News Releases

STAINES-UPON-THAMES, United Kingdom, Oct. 22, 2018 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, is reporting interim data¹ at the midway point of enrollment in the ongoing Phase 4, multicenter study assessing the efficacy and safety of H.P. Acthar Gel in patients with persistently active rheumatoid arthritis (RA) despite receiving disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids. The data will be reported in a poster presentation on Tuesday, Oct. 23 at the 2018 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting (Oct. 19-24) in Chicago, IL.

Earlier at this year's 2018 ACR/ARHP Annual Meeting, Mallinckrodt presented pre-clinical findings² on the immune modulatory effect of H.P. Acthar Gel in a rat adjuvant-induced arthritis (AIA) model and the effect on osteoclast-mediated bone resorption compared to an immunosuppressive steroid.

The Phase 4 study abstract can be accessed here. The pre-clinical study abstract can be accessed here. The poster presented at the 2018 ACR/ARHP Annual Meeting will be available on the company's website following the close of the conference Wednesday, Oct. 24.

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 RA including juvenile RA (selected cases may require low-dose maintenance therapy).

"A Multicenter Study Assessing the Efficacy and Safety of Repository Corticotropin Injection in Patients With RA: Preliminary Interim Data From the Open-Label Treatment Period" (Abstract 2528)

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 despite treatment with DMARDs and corticosteroids. The primary endpoint of the study is the proportion of patients reaching low disease activity (LDA) at 12 weeks. In this interim analysis at the midway point of study enrollment, researchers found that 61% of the 100 patients who had completed the open-label period achieved LDA at 12 weeks. The most common adverse events (AEs) reported – a secondary endpoint – were headache (10), urinary tract infection (4), hyperglycemia (3) and pharyngitis (3). Two patients reported serious AEs (chest pain and pneumonia).

"Rheumatoid arthritis disease activity measures are used to evaluate response to treatment and facilitate clinical decision-making in practice. The goal of treatment is ideally remission or low disease activity if remission cannot be reached. These interim findings help inform our understanding of the potential safety and effectiveness of H.P. Acthar Gel as a treatment option in patients with persistently active disease who were nonresponsive to disease-modifying anti-rheumatic drugs and low-dose prednisone with a known safety profile," 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. "The findings are a step in understanding the treatment of persistently active rheumatoid arthritis despite treatment with disease-modifying drugs and corticosteroids."

Key Findings:

• Preliminary data on 116 enrolled patients, of whom 100 have completed the open-label period (as of May 10, 2018), found:
• The interim analysis demonstrated there was a decrease in the mean Disease Activity Score 28-joint count Erythrocyte Sedimentation Rate (DAS28-ESR) scores from baseline through Week 12, with 61% of patients who completed the open-label period achieving low disease activity (LDA ≤3.2) at Week 12.
• Similarly, the percentage of patients who achieved ACR 20, 50, and 70 criteria increased over time from Week 4 through Week 12, with 85%, 66% and 34% of patients who completed the open-label period having achieved ACR 20, 50, and 70 responses, respectively at 12 weeks.
• Improvement in patient-reported outcomes (PRO) scores from baseline through Week 12 was observed.
• Adverse events observed were consistent with those in previous trials of H.P. Acthar Gel, and no new safety signals were reported.
• Fourteen subjects withdrew from the study.

Part 1 of the study 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 were evaluated for treatment response using the DAS28-ESR. Disease activity was also assessed by the proportion of patients who achieved 20%/50%/70% improvement in ACR response criteria (ACR20, ACR50, ACR70) at Week 12. Subjects who have achieved LDA will enter a double-blind randomized phase (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.

"We are committed to the ongoing study of H.P. Acthar Gel in rheumatology, building on the decades of clinical experience for the product and continuing to meet the needs of the rheumatology community," said Tunde Otulana, MD, Chief Medical Officer at Mallinckrodt. "The data being presented at the 2018 ACR/ARHP Annual Meeting seeks to provide insight into the clinical utility of H.P. Acthar Gel in rheumatoid arthritis in patients with persistently active disease."

Study Limitations

• These are interim results of 50% of patients enrolled; results may change when the study is fully enrolled.
• Because this is an interim report, significance tests were not conducted; thus, P-values are not reported.
• These results are from an open-label period; patients could not advance to the double-blind portion without achieving LDA by Week 12.
• Because this was known by the patients and investigators, there may have been a subconscious motivation in a majority of patients to dramatically "improve" between Weeks 8 and 12 rather than H.P. Acthar Gel becoming effective from Weeks 8 to 12.

The trial is now fully enrolled with 232 patients with persistently active RA despite treatment with corticosteroids and conventional synthetic and/or biologic DMARDs. 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.

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

"Repository Corticotropin Injection (H.P. Acthar^® Gel) Inhibits Bone Degradation in Rat Adjuvant-Induced Arthritis" (Abstract 57)

Findings from a pre-clinical study to investigate the immune modulatory effect of H.P. Acthar Gel in a rat adjuvant-induced arthritis (AIA) model and the effect on osteoclast-mediated bone resorption compared to an immunosuppressive steroid showed that treatment with H.P. Acthar Gel significantly inhibited the development of disease in the AIA rat model compared to prednisolone treatment alone over the course of treatment (15 days/eight total doses).

In addition, a histologic evaluation of inflammation and bone damage conducted at the end of the study showed there was a significant reduction in the number of osteoclasts in the inflamed joint following treatment with H.P. Acthar Gel. These data also suggest that in the pre-clinical model, treatment response is driven by suppression of joint inflammation and bone resorption. This information is based on pre-clinical data and its clinical relevance is unknown. Clinical studies will need to be conducted to confirm these results.

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.³ An estimated 1.5 million U.S. adults are living with RA.⁴ Treatment is aimed at stopping inflammation to put the disease in remission and relieve symptoms.⁵ 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.

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 RA, including juvenile RA (selected cases may require low-dose maintenance therapy)
• Monotherapy for the treatment of infantile spasms in infants and children under 2 years of age
• Treatment during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus
• 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.

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.

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. US-1800463 10/18

¹ Fleischmann R, Furst DE, Brasington R, Connolly-Strong E, Liu J, Barton M. 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. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/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/.  Accessed October 11, 2018.
² Wright D, Zweifel B, Settle S, Fitch R. Repository Corticotropin Injection (H.P. Acthar^® Gel) Inhibits Bone Degradation in Rat Adjuvant-Induced Arthritis Model. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/repository-corticotropin-injection-h-p-acthar-gel-inhibits-bone-degradation-in-rat-adjuvant-induced-arthritis-model/. Accessed October 11, 2018.
³ Mayo Clinic website. Rheumatoid Arthritis. Overview. Available at: https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648. Accessed October 11, 2018. 
⁴ What is Rheumatoid Arthritis? Arthritis Foundation. Available at: http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/what-is-rheumatoid-arthritis.php. Accessed September 10, 2018.
⁵ Arthritis Foundation. Rheumatoid Arthritis Treatment. Available at: http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php. Accessed September 10, 2018.

SOURCE Mallinckrodt plc