VBCN July 2014 Vol 1, No 2

july 2014 • VOL 1 • NO 2

www.ValueBasedNeurology.com

Rapid CD4 Cell Recovery with Neurologists Must Maintain Patient-Centered Care Even When Alemtuzumab Treatment Not Facing Economic Pressures a Biomarker for MS Activity AAN presidential address focused on value and quality

By Rosemary Frei, MSc

R Copyright © StockPhotoArt / Bigstock

By Wayne Kuznar

Philadelphia, PA—Neurologists are amidst a social transformation that threatens their professionalism, their ethical foundation, and their pa-

tients, said James L. Bernat, MD, Professor of Neurology and of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH. External pressures Continued on page 4

Could Immunotherapy Be the Future of Alzheimer’s Therapy?

By Mark Knight Philadelphia, PA—Immunization against amyloid-beta and tau protein, starting in the preclinical period, may represent the future in the treatment of Alzheimer’s disease (AD), said David M. Holtzman, MD, Chairman of Neurology, Washington University, St Louis, MO, during the presidential

plenary session at the 2014 American Academy of Neurology meeting.

The 2 main features of AD are (1) aggregation and deposition of amyloid-beta protein in the extracellular space, which produce a strong neuroinflammatory response, and (2) accumulation of the cytoplasmic tau Continued on page 15

esults of a new study suggest that the rate of peripheral CD4 replenishment after the administration of alemtuzumab, a lymphocyte-depleting anti-CD52 monoclonal antibody, does not correlate with multiple sclerosis (MS) activity in patients with relapsing-remitting MS. This post hoc analysis of data from clinical trials of patients with MS showed no correlation between levels of peripheral mononuclear cell subsets and disease activity, activity on magnetic resonance imaging (MRI),

Continued on page 7

Fourfold Variability Found in Hospital Charges for Stroke Diagnostic Tests

By Wayne Kuznar Philadelphia, PA—Some of the most expensive diagnostic tests for stroke or transient ischemic attack (TIA) do not affect patient management but expose patients to potential harm, said Pratik D. Bhattacharya, MD, MPH, Assistant Professor of Neurology, Wayne State University, Detroit, MI. “At some hospitals, the charge for a single diagnostic test is higher than

the Medicare reimbursement for the entire hospitalization,” Dr Bhattacharya said during a poster presentation at the 2014 American Academy of Neur­ology meeting.

Diagnostic testing is a major contributor to hospital charges for stroke and TIA. Neuroimaging was the largest growing cost component of inpatient stroke care from 1999 to 2007, increasContinued on page 14

inside HEALTH ECONOMICS . . . . . . . . . . .

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PARKINSON’S DISEASE. . . . . . . 10

MULTIPLE SCLEROSIS. . . . . . . . . . .

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IN THE LITERATURE . . . . . . . . . . . 11

EPILEPSY MANAGEMENT. . . . . . .

8

Early antiepileptic drug use saves costs Is no evidence of disease activity achievable?

Extended natalizumab dosing

Breakthrough seizures in treatmentadherent patients are costly

Personalized Medicine in Neurology™ . . . . . . . . . . . . . . . . . . . . . . .

Using genomics in clinical practice © 2014 Engage Healthcare Communications, LLC

or disability accumulation. One exception, however, was a lower CD4 T-cell count in patients who had accumulated disability in the first treatment cycle (Kousin-Ezewu O, et al.

Neurology. 2014;82:2158-2164).

Using a much larger cohort (N = 108 vs 56) and greater follow-up period (99 months vs 40 months) than an earlier study (Cossburn MD, et al.

Neurology. 2013;80:55-61), respectively, which suggested that peripheral CD4 recovery could be used to predict MS disease activity after treatment

Cortical thinning and cognitive function New program reduces time to tPA use Antidepressant may halt Alzheimer’s

STROKE . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Quality measures in emergency care

ALZHEIMER’S/DEMENTIA. . . . 15 Novel protocol improves cognition

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MIGRAINE THERAPY........... 16 Promising new monoclonal antibodies

American Health & Drug Benefits

Call for Papers

American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Adherence Concerns

• Health Information Exchange

• Pharmacogenomics

• Benefit Design

• Health Plan Initiatives

• Policy Issues

• Case Studies

• Innovations in Healthcare

• Prevention Initiatives

• Comorbidities and Cost Issues

• Literature Reviews

• Real-World Evidence

• Comparative Effectiveness Research

• Managed Care

• Reimbursement Strategies

• Decision-Making Tools

• Medicare/Medicaid

• Social Media in Healthcare

• Ethics in Medicine

• Patient Outcomes/Advocacy

• Survey Results

• Health Economics Research

• Pharmacoeconomics

• Value-Based Healthcare

Clinical Topics of High Interest: Aging—With the aging of the US population, there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

Allergies—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Under­treatment and lack of adherence are common obstacles to patient management.

Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Arthritis—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated.

Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies.

Gastrointestinal conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, and inflammatory bowel disorder, remains a challenge.

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Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

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Dr K ement an essor, Dep is a Dist h Carolin Bon s ag Sout .AHD Man istant Prof Dr Adam ity of www is Ass sciences; l Univers Neuro the Medica all at 13 20 e /Jun May o4 l 6, N Vol

MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

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neurologic disorders—The central nervous system is associated with many complicated medical disorders and an enormous economic burden.

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Articles must follow the Manuscript Instructions for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com or online

In This Issue

Publishing Staff

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Production Manager Melissa Lawlor

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Value-Based Care in Neurology, ISSN (applied), is published 3 times a year by Engage Healthcare Com­ munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Neurology is a trademark of Engage Health­ care Communi­ cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Care in Neurology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Neurology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

VOL. 1

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NO. 2

HEALTH ECONOMICS

IN THE LITERATURE

Early use of antiepileptic drugs saves costs More…

New initiative reduces time to tPA administration in acute stroke Antidepressant may halt Alzheimer’s progression More…

MULTIPLE SCLEROSIS Rapid cell recovery after alemtuzumab treatment not a biomarker for disease activity Is no evidence of disease activity achievable?

More…

EPILEPSY MANAGEMENT Breakthrough seizures in treatment-adherent patients are costly More…

Personalized Medicine in Neurology™

Using genomics in clinical practice in neurology More…

STROKE Fourfold variability in hospital charges for stroke diagnostics More…

ALZHEIMER’S DISEASE/DEMENTIA Immunotherapy may be the future of Alzheimer’s treatment More…

MIGRAINE MANAGEMENT Two promising monoclonal antibodies for migraine prevention

DRUG UPDATE

PARKINSON’S DISEASE Cortical thinning and cognitive function in early disease

Higher dose, fewer weekly injections of Copaxone approved by FDA for multiple sclerosis

Editorial Advisory Board Robert J. Adams, MS, MD Professor of Neuroscience University Eminent Scholar Director, South Carolina Stroke Center of Economic Excellence Director, REACH MUSC Telemedicine Services, Charleston, SC June Halper, MSN, APN-C, MSCN, FAAN CEO, Consortium of Multiple Sclerosis Centers Executive Director, IOMSN Hackensack, NJ Atheer A. Kaddis, PharmD Senior Vice President Diplomat Specialty Pharmacy Flint, MI

Maria Lopes, MD, MS Chief Medical Officer CDMI Health Cresskill, NJ

Daniel Kantor, MD Medical Director Neurologique President-Elect Duval County Medical Society Immediate Past President Florida Society of Neurology Ponte Vedra, FL Patricia Kennedy, RN, CNP, MSCN Nurse Educator Can Do Multiple Sclerosis Avon, CO

Matthew Mitchell, PharmD, MBA Director Pharmacy Services Murray, UT Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Charles Stemple, DO Corporate Medical Director, Policy Humana, OH

James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Mission Statement

Value-Based Care in Neurology provides a forum for payers, providers, and the entire neurology team to consider optimal, value-based care to patients with neurologic conditions. This publication is focused on evaluating the impact of cost and quality of care on patient outcomes via news coverage from major neurology meetings and the neurologic literature, supplemented with commentaries and perspectives from a variety of stakeholders involved in managing patients and paying for patient care.

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july 2014

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www.ValueBasedNeurology.com

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Health Economics

Neurologists Must Maintain Patient-Centered Care... and perverse incentives have served to promote behaviors that can diminish the professionalism of neurologists, said Dr Bernat.

He delivered these remarks during the Presidential Lecture at the 2014 American Academy of Neurology meeting. The conference drew more than 13,000 attendees and featured more than 2500 research abstracts.

The transformation of medicine to a business is a challenge to professionalism and ethics. As opposed to the learned profession of medicine, which presupposes concern for the best interest of the patient, “the purpose of a business is to make money for the owners or shareholders,” said Dr Bernat. “Patients are not a means to an end, they constitute the end itself.”

In the business model, procedures are incentivized over care, and providers are relegated to the nonprofessional status of service providers and are directed by others. The conflicts created by financial interest eclipse the physician’s primary duty to the patient, causing a loss of public confidence in the objectivity and integrity of physicians.

“Conflicts of interest make patients worry that decisions we make for them and with them may not be made for their best interests,” Dr Bernat said. Elimination or mitigation of conflicts can improve patients’ trust in physicians.

Quantity versus Quality Dr Bernat cited direct-to-consumer

advertising and marketing to create demand for medications and services, bypassing physicians, and patient inquiries into financial incentives for the

“Conflicts of interest make patients worry that decisions we make for them and with them may not be made for their best interests.”

—James L. Bernat, MD ordering of tests. In addition, patient care reimbursement too often rewards quantity over quality, he said. This commercialization often results in physician resignation when appropriate medical services or medications are denied by health insurers.

Physicians also contribute to their

deprofessionalization in many ways, Dr Bernat said. Medical societies are often used as guilds to protect the financial interests of physicians. Physician participation in speakers’ bureaus to help market products is an internal action that exemplifies the corrupting influence of money in medicine. Medicare data show higher utilization of tests and treatments as reimbursement for each declines. “Insurers therefore consider physicians to be businesspersons, despite the claim that they are professionals,” said Dr Bernat.

From Private Practice to Hospitals With the decline in established private practices, physicians are increasingly becoming hospital employees.

Among the liabilities of such arrangements, physicians can no longer control decisions that have an impact on patient care, and they must report to an administrator who has financial targets and other goals that may not align with those of the individual physician.

Electronic Health Records Although electronic health records (EHRs) can promote prescribing accuracy and can enhance documentation for patient care, they, too, often encourage copying and pasting of notes, clouding original authorship, and they may encourage “check-the-box” medicine, whereby histories are often conducted by having patients check

Continued from page 1

appropriate items in a list. EHRs are known to minimize patient interaction, said Dr Bernat, because physicians spend more time keyboarding and less time with patient communication. Perhaps their most pernicious liability, EHRs have evolved to document elements for billing rather than the medical encounter, Dr Bernat said.

Correctives to enhance the utility of EHRs include resisting the temptation to take shortcuts, careful editing to maintain accuracy when copying notes, and an office setup that maintains a line of sight with the patient rather than having the physician’s back turned to the patient while entering the medical record.

Patient-Centered Care and Quality Measures The depersonalization of medicine has contributed to physician burnout, because doctors are too often forced by regulations or circumstances to do substandard or meaningless work, said Dr Bernat. The requirements of Medicare billing codes are an example of a regulation that encourages physicians to maximize coding and billing irrespective of quality of care.

The ethos of doctoring to maintain patient-centered care should be preserved, Dr Bernat said. Quality-of-care measures should be developed that align care with patients’ values and preferences, while also maintaining physician well-being. n

Earlier Use of Adjunctive Antiepileptic Drugs in Patients with Refractory Disease Could Reduce Costs

By Wayne Kuznar Philadelphia, PA—Changing from monotherapy to the early initiation of adjunctive therapy with a second antiepileptic drug in patients with partial-onset seizures may lead to a substantial reduction in healthcare utilization and costs, according to a retrospective claims database analysis presented in a poster at the 2014 American Academy of Neurology meeting.

Despite slightly higher pharmacy costs, total monthly and epilepsy-related costs were approximately 40% lower with early adjunctive therapy opposed to sequential monotherapy, according to Jason Zhixiao Wang, PhD, Health Economics and Outcomes Research, Eisai, Inc, and colleagues.

4

“Early identification and appropriate medical management of patients with potentially refractory epilepsy may help achieve earlier and improved seizure control and reduce overall healthcare costs,” noted Dr Wang.

The investigators noted that patients with epilepsy in whom initial antiepileptic drug monotherapy fails are often switched to another monotherapy, even though the likelihood of response to another monotherapy is less than it is with adjunctive therapy.

The researchers used administrative claims from the MarketScan Commercial and Medicare databases that includes approximately 32 million covered lives to evaluate the econom-

value-based CARE in Neurology

I July 2014

“Early identification and appropriate medical management of patients with potentially refractory epilepsy may help achieve earlier and improved seizure control and reduce overall healthcare costs.”

—Jason Zhixiao Wang, PhD ic impact of moving from monotherapy to adjunctive therapy in patients with partial-onset seizures.

Patients with a diagnosis of partial-onset seizures who had at least 2 claims and received at least 2 prescriptions for an antiepileptic drug were initially identified. They were required to have at least 1 year of follow-up after the index date.

Overall, 15,007 patients with partial-onset seizures were identified from the database. Of these, 1349 (9%) patients had an antiepileptic drug treatment change from monotherapy to adjunctive therapy. All-cause and epilepsy-related resource utilization costs were evaluated.

Patients who were switched from monotherapy to adjunctive therapy had used monotherapy for an averVOL. 1

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NO. 2

Multiple Sclerosis

Is No Evidence of Disease Activity an Achievable Goal in Patients with RRMS?

By Wayne Kuznar Philadelphia, PA—Achieving no evidence of disease activity (NEDA) in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) is a clinically meaningful goal, but a strategy to achieve it remains untested, said Robert Bermel, MD, a neurologist at the Mellen Center for Multiple Sclerosis, the Cleveland Clinic, at the 2014 American Academy of Neurology meeting.

The idea of a “treat-to-target” strategy is adopted from rheumatologists who developed the strategy in the last decade for the treatment of rheumatoid arthritis. The principles are early and aggressive treatment with rapid treatment escalation to target remission.

Newer, more effective drugs for RRMS and the widespread availability of magnetic resonance imaging (MRI) to monitor the inflammatory component of the disease while the patient is receiving treatment make NEDA a worthwhile and potentially achievable management goal, said Dr Bermel.

Clinical and MRI monitoring while receiving therapy are common approaches, although there are no standards or defined targets in the clinic. As such, NEDA has been a therapy goal defined only in the clinical trial setting.

The adoption of a treatment target into clinical practice will mean overcoming challenges, including the need for agreement on how to define the target and how to accurately measure response to therapies for MS, said Dr

Bermel. The definition of NEDA used in clinical trials is the absence of new or enlarging T2 lesions, the absence of new gadolinium-enhancing lesions, an absence of relapses, and no confirmed worsening on the Expanded Disability Status Scale (EDSS) score.

golimod in the FREEDOMS study, and dimethyl fumarate in the DEFINE study at 2 years.

“There is a great deal of enthusiasm in using NEDA as a measure in clinical trials and in employing it in the MS clinic to potentially guide care as a

“There is a great deal of enthusiasm in using NEDA as a measure in clinical trials and in employing it in the MS clinic to potentially guide care as a treatment target.”

—Robert Bermel, MD

The concept of “disease-free status,” or NEDA, in RRMS was first reported after the completion of the AFFIRM study. Over 2 years, 37% of patients receiving natalizumab were free of disease activity compared with 7% of those receiving placebo.

Similar superiority in achieving NEDA versus placebo was demonstrated in post hoc analyses for daclizumab in the SELECT study and peg-interferon beta at 1 year, and for cladribine in the CLARITY study, fin-

treatment target,” said Dr Bermel.

Evidence is developing that achieving NEDA is clinically meaningful, he noted. In the AFFIRM study, NEDA status correlated strongly with brain atrophy, cognition, ambulation, vision, disability management, and patient-reported outcomes at 2 years.

Cognition was significantly improved, and measures of brain atrophy had a tendency to be lower in patients who met the NEDA criteria compared with patients who did not.

“It looks like 2 years of early treatment achieving NEDA actually portended quite the long-term benefit and segregation among groups,” Dr Bermel pointed out.

NEDA can be a realistic outcome goal, although existing immunomodulatory and disease-modifying drugs do not address the entire pathology of MS, he said. Up to 47% of patients in clinical trials have been able to achieve NEDA with a treat-to-target strategy, although a comprehensive strategy remains untested. “It’s quite possible that although we achieve suboptimal results with a single agent in a single clinical trial, when we implement a strategy of changing therapies based on the NEDA treatment target, that we can achieve significantly better results,” he said.

The evidence also supports that short-term disease control has longterm benefit. In the ASSURANCE study, early MRI relapses while receiving interferon predicted poor long-term outcome. In fact, “MRI activity on interferon was the dominant factor predicting EDSS worsening,” Dr Bermel said.

Implementing the NEDA strategy seems complex in the clinic, he noted, because there is no consensus on the appropriate way to analyze MRI, and there is no easy way to track the components of NEDA in most electronic medical records. Furthermore, the threshold to act, be it a new T2 lesion or a relapse, and how to act, are unclear. n

Health Economics Earlier Use of Adjunctive Antiepileptic Drugs... Continued from page 4 age of 269 days, and 51.3% of the patients used ≥2 sequential drugs as monotherapy before trying adjunctive therapy.

More patients were hospitalized

during the monotherapy portion of their treatment compared with patients using adjunctive therapy (38% vs 28%, respectively; P <.001), and more patients using monotherapy were hos-

at a glance ➤ Early introduction of adjunctive therapy for patients with partialonset seizures can reduce overall costs ➤ According to a new study, total healthcare costs are lower with adjunctive therapy than with sequential monotherapy

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➤ In this study, 35% of patients receiving monotherapy were hospitalized versus 28% with adjunctive therapy ➤ Overall costs were $4148 during monotherapy versus $2855 during adjunctive therapy

pitalized for epilepsy-related reasons than those using adjunctive therapy (28% vs 19%, respectively; P <.001).

Emergency department visits were also more common among patients using monotherapy than adjunctive therapy for all-cause visits (50% vs 46%, respectively; P <.001) and epilepsy-related (30% vs 22%, respectively; P <.001).

The adjusted average epilepsy-related monthly costs (in 2009 dollars) were: • $1579 in the monotherapy period • $886 in the adjunctive therapy period.

All-cause costs were: • $4148 in the monotherapy period july 2014

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• $2855 during adjunctive therapy.

“Healthcare costs were consistent­ ly lower in the adjunctive therapy period than the monotherapy period” (P <.001) across all medical categories, including hospitalizations, emergency department visits, and outpatient visits, noted Dr Wang.

The average monthly pharmacy costs were slightly higher during the adjunctive therapy period. The medication costs were similar between the monotherapy and adjunctive therapy periods: the antiepileptic drug costs were $187 and $193, respectively, and the overall prescription costs were $543 and $518, respectively. n

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5

Multiple Sclerosis

Medical Marijuana Helpful for Some MS Symptoms Insufficient evidence to support use in other neurologic diseases

By Wayne Kuznar Philadelphia, PA—A systematic literature review conducted by the American Academy of Neurology (AAN) shows that certain forms of medical marijuana can be useful to treat some symptoms of multiple sclerosis (MS), but the evidence is insufficient to support its use in other neurologic diseases, and there are a number of safety concerns with medical marijuana.

Barbara Koppel, MD, Chief of Neurology, Metropolitan Hospital in New York City, reported the results of the analysis at the 2014 meeting of the AAN, which was recently published in Neurology (2014;82:1556-1563).

Because studies used various doses and different preparations of marijuana, the analysis was conducted by the type of cannabinoid.

“The review finds that certain forms of medical marijuana can be helpful to treat some symptoms of MS, but it did not appear to be helpful in treating drug-induced movements of Parkinson disease,” Dr Koppel said. “There was not enough evidence found to show if medical marijuana is helpful in treating motor problems in Hun-

tington disease, tics in Tourette syndrome, and in reducing the number of seizures in epilepsy.”

The evidence indicates that pills and oral spray forms of marijuana can help treat some symptoms of MS, including spasticity; certain types of pain, including painful spasms, pain related to spasticity, and central pain; and symptoms of overactive bladder.

“Certain forms of medical marijuana can be helpful to treat some symptoms of MS.” —Barbara Koppel, MD

Most of the studies on MS examined pill or oral spray forms of marijuana, but 2 studies examined smoked medical marijuana for the treatment of the same symptoms. “However, these studies did not provide enough information to show if smoking marijuana is effective,” she said.

For patients with Parkinson disease (PD), medical marijuana in the

form of synthetic ∆9-tetrahydrocannabinol pills does not help reduce the number of involuntary abnormal movements induced by levodopa that can develop in the late stages of the disease.

There was not enough information to show if medical marijuana, including smoked marijuana, is safe and effective in the following neurologic diseases: the motor symptoms of Huntington disease, tics in Tourette syndrome, cervical dystonia, and seizures in epilepsy.

“In general, medical marijuana is prescribed as a treatment for use only when standard treatment was not helpful in controlling all of the patient’s symptoms, and the standard treatment was allowed to be continued during most of these studies,” said Dr Koppel.

The side effects with medical marijuana that were reported in more than 2 studies included nausea, fatigue, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness, fainting symptoms, and feelings of intoxication (feeling “high”), as well as reports of 2 seizures.

“Mood changes and suicidal thoughts are of special concern when a medication is used in patients with a neurologic illness, such as MS or PD, because they are at increased risk of depression and suicide,” Dr Koppel said. “The studies showed the risk of serious psychological effects overall to be 1%.”

Although seldom prescribed, she noted that patients may still be using it on their own, and patients who obtain cannabis from dispensaries in states where medical use is legal fail to get specific advice on its use from their physicians.

She concluded, “There is a place for it, and more work is going to need to be done to figure out exactly where its indications will be.”

Added Gary Gronseth, MD, Vice Chairman of Neurology, University of Kansas Medical Center, Kansas City, “When we say something like, there’s insufficient information or insufficient evidence to indicate that it’s effective for a condition, that’s not the same thing as saying that there’s evidence that it’s not effective for that condition, and that’s a common way that we confuse these statements.” n

Extended Natalizumab Dosing May Reduce PML Risk in Patients with Multiple Sclerosis Philadelphia, PA—Extending the dosing interval of natalizumab to every 6 to 8 weeks may lower the risk for progressive multifocal leukoencephalopathy (PML) without affecting efficacy in patients with multiple sclerosis (MS).

A review of 601 patients receiving extended dosing of natalizumab at MS centers in the United States found no cases of PML, said Joseph Herbert, MD, Director of the MS and Neuro­ rehabilitation Care Center, New York University, NY, at the 2014 American Academy of Neurology meeting.

The risk of PML in recipients of natalizumab who are seropositive for JC virus (JCV) antibodies is 0.7% without previous immunosuppression and 1.3% with previous immunosuppression. The current guidelines for the treatment of MS call for a standard 300-mg dose of natalizumab administered every 4 weeks.

It is thought that saturation of the alpha-4 integrin receptor underlies susceptibility to PML, because it leads to the excessive reduction in tissue compartment trafficking of the im-

6

mune cells that are required for JCV surveillance. The saturation of the alpha-4 integrin receptor on circulating lymphocytes depends on the serum concentrations of natalizumab.

After a single 300-mg dose of natalizumab infusion, alpha-4 integrin saturation reaches >80% and does not fall below 75% over 4 weeks.

“Our hypothesis is that probably we’re oversaturating the receptor, and thereby we’re being too aggressive about reducing the normal immune surveillance that takes place,” said Dr Herbert. “The original dosing, 300 mg every 4 weeks, was based on the premise that you needed to maintain maximal saturation of the receptor.

Usually with a biological there should be a weight-based calculation.”

Dr Herbert and colleagues hypothesized that extending the dose of natalizumab may produce intermediate alpha-4 integrin saturation that is still “MS protective” yet will permit antiJCV lymphocyte immune surveillance in the central nervous system and/or the peripheral circulation.

value-based CARE in Neurology

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They looked at data from 601 patients treated with extended nataliz­ umab dosing at 6 large MS centers in the United States. They defined extended dosing as every 4 weeks and 3 days to every 8 weeks and 5 days.

“When the patients hear it explained, and they see that you’re considering the risk,...the majority of patients...are opting to stay on the drug.”

—Joseph Herbert, MD The annualized relapse rate was 0.12, 0.18 among patients receiving early extended dosing, and 0.08 among those receiving late extended dosing. A total of 62% of patients had no clinical or radiologic evidence of disease activity. Extended dosing was discontinued in 32% of patients. There were no new cases of PML over 680

JCV antibody–positive person-years.

Thinner patients metabolize nataliz­ umab more poorly and are more susceptible to PML, said Dr Herbert.

“We’re going to have to develop algorithms that tie in the individual dose, the frequency of the dose, and the patient’s individual metabolism, body mass index, and JCV index, and determine the optimal integrin saturation that you’re trying to achieve in the serum for each patient,” he noted.

Dr Herbert said that he presents extended dosing of natalizumab as an option to his patients, and many of his patients are using a dosing schedule of every 6 to 8 weeks. “I explain to patients that what we’re doing is not proven, and so far there have been no PML cases,” he said.

“When the patients hear it explained, and they see that you’re considering the risk, and you’re taking some kind of action to minimize it, the majority of patients, even the JCV positive, are opting to stay on the drug. That may change once the first case of PML occurs.”—WK n VOL. 1

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Multiple Sclerosis

Rapid CD4 Cell Recovery with Alemtuzumab Treatment Not a Biomarker...

Continued from page 1

with alemtuzumab, “we fail to confirm the claim that accelerated CD4 T-cell recovery after treatment is a biomarker for recurrent MS disease activity following lymphocyte depletion with alemtuzumab,” wrote lead author Onajite Kousin-Ezewu, MRCP, and coinvestigators. “We also find no evidence that a CD4 T-cell count of greater than 388.5 × 106 cells/mL at 12 months has utility in selecting a group of patients who may benefit from more intensive monitoring or perhaps even prophylactic repeat dosing,” they noted.

In response to the earlier article suggesting that differential lymphocyte recovery could be used to predict posttreatment MS activity, KousinEzewu and colleagues analyzed data from clinical trials for 108 patients who had been followed for a median of 99 months after treatment with alemtuzumab. The data showed that within each treatment cycle, no differences were observed in the number of

CD4 T cells, CD8 T cells, CD19 B cells, CD56 natural killer (NK) cells, or monocytes between patients with and

“To those of us somewhat incredulously observing from afar, it seems inconceivable that such a powerful and valuable new component of our MS therapeutic armamentarium can continue to be denied to US patients.”

—Neil P. Robertson, MD, and Neil J. Scolding, PhD without clinically defined relapses.

Furthermore, using the Fisher’s exact test, no relationship was found be-

tween a CD4 cell count of more than 388.5 × 106 cells/mL at 12 months and risk of disease relapse.

In addition, no differences were seen in CD19 B-cell or CD56 NK-cell counts or monocytes between patients with and without active disease on MRI scans. Although higher CD4 cells and CD8 cells were present, on average, in the active MRI group than in the inactive group within treatment cycle 3, there were no differences in any other treatment cycle. Within each treatment cycle, there were no differences in levels of CD8 T cells, CD19 B cells, CD56 NK cells, and monocytes in relation to disability accumulation.

In an accompanying editorial, Neil P. Robertson, MD, and Neil J. Scolding, PhD, Department of Neurology, Cardiff University, Wales, United Kingdom, concurred that these results indeed suggest that alemtuz­ umab is not a biomarker for disease activity (Robertson NP, Scolding NJ.

Neurology. 2014;82:2150-2151). However, they added that “despite conflicting results, the pace and nature of lymphocyte reconstitution remains an attractive target for biomarker investigation.”

Drs Robertson and Scolding further questioned the decision by the US Food and Drug Administration in 2013 to not approve the drug for the treatment of MS: they posit the confusion why alemtuzumab, “having been approved for use in Europe but, to the dismay of many specialists, let alone patients, having so far been denied a license in the United States.”

Drs Robertson and Scolding conclude, “To those of us somewhat incredulously observing from afar, it seems inconceivable that such a powerful and valuable new component of our MS therapeutic armamentarium can continue to be denied to US patients,” while it is available to those in Australia, Canada, the European Union, and Mexico. n

Estriol Added to Glatiramer Acetate Improves Cognition, Reduces Relapse Rate in MS

By Mark Knight Philadelphia, PA—Estriol may represent a future novel treatment option for patients with relapsing-remitting multiple sclerosis (RRMS). In a phase 2 randomized, double-blind, placebo-­ controlled trial of women with RRMS, estriol, given with glatiramer acetate, reduced the relapse rate by almost 50% with only 1 year of treatment and improved cognition, reported Rhonda Voskuhl, MD, Director of the MS program, University of California, Los Angeles, at the 2014 meeting of the American Academy of Neurology.

Because MS relapses are decreased by approximately 80% during late pregnancy, the investigators tested the effect of estriol (an estrogen unique to pregnancy) in women aged 18 to 50 years with RRMS. Estrogen treatment has been shown to ameliorate MS and improve cognition in animal studies.

“It makes a lot of sense to have something circulating in the mother’s blood that would be neuroprotective, to protect the fetal developing nervous system,” Dr Voskuhl said.

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“Clearly, the effect [of estriol] is driven in these people who are doing more poorly on the PASAT. They were getting improvements of 12%, which is about a 6- to 7-point increase on the PASAT.” —Rhonda Voskuhl, MD

tate were randomized to oral estriol, 8 mg daily, plus standard MS treatment, or to placebo plus standard MS treatment.

The mean disease duration of participants was 3 years, and 99% of patients had at least 1 relapse in the preceding 24 months; of these, 29.4% had at least 1 enhancing lesion on a single screening magnetic resonance imaging. The mean Expanded Disability Status Scale (EDSS) score was 2.2.

The mean estriol levels at baseline were not different between the 2 groups, but they were significantly higher in the estriol group at months 3 to 24. After 12 months, the relapse rate (confirmed change in the EDSS by the examining neurologist) was 47% lower in the estriol group compared with placebo (P = .030 when adjusted for baseline characteristics). At 24 months, the relapse rate remained lower by 32% in the women assigned to estriol, but it was no longer significant (P = .152).

An improvement in cognitive test scores was also observed in the estriol group. The improvement from baseline on the 3-minute Paced Auditory july 2014

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Serial Addition Test (PASAT)3 and PASAT2 was significantly better in the estriol group at 12 months. “It was about a 5.5% to 6% change, which amounts to about a 3-point change in the PASAT,” Dr Voskuhl said.

The superiority of estriol at 12 months on the PASAT3 and PASAT2 scores was also significant in patients with a baseline PASAT3 score of <55 at baseline. “Clearly, the effect is driven in these people who are doing more poorly on the PASAT,” she said.

“They were getting improvements of 12%, which is about a 6- to 7-point increase on the PASAT.” In the second year, PASAT scores in the placebo group began to catch up with the estriol group, which reflects the effect of glatiramer acetate on cognition in year 2, said Dr Voskuhl. There was no effect of estriol on the EDSS. There were no gynecologic safety signals in the women taking estriol, she noted. The rates of uterine fibroids, uterine endometrial hypertrophy, abnormal uterine proliferation, and fibrocystic breast disease were not different between the 2 groups. n

www.ValueBasedNeurology.com

7

Epilepsy Management

Knowledge of Antiepileptic Drug Formulations Key to Accurate Prescribing

By Wayne Kuznar Philadelphia, PA—Multiple formulations and generic equivalents of anti­ epileptic drugs are prevalent, and choosing between them can help optimize seizure control and minimize adverse effects, said Carl W. Bazil, MD, PhD, Director, Comprehensive Epilepsy Center, Columbia University Medical Center, New York, at the 2014 American Academy of Neurology (AAN) meeting.

The availability of extended-release (ER/XR) formulations, intravenous (IV) agents, and generic equivalents can complicate the choice for the individual patient.

Extended-Release Formulations ER formulations are often chosen to minimize fluctuations in antiepileptic drug levels and to increase compliance, because they require fewer daily doses. Carbamazepine (Tegretol, Carbatrol), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenytoin, topiramate (Topamax), and valproate (Depakote) are all available in ER formulations.

The time to peak concentration is typically much later with ER versus immediate-release formulations. Delivery systems are usually considered proprietary, with the exception of the osmotic system used in Tegretol XR, which differs from the Carbatrol cap-

cause of saturable absorption.

Note that delivery systems are not equivalent, and “there may be differences between delayed release when more than 1 formulation is available,” Dr Bazil said.

Because peak and trough levels may not be reduced in amplitude with ER formulations, the best way to reduce fluctuation may be to use an ER form twice daily, advised Dr Bazil.

“There may be differences between delayed release when more than 1 formulation is available.”

—Carl W. Bazil, MD, PhD sule, containing beads with different dissolution times.

Because of the difference in delivery, the bioavailability of ER formulations is usually decreased compared with immediate-release formulations, “requiring a dose increase to maintain similar mean levels compared with immediate release,” said Dr Bazil. The exception is gabapentin, he said, because the delayed-release formulations result in increased bioavailability compared with immediate-release formulations be-

IV Formulations Antiepileptic drugs that are available in IV formulations include phenobarbital, phenytoin/fosphenytoin, valproate, levetiracetam, and lacosa­ mide (Vimpat).

IV antiepileptic drugs have a rapid onset, proving critical in patients who need immediate administration, as in acute repetitive seizures and status epilepticus. A large 1998 trial in status epilepticus showed that IV lorazepam was more effective than phenytoin, with no difference between phenobarbital and diazepam followed by phenytoin.

Generic Equivalents Although generic substitution may be requested by a patient or an insurer for cost reasons, a switch to the generic version of a drug may have clinical implications. The US Food and Drug Administration (FDA) mandates that peak levels (Cmax) and area under the

curve (AUC) for generic preparations must fall between 80% and 125% (on single-dose studies in normal volunteers) compared with the brand drug.

Because antiepileptic drugs have narrow therapeutic ranges, it has been argued that this confidence interval may be insufficient for patients with epilepsy. Furthermore, “the variability allowed by the FDA may be amplified when a number of generic preparations are available, as each is compared to the branded drug but not to each other,” Dr Bazil said.

A bioequivalence study of generic antiepileptic drugs that modeled potential changes between multiple generic drugs showed that the AUC varied by >15% only 1% of the time, but that Cmax variations of 15% to 25% occurred in 11% of studies (Krauss GL, et al. Ann Neurol. 2011;70:221-228). These results suggest that trough levels may vary with consequent risk of seizures, Dr Bazil said.

An earlier study by Zachry and colleagues showed that patients with epilepsy with serious events had 81% greater odds of a change between antiepileptic drug formulations within the previous 2 months compared with matched controls without events.

The AAN recommends monitoring drug levels to ensure equivalent absorption when changing to generic formulations. n

Breakthrough Seizures in Treatment-Adherent Patients Are Costly

Philadelphia, PA—Patients with breakthrough seizures despite adherence to antiepileptic drugs have much higher emergency department and inpatient utilization compared with patients without breakthrough seizures, according to a poster presented during the 2014 meeting of the American Academy of Neurology by Charles Makin, MS, MBA, Health Economics and Outcomes Research, IMS Health, and colleagues.

All-cause and healthcare-related costs were also significantly higher in the group with breakthrough seizures, according to a case-control study of a managed care population using an administrative claims database.

Because breakthrough seizure is lacking a distinct diagnostic code and a clear definition, measuring the true burden is difficult, Mr Makin noted.

8

Administrative claims in the IMS Health pharmacy database identified 5279 adults with epilepsy and evidence of a seizure, and a like number of matched controls. All patients were

“All-cause healthcare resource utilization was significantly higher for cases than for controls for almost all services assessed.”

—Charles Makin, MS, MBA required to be adherent to treatment with an antiepileptic drug. A breakthrough seizure was defined as an event occurring in a patient who had

value-based CARE in Neurology

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no evidence of seizures in the previous 6 months.

All-cause and epilepsy-related resource utilization and direct healthcare costs (in 2012 US dollars) were measured in the 6 months after the index seizure.

Overall, 75.8% of the cases had 1 seizure in the 6-month follow-up, 17.4% had 2 seizures, and 6.8% had ≥3 seizures. Adherence was the same in both groups.

“All-cause healthcare resource utilization was significantly higher for cases than for controls for almost all services assessed,” Mr Makin noted.

The cases filled a median of 7 all-cause prescriptions versus 6 prescriptions for controls, and the cases had higher rates of hospitalizations and emergency department visits. The all-cause healthcare utilization increased with

the number of breakthrough seizures during follow-up.

Significant Cost Differences Inpatient costs. The inpatient costs were 7 times higher for the cases versus for the controls (mean, $13,631 vs $1927, respectively) and the emergency department costs were 4 times higher for the cases than for the controls (mean, $1105 vs $265, respectively). The inpatient costs were the main driver of the higher total healthcare costs among the cases: inpatient costs were 57% of the mean total costs for the cases compared with 19% for the controls.

Pharmacy costs. The cases had significantly higher overall outpatient pharmacy costs and antiepileptic drug costs, whereas the controls had significantly higher pharmacy costs for non–antiepileptic drugs.

Continued on page 9

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Personalized Medicine in Neurology

™

Precision Medicine in the Treatment of Epilepsy

By Wayne Kuznar Philadelphia, PA—Genomic sequenc­ ing is starting to yield progress in unraveling the genetics of select forms of epilepsy, with some immediate clinical implications, said David B. Goldstein, PhD, Professor of Molecular Genetics, Microbiology, and Biology, and Director of the Center for Human Genome Variation, Duke University, Durham, NC, at the 2014 meeting of the American Academy of Neurology.

His laboratory is participating in Epilepsy 4000 (Epi4K), a series of worldwide research projects to explore whether de novo mutations affect the genes that are critical for neuronal function. Funded mostly by the National Institutes of Health, Epi4K is screening patient genomes for the relevant mutations that form the genetic basis for epileptic encephalopathies.

Genetic Mutations Through the use of exome sequencing, the project has already enabled the discovery of genetic alterations that may cause infantile spasm and LennoxGastaut syndrome, said Dr Goldstein.

“We pursued a genetic design that would allow us to effectively and economically identify de novo mutations in the protein encoding part of the human genome, the so-called exome,” he said. “We performed wholeexome sequencing on probands and their parents.”

For the study, the exome sequences of 264 children, 149 with infantile spasms and 115 with Lennox-Gastaut syndrome, were analyzed. The investigators confirmed 329 de novo mutations, with the average number of 1 de novo mutation in the study, which is consistent with other studies.

A likelihood analysis showed a significant excess of de novo mutations

“In this small study of just 264 individuals, we have convincing statistical evidence that we can genetically explain about 10% of the cases, considering both already known genes and genes that we have newly implicated.”

—David B. Goldstein, PhD in the 4264 genes that are the most intolerant to functional genetic variation in humans.

“In this small study of just 264 individuals, we have convincing statistical evidence that we can genetically explain about 10% of the cases, considering both already known genes and genes that we have newly implicated,” Dr Goldstein said.

Causal mutations were very rare, 6 of the 264 patients had GABA receptor mutations, and 7 of the 264 patients had mutations influencing vesicle trafficking.

“One slightly worrying note, how-

Breakthrough Seizures... Continued from page 8 Epilepsy-related costs. The cases had 21 times higher epilepsy-related inpatient costs compared with the controls (mean, $9446 vs $452, respectively) and 13 times higher emergency department costs (mean, $787 vs $58, respectively).

Adjusted costs. The cases had more than double the adjusted all-cause total healthcare costs and 8 times higher adjusted epilepsy-related total healthcare costs than the controls.

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$35,569 in patients with 2 seizures, and $52,230 in patients with ≥3 seizures. The mean inpatient costs were 51% to 69% of the mean total healthcare costs.

Better seizure control among treatment-adherent patients can potentially lower hospitalizations and emergency department admissions while improving patient outcomes and reducing costs. According to Mr Makin, the study highlights the need for improved antiepileptic drugs that could prevent breakthrough seizures.—WK n

ever, is that the mutations that influence the condition are very rare, and, in fact, so rare that almost every patient has a different underlying mutation,” said Dr Goldstein. “This is something that has actually concerned a lot of people for a long time about the whole program of personalized medicine.”

The way forward appears to be organizing patients based on the biologic processes that are dysregulated by individual mutations, and then to tailor treatment to the dysregulated biologic processes, he said.

Clinical Implications The progress being made into the genetics of epilepsies has immediate clinical implications. Duke University has a genome-sequencing clinic, where patients who are believed to have a genetic alteration but in whom traditional genetic testing has failed to classify the alteration, can be referred. These patients are then evaluated for possible whole-exome sequencing. This process

has yielded 2 positive findings. In 1 case, mutations in KCNT1 have been identified as causal for patients presenting with an unrecognized condition.

KCNT1 had recently been implicated in 2 different forms of epilepsy: autosomal dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures, said Dr Goldstein.

“Most important, oocyte modeling of the mutations showed that the mutations have a pronounced gain of function effect on the potassium channel that KCNT1 encodes,” he said.

The gain of function could be suppressed strongly by the antimalarial drug quinidine. For example, 1 patient, who had 40 nocturnal seizures by age 4 years and had regressed to a nonambulatory, nonverbal state, had a mutation sensitive to quinidine: his seizures were reduced immediately with quinidine therapy.

Another patient was found to have a mutation in SLC52A2, a riboflavin transporter, and has started riboflavin therapy. n

Using Genomics in Clinical Practice in Neurology Philadelphia, PA—Molecular subtyping and classification of patients for the selection of appropriate treatment and prognosis can now be used in routine clinical care in neurology, according to Teri Manolio, MD, PhD, Director, Division of Genomic Medicine, National Human Genome Research Institute, Rockville, MD, at the 2014 American Academy of Neurology meeting.

Dr Manolio described CharcotMarie-Tooth (CMT) disease as a paradigm of molecular subtyping. Almost 80 genes have been identified that are associated with this genetically heterogeneous disease. “One of the neat things about CMT is, given that it’s genetically very heterogeneous, it also has a classification system that was first built on nongenetic things, and then the genetics was added on top,” she said.

For a genetically heterogeneous condition such as CMT disease, whole-exome sequencing can be performed for less than the cost of a multigene panel.

Genetic Elements in CMT Disease A variety of forms of CMT disease july 2014

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are based on electrophysiology and genetic inheritance. For instance, CMT1 is characterized by abnormalities in myelin, whereas CMT2 is characterized by abnormalities in the axon.

CMT4 is autosomal dominant and affects the axon or myelin, and CMTX is caused by mutations in a gene on the X chromosome. Within each type is a subtype distinguished by the specific genes that are altered, which may respond to different treatments.

Approximately 70% of the cases of CMT1 are caused by a duplication in the PMP22 gene in the 17p12 region.

“There have been some investigations of silencers of those extra copies, such as ascorbic acid and progesterone antagonists, which haven’t worked well in humans, although they worked in animal models,” said Dr Manolio. Antisense nucleotides, which bind to the messenger RNA to keep it from being expressed, are also under investigation for this purpose.

Another potential strategy is to reduce the amount of neurotoxic aggregates in genes that contribute to CMT disease that cause protein misfolding; curcumin is currently under study. Histone deacetylase inhibi-

Continued on page 10

www.ValueBasedNeurology.com

9

Parkinson’s Disease

Cortical Thinning and Cognitive Function in Early Parkinson’s

By Rosemary Frei, MSc

R

esults of the largest study to evaluate the link between cognition and cortical thinning using 3T magnetic resonance imaging (MRI) show cortical thinning in patients with early-stage Parkinson’s disease (PD) that is associated with mild cognitive impairment (MCI) as reflected by lower cognitive function scores. This finding could lead to earlier diagnosis and treatment of PD, the researchers note (Pereira JB, et al. Neurology. 2014;82:2017-2025).

Other studies had already shown that “early MCI is associated with an increased risk of developing dementia in PD,” noted lead author Joana B. Pereira, PhD, with the Karolinska Institutet, Stockholm. “In this study, we showed that newly diagnosed, drug-naïve PD patients with MCI had cortical thinning in temporal, parietal and frontal regions already at early disease stages. This could serve as a marker of initial cognitive decline in PD.” Keith A. Josephs, MD, Professor of Neurology, Mayo Clinic, Rochester, MN, told Value-Based Care in Neurology that the study adds to “an already substantial literature” linking MCI in PD with significant neurodegeneration in the brain.

“The findings help shed light on the

“Newly diagnosed, drugnaïve PD patients with MCI had cortical thinning in temporal, parietal and frontal regions already at early disease stages.

This could serve as a marker of initial cognitive decline in PD.” —Joana B. Pereira, PhD neurobiological underpinnings of cognitive dysfunction in PD, and may ultimately allow the development of neuroimaging biomarkers that could

be useful for assessing future treatment,” said Dr Josephs.

The 123 patients with PD and 56 controls without PD were part of the Parkinson’s Progression Markers Initiative. The patients with PD had been diagnosed within the previous 2 years and had not been treated for the disease.

Of the 123 patients with PD, 33 showed evidence of MCI based on the modified Movement Disorder Society (MDS) Task Force definition (PD-MCIMDS). In addition, 18 patients were classified as having MCI based on their cognitive domain scores (PD-MCIDomain). In all, 16 individuals had MCI according to both definitions.

The 3T MRI scans revealed cortical thinning in the right inferior temporal gyrus in patients with PD who were cognitively normal (PD-CN) compared with the controls, when the researchers used the PD-MCI-MDS definition (this difference was not present when they used the PD-MCIDomain). Furthermore, thinning in this region was present in patients with PD-MCI, using both definitions, compared with the controls, and this group also had even more thinning in the left inferior temporal gyrus.

The novelty of this study is the assessment of treatment-na�ve patients

with PD at the earliest stages of cognitive impairment. “The regional cortical thinning in PD-CN patients we observed suggests that cortical changes are already present at time of diagnosis, before meeting criteria for MCI,” Dr Pereira and colleagues note. The cortical changes finding in patients with PD-CN “suggest to be a preclinical biomarker of cognitive decline even in patients with normal cognition at baseline,” they emphasize.

In addition, the researchers found correlations between higher visuospatial scores and thicker bilateral superior parietal, left-hemisphere temporal, and precentral regions. Moreover, the executive attention domain scores were correlated with cortical thickness in a number of regions, including the superior frontal, precentral, temporal, and parietal areas.

Performance in the verbal encoding memory subtest correlated with increased thickness in the middle, superior, and inferior temporal areas in both hemispheres. There were no significant correlations between thickness and delayed recall scores or disease duration.

These study results show “that better scores on cognitive tests are associated with greater cortical thickness in patients,” said Dr Pereira. n

Personalized Medicine in Neurology

™

Using Genomics in Clinical Practice... Continued from page 9 tors that target the axonal transport defects in CMT disease are also under investigation.

Stevens-Johnson Syndrome Genetics can also be used to identify patients who are at high risk for drug adverse effects, as is the case with Stevens-Johnson syndrome (SJS), a severe immune complex–mediated hypersensitivity reaction that causes epidermal blistering and sloughing that can occur in recipients of carbamazepine (Tegretol).

In 2004, the HLA-B*1502 allele was identified in 100% of 44 patients who developed SJS while receiving treatment with carbamazepine compared with 3% of those who were carbamazepine-tolerant and 8.6% of the general population. Other variants have been identified in association with carba-

10

mazepine-induced SJS, particularly in patients of European ancestry, said Dr Manolio. “HLA-A*3101 is associated not only with Stevens-Johnson syn-

any hypersensitivity reaction by 9, in patients receiving carbamazepine.

More than 90% of patients who have hypersensitivity reactions to car-

“We do have a consistent, reliable method to figure out who has this allele, and this is called sequencing for genotype.”

—Teri Manolio, MD, PhD

drome but some of the milder forms of hypersensitivity,” she said. The presence of this variant increased the odds of having SJS by 26, and the odds of

value-based CARE in Neurology

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bamazepine will do so within the first few months of treatment. Patients who have been taking carbamazepine for more than a few months are at low

risk for carbamazepine-associated SJS. A 2011 systematic review showed a pooled odds ratio for SJS of 113 for Asian patients with the HLA-B*1502 allele and of 9.5 for all ethnicities with the HLA-A*3101 allele.

The US Food and Drug Administration (FDA) recommends testing all patients of Asian descent for the HLAB*1502 allele before prescribing carbamazepine. The FDA advises clinicians to determine if a patient has ancestry across broad areas of Asia before prescribing carbamazepine. This requires clinicians to know what Asian ancestry means, and for them to use a consistent, reliable method to figure out which patients have this ancestry.

Dr Manolio said, “We do have a consistent, reliable method to figure out who has this allele, and this is called sequencing for genotype.”—WK n VOL. 1

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In the Literature National Initiative Improves Time to tPA Administration in Stroke

When administered early, intravenous tissue plasminogen activator (tPA), an enzyme that helps dissolve clots, reduces long-term disability in patients with stroke. Because rapid treatment is crucial, national guide-

AUBAGIO® (teriflunomide) tablets for oral administration

lines recommend that hospitals complete the evaluation of patients with acute ischemic stroke and begin tPA therapy for eligible patients within 60 minutes of their arrival at the hos­pital.

However, evidence shows that <30% of patients receive tPA within this window, and that this has improved minimally over time. Live7” A new study review-

Rx Only

Brief Summary of Prescribing Information

WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Risk of Teratogenicity Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment [see Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.1)].

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patients on placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.

One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. Teriflunomideinduced liver injury in this patient could not be ruled out.

Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue teriflunomide and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered.

5.2 Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women.

However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)].

Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus.

The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)].

Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk. [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)] 5.3 Procedure for Accelerated Elimination of Teriflunomide Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures: • Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.

• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.

5.4 Bone Marrow Effects/Immunosuppression Potential/Infections White Blood Cell (WBC) count decrease A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 10% and 15% of patients on AUBAGIO 7 mg and 14 mg , respectively, compared with 5% of patients on placebo; lymphocyte count <0.8×109/L was observed in 7% and 10% of patients on AUBAGIO 7 mg and 14 mg, respectively, compared with 5% of patients on placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.

Risk of Infection / Tuberculosis Screening Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.

AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.

In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with teriflunomide 7 mg (1.4%) or 14 mg (2.2%) compared to placebo (2.1%).

ceived tPA at 1030 participating hospitals. The time to treatment and incidence of complications were compared before the initiative was launched (2003-2009) and after its implementation (2010-2013). The initiative included 10 key strategies to achieve faster door-to-needle (DTN) times for tPA administration, provided clinical deci-

Continued on page 12

Live10”

1. INDICATIONS AND USAGE AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis [see Clinical Studies (14) in the full prescribing information].

2. DOSAGE AND ADMINISTRATION The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

Monitoring to assess safety • Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)].

• Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].

• Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test [see Warnings and Precautions (5.4)].

• Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.9)].

4. CONTRAINDICATIONS 4.1. Severe Hepatic Impairment Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].

4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception AUBAGIO may cause fetal harm when administered to a pregnant woman.

In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically.

Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)].

AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)].

Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling. [see Warnings and Precautions and Use in Specific Populations (5.2, 8.1)] 4.3. Current treatment with leflunomide Co-administration of teriflunomide with leflunomide is contraindicated.

5. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)].

In placebo-controlled trials, ALT greater than three times the ULN occurred in 14/429 (3%) and 21/415 (5%) of patients on teriflunomide 7 mg and 14 mg, respectively, and 17/421 (4%) of

ing the results of the Target: Stroke program, a national quality improvement initiative launched in 2010, shows that hospitals participating in this program have significantly reduced the time to tPA administration (Fonarow GC, et al. JAMA. 2014;311:1632-1640).

The data come from 71,169 patients with acute ischemic stroke who re-

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In the Literature National Initiative Improves Time... Continued from page 11

sion support tools, facilitated hospital participation, and encouraged sharing of best practices. The primary end points were DTN times for tPA administration in ≤60 minutes and the in-hospital risk-adjusted mortality, symptomatic intracranial hemor-

rhage, ambulatory status, and discharge destination.

The average median DTN time for tPA administration preintervention was 77 minutes, which decreased to 67 minutes postintervention. The median DTN was 74 minutes during the fourth quarter of 2009, immediately before the initiation of Target: Stroke; this de-

clined to 59 minutes by the third quarter of 2013, resulting in a 15-minute reduction. The rate of tPA administration in ≤60 minutes increased from 29.6% preintervention to 53.3% postintervention. In addition, there was more than a 4-fold increase in the annual rate of improvement in the proportion of patients with DTN of ≤60 minutes after Live7”

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AUBAGIO® (teriflunomide) tablets for oral administration and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.11 Concomitant Use with Immunosuppressive or Immunomodulating Therapies Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.

In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment [see Warnings and Precautions (5.3)].

6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: • Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)] • Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)] • Peripheral Neuropathy [see Warnings and Precautions (5.5)] • Acute Renal Failure [see Warnings and Precautions (5.6)] • Hyperkalemia [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.8)] • Blood Pressure Effects [see Warnings and Precautions (5.9)] • Respiratory Effects [see Warnings and Precautions (5.10) The most frequent adverse reactions for AUBAGIO (incidence ≥10% and ≥2% greater than placebo) in the placebo-controlled studies were ALT increased, alopecia, diarrhea, influenza, nausea, and paresthesia. Alopecia was the most common cause of discontinuation because of adverse events in controlled clinical studies as compared to placebo (0.5% and 1.4% of patients on AUBAGIO 7 mg and 14 mg, respectively, and 0% on placebo).

If desired, teriflunomide can be rapidly cleared from the body by the use of an accelerated elimination procedure [see Warnings and Precautions (5.3)].

6.1 Clinical Trial Experience A total of 844 patients on teriflunomide (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of MS (RMS). Approximately 72% of patients were female and the mean age was 38 years.

Study 1 was a 108-week placebo-controlled clinical study in 1086 RMS patients treated with teriflunomide 7 mg (n=368), teriflunomide 14 mg (n=358), or placebo (n=360).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriflunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) Teriflunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) INFECTIONS AND INFESTATIONS Influenza 12% 9% 10% Upper respiratory tract infection 9% 9% 7% Bronchitis 8% 5% 6% Sinusitis 6% 4% 4% Cystitis 4% 2% 1% Gastroenteritis viral 4% 2% 1% Oral herpes 4% 2% 2% BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 4% 2% 0.3% Leukopenia 1% 2% 0.3% IMMUNE SYSTEM DISORDERS Seasonal allergy 3% 2% 1% PSYCHIATRIC DISORDERS Anxiety 4% 3% 2% NERVOUS SYSTEM DISORDERS Headache 19% 22% 18% Paraesthesia 10% 9% 8% Sciatica 3% 1% 1% Burning sensation 3% 2% 1% Carpal tunnel syndrome 3% 1% 0.3% EYE DISORDERS Vision blurred 3% 3% 1% Conjunctivitis 1% 3% 1% CARDIAC DISORDERS Palpitations 2% 3% 1%

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However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting, in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.

In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO. Vaccination No clinical data are available on the efficacy and safety of vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is, however, not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO. Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO. 5.5 Peripheral Neuropathy In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking AUBAGIO than in patients taking placebo. In one 108-week placebo-controlled study in 1086 patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.2% (4 patients) and 1.9% (6 patients) on 7 mg and 14 mg of AUBAGIO, respectively, compared with 0% on placebo. Treatment was discontinued in 2 patients with polyneuropathy, one on each dose; one of them recovered following treatment discontinuation. The other cases of peripheral neuropathy did not resolve with continued treatment. There have also been reports of peripheral neuropathy in patients receiving leflunomide.

Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.6 Acute Renal Failure In placebo-controlled trials, 10 of 844 (1.2%) of AUBAGIO-treated subjects had transient acute renal failure with a creatinine measurement increased by 100% or more of their baseline serum creatinine value, compared to 0 of 421 placebo-treated subjects. Seven of the 10 subjects had a nadir creatinine clearance less than 30 cc/minute. In each of the 10 subjects, the serum creatinine level was normal on the next reported measurement (6–48 days from the increase in creatinine) with continued teriflunomide use. These increased creatinine measurements occurred between 12 weeks and 2 years after first dose of teriflunomide. Of the 6 subjects with available serum potassium measurements, 3 (50%) had hyperkalemia (measurements of 6.7, >7.3, and >7.3 mmol/L). No associated symptoms were documented.

AUBAGIO causes increases in renal uric acid clearance with mean decreases in serum uric acid of 20–30%. Acute uric acid nephropathy is a likely explanation for the cases of transient acute renal failure seen with teriflunomide. Although symptoms associated with acute uric acid nephropathy, such as loin pain or flank pain, were not reported, this information was not systematically collected. No inciting factors, such as dehydration, exercise, or increase in physical activity in the 30 days prior to the adverse event were reported, but this information was not systematically collected.

5.7 Hyperkalemia In placebo-controlled trials, treatment-emergent hyperkalemia >7.0 mmol/L occurred in 8/829 (1.0%) of teriflunomide-treated subjects, compared to 1/414 (0.2%) of placebo-treated subjects.

Two teriflunomide-treated subjects had hyperkalemia >7.0 mmol/L with acute renal failure.

Possible causes in other cases were not documented. Check serum potassium level in AUBAGIO-treated patients with symptoms of hyperkalemia or with acute renal failure.

5.8 Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.9 Blood Pressure Increase In placebo-controlled studies, mean change from baseline in systolic blood pressure was 2.9 mmHg and 2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -1.3 mmHg for placebo.

The change from baseline in diastolic blood pressure was 1.4 mmHg and 1.3 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.9 mmHg for placebo. Hypertension was reported as an adverse reaction in 4% of patients treated with 7 mg or 14 mg of AUBAGIO, compared with 2% on placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO. 5.10 Respiratory Effects Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy

the initiation of the intervention.

This faster treatment time resulted in improved clinical outcomes in the postintervention period versus in the preintervention period. Improvements included reduced in-hospital deaths (8.2% vs 9.9%, respectively); fewer treatment complications (5.5% vs 6.7%, respectively); more frequent indepen-

In the Literature dence with walking (45.4% vs 42.2%, respectively); symptomatic intracranial hemorrhage within 36 hours (4.7% vs 5.7%, respectively); and discharge to home (42.7% vs 37.6%, respectively).

These improved outcomes reinforce the importance of faster administration of intravenous tPA, as shown with the implementation of Target: Stroke.

Antidepressant May Deter Progression of Alzheimer’s Disease

The often-prescribed antidepressant citalopram (Celexa), a selective serotonin reuptake inhibitor (SSRI), appears to reduce the formation of amyloid plaques that are associated with Alzheimer’s disease, Live7” according to new

Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriflunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) (continued) Teriflunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) VASCULAR DISORDERS Hypertension 4% 4% 2% GASTROINTESTINAL DISORDERS Diarrhoea 18% 15% 9% Nausea 14% 9% 7% Abdominal pain upper 6% 5% 4% Toothache 4% 4% 2% Abdominal distension 1% 2% 0.3% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia 13% 10% 3% Acne 3% 1% 1% Pruritus 3% 4% 2% MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Musculoskeletal pain 4% 5% 3% Myalgia 3% 4% 2% INVESTIGATIONS Alanine aminotransferase 14% 12% 7% increased 3% 5% 1% Gamma-glutamyltransferase increased Aspartate aminotransferase 3% 2% 1% increased Weight decreased 2% 3% 1% Neutrophil count decreased 2% 3% 0.3% White blood cell count decreased 1% 3% 0%

AUBAGIO® (teriflunomide) tablets for oral administration Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity.

At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Use in Males AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Pregnancy Registry Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447, option 2.

8.3 Nursing Mothers Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of AUBAGIO did not include patients over 65 years old.

8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated.

Teriflunomide is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1) and Warnings and Precautions (5.1)].

8.7 Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

10. OVERDOSAGE There is no experience regarding teriflunomide overdose or intoxication in humans.

Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.

In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination [see Warnings and Precautions (5.3)].

Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 A SANOFI COMPANY September 2012a TER-BPLR-SA-SEP12

tested a variety of SSRIs on lowering concentrations of amyloid.

A new randomized, double-blind, placebo-controlled study was performed to determine the central nervous system effect of 60 mg of citalopram (given in 2 doses of 30 mg each) in 23 healthy patients aged 18 to 50 years who were not cognitively impaired or depressed. Patients were randomized to placebo or to a dose of 30 mg of citalopram 8 hours and 6 hours before the start of the labeling study. The production and concentrations in cerebrospinal fluid (CSF) of amyloid beta were measured prospectively using stable isotope labeling kinetics, with CSF sampling during the acute dosing of citalopram. Treatment with citalopram was associated with a 38% decrease in total CSF amyloid-beta concentrations over the 37-hour sampling period compared with placebo. Furthermore, the mean production rate of amyloid beta within CSF calculated over 13 to 22 hours was significantly lower in the group receiving citalopram versus the group receiving placebo, resulting in a 37% decrease in the production of amyloid beta.

These findings demonstrate that the ability to safely decrease the concentration of amyloid beta is potentially important as a preventive strategy for Alzheimer’s disease. Prospective trials in older, cognitively normal individuals should now test SSRI exposure to determine if the reduction in amyloid beta is sustainable.

Intracerebral Hemorrhage Rates Declining, but Mortality Rates Rising

Live10”

Cardiovascular deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment.

A relationship between teriflunomide and cardiovascular death has not been established.

Hypophosphatemia In clinical trials, 18% of teriflunomide-treated subjects had mild hypophosphatemia (≥ 0.6 mmol/L and < lower limit of normal), compared to 9% of placebo-treated subjects; 5% of teriflunomide-treated subjects had moderate hypophosphatemia (≥0.3 mmol/L and <0.6 mmol/ L), compared to 1% of placebo-treated subjects. No subject in either treatment group had a serum phosphorus <0.3 mmol/L. 7. DRUG INTERACTIONS Effect of teriflunomide on CYP2C8 substrates There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone is recommended as they may have higher exposure.

Effect of teriflunomide on warfarin A 25% decrease in peak international normalized ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is recommended.

Effect of teriflunomide on oral contraceptives There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide. Consideration should be given to the type or dose of oral contraceptives used in combination with teriflunomide.

Effect of teriflunomide on CYP1A2 substrates Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55% respectively, suggesting that teriflunomide may be in vivo a weak inducer of CYP1A2. Therefore, patients should be monitored when teriflunomide is coadministered with drugs metabolized by CYP1A2 (such as duloxetine, alosetron, theophylline, and tizanidine), as the efficacy of such drugs could be reduced.

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4.2) and Warnings and Precautions (5.2)] When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).

research in mice and a small cohort of healthy individuals (Sheline YI, et al.

Sci Transl Med. 2014;6:236re4). The accumulation of amyloid-beta peptide in the brain and its aggregation into amyloid plaques are currently considered triggers in the pathogenesis of Alzheimer’s disease. The study findings support preliminary animal studies that

Stroke mortality has seen a decline in recent years; however, trends in the incidence of intracerebral hemorrhage (ICH) remain unclear. Understanding trends in the incidence of ICH, case fatality, and long-term mortality can help to gauge the effectiveness of stroke prevention and treatment. Researchers investigated current trends in incidence and mortality over a 10year period in a population-based study (Zahuranec DB, et al. Neurology.

2014;82:2180-2186).

Cases of spontaneous ICH were identified among patients aged ≥44 years who presented to 1 of 7 hospitals in Nueces County, TX, from 2000 to 2010 using rigorous case ascertainment methods within the Brain Attack Surveillance in Corpus Christi Project. Annual population counts were taken from the US Census, and deaths were determined from state and national databases. The age-, sex-, and ethnicity-adjusted incidences were estimated for each year, as well as mortality risk after ICH. The results showed a declining inci-

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Stroke

Fourfold Variability Found in Hospital Charges... ing in cost by 213% after adjusting for inflation. A 2009 study from the National Cancer Institute estimated that computed tomography (CT) scans performed in 2007 will cause an excess of 29,000 cancers and 14,500 deaths as a result of radiation exposure.

As part of their study, Dr Bhattacharya and colleagues investigated the variability in cost between tests within a single metropolitan area and the charges for tests of questionable utility.

Hospital charges were ascertained from the website www.newchoice health.com. The least expensive and most expensive charges for a “basic workup,” including brain CT, carotid ultrasound, and transthoracic echocardiography, were computed. Charges for additional tests, such as CT angio­ graphy (CTA) and magnetic resonance angiography (MRA) of the brain and neck, were also assessed. The charges were assessed at hospitals in 1 metropolitan area.

“Necessity was based on clinical trial data,” said Dr Bhattacharya. “For instance, we have a couple of clinical trials published in the past few years that demonstrate that you can detect

“At some hospitals, the charge for a single diagnostic test is higher than the Medicare reimbursement for the entire hospitalization.”

—Pratik D. Bhattacharya, MD, MPH areas of narrowing in the carotid arteries, but it may not necessarily change your treatment strategy. Based

on these data, we suspected that the MRA or CTA may not necessarily change the treatment strategy.”

The charges for individual diagnostic tests ranged from $250 to $8900.

The variability in charges for individual tests for the most expensive hospital compared with the least expensive hospital ranged from 2.9 (magnetic resonance imaging [MRI] of the brain) to 8.1 (transesophageal echocardiography). The least expensive charge for a basic workup was $2225 and the most expensive was $8850.

The charges tended to be highest for tests of dubious value, Dr Bhattacharya said. “Based on our practice, we see that they’re ordered very frequently,” he said, “but I don’t know that there’s formal evidence to show how often they are being ordered.”

The tests with charges of at least $5000 at the most expensive hospitals included sleep study ($5100), brain MRI ($6800), neck MRA ($7700), CT angiography of the brain ($8300), neck CT angiography ($8400), brain MRA ($8600), and transesophageal echocardiography ($8900).

Whether transparency in pricing

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at a glance ➤ Diagnostic testing is a major contributor to hospital charges for stroke and TIA ➤ Analysis of individual diagnostic tests showed charges ranging from $250 to $8900 among facilities ➤ The least expensive charge for a basic workup was $2225; the most expensive charge was $8850 ➤ The tests with highest charges at the most expensive hospitals were sleep study ($5100), brain MRI ($6800), neck MRA ($7700), CT angiography of the brain ($8300), neck CT angiography ($8400), brain MRA ($8600), and transesophageal echocardiography ($8900)

affects costs for common diagnostic tests in stroke requires further study, said Dr Bhattacharya. n

Some Quality Measures Used in Emergency Care of Acute Ischemic Stroke Not Well-Validated

By Rosemary Frei, MSc

A

systematic review of existing quality measures for the emergency care of acute ischemic stroke has revealed that only 3 measures meet all of the American College of Cardiology (ACC)/American Heart Association (AHA) evaluation criteria (Sauser K, et al. Ann Emerg Med. 2014 Mar 7 [Epub ahead of print]).

“It is…important that the focus be on processes strongly supported by the evidence. For example, the magnitude of the relationship between patient outcomes and imaging within 45 minutes is not fully established; thus, if hospitals are to reengineer door-to-imaging systems to improve thrombolytic delivery, these relationships ought to be better quantified,” noted Kori L. Sauser, MD, MSc, Clinical Lecturer, Emergency Medicine, University of Michigan, Ann Arbor, and her colleagues.

Of the 976 articles reviewed, 4 articles were included in the final analysis; most of the others were not conducted in the United States. The team also found 6 groups that used the Internet

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to disseminate information on quality measure programs for the emergency care of acute ischemic stroke.

and 1 related to mortality.

A panel of 5 experts in emergency medicine, stroke neurology, internal

“Future quality measures for emergency care of ischemic stroke must have a strong evidence base and be tied to clinically meaningful outcomes.

Possibilities include out-ofhospital measures targeting emergency medical services coordination or blood pressure control.”

—Kori L. Sauser, MD, MSc, and colleagues In total, the articles and websites included 7 quality measures: 2 related to brain imaging, 3 to thrombolytic therapy, 1 to dysphagia screening,

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medicine, stroke epidemiology, and stroke quality improvement evaluated whether these measures met each of the 4 ACC/AHA criteria.

The 3 measures that did meet the criteria are: • Brain imaging within 24 hours of arrival at the emergency depart­ment • Thrombolytic therapy within 3 hours of symptom onset • Thrombolytic therapy within 60 minutes of arrival at the emergency department.

The other 4 measures that are used by many experts—a brain-imaging report generated within 45 minutes of arrival at the emergency department, consideration for antithrombolytic therapy, dysphagia screening, and mortality rate—did not meet all of the ACC/AHA criteria.

“This highlights the challenge of developing quality measures for the emergency care setting....Future quality measures for emergency care of ischemic stroke must have a strong evidence base and be tied to clinically meaningful outcomes. Possibilities include out-of-hospital measures targeting emergency medical services coordination or blood pressure control,” the group concluded. n VOL. 1

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Alzheimer’s Disease/Dementia

Could Immunotherapy Be the Future of Alzheimer’s... protein in neurofibrillary tangles. In certain dementias other than AD, tau accumulation may be the key event.

“There is overwhelming evidence that the aggregation of the amyloid beta peptide into different conformations leads to both local toxicity and inflammation, but importantly, it also contributes to exacerbation of tau, not just forming during normal aging in the hippocampus and adrenal cortex, but is spread into other parts of the neocortex,” said Dr Holtzman.

Mutations in the amyloid precursor protein (APP) associated with early-­ onset AD increase the production of amyloid beta42, which is more fibrillogenic than other amino acids that make up APP. Cerebrospinal fluid tau and amyloid beta42 predict progression from cognitively normal to very mild cognitive impairment (MCI) and from MCI to AD. Support for an immunologic approach was provided by studies showing that active immunization with amyloid beta42 in animals with certain phenotypes results in a marked decrease in amyloid-beta deposits and improved learning. Subsequent studies showed that providing monoclonal antibodies to the amy-

loid-beta peptide before amyloid deposition onset reduces amyloid-­ beta deposits.

Two humanized anti–amyloid-beta antibodies—bapineuzumab (3D6) and solanezumab (m266)—entered clinical trials in patients with AD. Antibodies against amyloid beta work by several mechanisms, depending on the conformation the antibody is directed against, said Dr Holtzman. One mechanism is the clearance of amyloid plaques by phagocytosis. Another is shifting the equilibrium from amyloid plaques to amyloid-beta monomers, “analogous to turning off the water faucet with a full sink of water but the stopper is slightly leaky,” he said.

The blockade of soluble amyloid-beta toxicity, analogous to neutralizing the part of amyloid-beta damage that damages nerve cells, is another potential mechanism.

Immunotherapy Too Late in Progressed Disease?

When given to older animals with amyloid plaques, m266 could not remove plaques from the brain, but it was associated with rapid improvement in behavioral tests.

The first clinical trials of passive immunization were in patients with “massive amounts of amyloid deposition throughout the neocortex” and a lot of neurofibrillary pathology, Dr Holtzman said.

“Because solanezumab appeared to slow cognitive decline in mild dementia, it is being tested specifically... in mild AD.” —David M. Holtzman, MD Phase 3 trials of bapineuzumab and solanezumab in patients with mild-­tomoderate AD had no effect on cognitive decline.

Certain secondary cognitive end points favored solanezumab in its 2 trials, and when the patients with mild dementia were considered separately, solanezumab was associated with a significant 33% reduction in

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cognitive decline.

One interpretation is that starting anti–amyloid-beta therapies in patients with moderate dementia is “likely to be too late for this approach,” Dr Holtzman said. “Because solanezumab appeared to slow cognitive decline in mild dementia, it is being tested specifically in a third large phase 3 trial in mild AD. This makes sense.”

Neither solanezumab nor bapineuzumab appear effective at removing existing amyloid plaques, he said, although they can potentially neutralize toxic species of amyloid beta. Combination therapies may have a better chance at removing amyloid plaques and decreasing amyloid-beta toxicity.

Targeting Tau Animal experiments show that antitau antibodies can strongly decrease tau pathology and improve behavior, which suggests the potential of tau immunotherapy as a therapeutic approach, said Dr Holtzman. Several studies are scheduled to begin in humans to determine the safety of tau immunotherapy. If successful, tau immunotherapy will proceed to efficacy studies in AD and other dementias. n

Novel Protocol Improves Cognition, Outperforms Community Treatment of Dementia

By Wayne Kuznar Philadelphia, PA—A protocol that identifies reversible or modifiable contributory factors to cognitive impairment when used in combination with the aggressive use of approved antidementia medications can improve the cognitive status of patients with dementia or mild cognitive impairment.

The protocol consists of a comprehensive assessment and treatment of cognitive impairing conditions, such as hypoxia, hyperhomocysteinemia, iron deficiency, and bradycardia. The approach outperformed the standard of care received in the community on the outcome of cognition over 2 years, reported Emily F. Clionsky, MD, Chief Medical Officer, Clionsky Neuro Systems, Springfield, MA, at the 2014 American Academy of Neurology meeting.

The need for a more effective approach to managing dementia is urgent, said Dr Clionsky, because current medications have limited benefit.

Dementia Protocol Dr Clionsky’s protocol measures heart rate and O2 status at rest and VOL. 1

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nocturnally, and homocysteine and iron levels are assessed regularly. “If a patient is hypoxic, the microvasculature will be abnormal at a molecular level,” she said. “Fix the lack of oxygen, and you’re going to help the cell itself stay stable and reduce reactive oxygen species.”

“I take the standard antidementia drugs, and I drive them to as high a dose as I possibly can.”

—Emily F. Clionsky, MD A sleep study is ordered if the patient’s score on the Memory Orientation Screening Test (MOST) is >16, and positive airway pressure treatment is started if sleep apnea is diagnosed. Memantine (Namenda) is then initiated and is followed by the addition of an acetylcholinesterase inhibitor, titrated to the highest dose tolerated without side effects.

“I take the standard antidementia

drugs, and I drive them to as high a dose as I possibly can,” Dr Clionsky said. “Some patients were on rivastigmine at 19 mg before the Food and Drug Administration ever cleared the 13.3-mg dose.”

Donepezil (Aricept), which is known to slow heart rate, is avoided if the patient has bradycardia. “Before I’ll treat with an acetylcholinesterase inhibitor, I’ll fix the low heart rate,” Dr Clionsky said.

Benzodiazepines, narcotics, and sleep medications (other than eszopiclone [Lunesta]) are avoided and urinary incontinence medications are discontinued. Cognition is reassessed every 8 to 12 weeks after an intervention or a treatment change. Patients are screened for neuropathy and are treated if it is present, and supervised gait training is ordered. Exercise and social activity are prescribed, and family support is encouraged.

Improvement in Cognition The longitudinal analysis reported here compared 362 heterogeneous july 2014

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patients who were managed with the protocol and a matched cohort of 280 patients receiving standard care in the community. Cognition was the primary outcome measure using the MOST. In all, 82.6% of the protocol-managed patients were hypoxic. A total of 30% of patients had nocturnal hypoxia, and 20% showed nocturnal hypoxia during a sleep study. “More important, that same group of patients had about an 80% rate of bradycardia,” Dr Clionsky said.

In the 2-year comparison, the mean MOST score was 17.82 with the advanced protocol versus 12.12 with standard community care (P = .001).

The score of 17.82 in the group treated according to the advanced dementia protocol represents a 17.3% improvement from baseline, whereas those treated in the community saw their score drop by approximately 25%.

“The results in the community care group are what we see with typical dementia drugs,” said Dr Clionsky.

“We saw stabilization and improvement in the protocol group.” n

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Migraine Therapy

Two Monoclonal Antibodies Hold Promise of Migraine Prevention

By Wayne Kuznar Philadelphia, PA—Two investigational monoclonal antibodies against the calcitonin gene-related peptide (CGRP) proved safe and effective at preventing migraine in a pair of phase 2, placebo-­ controlled, proof-of-concept trials, researchers reported at the 2014 American Academy of Neurology meeting.

These findings warrant “cautious optimism that a new mechanism-based, disease-specific migraine prevention is in sight,” said David W. Dodick, MD, FACP, Professor of Neurology, Mayo Clinic, Phoenix, AZ, and lead investigator of one of the trials.

CGRP is a therapeutic target because this sensory neuropeptide is released during migraine and acts as a trigger for attacks, Dr Dodick said. It is involved in neurogenic inflammation and promotes vasodilation. Levels of CGRP are normalized by triptan drugs.

Several CGRP receptor antagonists have demonstrated efficacy in the acute treatment of migraine.

CGRP Receptor LY2951742 Dr Bodick presented a study involv-

These findings warrant “cautious optimism that a new mechanism-based, disease-specific migraine prevention is in sight.”

—David W. Dodick, MD, FACP ing the CGRP receptor LY2951742, which has >10,000-fold selectivity for CGRP compared with related peptides.

A total of 217 patients who had mi-

graines on 4 to 14 days monthly received 150-mg injections of LY2951742 or placebo every 2 weeks for 12 weeks.

At baseline, patients had a mean of 7 migraine days monthly.

The mean reduction in monthly migraines was 4.2 days in the LY2951742 group compared with 3 monthly migraines with placebo (P = .003). By month 3, there were 3 times more responders (defined as >50% reduction in migraine days) with LY2951742 than with placebo.

LY2951742 was safe and well toler­ ated, with no clinically meaningful changes on patients’ electrocardiograms, no prolongation of the QT interval, and no evidence of hepatotoxicity. The adverse events that occurred more often with LY2951742 included injection-site pain, upper respiratory tract infections, and abdominal pain.

CGRP Receptor ALD403 The second study involved the CGRP receptor ALD403 in 163 patients who had 5 to 14 migraine days monthly. They were randomized to a single

hour-long infusion of 1000 mg of ALD403 or to placebo and were followed for 3 months. Migraine data were collected electronically from patient diaries.

ALD403 met the primary end point of significantly reducing the mean monthly migraine days compared with placebo (–5.6 days vs –4.6 days) during weeks 5 to 8, reported Peter J. Goadsby, MD, PhD, DSc, King’s College London, England, and Director, Headache Center, University of California, San Francisco. However, the difference was no longer significant at week 12.

Depending on the month of observation, ALD403 resulted in a 100% reduction in migraines in 27% to 41% of patients. Approximately 16% of patients in the ALD403 group were free of migraines for the full 3-month study period compared with none of the patients in the placebo group.

There were no biochemical changes in the ALD403 group and the agent appeared safe—the rates of adverse events were 56% with ALD403 and 50% with placebo. n

Breath-Powered Intranasal Sumatriptan Has Rapid Absorption, Provides Fast Migraine Relief Philadelphia, PA—A breath-powered intranasal powder form of sumatriptan produces fast and sustained relief of migraine, according to the results of a phase 3, placebo-controlled trial presented at the 2014 American Academy of Neurology meeting.

Approximately 66% of patients using the powder form of sumatriptan had headache relief within 2 hours, and more than 33% were pain-free; these effects were maintained for 48 hours.

This new delivery system uses a closed-palate breath-powered device to deliver sumatriptan powder to deep nasal passages, where it is absorbed faster compared with conventional nasal sprays, said Roger K. Cady, MD, Founder, Headache Care Center, Springfield, MO, and lead investigator of the study.

Patients with migraine frequently cite the slow onset of action of oral triptans as a reason for dissatisfaction, Dr Cady said.

“This is really a very unique way of delivering drugs using the nasal mucosa,” said Dr Cady. “The standard liquid-based nasal sprays can be very

16

useful, but the problem is that often the spray doesn’t get beyond the nasal valve and tends to run out the front.

And if it gets on the floor of the nasal cavity, it’s often swallowed. So, very often the results are inconsistent.”

The breath-powered device counters these potential problems. One part of the device is placed into the nostril and the other part in the mouth. “Instead of trying to coordinate sniffing and spraying, the patient blows out, and then the device delivers a powder form of sumatriptan, which adheres to the nasal mucosa,” Dr Cady said.

The region deep into the nasal cavity has a large surface to facilitate rapid absorption. In a pharmacokinetic study, the intranasal powder form of sumatriptan absorbed faster than the conventional nasal spray.

The intranasal powder form was tested in a phase 3, multicenter, double-blind, placebo-controlled, single-­ dose, parallel-group study of 230 patients who had 1 to 8 migraines monthly in the previous 12 months.

For the treatment of a single migraine of moderate or severe intensity, pa-

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tients received 1 half-dose of powder sumatriptan (11 mg per capsule, for a total of 22 mg of sumatriptan) delivered into each nostril or placebo.

“Instead of trying to coordinate sniffing and spraying, the patient blows out, and then the device delivers a powder form of sumatriptan.”

—Roger K. Cady, MD At 120 minutes after dosing, 68% of patients assigned to powder sumatriptan reported headache relief compared with 45% of patients receiving placebo (P <.01). The difference in headache relief between the 2 groups achieved statistical significance (P <.05) at 30 minutes, when 42% of patients receiving active treatment and 27% receiving placebo reported relief.

Meaningful relief (70% vs 45%, respectively; P = .004) and complete relief (34% vs 17%, respectively; P = .008)

of headache also occurred significantly more often at 120 minutes with powder sumatriptan than with placebo.

Sustained headache relief and sustained freedom from pain (at 24 hours and 48 hours) without rescue medication were significantly more likely with active treatment, and rescue medication was required significantly less often in patients assigned to powder sumatriptan compared with placebo (37% vs 52%, respectively; P <.05).

“Given the small drug exposure, there are very few side effects that we would associate with triptans,” said Dr Cady.

The incidence of migraine-associated symptoms, such as nausea, vomiting, photophobia, and phonophobia, was reduced with powder sumatriptan, but the differences failed to achieve significance.

The most common adverse events associated with powder sumatriptan were product taste, nasal discomfort, and rhinitis; these were transient and mostly of mild-to-moderate severity.

There were no serious adverse events in the active treatment group.—WK n VOL. 1

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Drug Update

Higher Dose, Fewer Weekly Injections of Copaxone (Glatiramer Acetate) Approved by the FDA for Patients with Relapsing Forms of Multiple Sclerosis

By Loretta Fala, Medical Writer

M

ultiple sclerosis (MS), a chronic inflammatory disease, is one of the leading causes of neurologic disability in young adults.1 In addition to damaging the myelin sheath of nerve fibers, MS causes degeneration of nerve fibers in the brain and spinal cord. MS can also lead to impaired movement, coordination, sensation, and cognition.1 An estimated 2.3 million people worldwide are affected by MS.2 Although the exact prevalence of MS in the United States is not known, it is estimated that 350,000 to 400,000 people may be affected by the disease.2,3 These estimates may be understated because individuals with mild forms of MS may go undiagnosed. MS is most common in Caucasians of northern European descent, and it is 2 to 3 times more common in women than it is in men—suggesting that hormones may contribute to susceptibility.4 Although MS can start in individuals aged between 10 and 80 years, it more often begins between the ages of 20 and 40 (mean age, 32 years).3 MS is generally associated with episodes of numbness, weakness, or dys­ coordination in an arm, leg, or both.3 Symptoms may also include sensory or motor changes to one side of the body, diplopia, optic neuritis, or ataxia. Other symptoms of MS include bladder and bowel dysfunction, fatigue, decreased memory, and depression.3 MS imposes a substantial economic burden that encompasses direct medical costs and indirect costs result­ ing from reduced productivity and health-related quality of life. In the United States, MS-related costs exceed $10 billion annually.3 Evidence suggests that indirect costs increase as the severity of MS progresses.5 A review of 15 studies showed that the total healthcare costs for MS ranged from $8528 to $54,244 per patient per year, with direct costs accounting for 77% and indirect costs accounting for 23% of the total costs.6 Another systematic review showed that although direct costs contributed to costs in the earlier stages of MS, they were exceeded by indirect costs incurred during later stages or increased disease severity, most likely because of relapses and lost productivity.7 Interventions that delay the progression of MS may help to im-

prove patient outcomes (eg, quality of life) and reduce costs.3,7 MS is characterized by episodes of relapses that are initially followed by remissions. Over time, recovery may be incomplete, leading to a progressive decline.1 The 2 major clinical patterns of MS are relapsing disease, characterized by clearly defined relapses or exacerbations; and progressive disease, characterized by a gradual but steady worsening of disability.8 Relapsing-remitting MS (RRMS) involves episodes that last days to weeks, with full or partial recovery and no disease progression between attacks. An estimated 85% of patients with MS initially have the relapsing-­ remitting form of the disease. The progressive forms of MS include primary-­ progressive, secondary-progres­sive, and progressive-relapsing.8 MS is often difficult to diagnose and is challenging to manage, given the ebb and flow of the disease course and symptoms. Nevertheless, early diagnosis and treatment, as well as adherence to prescribed treatment, are essential for optimal outcomes.3 Early, appropriate treatment can substantially slow disease progression, but if left untreated, MS can lead to disability.3 The disease-modifying therapies have been shown to be effective at reducing disease activity and disease progression in many patients with relapsing forms of MS.9 The disease-­ modifying therapies include the beta interferons (ie, interferon beta-1a and interferon beta-1b), glatiramer acetate, natalizumab, and 3 oral therapies, including fingolimod, teriflunomide, and dimethyl fumarate. Corticosteroids may also be used to reduce inflammation during a relapse.9 In March 2014, the American Academy of Neurology published evidence-based practice guidelines for alternative and complementary medicines for MS.10 Symptom-management strategies for MS include physical therapy, muscle relaxants, dalfampridine (to improve walking speed), medications to reduce fatigue, and medications for depression, pain, bladder, or bowel control. In addition, sufficient rest, exercise, balanced nutrition, and stress relief may help to alleviate MS symptoms.11 A New Therapeutic Option Requiring Fewer Weekly Injections On January 28, 2014, the US Food

ALA Trial: Clinical End Points of Glatiramer Acetate versus Placebo in Patients Table 1 G with RRMS Glatiramer acetate Confirmed relapses 40 mg/mL Placebo during 12 months (N = 943) (N = 461) P value Adjusted mean estimates, N

0.331

Relative risk reduction, %

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<.001

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RRMS indicates relapsing-remitting multiple sclerosis.

Source: Copaxone (glatiramer acetate) injection prescribing information; January 2014. and Drug Administration (FDA) approved a higher-dose (40 mg/mL), lower-frequency (3 times weekly) regi­ men for glatiramer acetate (Copaxone; Teva Pharmaceuticals) for the treatment of patients with relapsing forms of MS.12 In 1996, the FDA approved glatiramer acetate 20 mg/mL injection administered once daily for RRMS.13 The FDA approval of glatiramer acetate 40 mg/mL 3 times weekly was based on findings from the multicenter GALA trial.14 According to the principal study investigator Omar Khan, MD, Wayne State University School of Medicine, Detroit, MI, “The availability of 3 times a week Copaxone 40 mg/mL is a significant advancement for patients as they now have the option of effective and safe treatment with Copaxone, while reducing the number of injections by 60%.”12 Mechanism of Action The exact mechanism by which glatiramer acetate exerts its effects is not fully understood. However, gla­ tiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS.15 Dosing and Administration Glatiramer acetate is for subcutaneous injection only. The dosing schedule is dependent on the drug strength that is selected. The recommended doses for glatiramer acetate are 20 mg/mL administered once daily, or 40 mg/mL administered 3 times weekly and at least 48 hours apart. The 20-mg/mL dose and the 40-mg/mL dose are not interchangeable.15 GALA: A Phase 3 Clinical Trial The safety and efficacy of glatira­ mer acetate 40 mg/mL were demonstrated in the GALA trial, a double-­

Copyright © 2014 American Health & Drug Benefits.

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blind, placebo-controlled trial of 1404 patients with RRMS who were randomized in a 2:1 ratio to receive either glatiramer acetate 40 mg/mL (N = 943) or placebo (N = 461) 3 times weekly for 12 months.14,15 In this trial, the patients had a median of 2 relapses within 2 years before screening, and they had not received any interferon-beta for at least 2 months before screening. The patients’ baseline Expanded Disability Status Scale scores ranged from 0 to 5.5, with a median score of 2.5. Neurologic evaluations were performed at baseline, every 3 months, and at unscheduled visits for a suspected relapse or early termination. Magnetic resonance imaging (MRI) was conducted at baseline, at months 6 and 12, or at early termination. Overall, 91% of patients assigned to glatiramer acetate and 93% of patients assigned to placebo completed treatment at 12 months.14,15

Efficacy

The primary outcome measure in the GALA study was the total number of confirmed relapses, defined as the persistence of neurologic symptoms for at least 24 hours and confirmed on examination with objective signs.14 Patients with RRMS who received glatiramer acetate 40 mg/mL 3 times weekly showed a 34% reduction in risk of confirmed relapses compared with patients receiving placebo (0.331 vs 0.505; P <.001; Table 1).14,15 The effect of glatiramer acetate on several MRI variables, including the number of new or enlarging T2 lesions and the number of enhancing lesions on T1-weighted images, was assessed at months 6 and 12.14 Compared with patients taking placebo, patients who received glatiramer acetate 40 mg/mL 3 times weekly had a 35% reduction in new or newly enlarging T2 lesions (3.650 vs 5.592;

Continued on page 18

www.ValueBasedNeurology.com

17

Drug Update

Higher Dose, Fewer Weekly Injections of Copaxone... Continued from page 17 Table 2 GALA Trial: MRI End Points of Glatiramer Acetate versus Placebo in Patients with RRMS Glatiramer acetate 40 mg/mL Placebo MRI end points (N = 943) (N = 461) P value Cumulative new or enlarging T2 lesions at months 6 and 12 Adjusted mean estimates, N Relative risk reduction, %

Injection-site erythema

22

2

Nasopharyngitis

11

9

Injection-site pain

10

2

Injection-site edema

6

0

Injection-site mass

6

0

Injection-site pruritus

6

0

Pyrexia

3

2

Influenza-like illness

3

3

Respiratory tract infection, viral

3

2

should be advised to follow proper injection techniques and to rotate injection sites with each injection.15 Immune response modification. Because glatiramer acetate can modify the immune response, it may interfere with immune functions.15

Dyspnea

3

0

Vasodilation

3

0

Chills

2

0

Chest pain

2

1

Nausea

2

1

Erythema

2

0

Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies with glatira­mer acetate in pregnant wom­ en. Glatiramer acetate should be used during pregnancy only if clearly needed.15 Nursing mothers. It is not known whether glatiramer acetate is excreted in human milk. Caution should be exercised when glatiramer acetate is administered to a nursing woman.15 Pediatric use. The safety and effectiveness of glatiramer acetate have not been established in patients aged <18 years.15 Geriatric use. Glatiramer acetate has not been studied in elderly patients.15

Injection-site inflammation

2

0

Rash

2

1

3.650

5.592

<.001

35

Cumulative enhancing lesions on T1-weighted images at months 6 and 12 Adjusted mean estimates, N Relative risk reduction, %

0.905

1.639

<.001

45

MRI indicates magnetic resonance imaging; RRMS, relapsing-remitting multiple sclerosis.

Source: Copaxone (glatiramer acetate) injection prescribing information; January 2014.

P <.001), and a 45% reduction in the cu­ mulative number of T1 lesions (0.905 vs 1.639; P <.001; Table 2).12,14

Safety

The most common (≥10% and ≥1.5 times higher than placebo) adverse reactions in the GALA trial were injection-site reactions.14,15 Adverse reactions reported in ≥ 2% of patients receiving glatiramer acetate 40 mg/mL versus placebo are shown in Table 3.15 Warnings and Precautions Contraindications. Glatiramer acetate is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.15 Immediate postinjection reaction.

Flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria may occur immediately after injection. Generally, the onset of these symptoms occurs several months after initiation of treatment.15 Chest pain. Chest pain may occur in the context of immediate postinjection or on its own. In clinical trials, chest pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients had more than 1 such episode; these episodes usually began at least 1 month after treatment was initiated.15 Lipoatrophy and skin necrosis. Lipo­ atrophy and, rarely, injection-site skin necrosis may occur at injection sites. To help minimize these events, patients

Intracerebral Hemorrhage Rates... Continued from page 13

dence of ICH, but case fatality and long-term mortality were unchanged among the 734 ICH cases that met the inclusion criteria. The age-, sex-, and ethnicity-adjusted ICH annual incidence rates were 5.21 per 10,000 in 2000 and 4.3 per 10,000 in 2010. The estimated 10-year change in annual incidence

18

Table 3 Adverse Reactions in ≥2% of Patients Receiving Glatiramer Acetate Glatiramer acetate 40 mg/mL, % Placebo, % Adverse reaction (N = 943) (N = 461)

Source: Copaxone (glatiramer acetate) injection prescribing information; January 2014. showed a significant reduction in risk of confirmed relapses compared with patients receiving placebo. Moreover, patients receiving glatiramer acetate had a significant reduction in new or newly enlarging T2 lesions and in the cumulative number of T1 lesions compared with patients taking placebo.

The most common adverse reactions associated with 40 mg/mL glatiramer acetate were injection-site reactions. n

Conclusion The recent FDA approval of gla­ tiramer acetate 40 mg/mL 3 times weekly marks the availability of a new, more convenient therapeutic option for patients with RRMS—offering appropriate patients a treatment that requires fewer subcutaneous injections weekly.

In the phase 3 GALA trial, patients with RRMS who received glatiramer acetate 40 mg/mL 3 times weekly

References

rate of ICH was −31% (95% confidence interval [CI], −47% to −11%).

The decline in incidence rates over time was most prominent in patients aged ≥75 years or 60 to 74 years. The incidence of ICH was higher in Mexican Americans than in non-Hispanic whites (overall risk ratio, 1.75; 95% CI, 1.48-2.07), with a greater difference observed in patients aged 45 to 59

years than in older patients.

The annual demographic-adjusted 30-day case fatality rates ranged from 28.3% in 2006 to 46.5% in 2008. When time was used as a linear variable, no change was seen in demographic-­ adjusted ICH fatality over time. In addition, no change over time was seen in long-term, 3-year mortality. The researchers observed a trend toward a

value-based CARE in Neurology

I July 2014

1. National Institutes of Health. Multiple sclerosis. Fact sheet. Updated October 2010. http://report.nih.gov/ nihfactsheets/Pdfs/MultipleSclerosis%28NINDS%29. pdf. Accessed June 17, 2014.

2. National Multiple Sclerosis Society. MS prevalence. www.nationalmssociety.org/About-the-Society/ MS-Prevalence. Accessed April 22, 2014.

3. Fox RJ. Cleveland Clinic. Multiple sclerosis. August 1, 2010. www.clevelandclinicmeded.com/medicalpubs/ diseasemanagement/neurology/multiple_sclerosis.

Published August 1, 2010. Accessed April 21, 2014.

4. National Multiple Sclerosis Society. Who gets MS? (Epidemiology). www.nationalmssociety.org/Whatis-MS/Who-Gets-MS. Accessed April 22, 2014.

5. Wundes A, Brown T, Bienen EJ, Coleman CI. Contribution of intangible costs to the economic burden of multiple sclerosis. J Med Econ. 2010;13:626-632.

6. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647.

7. Naci H, Fleurence R, Birt J, Duhig A. Economic burden of multiple sclerosis: a systematic review of the literature. Pharmacoeconomics. 2010;28:363-379.

8. National Multiple Sclerosis Society. Multiple sclerosis bilingual fact sheet. July 2007. www.nationalms society.org/NationalMSSociety/media/MSNational Files/Brochures/Brochure-Hoja-bilingue-de-informa cion-sobre-la-esclerosis-multiple-Multiple-SclerosisBilingual-Fact-Sheet.pdf. Accessed April 22, 2014.

9. National Multiple Sclerosis Society. Medications. www.nationalmssociety.org/Treating-MS/Medica tions. Accessed April 22, 2014.

10. Yadav V, Bever C Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82:1083-1092.

11. Mayo Clinic staff. Mayo Clinic. Diseases and conditions: multiple sclerosis. December 15, 2012. www.mayo clinic.org/diseases-conditions/multiple-sclerosis/ basics/definition/con-20026689. Accessed April 22, 2014.

12. Teva Pharmaceuticals. Teva announces U.S. FDA approval of three-times-a-week COPAXONE (glatira­ mer acetate injection) 40 mg/dL. January 28, 2014. www. tevapharm.com/Media/News/Pages/2014/1894510. aspx?year=2014. Accessed April 22, 2014.

13. Jeffrey S. FDA approves 3-times-a-week Copaxone in MS. Medscape Medical News. January 29, 2014. www. medscape.com/viewarticle/819910. Accessed April 16, 2014.

14. Khan O, Rieckmann P, Boyko A, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73:705-713.

15. Copaxone (glatiramer acetate) injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; January 2014.

lower risk of death for Mexican Americans compared with non-Hispanic whites in 30-day case fatality and 3-year mortality.

The declining incidence of ICH is possibly representative of the increasingly improved population control of hypertension. Yet, case fatality and long-term mortality were unchanged in this population-based study. n VOL. 1

I

NO. 2

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