JMCP
`
`J O U R N A L O F M A N A G E D C A R E P H A R M A C Y ®
`
`Meeting the Challenge of Incorporating Injectable Biologics
`Into Managed Care: Multiple Sclerosis and Psoriasis
`
`JMCP
`
`Imelda C. Coleman, PharmD; Richard Cook, PharmD; Jay N. Gade, MD, PhD; Douglas S. Hum, RPh;
`Ben Johnson, RPh, MBA; Terry Maves, RPh; William J. Mazanec, PharmD, MBA; James R. Miller, MD;
`Woodrow J. Proveaux, PharmD; Sheldon J. Rich, RPh, PhD; Howard S. Rossman, DO, FACN; and William H. Stuart, MD
`
`Supplement
`June 2004
`Continuing Education Program
`
`Sawai (IPR2019-00789), Ex. 1041, p. 001
`
`

`

`Supplement
`Policy Statement
`
`Standards for Supplements to the
`
`Journal of Managed Care Pharmacy
`
`Supplements to the Journal of Managed
`Care Pharmacy are intended to support
`medical education and research in areas of
`clinical practice, health care quality
`improvement, or efficient administration
`and delivery of health benefits. The fol-
`lowing standards are applied to all JMCP
`supplements to assure quality and assist
`readers in evaluating potential bias and
`determining alternate explanations for
`findings and results.
`
`1. Disclose the principal sources of fund-
`ing in a manner that permits easy recogni-
`tion by the reader.
`
`2. Disclose the existence of all potential
`conflicts of interest among supplement
`contributors, including financial or per-
`sonal bias.
`
`3. Describe all drugs by generic name
`unless the use of the brand name is neces-
`sary to reduce the opportunity for confu-
`sion among readers.
`
`4. Strive to report subjects of current inter-
`est to managed care pharmacists and other
`managed care professionals.
`
`5. Seek and publish content that does not
`duplicate content in the Journal of Managed
`Care Pharmacy.
`
`6. Subject all supplements to expert peer
`review.
`
`F A C U L T Y
`
`Imelda C. Coleman, PharmD, is currently the clinical pharmacist at BlueCross and BlueShield of
`Louisiana. She received her BS in pharmacy from the University of Mississippi and PharmD from Xavier
`University of Louisiana. Upon completion of her pharmacy practice residency at the University of
`Mississippi Medical Center, she worked at the Ochsner Clinic Foundation, New Orleans, Louisiana,
`managing pharmacy risk for the 500-physician group. Coleman is a member of the Academy of Managed
`Care Pharmacy, where she serves on the Special Projects Committee.
`
`Richard Cook, PharmD, is manager, clinical and quality programs, Blue Care Network of Michigan,
`Grand Rapids.
`
`Jay N. Gade, MD, PhD, is in private practice in southern Oregon at the Dermatology and Laser Center
`of Roseburg. In addition, he is the clinical director of research at the center. He is also a Seminars in
`Psoriasis faculty member at the University of Alabama, Birmingham. Gade is a member of the Oregon
`Dermatology Association, Oregon Medical Association, and American Academy of Dermatology. He
`received his PhD in biochemistry and molecular biology from the Oregon Health Sciences University.
`His research focused on protein crosslinking systems in artificial skin development. Gade received his
`medical degree from the Oregon Health Sciences University and completed his residency in dermatology
`at Wake Forest University, serving as chief resident.
`
`Douglas S. Hum, RPh, is director of pharmacy services at Medica, Minneapolis, having served in that
`capacity since 2001. The department was nominated for a 2003 company-sponsored service/perform-
`ance excellence award for achieving significant medical cost savings toward overall company goals in
`2003. Hum is a graduate of the University of Minnesota College of Pharmacy, where he was awarded a
`Samuel W. Melendy undergraduate research scholarship in pharmacology. He has 24 years of practice as
`a pharmacist in hospital, retail, and managed care settings, including 8 years at AdvancePCS, now
`Caremark.
`
`Ben Johnson, RPh, MBA, is pharmacy contract manager for Intermountain Health Care, Salt Lake City,
`Utah. He is responsible for all pharmacy contracting in the integrated delivery system. Johnson works
`on several clinical committees including asthma, lower respiratory tract infection, cardiology, multiple
`sclerosis, and preventive medicine. He served as the pharmacy director for the 2002 Olympic Winter
`Games in Salt Lake City.
`
`Terry Maves, RPh, has been a community and pharmacy leader in northeast Wisconsin for more than
`25 years. He is the pharmacy director for Touchpoint Health Plan, based in Appleton, Wisconsin, which,
`for the second consecutive year, has been named by the National Committee for Quality Assurance as
`the number one health plan in the nation in delivering preventive care and managing chronic diseases.
`Maves has recognized the pharmacist’s ability to intervene on the patient’s behalf to improve patient
`therapies. He helped create the Everyone Teaching Compliance program, which helps health care
`providers coordinate care to improve medication utilization for 12 disease states. This program earned
`Maves recognition as the Innovative Pharmacist of the Year in 2000 for the state of Wisconsin. In addi-
`tion to increasing pharmacist’s involvement in the delivery of health care, he has created and imple-
`mented a cognitive reimbursement program and made this program available to all pharmacies in the
`Touchpoint Health Plan area. A leader in patient consultation and education, his role as a well-known
`preceptor, professional, and public speaker also demonstrates his commitment to the field of pharmacy.
`
`William J. Mazanec, PharmD, MBA,
`is vice president, clinical and formulary management, of
`CuraScript Inc., based in Orlando, Florida. He is responsible for support of its strategic clinical mission
`by providing clinical support to client account management. Mazanec works with managed care part-
`ners to develop and implement programs that integrate pharmacy activities with health plan manage-
`ment to control costs and utilization of pharmaceuticals. In his role, he conducts pipeline monitoring for
`product development within the biotechnology and pharmaceutical industry.
`For the past 15 years, Mazanec has served in various capacities in managed care, including director
`of pharmacy for AvMed Health Plan and director of pharmacy operations, Aetna U.S. Healthcare, where
`he oversaw Integrated Pharmacy Solutions Inc., a business component of Prudential Healthcare.
`Mazanec received his doctor of pharmacy degree from the University of Florida College of Pharmacy,
`with a special emphasis on disease state management and clinical interventions. He earned an MBA from
`the Crummer Graduate School of Business at Rollins College and a bachelor’s degree in pharmacy with
`a minor in radiopharmacy, in cooperation with the Harvard University joint program in nuclear medi-
`cine, from the Massachusetts College of Pharmacy.
`
`Sawai (IPR2019-00789), Ex. 1041, p. 002
`
`

`

`James R. Miller, MD, has recently retired after serving as director of the Multiple Sclerosis Center of Columbia-Presbyterian Medical
`Center in New York City for 20 years. He has lectured widely on the pathogenesis and treatment of multiple sclerosis and allied dis-
`eases as well as in the field of infections of the central nervous system. He has also written a variety of articles on these subjects and
`contributed chapters to several standard neurological textbooks. In retirement, Miller continues to lecture both to medical and patients
`groups concerning multiple sclerosis.
`
`Woodrow J. Proveaux, PharmD, is the clinical pharmacy director at CareFirst BlueCross BlueShield in Baltimore, Maryland, and
`precepts a post-PharmD resident and a pharmacoeconomics fellow each year. He has extensive experience in teaching and coordi-
`nating clinical pharmacy practices at both West Virginia University and King Saud University. His research and scholarly activities
`include 14 journal publications as well as various chapter and book reviews and presentations to local, state, national, and interna-
`tional groups. He received his doctor of pharmacy degree from the University of Michigan after completing undergraduate work at
`the University of Georgia and the Southern Technical Institute.
`
`Sheldon J. Rich, RPh, PhD, is president of SJR Associates, LLC, a health care consulting company in West Bloomfield, Michigan. He
`has more than 20 years experience in the pharmacy field, having practiced in hospital, retail, and managed care pharmacy. Nationally
`recognized as a lecturer and moderator, his recent consulting assignments have included acting as interim pharmacy director at a large
`managed care plan, developing a pharmaceutical manufacturer rebate program for a large group purchasing organization, assisting
`numerous physician practice groups in managing pharmacy costs and shared risk contracts, providing managed care training for var-
`ious pharmaceutical manufacturers, and developing and moderating clinical advisory boards.
`Prior to starting his own consulting practice, Rich was director of pharmacy programs at SelectCare, Troy, Michigan, where he
`developed a nationally recognized, cost-effective pharmacy program and pharmacy network. He was responsible for development of
`drug utilization review programs, served as the chairperson of the pharmacy and therapeutics committee, and developed a compre-
`hensive drug formulary. Rich earned his pharmacy degree from the University of Michigan. He also holds a doctorate in theocentric
`business ethics. He has held the position of clinical assistant professor at the University of Michigan since 1982 and has held a dual
`appointment as an adjunct assistant professor with the College of Pharmacy and Allied Health Professions at Wayne State University
`since 1994.
`Rich has moderated more than 100 meetings and advisory boards, published numerous journal articles, and contributed to
`2 textbooks. He served for 8 years on the Michigan Board of Pharmacy, 3 years as chairperson. Rich has received numerous profes-
`sional awards and honors and is a member of several professional organizations.
`
`Howard S. Rossman, DO, FACN, is a senior partner of the Michigan Institute of Neurological Disorders (MIND) in Farmington
`Hills, an organization with which he has been associated since 1978. He is medical director of the Multiple Sclerosis Center at MIND
`and has been involved in 10 major clinical trials for potential new MS therapeutics since 1999, 7 of which are currently ongoing. In
`addition, Rossman is a clinical professor of neurology at Michigan State University and chairman of the neurology department at
`Botsford General Hospital, an affiliate of Michigan State University, where he directed the residency training program for 19 years until
`2002. He is still actively involved in the training of medical students, interns, and neurology residents.
`Rossman received his undergraduate degree from the University of Michigan and his medical training at the Michigan State
`University College of Osteopathic Medicine. He completed his residency in neurology at Botsford General Hospital, an affiliate of
`Michigan State University. Rossman is a member of the Consortium of MS Centers and a fellow of the American College
`of Neuropsychiatrists, where he served as president from 1994 to 1995.
`
`William H. Stuart, MD, received his medical degree from Northwestern University Medical School and completed an internship at
`Cleveland Metropolitan General Hospital and a residency in internal medicine at Northwestern. He subsequently served as an
`epidemic intelligence service officer at the Communicable Disease Center (CDC) in Atlanta, Georgia, and completed a fellowship in
`neurology at Emory University Medical School. Upon completion of this training and serving at the National Institute of Neurological
`Disorders and Stroke, Rockville, Maryland, he entered private practice in the Atlanta area, forming the Atlanta Neurological Clinic,
`subsequently renamed the Peachtree Neurological Clinic in 1990.
`One of the founding members of the American Society of Neuroimaging in 1975, Stuart served as its president in 1984 and 1985.
`In 1980, he became a member of the Practice Committee of the American Academy of Neurology, (AAN), remaining active on that
`committee until 1991 and serving as its chairman from 1985 through 1991. He was a member of the Executive Committee of AAN
`for several years and served as treasurer. His most recent activity with AAN was aiding in the formation of the academy’s MS section
`and serving on the Long-Range Planning Committee.
`Stuart began his focused interest in multiple sclerosis in 1988, developing the Multiple Sclerosis Comprehensive Care and
`Research Center at Shepherd Center, Atlanta, in 1991. In 2001, he became medical director of the MS Center of Atlanta and the MS
`Research Network of Georgia. His interest in MS has focused on early treatment and aggressive combination therapy for patients with
`breakthrough disease.
`He has maintained a broad interest in education and served as a clinical professor of neurology at Emory University Medical
`School from 1987 to 2003. He was named Clinical Teacher of the Year at Piedmont Hospital in 1987 and 1988. He has lectured wide-
`ly in evolving treatments in MS. Stuart’s board certification includes the American Board of Internal Medicine and the American Board
`of Psychiatry and Neurology. He serves on the boards of the National MS Society—Georgia Chapter (and its Medical Advisory Board)
`and Millennium Medical Communications, Inc.
`
`Sawai (IPR2019-00789), Ex. 1041, p. 003
`
`

`

`The full text of this supplement is available at http://amcp.cecity.com/login.htm.
`
`Table of Contents
`Meeting the Challenge of Incorporating Injectable
`Biologics Into Managed Care: Multiple Sclerosis and Psoriasis
`
`S3
`
`S4
`
`Program Overview
`Sheldon J. Rich, RPh, PhD
`
`The Importance of Early Diagnosis of Multiple Sclerosis
`James R. Miller, MD
`
`S12 Neutralizing Antibodies to Multiple Sclerosis Treatments
`Howard S. Rossman, DO, FACN
`
`S19 Clinical Management of Multiple Sclerosis:
`The Treatment Paradigm and Issues of Patient Management
`William H. Stuart, MD
`
`S26 Stepped-Care Approach to Treating MS: A Managed Care Treatment Algorithm
`Sheldon J. Rich, RPh, PhD; Imelda C. Coleman, PharmD; Richard Cook, PharmD; Douglas S. Hum, RPh;
`Ben Johnson, RPh, MBA; Terry Maves, RPh; William J. Mazanec, PharmD, MBA; James R. Miller, MD;
`Woodrow J. Proveaux, PharmD; Howard S. Rossman, DO, FACN; and William H. Stuart, MD
`
`S33 Clinical Update on Alefacept: Consideration for Use in Patients With Psoriasis
`Jay N. Gade, MD, PhD
`
`S38 Considerations for Assessing the Cost of Biologic Agents in the Treatment of Psoriasis
`Sheldon J. Rich, RPh, PhD
`
`S42 Continuing Education*: Record of Completion, Posttest, and Program Evaluation
`
`Target Audience:
`This program has been designed to meet the educational needs of pharmacists and other health care practitioners
`in a managed care environment.
`
`Learning Objectives
`After completing this continuing education module, the pharmacist will be able to
`1. verbalize the importance and long-term potential of injectable biologic therapies for the treatment of
`multiple sclerosis (MS) and psoriasis;
`2. describe strategies and considerations that optimize treatment success and ensure appropriate resource
`utilization for biologic therapies in MS and psoriasis;
`3. recognize the complexity of treating MS and the importance of individualizing therapy and planning for
`long-term management of the disease;
`4. employ (a) treatment protocols developed by neurologists for appropriate use of biologics in MS and
`(b) interventions for managing MS symptoms and treatment side effects;
`5. describe an MS treatment algorithm developed by managed care professionals that provides guidelines for
`long-term disease management, including treatment initiation, recommended evaluations, and disease
`progression;
`6. understand current clinical data concerning alefacept’s use in the treatment of patients with moderate-to-severe
`psoriasis, including long-term benefits and safety and tolerability considerations; and
`7. identify key considerations for evaluating the cost implications and drug utilization for biologic therapies in
`psoriasis.
`
`This supplement was supported by an unrestricted grant from Biogen Idec Inc.
`*A total of .20 CEUs (2 contact hours) will be awarded for successful completion of this continuing education program
`(Program No. 233-000-04-040-H04).
`Copyright© 2004, Academy of Managed Care Pharmacy, Inc. All rights reserved. No part of this publication may be reproduced or transmitted
`in any form or by any means, electronic or mechanical, without written permission from the Academy of Managed Care Pharmacy.
`All articles published represent the opinions of the authors and do not reflect the official policy or views of the Academy of Managed Care Pharmacy, the
`authors’ institutions, or Biogen Idec Inc., unless so specified.
`
`Sawai (IPR2019-00789), Ex. 1041, p. 004
`
`

`

`P R O G R A M O V E R V I E W
`
`SHELDON J. RICH, RPh, PhD
`
`T he development of injectable biologic agents has revolution-
`
`ized the treatment of numerous diseases, including multiple
`sclerosis (MS) and psoriasis. These agents have the potential
`for long-term benefits, including reduced disease activity, improved
`quality of life, and decreased utilization of total health care services.
`As newly approved biologics for the treatment of MS and psoriasis
`become available, managed care decision makers must determine the
`appropriate use of these agents based on long-term efficacy, safety, and
`cost. The goal of this supplement is to provide information from clin-
`ical trials and from the experience of renowned specialists to aid in
`this endeavor.
`Multiple sclerosis is a chronic, multifocal, demyelinating disease
`of the central nervous system (CNS). The onset of MS typically occurs
`in early adulthood,1 and MS is the leading cause of nontraumatic CNS
`morbidity in young and middle-aged adults.2 In the United States, the
`annual per-patient cost of MS has been estimated at $34,000, with a
`total lifetime per-patient cost of $2.2 million; a conservative estimate
`of the national annual cost is $6.8 billion.3 MS is a complex and het-
`erogeneous disease, with high intrapatient and interpatient variability
`in its clinical course and manifestations. Consequently, physicians
`who treat patients with MS must tailor treatment to individual
`patients and actively plan for the long-term management of the
`disease.
`Four articles in this supplement focus on the role of biologics in
`the management of MS. The first article, by James R. Miller, MD, pro-
`vides an overview of the 4 biologic agents that are available in the
`United States for the treatment of relapsing-remitting MS as well as
`the complexities involved in the diagnosis and clinical course of MS.
`Data supporting early treatment of patients at high risk for MS also are
`discussed. The second article, by Howard S. Rossman, DO, FACN,
`reviews data on the development of neutralizing antibodies (NAbs) to
`biologic agents used to treat MS. Studies show that differences exist
`among biologics regarding the risk of developing NAbs and that these
`NAbs reduce or abolish the therapeutic effects of biologics. The
`article also discusses the implications of NAbs for neurologists and
`managed care professionals.
`The third article, by William H. Stuart, MD, presents an MS treat-
`ment algorithm recently developed by a panel of neurologists who are
`MS experts. This algorithm provides best-practice guidelines on choos-
`ing the appropriate biologic agent for initiating therapy, managing
`occasional relapses, and selecting agents that can be added to
`biologics in patients whose disease progresses while they are on
`treatment. The fourth article, by my colleagues and me, provides a
`model treatment algorithm for use in the managed care setting, which
`was developed by a group of managed care professionals. This model
`
`Author
`
`SHELDON J. RICH, RPh, PhD, is president, SJR Associates, LLC, West
`Bloomfield, Michigan; clinical assistant professor, University of Michigan, Ann
`Arbor; and adjunct assistant professor, Wayne State University, Detroit, Michigan.
`
`AUTHOR CORRESPONDENCE: Sheldon J. Rich, RPh, PhD, President, SJR
`Associates, LLC, 4223 Fieldbrook Rd., West Bloomfield, MI 48323-3207.
`Tel: (248) 932-8500; Fax: (248) 932-2972; E-mail: SJRAssociates@aol.com
`
`Copyright© 2004, Academy of Managed Care Pharmacy. All rights reserved.
`
`MS algorithm provides health care professionals with guidelines on the
`following disease management issues: when to initiate treatment, how
`to select a biologic agent as the initial therapy, the use of magnetic
`resonance imaging in the diagnosis and management of patients with
`MS, when to test for NAbs and how to manage patients who have
`positive test results for NAbs, and how to manage patients who
`experience progression during treatment. An algorithm for NAb
`testing also has been proposed that, while recognizing the authority of
`the physician to make ultimate prescribing decisions, can be
`incorporated into a patient’s care path to ensure the quality of care
`without placing a burden on the patient.
`An estimated 4.5 million adults in the United States have psoria-
`sis, and approximately one third (1.5 million) of these individuals
`have moderate-to-severe disease.4 The financial burden of psoriasis is
`substantial, with annual U.S. economic costs estimated at $4.3 bil-
`lion.5 Patients with moderate-to-severe psoriasis typically require
`chronic treatment with systemic therapy or phototherapy. Although
`conventional systemic agents can be effective in producing short-term
`reductions in disease severity, the long-term, chronic use of these treat-
`ments is limited by safety and tolerability concerns. Novel injectable
`biologics, which have been developed based on an understanding of
`the role of T cells in the pathogenesis of psoriasis, have advanced the
`treatment of moderate-to-severe psoriasis.
`Alefacept was the first biologic therapy approved for the treatment
`of moderate-to-severe chronic plaque psoriasis in the United States,
`and it has been available here for more than 1 year. Two articles in this
`supplement review the use of alefacept in the treatment of psoriasis.
`The article by Jay N. Gade, MD, PhD, provides an update on the clin-
`ical efficacy and safety of alefacept in patients with psoriasis. Alefacept
`has proven to be an effective intermittent therapy for psoriasis that
`offers patients extended treatment-free and disease-free periods. As a
`result of prolonged remissions, overall drug utilization may be reduced.
`In the second article, I review key considerations for the long-
`term assessment of biologic therapies in psoriasis. These
`considerations establish the importance of efficacy, safety, and cost
`parameters measured over a longer course of therapy than the
`traditional 3-month or 6-month time period utilized to date.
`It is hoped that the timeliness and clinical relevance of the infor-
`mation provided in this Journal supplement will assist you in improv-
`ing the care of your patients with MS or psoriasis and will ensure the
`use of biologic therapies in the most cost-efficient manner.
`
`REFERENCES
`
`1. Wingerchuk DM, Lucchinetti CF, Noseworthy JH. Multiple sclerosis: current
`pathophysiological concepts. Lab Invest. 2001;81:263-81.
`2. The Canadian Burden of Illness Study Group. Burden of illness of multiple
`sclerosis: Part II: quality of life. Can J Neurol Sci. 1998;25:31-38.
`3. Whetten-Goldstein K, Sloan FA, Goldstein LB, Kulas ED. A comprehensive
`assessment of the cost of multiple sclerosis in the United States. Mult Scler.
`1998;4:419-25.
`4. National Psoriasis Foundation. Benchmark survey on psoriasis and psoriatic
`arthritis. Summary of top-line results. Available at: http://www.psoriasis.org/
`files/pdfs/press/npfsurvey.pdf. Accessed April 4, 2004.
`5. National Psoriasis Foundation. How much does skin disease cost? Available
`at: http://www.psoriasis.org/news/news/2002/20020919_ burden.php.
`Accessed April 18, 2004.
`
`www.amcp.org Vol. 10, No. 3, S-b June 2004 JMCP Supplement to Journal of Managed Care Pharmacy S3
`
`Sawai (IPR2019-00789), Ex. 1041, p. 005
`
`

`

`The Importance of Early Diagnosis of Multiple Sclerosis
`
`JAMES R. MILLER, MD
`
`ABSTRACT
`
`OBJECTIVE: To describe the current understanding of the diagnosis and treat-
`ment of multiple sclerosis (MS) and to explore the use of magnetic resonance
`imaging (MRI) assessment as a prognostic tool and an indicator in the diagnosis
`of MS.
`
`SUMMARY: MS is a chronic, progressive, demyelinating disease of the central
`nervous system that is associated with a significant economic burden. At this
`time, immunomodulatory agents (interferon beta-1a (IFNβ-1a) [Avonex], IFNβ-1a
`[Rebif], IFNβ-1b [Betaseron], and glatiramer acetate [Copaxone]) are first-line
`agents, which are reported to reduce relapse rates.
`The diagnostic criteria for MS have evolved over time to include MRI findings
`as an integral part of the diagnosis. However, the most recent criteria (McDonald)
`are focused on the diagnosis of definite MS and do not address the status of
`patients with a first demyelinating event (clinically isolated syndrome [CIS]).
`This is an important issue because a CIS is highly predictive of developing fur-
`ther inflammation and definite MS when the episode occurs in conjunction with
`lesions on the initial MRI. Many times, MRI findings do not correlate with clinical
`symptoms, and clinically silent lesions are identified. Therefore, the use of MRI is
`salient to the early diagnosis of high-risk patients.
`The evolution of thought concerning early treatment in MS is based on an
`increased understanding of the pathology of the disease. Axonal loss occurs
`early in the disease process, and both white matter and gray matter are affected.
`Studies that have analyzed early treatment in patients highly likely to have MS
`(clinically isolated events with evidence of lesions on MRI) report significant
`benefits in delaying further changes on MRI and further attacks. Patients who
`begin treatment later do not reap the same benefits as those who begin
`treatment earlier during the disease course.
`
`CONCLUSION: Patients with clinically isolated events should be referred promptly
`to a neurologist for assessment, including MRI scans. An early recognition of
`the inflammatory process enables patients to begin treatment with an immuno-
`modulatory agent even before the technical diagnosis of definite MS so that the
`degenerative progression of MS can be retarded.
`
`KEYWORDS: Magnetic resonance imaging, Interferon beta, Glatiramer acetate,
`Multiple sclerosis, Diagnosis
`
`J Manag Care Pharm. 2004;10(3)(suppl S-b):S4-S11
`
`Author
`
`JAMES R. MILLER, MD, was director (now retired), Multiple Sclerosis
`Center, Columbia-Presbyterian Medical Center, Columbia University,
`New York, New York.
`
`AUTHOR CORRESPONDENCE: James R. Miller, MD, 88 Fieldpoint Dr.,
`Irvington, NY 10533. Tel: (914) 591-4712; Fax: (914) 591-0724;
`E-mail: jrm6@columbia.edu
`
`Copyright© 2004, Academy of Managed Care Pharmacy. All rights reserved.
`
`M ultiple sclerosis (MS) is an immune-mediated demyeli-
`
`nating disease of the central nervous system (CNS).
`This treatable but uncurable degenerative disease
`affects approximately 400,000 people in the United States.1
`Common symptoms of MS include spasticity, fatigue, sexual dys-
`function, bladder dysfunction, pain, cognitive dysfunction,
`depression, bowel dysfunction, and weakness. The average age of
`onset of MS is 30 years.2 Because this is the age when individuals
`may be beginning a family and workers have not typically
`reached their full earning potential, it has a particularly devastat-
`ing impact on family, social, and professional relationships.
`MS is associated with a considerable economic burden.
`National costs of MS are estimated to range from $6.8 to $11.9
`billion annually (approximately $34,000 per patient).3 The major
`components of these costs include earnings loss (incurred by the
`patient with MS) and costs of informal care (unpaid personal
`assistance).3 According to a survey of MS patients, the annual loss
`in earnings was $17,900; this amount was even greater
`($41,000) for men younger than 65 years.3 In that same study,
`the annual expenditures for informal care were $6,452, which
`translated to about one fifth of the annual per-patient costs of
`MS.3 Other large expenditures included costs for hospitalization
`and physician visits.3
`In 90% of patients, MS’s natural progression traditionally has
`been categorized in sequential stages, which include subclinical
`disease, monosymptomatic disease, relapsing-remitting disease
`(RRMS), and then secondary progressive MS (SPMS). Clinicians
`diagnose definite MS after a second attack occurs or evidence of
`new MS lesions are visualized on magnetic resonance imaging
`(MRI).4 The clinical course of RRMS is described as clearly
`defined relapses with at least partial recovery of deficits. Periods
`between relapses are characterized by a lack of disease progres-
`sion.5 In contrast, SPMS occurs when some deficits begin to
`progress even between obvious relapses. Relapses occur less fre-
`quently than during the RRMS phase or do not occur at all.5
`The progression of MS is discernible when the recovery
`between relapses is incomplete, with a sustained worsening on
`the Expanded Disability Status Scale (EDSS) or other rating scales;
`lesion burden assessed by MRI is increased; cognitive dysfunction
`accumulates; and brain atrophy advances.6-8 In some patients, the
`cognitive effects of MS may be more severe than the physical
`effects during the early stages of the disease. If MS is left
`untreated, patients with RRMS develop SPMS (50% by
`10 years; 90% by 30 years).2,9
`
`II Treatment of Multiple Sclerosis
`
`Only a small subset of the medical community makes treatment
`decisions in patients with MS. Because MS is a chronic degener-
`ative disease, treatment must be continuous, not intermittent. At
`this time, immunomodulatory agents (IMAs) are considered first-
`
`S4 Supplement to Journal of Managed Care Pharmacy JMCP June 2004 Vol. 10, No. 3, S-b www.amcp.org
`
`Sawai (IPR2019-00789), Ex. 1041, p. 006
`
`

`

`The Importance of Early Diagnosis of Multiple Sclerosis
`
`Summary of Studies Reporting Development
`of Clinically Definite Multiple Sclerosis (CDMS)
`in Patients Who Have Clinically Isolated
`Demyelinating Events With Lesions Assessed
`by Magnetic Resonance Imaging at Baseline
`Baseline
`Findings
`Predictive of
`CDMS
`4 lesions,
`or 3 lesions
`with 1
`periventricular
`lesion
`9 lesions
`≥3 lesions
`≥3 mm in size
`
`Criteria
`for CDMS
`Schumacher
`criteria15
`
`Patients Who
`Developed CDMS
`95% (18/19)
`
`Poser et al.16
`Second attack
`confirmed by
`examination,
`with new
`neurologic
`disability
`Poser et al.16
`
`80% PPV*
`51% cumulative
`probability
`
`83% (45/54)
`
`Poser et al.16
`
`82% (37/45)
`
`Poser et al.16
`
`70% PPV
`
`Poser et al.16
`
`88% (44/50)
`
`TABLE 1
`
`Reference
`Paty et al.18
`
`Barkhof et al.19
`Optic Neuritis
`Study Group20
`
`Follow-up
`(Years)
`1
`
`≥2
`5
`
`O’Riordan et al.21
`
`5–10
`
`Sailer et al.22
`
`10
`
`Brex et al.23
`
`1
`
`≥1 asymptomatic
`lesion compatible
`with demyelination
`≥1 asymptomatic
`lesion compatible
`with demyelination
`≥1 gadolinium-
`enhancing lesion
`at baseline and
`at 3 months
`≥1 asymptomatic
`lesion compatible
`with demyelination
`*PPV = positive predictive value.
`
`Brex et al.17
`
`14.1
`
`line treatments for patients with RRMS, including the following:
`intramuscular (IM) interferon beta-1a (IM IFNβ-1a) [Avonex,
`Biogen Idec Inc., Cambridge, MA]), subcutaneous (SC) IFNβ-1a
`(SC IFNβ-1a [Rebif, Serono, Rockland, MA]), SC IFNβ-1b
`(Betaseron, Berlex Laboratories, Montville, NJ), and SC glatiramer
`acetate (Copaxone, Teva Pharmaceutical Industries, Kansas City,
`MO). Another agent, mitoxantrone (Novantrone, Immunex Corp.,
`Seattle, WA), is indicated for reducing the progression of neuro-
`logic disability and the frequency of clinical relapses in patients
`with secondary (chronic) progressive, progressive relapsing, or sig-
`nificantly worsening RRMS. IMA treatment goals include reducing
`inflammation, reducing the relapse rate, slowing disability, slowing
`the accumulation of cognitive dysfunction, reducing the progres-
`sion of brain atrophy, and improving quality of life.
`Several large randomized trials demonstrate that IMAs reduce
`attack rates.10-13 Direct comparisons among the trials are impossi-
`ble, but these data suggest that all agents reduce relapse rates sim-
`ilarly. For example, the phase III trial of IM IFNβ-1a reported a
`32% reduction in relapses among patients who were treated for
`2 years.11 Similarly, the mean percentage reduction in relapse rates
`over 2 years was 33% in patients who received SC IFNβ-1a.12
`Two-year data from the SC IFNβ-1a trial revealed a 34% reduction
`in patients who recei