Mallinckrodt Announces Data Publication on the Treatment Effectiveness of Acthar® Gel (Repository Corticotropin Injection) for Resolution of Multiple Sclerosis Relapse in a U.S. Health Plan Population

STAINES-UPON-THAMES, United Kingdom, Nov. 7, 2019 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a global biopharmaceutical company, today announced the publication of "Treatment Effectiveness for Resolution of Multiple Sclerosis Relapse in a U.S. Health Plan Population" in an electronic publication posted in advance of print publication in the peer-reviewed journal Neurology and Therapy. Results from the analysis showed that multiple sclerosis (MS) relapse patients taking Acthar^® Gel (repository corticotropin injection) had a higher relapse resolution rate than those taking intravenous immunoglobulin (IVIG) or plasmapheresis (PMP) treatment.

MS is a chronic, degenerative disease that can cause numerous impairments including fatigue, balance/coordination issues, numbness or tingling, vision problems, muscle spasms, tremors and emotional changes¹, and some people with MS experience relapses while on standard disease-modifying therapies.²

Acthar Gel is U.S. Food and Drug Administration (FDA)-approved for the treatment of acute exacerbations of MS in adults. Controlled clinical trials have shown Acthar Gel to be effective in speeding the resolution of acute exacerbations of MS. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.³ Please see Important Safety Information for Acthar Gel below.

"The management of MS relapse is an ongoing challenge, in particular for those patients who need additional treatment options after first-line agents such as corticosteroids," said George Wan, Ph.D., Vice President and Global Head of Health Economics and Outcomes Research at Mallinckrodt. "We are committed to working toward a better understanding of the potential clinical and health economic outcomes associated with Acthar Gel and other late-line treatments for MS relapse to help guide clinical practice and potentially improve outcomes for patients. In addition, we look forward to the results of Mallinckrodt's ongoing, randomized, double-blind, placebo-controlled OPTIONS study, which we anticipate will provide data on some of the more difficult-to-treat MS patients in the future."

"Treatment Effectiveness for Resolution of Multiple Sclerosis Relapse in a US Health Plan Population" evaluated the rate of MS relapse occurrence, frequency of use of MS relapse treatments including corticosteroids, and relapse treatment effectiveness (or relapse resolution rates) for corticosteroid treatment alternatives – Acthar Gel, IVIG, and PMP. No minimum health plan enrollment was required. The data were originally shared in a poster presentation at MSParis2017, the joint ECTRIMS-ACTRIMS meeting.⁴

Key findings⁵

• 9,574 patients with relapse episodes were identified with 25,162 relapse episodes [mean (SD) of 2.6 (4.0) relapse episodes per person]. The mean follow-up time per patient was 2.7± 2.1 years.
• The majority of patients (74.0 percent) had <2 relapse episodes and 26.0 percent of patients experienced two or more relapse episodes per year. 36.9 percent of patients had ≥1 unresolved relapse events during the study period which required additional relapse therapy beyond the initial relapse treatment received. 
• The frequencies of relapse treatment alternatives used were as follows: IVIG (6.0 percent), Acthar Gel (2.2 percent), and PMP (1.5 percent).
• 90 percent of initial relapse events within the first relapse episodes were treated with corticosteroids
• Relapse resolution rates differed by treatment. Acthar Gel had the highest proportion of patients achieving relapse resolution (96.9 percent), compared with IVIG (43.9 percent) and PMP (50.7 percent).

Methods⁵

• A retrospective analysis of patients 18-89 years experiencing MS relapse from January 1, 2008 to June 30, 2015 was conducted using administrative claims data from Humana Inc.
• MS relapse was estimated based on established claims-based methodology; and was defined as an inpatient admission or hospitalization with a principal diagnosis of MS or an outpatient visit or emergency department visit with a diagnosis of MS, followed by a medical or pharmacy claim for a relapse treatment of interest (oral corticosteroids, intravenous corticosteroids, Acthar Gel, PMP or IVIG) within 30 days.
• Treatment was deemed effective in resolving the relapse (relapse resolution) if no additional relapses followed within the episode; otherwise, the relapse was considered unresolved.
• A 30-day time frame was used as a marker to correlate MS relapse as either one unresolved relapse if within 30 days of the first visit for relapse or a new relapse if greater than 30 days from the first visit for relapse.

Limitations⁶

• Administrative claims data are collected for reimbursement purposes, and thereby may lack important clinical detail, such as disease severity. Claims are often used in MS relapse studies. Here, a number of definitions used in prior studies were implemented in order to mitigate this limitation.
• Relapses were identified based on treatment-seeking behavior using an established claims-based algorithm; treatment received/prescribed outside a healthcare visit was not addressed.
• Index relapse events were first observed, which may/not be the actual first events. However, relapse resolution was based on the occurrence of subsequent relapses, not prior relapses.
• Variation in treatment regimens would impact the rate of relapse resolution.
• Acthar Gel and PMP/IVIG have not been studied head-to-head in any randomized, controlled clinical trials.
• Not all improvements can be solely attributed to Acthar Gel.
• The study assessed response to Acthar Gel and did not capture safety.

The analysis was conducted by Mallinckrodt.

About Multiple Sclerosis
MS is a neurologic disorder that affects the central nervous system (i.e., the brain and spinal cord).⁷ Symptoms can include fatigue, balance/coordination issues, numbness or tingling, vision problems, muscle spasms, tremors and emotional changes.¹ More than eight in 10 people with MS will experience a relapse, or flare-up, that brings new or worsening symptoms.⁸ 

Acthar Gel (repository corticotropin injection) Indications
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)
• The treatment of symptomatic sarcoidosis
• 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 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)
• 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 consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's 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. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. 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 Acthar Gel including expectations regarding related clinical trials, its potential impact on patients and anticipated benefits associated with its use. 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.

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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.

© 2019 Mallinckrodt. US-1901843 10/19

References

______________________________
¹ Multiple Sclerosis: Hope Through Research. National Institute of Neurological Disorders and Stroke. 2012. Available at https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research#3215_29. 
² Coyle PK, Krieger S. Managing acute relapses in multiple sclerosis CME. Medscape Education Neurology & Neurosurgery. 2013. Available at: http://www.medscape.org/viewarticle/779270_print.
³ Acthar^® Gel (repository corticotropin injection) (prescribing information). Mallinckrodt ARD LLC.
⁴ Nazareth, T., Manasi, D., Sheer, R., Yu, T. & Schwab, P. (2017, October). MS Relapse Treatments and Relapse Resolution: Retrospective Study Results from a US Health Plan. Poster session presented at MSParis2017, the joint ECTRIMS-ACTRIMS meeting in Paris, France.
⁵ Nazareth, T., Datar, M. & Yu, T. Treatment Effectiveness for Resolution of Multiple Sclerosis Relapse in A US Health Plan Population. Neurology and Therapy. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31564036.
⁶ Data on File, Mallinckrodt, 2019.
⁷ Willis BMJ Best Practice Multiple Sclerosis. October 2018. p. 4.
⁸  Tillery EE, Clements JN, Howard Z. What's new in multiple sclerosis? The Mental Health Clinician. 2017; 7(5) 213-220.

SOURCE Mallinckrodt plc

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