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Mallinckrodt Posts Data From Legacy H.P. Acthar® Gel (Repository Corticotropin Injection) Pilot Study To clinicaltrials.gov

-- Under-powered Phase 2A pilot study of H.P. Acthar Gel in Diabetic Nephropathy patients failed to fully enroll due to trial design challenges; data insufficient to support clinically relevant conclusions --

July 25, 2017

Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today posted data to the ClinicalTrials.gov website. The data derived from a legacy Phase 2A pilot study designed and begun under previous ownership to explore an additional new indication for H.P. Acthar^® Gel (repository corticotropin injection) to treat diabetic nephropathy (DN). The under-powered pilot study did not achieve targeted enrollment levels due to a number of trial design challenges nor did it generate data sufficient to support clinically relevant conclusions. At present Mallinckrodt does not intend to pursue this new indication further.

The Phase 2A pilot study was entitled "A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Adaptive Design Pilot Safety and Efficacy Study of H.P. Acthar Gel (Acthar) in Patients with Diabetic Nephropathy and Proteinuria." Find more information about the trial results here on the ClinicalTrials.gov website.

Over the past two plus years, Mallinckrodt has been systematically completing all legacy studies that had been initiated by the previous owner of H.P. Acthar Gel and which were ongoing at the time of the acquisition. Several of those studies, including this Phase 2A pilot evaluating a potential new indication for H.P Acthar Gel in treatment of DN patients, were small, underpowered trials.

Steven Romano, M.D., Chief Scientific Officer and Executive Vice President at Mallinckrodt, said, "Given the design challenges associated with this particular study, we knew it had a low probability of providing definitive answers to challenging clinical questions, but we were committed to finishing out the work that was begun. Since acquiring H.P. Acthar Gel in 2014, we have initiated six well-designed, company-sponsored clinical studies, targeting combined enrollment of more than 1,100 patients. We believe these Mallinckrodt-sponsored studies have a higher probability of generating clinically meaningful data."

Romano continued, "In many conditions, the efficacy of medicines in treating different symptoms or features of the disease varies based on the underlying cause. Just as one antibiotic may be effective for controlling fever associated with a specific bacterial infection, but not for another, a treatment effective in management of proteinuria associated with one illness may not be effective in another. The pathophysiology of DN has features distinct from other idiopathic causes of proteinuria, and is a very challenging condition that many drug developers have struggled to address." 

"Although a previous independent pilot study (Tumlin et al, 2013[1]) demonstrated a potential benefit from Acthar in some patients with DN, and this Mallinckrodt pilot study suggested a dose-related attenuation in the decline of  eGFR  at week 36[2], the company's study failed to demonstrate a statistically significant improvement for the reasons and limitations mentioned," Romano concluded.

Importantly, no new safety issues were identified in this study and, notably, control of diabetes (as measured by HbA1c) did not differ between the H.P. Acthar Gel and placebo groups. As noted previously, Mallinckrodt does not intend to pursue this indication further.

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 infantile spasms (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.

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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