dollars since acquiring the product.

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. The per-patient cost of Acthar in Medicare reflects the relatively  small numbers of patients being treated with the drug - consistent with its use  for only the hard-to-treat patients for whom other alternatives have been  ineffective or are no longer tolerated.

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 Acthar’s use as a proven therapy. The  prior-authorization and reimbursement processes used by commercial payers rely  on these criteria.

Summary
Mallinckrodt strongly believes in the product’s efficacy in  its approved indications and will continue significant investment for 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 Acthar 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  select cases of rheumatoid arthritis, to tide patients over an acute episode or  exacerbation.
   
• Treatment of symptomatic sarcoidosis.

For more information about Acthar, please visit www.acthar.com. Full Prescribing Information  may be accessed here.

Important Safety Information 

 
• 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.
 
• 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.
 
• 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