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STAINES-UPON-THAMES, United Kingdom, Oct. 26, 2017 /PRNewswire/ -- Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, announced results from two retrospective analyses on multiple sclerosis (MS) relapses and the impact of H.P. Acthar^® Gel (repository corticotropin injection) and non-corticosteroid (CS) relapse treatment alternatives intravenous immunoglobulin (IVIG) or plasmapheresis (PMP) on unresolved relapse rates. Results from both analyses (Poster P809 and e-Poster EP1425) showed H.P. Acthar Gel had a higher relapse resolution rate, relative to PMP and IVIG. The two company-sponsored analyses are being presented at MSParis2017, the 7^th Joint ECTRIMS-ACTRIMS meeting, from October 25-28, in Paris, France.

Unresolved relapse may contribute to residual deficits and a progression of disability for diagnosed patients.^1,2 H.P. Acthar Gel is U.S. Food and Drug Administration (FDA)-approved for treatment of acute exacerbations of MS in adults and is effective in speeding the resolution of exacerbations.³ However, there is no evidence that H.P. Acthar Gel affects the ultimate outcome or natural history of MS.

"The management of MS relapse is an ongoing challenge further hampered by the lack of information on the real-world use of various relapse treatments," said Tunde Otulana, MD, Chief Medical Officer at Mallinckrodt. "These analyses demonstrated the distribution of unresolved relapse rates and healthcare resource utilization for later-line MS relapse treatments. The data add to a growing body of knowledge surrounding the use of H.P. Acthar Gel."

Both analyses were from a single real-world retrospective, observational, cohort study conducted by researchers at Humana Comprehensive Health Insights (CHI) and Mallinckrodt using Humana health insurance administrative claims data. Humana CHI conducted the analyses, which utilized medical and pharmacy claims of adults with MS, ages 18-90, enrolled in Humana Commercial and Medicare Advantage health plans between January 1, 2008 and July 31, 2015. An MS relapse event was defined as a claim with a diagnosis of MS, followed by receipt of a relapse therapy or procedure (CS, H.P. Acthar Gel, PMP, or IVIG) within 30 days. A relapse event was considered unresolved if the next relapse occurred within 30 days of the prior relapse. In these analyses, a relapse episode comprised all relapse events (i.e., one or more) occurring within 30 days of the first event.

Multiple Sclerosis Relapse Treatments and Relapse Resolution: Retrospective Study Results from a U.S. Health Plan [Poster P809] evaluated the rate of MS relapse occurrence, use of MS relapse treatments including corticosteroids, and unresolved relapse rates by relapse treatment alternatives – H.P. Acthar Gel, IVIG, or PMP. No minimum health plan enrollment was required.

Key highlights include:

• 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%) had <2 relapse episodes and 26.0% of patients experienced two or more relapse episodes (>1 relapse event per episode) per year. 36.9% of patients had ≥1 unresolved relapse event during the single study period which required additional relapse therapy beyond the initial relapse treatment received.  
• Over 90% of index relapse events within the index relapse episodes were treated with CS, in accordance with Humana's coverage policy.
• The frequencies of relapse treatment alternatives used were as follows: IVIG (6.0%), H.P. Acthar Gel (2.2%), and PMP (1.5%).
• Unresolved relapse rates differed by treatment. H.P. Acthar Gel had the highest proportion of patients with no unresolved relapses (96.9%), compared with IVIG (43.9%) and PMP (50.7%).

Relapse Resolution and Healthcare Resource Use in Patients with Multiple Sclerosis: A Retrospective Study of Relapse Therapy Alternatives to Corticosteroids [e-Poster EP1425] is an analysis that compared the distribution of unresolved relapse rates and healthcare resource use (HCRU) – inpatient stays (IP), outpatient visits (OP) and Emergency Department (ED) visits – in patients initiating MS relapse treatments with H.P. Acthar Gel, PMP and IVIG. Patients were followed for one- and two-year periods.

Key highlights include:

• Index event analyses of the index relapse episode in patients with 1-year follow-up indicated 95.7% of patients receiving H.P. Acthar Gel had no unresolved relapses, compared to 66.0% of patients receiving PMP/IVIG. This difference was consistent in direction and overall magnitude in analyses of patients with 2-year follow-up.
• Patients taking H.P. Acthar Gel appeared to be different than those taking PMP/IVIG.
• The cohort of patients on H.P. Acthar Gel had greater presence of MS impairment indicators – a significant increase of Expanded Disability Status Scale Derived Disability Indicators [EDSS-DDI] (1.1 vs. 0.8), neurological impairment indicators [RNII] (2.3 vs. 1.8), and use of Ampyra^® (for walking impairment; 46 vs <10) (all p<0.01). In keeping, a higher proportion of patients on H.P. Acthar Gel were enrolled in Medicare Advantage.
• No significant differences were seen between H.P. Acthar Gel and PMP/IVIG for ED visits, rehab services, MRI services and DMT Proportion of Days Covered (PDC).
• No differences were seen in adherence to disease-modifying therapies (DMTs) nor in age.
• Compared to patients on PMP/IVIG, patients on H.P. Acthar Gel had significantly lower all-cause HCRU at one-year follow-up, except for ED visits. This was seen in total service visits, driven by lower inpatient and outpatient visits (all p≤0.01). Lower IP use in the H.P. Acthar Gel group is consistent with a prior claims study.⁴

Poster P809 and e-Poster EP1425 Limitations

• 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.
• PMP and IVIG may differ in relapse-resolution effectiveness; they were combined here. Since PMP/IVIG are administered as outpatient procedures, OP visits may inherently be higher.
• Treatment regimens involving use of PMP and IVIG in MS relapse are unclear.
• H.P. Acthar Gel and PMP/IVIG have not been studied head-to-head in any randomized, controlled clinical trials.

The posters with additional study details are available on the Mallinckrodt website.

ABOUT MULTIPLE SCLEROSIS
MS is a neurologic disorder that affects the central nervous system (i.e., the brain and spinal cord).⁵ An MS relapse, or flare-up, can bring new or worsening symptoms.⁶ Symptoms can include fatigue, balance/coordination issues, numbness or tingling, vision problems, muscle spasms, tremors and emotional changes.⁷ 

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:

• 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
• 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
• 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
• 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 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; 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.

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. ©2017 Mallinckrodt. ARDUS/01-01/1017/0089 10/17.

CONTACTS

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

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

¹ Goodin DS, Frohman EM, Garmany GP, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.  Neurol. 2002;58(2):169-178. 
² Berkovich RR. Acute multiple sclerosis relapse. Continuum. 2016;22:799-814.
³ H.P. Acthar Gel Product Information.
⁴ Gold LS, Suh K, Schepman P, et al. Healthcare Costs and Resource Utilization in Patients with Multiple Sclerosis Relapses Treated with H.P. Acthar Gel. Adv Ther (2016) 33:1279–1292. https://link.springer.com/content/pdf/10.1007%2Fs12325-016-0363-0.pdf.
⁵ Common Questions. Multiple Sclerosis Foundation. Symptoms of Multiple Sclerosis. Available at: https://msfocus.org/Get-Educated/Common-Questions#WhatisMultipleSclerosis. Accessed March 24, 2017.
⁶ National Multiple Sclerosis Society. Relapsing-remitting MS (RRMS). Accessed April 19, 2016 at http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Relapsing-remitting-MS
⁷ Multiple Sclerosis Foundation. Symptoms of Multiple Sclerosis. Accessed October 17, 2017 at http://msfocus.org/Symptoms-of-Multiple-Sclerosis.aspx

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