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Mallinckrodt Presents Preliminary Interim Findings of Rheumatoid Arthritis Phase 4 Clinical Study for H.P. Acthar® Gel (Repository Corticotropin Injection)

-- Data Presented at Annual European Congress of Rheumatology (EULAR 2018) --

STAINES-UPON-THAMES, United Kingdom – June 16, 2018 – Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today presented preliminary interim data from the company-sponsored Phase 4 clinical trial of H.P. Acthar® Gel for Rheumatoid Arthritis (RA) patients at the Annual European Congress of Rheumatology (EULAR 2018), held in Amsterdam, Netherlands. The study is assessing the efficacy and safety of H.P. Acthar Gel in RA patients with persistently active disease.

The presentation was entitled “A Multicenter Study Assessing the Efficacy and Safety of Repository Corticotropin Injection in patients with Rheumatoid Arthritis: Preliminary Interim Data from the Open-Label Treatment Period,” and the poster can be accessed here.

Tunde Otulana, MD, Chief Medical Officer at Mallinckrodt, said, “Patients with persistently active rheumatoid arthritis may have symptoms and signs of joint inflammation despite the use of disease-modifying therapies and corticosteroids. Mallinckrodt is committed to conducting studies in rheumatoid arthritis patients to better understand the potential utility of H.P. Acthar Gel in affecting persistent disease activity in these individuals and we are encouraged by the interim clinical trial results.”

H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved as 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).

“The goal of treating RA is to achieve remission or low disease activity. The preliminary results of this study suggest that H.P. Acthar Gel may provide benefit to appropriate patients who are experiencing disease activity in spite of treatment with disease-modifying anti-rheumatic drugs and low-dose prednisone,” said Dr. Roy Fleischmann, Co-Medical Director of the Metroplex Clinical Research Center and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center in Dallas. “This study is an important step to determining the efficacy and safety of this treatment for patients with persistently active RA.”

Study Details and Key Findings

The study is a Phase 4, multicenter, two-part study assessing the efficacy and safety of H.P. Acthar Gel in adult subjects with rheumatoid arthritis with persistently active disease that is currently enrolling patients. Part 1 is an Open Label Period in which all eligible subjects receive H.P. Acthar Gel for 12 weeks. After 12 weeks of treatment with H.P. Acthar Gel, subjects will be evaluated for treatment response using the Disease Activity Score 28-joint count Erythrocyte Sedimentation Rate (DAS28-ESR). Subjects who have achieved low disease activity will enter a double-blind randomized maintenance period (Part 2) and be randomized in a 1:1 ratio to receive either H.P. Acthar Gel or matching placebo for an additional 12 weeks.

The goal is to enroll approximately 230 patients with persistently active RA despite treatment with corticosteroids and conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) at up to 100 sites for the primary outcome. The primary endpoint in this study is the proportion of subjects with DAS28-ESR <3.2 at Week 12. The Secondary Outcome Measures include the proportion of subjects who maintained DAS28-ESR <3.2 from Week 12 through Week 24.2

Interim findings:

• Efficacy was evaluated at baseline, and then weeks 4, 8, and 12 using:
• DAS28-ESR (including tender and swollen joint counts, erythrocyte sedimentation rate and the investigator general health visual analog scale (MD-VAS));
• Patient-Reported Outcomes (PROs); and
• The ACR response criteria with improvements of 20%, 50% and/or 70%. An ACR score is a standardized percentage indicating how much a patient’s RA has improved, based on guidelines set forth by the American College of Rheumatology.

• Preliminary data on 58 enrolled patients, of which 48 have completed the open label period (as of 19 April 2018), found:
• The interim analysis demonstrated a decrease in the mean DAS28-ESR scores from baseline through Week 12 with 58% of patients achieving low disease activity (LDA; < 3.2) at Week 12;
• Similarly, the percentage of patients that achieved ACR 20, 50, and 70 criteria increased over time from Week 4 through Week 12 with 85%, 60% and 38% of patients having achieved ACR 20, 50, and 70 response, respectively; and
• Improvement in PRO scores from baseline through Week 12 were observed.

• Twenty-eight adverse events (AEs) have been reported among the 58 patients enrolled; the most common AEs were headache and hyperglycemia in five and three patients, respectively. Two serious AEs were reported by two patients (chest pain and pneumonia); one patient (pneumonia) withdrew from the study.

Study Limitations

• The data reported herein is from a preplanned 25% data review of the open label arm of an ongoing study, and thus full results of the trial may vary.
  
• The results reported may not be solely attributable to H.P. Acthar Gel as the patients were on concomitant medications.

Find more information about the study here on the ClinicalTrials.gov website.

ABOUT RHEUMATOID ARTHRITIS
RA is an autoimmune disease. It is a chronic condition that causes pain, stiffness, and swelling of the joints—all symptoms caused by inflammation. An estimated 1.5 million U.S. adults are living with RA.   Treatment is aimed at stopping inflammation to put the disease in remission and relieve symptoms.  Nonsteroidal anti-inflammatory drugs are used to ease symptoms whereas corticosteroids, disease-modifying anti-rheumatic drugs and biologics are used to slow down the disease activity.4

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:

• 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 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
• 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.

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; analgesics and gastrointestinal products. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

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CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTS
This release includes forward-looking statements concerning H.P. Acthar Gel including expectations with regard to the study described in this release, as well as future research plans and potential impact on patients. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.

CONTACTS

Investor Relations
Daniel J. Speciale, CPA
Investor Relations and Strategy Officer
314-654-3638
daniel.speciale@mnk.com

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

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

Mallinckrodt, the "M" brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. Other brands are trademarks of a Mallinckrodt company or their respective owners. © 2018 Mallinckrodt. ARDUS/01-18/0618/0002 06/18