Value-Based Care in Neurology by The Lynx Group

JULY 2016 • VOL 3 • NO 2

www.ValueBasedNeurology.com

Better Care Is Less Costly: Quality Improvement Through Process Management By Chase Doyle

New Indications for Novel Antiepileptic Drugs May Offer Advantages for Patients with Seizures By Corbin Davis

lthough there have been im portant improvements in anti epileptic drug (AED) therapy options in recent years, many patients with epilepsy still have disease refracto ry to certain therapies. A survey of the newest AEDs shows clinical progress and improved outcomes, but also room for improvement. “The 4 newest AEDs have possible advantages over previously approved drugs. However, at this point, none is

clearly better or considered suitable for first-line therapy,” said Carl W. Bazil, MD, PhD, Director, Comprehensive Epilepsy Center, Columbia University, New York, at the 2016 American Acad emy of Neurology annual meeting. Clobazam

Clobazam (Onfi) has been available in many developed countries for de cades. It was approved by the FDA in 2011 as an orphan drug for the adjunc Continued on page 14

his year’s Presidential Lecture at the 2016 American Acade my of Neurology annual meet ing in Vancouver, BC, was delivered by Brent C. James, MD, MStat, Exec utive Director and Quality Officer, In

termountain Healthcare Leadership Institute, Salt Lake City, UT. Clinicians at Intermountain Health care Leadership Institute are saving lives and millions of dollars by apply ing rigorous measurement tools to rou Continued on page 4

Monoclonal Antibodies: The Future of Migraine Therapy By Corbin Davis

igraines are among the most common disorders around the world, and they are also one of the leading causes of disability. And yet, the current list of preventive medications for migraines primarily includes drugs

that were developed for other indications and co-opted for migraine therapy. However, research presented at the 2016 American Academy of Neurology annual meeting reveals new therapeutic targets for headache. Combined with a Continued on page 16

Ocrelizumab Promotes No Evidence of Disease Activity in Multiple Sclerosis

First therapy to receive breakthrough therapy status for this disease By Chase Doyle

wo large, phase 3 clinical trials demonstrated that targeting B-cells can have a significant im pact on disease progression in patients with relapsing multiple sclerosis (MS). In a head-to-head comparison of the investigational ocrelizumab (Ocrevus) with interferon beta-1a (Rebif), a great

Continued on page 10

INSIDE FDA NEWS. . . . . . . . . . . . . . . . . . . . . . . . . .

MULTIPLE SCLEROSIS. . . . . . . . .

VALUE IN NEUROLOGY. . . . . . . . .

NEUROLOGIC DISORDERS. . .

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

EPILEPSY/SEIZURES . . . . . . . . . . . .

DRUG UPDATE . . . . . . . . . . . . . . . . . .

Nuplazid first drug for Parkinson’srelated hallucinations and delusions

Alemtuzumab most cost-effective for no disease activity in MS MS tops neurology drug costs in Medicare payments

er proportion of patients who received ocrelizumab had no evidence of disease activity (NEDA) during the 96-week study than did patients who received interferon beta-1a, with the elimination of new or enlarging T2 lesions in nearly all patients after week 24. Touted as a “wonderful achievement”

Dichlorphenamide improves outcomes in periodic paralysis

Natalizumab beneficial in slowing disability progression in MS Zika virus linked to Guillain-Barré syndrome

Individualizing antiepileptic drug therapy Zinbryta: first once-monthly, selfadministered treatment for MS

ENGAGE

HEALTHCARE COMMUNICATIONS, LLC

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President/Group Publisher John W. Hennessy jhennessy2@the-lynx-group.com Manager, Client Services Firas Kwara fkwara@the-lynx-group.com Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Editorial Assistant Cara Guglielmon Senior Production Manager Melissa Lawlor

VALUE IN NEUROLOGY

MULTIPLE SCLEROSIS

Ozanimod achieves very low relapse rate in MS More…

Benefits of early aggressive therapy debated More…

FDA NEWS

NEUROLOGIC DISORDERS

Nuplazid first drug approved for hallucinations and delusions associated with Parkinson’s disease More…

Zika virus linked to Guillain-Barré syndrome

VALUE IN NEUROLOGY Alemtuzumab most cost-effective MS treatment for achieving no disease activity

IN THE LITERATURE Multiple sclerosis tops neurology drug costs in Medicare payment More…

President/CEO Brian Tyburski Senior Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President, Finance Andrea Kelly Senior Financial Assistant Audrey LaBolle Director, Human Resources Jennine Leale Medical Director Julie Strain Director, Strategy & Program Development John Welz Editorial Director Susan Berry Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Design Managers Chris Alpino Lora LaRocca Director, Digital Marketing Samantha Weissman Digital Content Manager Anthony Trevean Digital Editor John Parkinson Digital Media Specialist Charles Easton IV Junior Digital Content Manager Walford Guillaume Junior Digital Developer Christina Bethencourt Executive Administrative Assistant/Office Manager Dana Rivera Administrative Assistant Colette Puhalski IT Manager Kashif Javaid Office Coordinator Robert Sorensen

President Abigail Adair Account Group Supervisor Karie Gubbins Account Supervisors Alex Charles Deanna Martinez Senior Account Executive Jeremy Shannon Project Coordinator Beagy Fils-Aime Business Development Advisor Saher Almaita

EPILEPSY/SEIZURES Novel antiepileptic drugs may offer advantages More…

MIGRAINE UPDATE Monoclonal antibodies for migraine therapy More…

ALZHEIMER’S DISEASE Lifestyle enrichment and Alzheimer’s biomarkers

DRUG UPDATE

EMERGING THERAPIES Ocrelizumab promotes no evidence of disease activity in multiple sclerosis More…

Zinbryta: first once-monthly, self-administered treatment 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

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

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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. EHC1105-2

Value in Neurology

Better Care Is Less Costly: Quality Improvement... tine patient care. They are showing that the future of medicine, and neurology, may be driven more by the science of implementation than by technical innovation. “We count our successes in lives. Each year, I can document well more than 2000 Intermountain patients who would have died, but did not,” said Dr James. “Moreover, from a purely finan cial perspective, this has a more finan cial upside than developing and apply ing new technologies.” Shared Baseline Protocols

Dr James reported that there are sev eral problems with “best care” protocols, including that level 1, 2, or 3 evidence is only available a small percentage of the time; expert consensus is unreliable; and that guidelines do not guide prac tice, because no 2 patients are the same. Conversely, shared baseline protocols use data-driven process management to deliver better patient care. Dr James recommends the following steps to im plement the shared baseline protocol: 1. Identify a high-priority clinical pro cess (eg, for sepsis) 2. Build an evidence-based best practice protocol. This is always imperfect be cause of poor evidence and unreliable consensus, but the model is essential for what follows 3. Blend this protocol into clinical workflow, which provides clinical de cision support. Dr James stressed the importance of not relying on human memory, noting “Make ‘best care’ the lowest energy state, the default choice that happens automatically, unless someone must modify” 4. Embed data systems to track protocol variations and the short-term and long-term patient results, including clinical, cost, and satisfaction out comes. “Anytime somebody varies from protocol, you need to know that a variance has occurred. Side by side with the workflow, track what hap

In addition to the improvement in clinical outcomes, the sepsis bundle has also reduced the cost of care at Inter mountain by $1.3 million annually and has lowered its actual operating margins by $720,000. This approach has also led

to unorthodox organizational goals, such as reducing revenues. “If you’re reducing revenues by deliv ering better, more cost-effective care, it makes perfect sense. Our operating mar gins are the strongest we’ve ever seen,” said Dr James. “We’re showing that better care is cheaper care. Better clinical results nearly always produce lower costs,” Dr James added. More than 50% of all those cost-sav ings will take the form of unused capaci ty, such as fixed costs (eg, empty hospital beds), empty clinical patient appoint ments, and reduced procedure, imaging, and testing rates. This, in turn, is bal anced by dramatically growing demand. “We’re creating the capacity for that extra demand without building more hospitals or scanners. Our current phy sician and nurse workforce can meet those needs. It’s called increased pro ductivity…balanced by increasing de mand,” Dr James explained. However, this methodology implies a partnership between the medical and nursing staff and administration, and it is not about putting administrators in control, he emphasized. “The only way we’re going to survive is for physicians and nurses to step out and create a new future that works for all of us in close partnership with our ad ministrative colleagues,” Dr James said. Considerable work remains, but de spite the challenge, Dr James’s opti mism is unwavering. In his vision, a new healthcare delivery model involves the right care, delivered at the right time, at the lowest necessary cost, and under each patient’s full knowledge and control. Accomplish this, and the re sults will be nothing short of transfor mative, he said. “Medicine is still the best profession the world has ever seen,…and we have not yet begun to understand how good we can be for our patients,” he concluded. n

versus the interferon beta-1a group. The second study compared daclizumab with placebo in 412 patients with re lapsing MS. Daclizumab had a 54% re lapse reduction, a 57% reduction in disease progression, a 70% reduction in new or newly enlarging T2 hyperin tense lesions, and a 69% reduction in new T1 Gd-enhancing lesions versus interferon beta-1a. Of note, 81% of pa tients using daclizumab were relapse-

free compared with 64% in the interfer on beta-1a group. The most common adverse events re ported with daclizumab in the 2 studies included nasopharyngitis, upper respira tory tract infection, eczema, rash, influen za, dermatitis, depression, oropharyngeal pain, lymphadenopathy, and increased alanine aminotransferase levels. Daclizumab was approved with a boxed warning about the serious risk for

to focus on a relatively narrow band of factors, where you can be maximally effective,” he advised. New Standard for Sepsis Care Saves Lives

“Each year, I can document well more than 2000 Intermountain patients who would have died, but did not. Moreover, from a purely financial perspective, this has a more financial upside than developing and applying new technologies.” —Brent C. James, MD, MStat

pens with your patients” 5. Demand that clinicians vary care based on the needs of patients. “We don’t just encourage this, we demand it. I can never get a guideline that fits every patient. That’s why we have doctors; I need a thinking-minded interface,” Dr James remarked 6. Feed data back in a lean learning loop and continuously update and im prove the protocol. Because theory is always an abstraction, the last step may be the most important; valida tion data are needed to show where the model really produces. “It’s im portant to tune one’s theory to reali ty,” noted Dr James. The result is to take a complex envi ronment and to “allow the human mind

Continued from the cover

According to the Centers for Disease Control and Prevention, one of the leading causes of hospital deaths is sep sis, and the rate of inpatient deaths re sulting from septicemia is rising. Before implementing the shared baseline pro tocol at Intermountain, the mortality rate for sepsis resulting from emergency department transfers to the intensive care unit was approximately 20%. “This rate was one of the best in the nation. We now average 8.1%, which is a new standard for sepsis care,” Dr James reported. The sepsis bundle alone has translat ed to more than 125 additional lives saved annually. When combined with other protocols, the data-driven, clini cal management approach is responsi ble for more than 2000 lives annually. “Mortality is just the tip of the ice berg. We’ve also seen a dramatically bigger impact in terms of function re stored and suffering averted,” he said.

“We’re showing that better care is cheaper care. Better clinical results nearly always produce lower costs.” —Brent C. James, MD, MStat

Clinical Outcomes Drive Cost Outcomes

FDA News Zinbryta a New Treatment Available for Relapsing Multiple Sclerosis

On May 27, 2016, the FDA ap proved daclizumab (Zinbryta; Biogen/ AbbVie), a long-acting injection, for the treatment of adults with relapsing forms of multiple sclerosis (MS). Daclizumab can be self-administered by the patient. Daclizumab is recommended for patients who had an inadequate response to ≥2

drugs for MS, because of its safety profile. Daclizumab was approved for relaps ing MS based on 2 double-blind, con trolled clinical trials that used 150 mg of daclizumab, administered once month ly. The first trial compared daclizumab with interferon beta-1a (Avonex) in 1841 patients with relapsing MS. The daclizumab group had a 45% relapse reduction and a 54% reduction in new or enlarging T2 hyperintense lesions

Value in Neurology

Alemtuzumab Most Cost-Effective Multiple Sclerosis Treatment for Achieving No Evidence of Disease Activity By Corbin Davis

cost-effectiveness analysis of relapsing-remitting multiple sclerosis (MS) therapies has shown the importance of using firstline treatments first to treat the dis ease. In terms of achieving no evi dence of disease activity (NEDA), the most effective treatment strategy was natalizumab in the first-line setting, followed by alemtuzumab as first-line treatment, according to a presentation at the 2016 American Academy of Neurology annual meeting. Based on the researchers’ model, however, alemtuzumab was the most cost-effective treatment strategy, yield ing a cost-effectiveness of $79,086 per quality-adjusted life-year (QALY). “Despite a slightly higher 3-year util ity, natalizumab’s costs far exceeded even the most liberal willingness-to-pay thresholds. Alemtuzumab was the most cost-effective treatment option,” said Daniel Ontaneda, MD, Mellen Center for Multiple Sclerosis, Cleveland Clin ic, OH. Although NEDA has become an at tainable goal using currently approved MS therapies, the cost of disease-modi fying therapies (DMTs) has risen dra matically in recent years. In addition, although the optimal sequence of ther apy remains unknown, a clinical trial to answer this question would be difficult to conduct, Dr Ontaneda reported. “The comparison of different treat ment sequences in terms of both effica cy and cost is of interest to physicians

who must make decisions regarding DMT selection in the clinic, and also to health agencies interested in using the optimal cost-effective medication se quence,” he said.

3 years. Yearly utilities were discounted for disease activity (NEDA rates), com plications, and death. The 3-year cost of each intervention was calculated as the sum of 3 annual costs. The researchers modeled “only the most significant and life-changing risks associated with MS disease therapies,” such as progressive multifocal leukoen cephalopathy, idiopathic thrombocyto penic purpura, and Berger’s disease, Dr Ontaneda noted. The willingness-to-pay threshold was set at $50,000 per QALY, although $150,000 per QALY may be considered appropriate as well. Cost Outcomes

“Despite a slightly higher 3-year utility, natalizumab’s costs far exceeded even the most liberal willingnessto-pay thresholds. Alemtuzumab was the most cost-effective treatment option.” —Daniel Ontaneda, MD

Study Details

The researchers grouped treatment strategies in relation to the route of ad ministration and overall efficacy during

The drugs with the highest NEDA values in clinical trials were the most cost-effective. Despite being the most effective treatment strategy, natalizumab as firstline therapy had a 3-year cost of medi cation of $192,699. Compared with alemtuzumab, natalizumab’s incremen tal cost-effectiveness ratio (ICER) was $2,834,955, putting it significantly above the willingness-to-pay range of $50,000 to $150,000 per QALY. This was attributed to the relatively small difference in efficacy (0.0122), with a large cost differential of $34,699, said Dr Ontaneda, adding that the effi cacy of the remaining treatment strate gies was similar, with all strategies being more expensive and less effective than alemtuzumab.

at a glance irst-line natalizumab was the F most effective MS therapy for achieving NEDA, followed by alemtuzumab Alemtuzumab was the most cost-effective treatment for MS, with a cost-effectiveness of $79,086 per QALY Compared with alemtuzumab, natalizumab’s ICER exceeded $2.8 million, which was attributed to a small difference in efficacy, with a large difference in cost

“With a 3-year cost of $158,000 and an effectiveness of 1.998, the most cost-effective treatment strategy was alemtuzumab, yielding a cost-effective ness of $79,086 per QALY. Given the extremely high ICER, natalizumab continues to be less cost-effective com pared with alemtuzumab,” said Dr Ontaneda. The results were robust, and the cost-effectiveness did not change with sensitivity analyses, although the re searchers noted limitations in modeling a complex disease state. “Data are limited by the adequacy of the model, which is unable to capture the entire complexity of DMT efficacy and risk,” Dr Ontaneda concluded. n

FDA News Zinbryta a New Treatment Available... Continued from page 4

hepatic injury, including autoimmune hepatitis and other immune-mediated disorders. Transaminase and bilirubin levels should be evaluated before start ing daclizumab therapy, and patients should be monitored monthly and up to 6 months after stopping therapy. Dac lizumab is distributed through a Risk Evaluation and Mitigation Strategies program only.

Nuplazid First Drug Approved for Hallucinations and Delusions Associated with Parkinson’s Disease

On April 29, 2016, the FDA ap proved pimavanserin (Nuplazid; Aca

dia), an atypical antipsychotic, for the treatment of hallucinations and delu sions associated with Parkinson’s dis ease. Pimavanserin is the first drug ap proved by the FDA for hallucinations and delusions that are associated with Parkinson’s disease. “Hallucinations and delusions can be profoundly disturbing and disabling. Nuplazid represents an important treatment for people with Parkinson’s disease who experience these symp toms,” said Mitchell Mathis, MD, Di rector of the FDA’s Division of Psychi atry Products. As many as 50% of patients with Par kinson’s disease experience hallucina tions and delusions; these serious symp toms can add to the burden of physical

limitations in patients with this disease. Pimavanserin was approved under the FDA’s priority review status and was earlier granted a breakthrough therapy designation in an effort to expedite the development and approval process. Al though its mechanism of action is still not fully understood, the effect of pima vanserin may be mediated through a combination of inverse agonist and an tagonist activity at serotonin 2A recep tor (5-HT2A) and, to a lesser extent, at serotonin 5-HT2C receptors. The efficacy of pimavanserin was established in a randomized, placebo- controlled, parallel-group, 6-week clin ical trial involving 199 patients with Parkinson’s disease who experienced hallucinations and/or delusions. Pa

tients receiving pimavanserin had less frequent and/or less severe hallucina tions and delusions, without worsening the primary motor symptoms of Par kinson’s disease, compared with those receiving placebo. The most common adverse effects associated with pimavanserin were pe ripheral edema and a confused state. Pimavanserin was approved with a boxed warning cautioning healthcare professionals about the risk for death in elderly patients with dementia-related psychosis who use antipsychotic drugs. Pimavanserin is not approved for the treatment of patients with dementia-re lated psychosis that is unrelated to hal lucinations and delusions associated with Parkinson’s disease psychosis. n

In the Literature Multiple Sclerosis Tops Neurology Drug Costs in Medicare Payments

Medicare spent $103 billion alone on prescription drugs in 2013. Despite a relatively small number of providers, neurologists account for one of the highest total prescription and per-claim costs. A new retrospective, cross-sec tional analysis of the 2013 Medicare Part D payments focused on the cost of drugs prescribed by neurologists in re cent years (De Lott LB, et al. Neurology. 2016;86:1491-1498). Of the 1,049,381 unique providers or facilities recorded by Medicare in 2013, 13,060 (1.2%) were neurologists, repre senting 99.3% of all active practicing neurologists. A total of $5 billion (4.8%) of the $103.6 billion in Medicare Part D drug payments in 2013 were in neurolo gist-prescribed drugs—the third highest of all specialties; the majority (75.7%) of drug claims were for generic medica tions. The median payment per neurol ogist claim was $176 and the median monthly payment was $141—the fifth highest among specialties.

“MS drugs in the United States are extremely expensive, prices vary little, and costs have risen although more medications have entered the market.”

Multiple sclerosis (MS) drugs had the highest total payments for drugs prescribed by neurologists, accounting for $1.8 billion, representing 44.1% of total payments for drugs prescribed by neurologists. At the time, no MS drugs were available as generics, and monthly payments for the medications available in 2013 ranged from $4149 monthly for teriflunomide (Aubagio) to $5072 monthly for fingolimod (Gilenya). An tiepileptic drugs were the second high est category of drug payments by neu rologists, accounting for $499 million, 33.6% of which was from generics. The next highest categories were dementia medications ($389 million), Parkin son’s disease medications ($332 mil lion), and neuropathic pain medica tions ($215 million). If all brand-name neurologist-pre scribed medications were substituted with generics, the total payments for neurology drugs would decrease by $269 million (6.5%). If Medicare pric es were the same as Veterans Affairs (VA) pricing for specific diseases, the total payments would result in $1.5 billion in savings. For example, for MS

drugs, VA drug pricing would reduce payments by $724 million if prescribed by neurologists. “MS drugs in the United States are extremely expensive, prices vary little, and costs have risen although more medications have entered the market,” the researchers noted, adding that un like other countries and the VA sys

tem, Medicare is prohibited from di rectly negotiating drug prices. They made several suggestions on how to lower drug expenditures. One option is allowing Medicare to negoti ate drug prices directly with pharma ceutical companies, although this is controversial. Another option is limit ing the use of brand-name drugs

through federal policies that permit di rect substitution of generic drugs.

Considering a Patient’s Immune Status May Improve Treatment Outcomes in Glioblastoma

Glioblastoma is the most common and aggressive form of brain cancer,

In the Literature with a poor prognosis. Considering the poor outcome after standard treatment, immunotherapy as an additional ap proach is under investigation. Several immune-related parameters have also been reported for predicting patient prognosis, underscoring the impor tance of distinct immune status in de termining glioma outcome. Despite

growing interest in immunotherapies, few studies have systematically investi gated the immune microenvironment in glioma. A new study now investigat ed the value of the patient’s immune status on prognosis in glioblastoma (Cheng W, et al. Neurology. 2016;86: 2226-2234). Using messenger RNA microarray

from the Chinese Glioma Genome Atlas database, the researchers ob tained whole genome expression data from 297 patients with brain cancer. The researchers profiled the immunerelated phenotype according to histo logic grade and classification. A histo logic diagnosis defined 170 of the tumors as lower-grade glioma (grade II

or III) and 127 as glioblastoma. Of the 322 immune-related genes analyzed, 8 genes were shown to play a role in glioblastoma. Patients with glioblastoma were classified as high- or low-risk profiles based on the 8-genes signature. The overall survival after diagnosis was sig nificantly shorter in high-risk patients Continued on page 8

In the Literature Considering a Patient’s Immune... Continued from page 7

were validated externally with an inde pendent cohort of 536 patients with (348 days) compared with low-risk glioblastoma from the Cancer Genome patients (493 days). Atlas database. Similarly, the median progression- This local immune signature in free survival was significantly reduced glioblastoma may help to expedite the in high-risk patients compared with development of immunotherapy for low-risk patients (242 days vs 369 days, patients with this deadly form of respectively; P <.005). The findings brain cancer.

AAN Updates Its Quality Measures for Parkinson’s Disease to Improve Patient Care

Parkinson’s disease is one of the most common neurologic disorders involv ing motor and nonmotor features that are often underdiagnosed and have lim ited treatment options.

The American Academy of Neurolo gy (AAN) has created quality measure ments to address the gaps in care for patients with Parkinson’s disease. In 2014, the AAN formed a multidisci plinary work group to update the 2010 measurements to help facilitate better care for patients with this disease. The AAN recently published an executive

In the Literature summary that details the updated qual ity measurements (Factor SA, et al. Neurology. 2016;86:2278-2283). “The new quality measure set was developed to promote quality im provement, drive improved outcomes for patients with PD [Parkinson’s dis ease], and assist in establishing thresh old performance rates, and through

“The new quality measure set was developed to promote quality improvement, drive improved outcomes for patients with PD, and assist in establishing threshold performance rates, and through continued data gathering to drive quality improvement.”

continued data gathering to drive quality improvement,” stated the researchers. The updated quality measurement set includes 11 measures, 7 of which were maintained or revised from the original set and 4 new quality measures. These 11 measures include: • Annual diagnosis review • Avoiding dopamine-blocking medi cations • Assessing for psychiatric symptoms • Assessing for cognitive impairment or dysfunction • Assessing for symptoms of autonomic dysfunction • Checking for sleep disturbances • Recording falls outcomes • Discussing with patients rehabilita tion options • Counseling patients about regular exercise • Asking about medication-related motor complications • Discussing advance care planning. Data have shown that exercise has many important health benefits that should be recommended to all patients with Parkinson’s disease. As for avoiding dopamine-blocking agents, the group said it was an important measure in ambulato ry and hospital practice settings. The prescribing of dopamine-blocking agents is a common medical error that can result in worsening of motor symptoms in pa tients with Parkinson’s disease and lead to further disability and falls. The group noted 2 exceptions—quetiapine and clozapine—but these 2 drugs should also be used with caution.

The group recommend that all patients with Parkinson’s disease have an advance care directive. The group changed the fall measure from a process to an outcome mea sure. The group recommends that when any fall occurs, patients should be referred for multidisciplinary gait assessment and should be counseled about the importance of exercise for preventing falls. Finally, advance care directives was added to help ensure that a patient’s treatment preferences and treatment goals are being considered. The work group recommends that all patients with Parkinson’s disease have an advance care directive completed or have a des ignated power of attorney for medical decisions in the last 12 months of life. These updated quality measures pro vide opportunities for improved care and treatment for patients with Parkin son’s disease. AAN will continue to update the measures every 3 years. n

Emerging Therapies

Ocrelizumab Promotes No Evidence of... by the study’s lead investigator Antho ny L. Traboulsee, MD, Director, UBC Hospital MS Clinic, Vancouver, British Columbia, Canada, these results signal a promising advancement in the treat ment of patients with MS. “This new, potential treatment has a very profound impact on preventing protocol-defined relapses. Over 96 weeks, approximately 80% of patients were free of relapses, 90% of patients were free of disability progression, and 95% of patients were free of new en hancing lesions, a classic biomarker of MS disease activity,” said Dr Traboulsee at the 2016 American Academy of Neurology annual meeting.

Continued from the cover

“Over 96 weeks, approximately 80% of patients were free of relapses, 90% of patients were free of disability progression, and 95% of patients were free of new enhancing lesions.”

untreated disease, proving a “very infor mative population,” said Dr Traboulsee. NEDA––a composite measure of dis ease activity defined as no MS relapses, no confirmed disability progression, and no new or enlarging T2 lesions or gado linium-enhancing T1 lesions––was ana lyzed, with magnetic resonance imaging (MRI) outcomes assessed at baseline, 24 weeks, 48 weeks, and 96 weeks. In OPERA I, 81% of patients who received ocrelizumab did not have dis ease relapse compared with 68% of pa tients who received interferon beta-1a; the proportion of patients with no dis ability progression was 91% with ocre lizumab and 84% with interferon beta-1a. When these measures were combined, 76% of patients who re ceived ocrelizumab were free of disease activity compared with 63% of patients who received interferon beta-1a. Approximately 48% of patients in

the ocrelizumab group in OPERA I had NEDA at 96 weeks versus 29% in the interferon beta-1a group, a 64% relative increase in preventing disease activity with ocrelizumab. MRI analysis showed that 95% of patients using ocrelizumab had no evidence of serious disease activity versus 73% of patients using interferon beta-1a. The results of OPERA II were nearly identical to OPERA I. “These are very impressive numbers, especially when you consider that ocre lizumab was compared to an active ther apy, not placebo. When we think of the early studies with interferon, the reduc tion was about 30% relative to placebo, so this is quite a steep improvement,” said Dr Traboulsee. Overall, 63% of patients who re ceived ocrelizumab were free of new T2 lesions during the study, Dr Traboulsee said, noting that after week 24, that number increased to 96%. “We’ve made a giant leap forward over the past 20 years of treating MS. With a variety of mechanisms, we have increased the efficacy of treatment and expectations of patients with this dis ease,” said Dr Traboulsee. “Today, be cause of this novel approach through B-cell depletion, we can see a very highly effective treatment emerging for MS.” n

Emerging Disease-Modifying Therapies for Multiple Sclerosis

SEE ALSO PAGES 12, 13

The OPERA I/II Clinical Trials

Although B-cells have been implicat ed in MS as components of pathogene sis, it was not known whether B-cell depletion would have an impact on disease activity, according to Dr Tra boulsee. Ocrelizumab is a humanized

—Anthony L. Traboulsee, MD

monoclonal antibody that targets CD20, a protein located on the surface of some, but not all, B-cells. In the OPERA I and OPERA II clini cal trials, identical, phase 3, double-blind, double-dummy studies, patients were randomized in a 1:1 ratio to ocrelizumab 600 mg via intravenous infusion every 24 weeks or subcutaneous interferon beta- 1a 44 μg 3 times weekly for 96 weeks. Each study included 828 patients with early, relapsing-remitting MS. Approxi mately 70% of patients had previously

On February 17, 2016, the FDA granted a breakthrough therapy status to ocrelizumab for the treatment of patients with primary progressive MS. “Ocrelizumab is the first investigational medicine for MS to be granted Breakthrough Therapy Designation by the FDA,” said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development, in a statement. “With no approved treatments for primary progressive MS, ocreliz umab has the potential to address an important unmet need.”

By Chase Doyle

lthough multiple sclerosis (MS) is dominated by a progressive phase of the disease, few thera pies are available to modify clinically defined progression. There is a significant unmet need for treatments targeting the delayed neurodegenerative components of the disease, said Gavin Giovannoni, MBBCh, PhD, Chair of Neurology, Bliz ard Institute of Cell and Molecular Sci ence, Queen Mary University of Lon don, England, at the 2016 American Academy of Neurology annual meeting. “We need a multilayered approach to target the pathogenic processes that underpin progressive MS. This includes antiinflammatory therapies targeting both adaptive and innate immune mechanisms, neuroprotective therapies, and remyelination strategies,” noted Dr Giovannoni. “The aim of neuroreparation is to re

“We need a multilayered approach to target the pathogenic processes that underpin progressive MS. This includes antiinflammatory therapies targeting both adaptive and innate immune mechanisms, neuroprotective therapies, and remyelination strategies.” —Gavin Giovannoni, MBBCh, PhD

store lost function. Enhancing mecha nisms related to axonal and synaptic plasticity with pharmacologic interven tions remains an area of active re search,” he added. Neuroprotection

Based on the current understanding

of MS, neuroprotective strategies are needed for acute MS with actively inflamed lesions, and for chronic MS to target delayed, secondary neurodegeneration. “Neuroprotection is indicated in all stages of the disease to try to delay and prevent neuroaxonal loss to maintain

reserve capacity,” Dr Giovannoni explained. Several neuroprotective therapies are being investigated for MS, including: • Sodium channel blockers (phenytoin, lamotrigine, riluzole, oxcarbazepine) • Acid-sensing ion channel 1 blockers (amiloride) • Selective serotonin reuptake inhibi tors (fluoxetine) • Phosphodiesterase inhibitors (ibudilast) • Microglial inhibitors (laquinimod, minocycline) • Drugs targeting mitochondrial func tion (biotin, idebenone, MitoQ). There is no point in using neuropro tection strategies unless they are used in combination with an anti-inflammatory regimen to “switch off autoimmune-driv en focal inflammation that is the main driver of both acute and chronic neuro axonal loss,” said Dr Giovannoni.

Emerging Therapies

Dichlorphenamide Improves Outcomes in Periodic Paralysis By Chase Doyle

pivotal phase 3 clinical trial demonstrated that dichlor phenamide (Keveyis) signifi cantly reduced the rate and severity of hypokalemic episodes in patients with periodic paralysis, a rare muscle disease affecting children and young adults. In addition, a parallel phase 3 clinical trial with dichlorphenamide showed a simi lar treatment effect in patients with hyperkalemic periodic paralysis but failed to demonstrate significance be cause of recruitment issues. “According to pivotal phase 3 data, hypokalemic subjects demonstrated im proved attack frequency, severity, and quality of life. Dichlorphenamide was also well tolerated, with few safety- related withdrawals,” said James Burge, MD, Consultant in Clinical Neuro physiology, King’s College Hospital NHS Foundation Trust, London, En gland, at the 2016 American Academy of Neurology annual meeting. “Treatment effects on attack rates appeared consistent in both trials, but, partly due to small sample size, were in conclusive for hyperkalemic patients,” Dr Burge added. A rare disease affecting an estimated 1 in 100,000 individuals, periodic pa ralysis is defined as a muscle channelo pathy marked by sudden episodes of muscle weakness and long-term pro gressive weakness. Hypokalemic paral ysis is caused by decreased levels of po tassium in the blood and can persist from 2 to 72 hours. Conversely, hyper

kalemic paralysis is caused by increased potassium levels in the blood, and is characterized by more transient epi sodes of weakness, enduring a few min utes to up to 1 hour. Although hypokalemic episodes are typically triggered by carbohydrate-rich meals, which lower potassium levels in the blood, hyperkalemic episodes are usually related to exercise. “For kids experiencing their first epi sode, it can be very frightening. They’re unable to move because of arm and leg paralysis, and they often end up in the emergency room,” said Dr Burge. In addition to dichlorphenamide, treatment options for patients with pe riodic paralysis include off-label use of acetazolamide (Diamox), diuretics, and avoiding potassium-rich foods. Although the 2 clinical trials were ini tially designed to compare the safety and efficacy of dichlorphenamide with that of acetazolamide and placebo, patients who had formerly been taking dichlor phenamide were reluctant to switch to acetazolamide, because it proved to be less effective than dichlorphenamide. Significant Benefits

The 2 multicenter, randomized, dou ble-blind, placebo-controlled, paral lel-group clinical trials—one including 44 patients with hypokalemic periodic paralysis and the other including 21 pa tients with hyperkalemic periodic paral ysis—used identical protocols comparing dichlorphenamide with placebo and last

ing 9 weeks. Each study was subsequently followed by a 1-year, open-label exten sion period in which all patients received dichlorphenamide.

“According to pivotal phase 3 data, hypokalemic subjects demonstrated improved attack frequency, severity, and quality of life. Dichlorphenamide was also well tolerated, with few safety-related withdrawals.” —James Burge, MD

The median weekly attack rate in the double-blind phase of the study was sig nificantly lower in the dichlorphenam

Emerging Disease-Modifying Therapies... Similarly, remyelination strategies will only work if there is preservation of ax ons that target remyelination, he added. “What is the point of promoting remyelination if the initial autoim mune-driven inflammatory events are not suppressed? The newly formed my elin may simply become a target for further rounds of inflammatory attack,” he emphasized. Remyelination

Several potential remyelination thera pies are in preclinical and/or early clinical development. Meanwhile, magnetic res onance imaging and positron emission tomography imaging are being used to assess whether remyelination strategies are feasible in vivo, said Dr Giovannoni.

“The inhibition of LINGO-1…presents a novel therapeutic approach for the treatment of MS.” —Gavin Giovannoni, MBBCh, PhD

The most advanced remyelination therapy targets LINGO-1, a protein that interacts with the Nogo receptor to inhibit myelination. “Across several animal models, LIN GO-1 inhibition has been shown to promote neuron and oligodendrocyte survival, axon regeneration, oligoden

ide group compared with the placebo group (0.3 vs 2.4, respectively). Dichlorphenamide also had a signifi cant treatment effect on several second ary end points, including attack duration, severity, and quality of life. In addition, the physical component score on the Short Form-36 was improved in patients who received dichlorphenamide. The benefit of dichlorphenamide on the attack rates was maintained in the open-label extension period, and pa tients who switched from placebo to dichlorphenamide also saw a marked reduction in the frequency and severity of attacks. The most common adverse events with dichlorphenamide were paresthe sia (47%) and confusion (19%). Al though 3 patients (2 patients with hy perkalemic paralysis and 1 with hypokalemic paralysis) who received dichlorphenamide withdrew from the double-blind phase because of adverse events, “the majority of patients tolerat ed side effects very well,” Dr Burge said. Because of the small number of pa tients who were recruited to participate, the study results were not significant; however, dichlorphenamide is a safe and effective treatment option for both forms of periodic paralysis, Dr Burge emphasized. In August 2015, dichlorphenamide became the first FDA-approved treat ment option for patients with primary hypokalemic or hyperkalemic periodic paralysis. n

Continued from page 10

drocyte differentiation, remyelination and functional recovery. The inhibition of LINGO-1 therefore presents a novel therapeutic approach for the treatment of MS,” said Dr Giovannoni. In a randomized, double-blind, place bo-controlled clinical trial known as RENEW, patients with a first episode of unilateral acute optic neuritis who re ceived anti–LINGO-1 showed im proved optic nerve conduction latency at week 24 in the per-protocol analysis. “This is consistent with remyelination following a first episode of acute optic neuritis,” said Dr Giovannoni. In addition to anti–LINGO-1, the following remyelination therapies are being assessed in preclinical and/or clin ical trials:

• Retinoid X receptor agonists (IRX4204) • Muscarinic antagonists (benztropine) • Antihistamine H3 antagonists (GSK239512, clemastine) • Anti-SEMA4D (VX15) • Biotin. Alternative Hypothesis

Although the working hypothesis is that MS is an autoimmune disease, skep tics in the field remain open to the possi bility that MS may be caused by a virus. “The viral hypothesis is that damage of the oligodendrocytes, due to direct viral infection, secondarily triggers a focal inflammatory reaction. One way of proving, or disproving, this hypothe sis is through well-designed clinical tri als,” said Dr Giovannoni. n

Multiple Sclerosis

Experts Debate the Benefits of Early Aggressive Therapy in Multiple Sclerosis By Chase Doyle

ultiple sclerosis (MS) is the leading cause of irreversible neurologic disability in young women in the United States, and the second leading cause of neurologic dis ability in young men. In a series of de bates at the 2016 American Academy of Neurology annual meeting, expert physicians addressed current and con troversial issues in neuroscience, includ ing the early aggressive treatment of patients with MS. Timothy L. Vollmer, MD, Co-Direc tor of the Rocky Mountain MS Center at Anschutz Medical Center, Universi ty of Colorado, Aurora, advocated the merits of early aggressive treatment for the majority of patients with MS, and Brian G. Weinshenker, MD, Professor of Neurology, Mayo Clinic, Rochester, MN, argued that aggressive treatment should be limited to patients with ag gressive disease. Early treatment of MS with dis ease-modifying therapies (DMTs) im proves long-term outcomes, according to Dr Vollmer. “With careful patient selection and monitoring, highly effective DMTs can be used in early MS, and should result in improved late-life neurologic func tion, improved quality of life, and de creased health-related costs. However, because there are risks from the disease and the therapies, shared decision-mak ing is important,” he said. Although DMTs slow the progres sion of disability and decrease the rate of conversion from relapsing-remitting MS (RRMS) to secondary progressive MS, 50% of patients with RRMS will progress to secondary progressive MS after 10 years, if left untreated. Preserving Brain Reserve

The primary goal of treating MS with DMTs is to maximize lifelong

brain health, said Dr Vollmer. Preserv ing brain volume in early MS is critical to preserving brain reserve to “buffer for the effect of MS and normal aging in late life,” Dr Vollmer emphasized. The frequency of relapses and new magnetic resonance imaging (MRI) le sion formation are greatest at the onset of MS and decline with age, Dr Voll mer said. In addition, >90% of newly

tive treatment of MS is essential. “Help patients adopt a healthy, ac tive lifestyle to avoid comorbidities that would also tax brain reserve, and help them build cognitive reserve through exercise and learning. Use the most effective DMT with an acceptable safety profile for the individual patient with MS as early in the disease course as possible,” said Dr Vollmer.

“Use the most effective DMT with an acceptable safety profile for the individual patient with MS as early in the disease course as possible.”

“Predicting disease course is imperfect, but a reasonable guess is possible at first presentation based on a combination of demographic, clinical, and radiologic findings…. We must avoid escalation for progressive disability without attacks or MRI disability.”

—Timothy L. Vollmer, MD

active MRI lesions are clinically silent (ie, not associated with a relapse) but still result in brain atrophy. “The rate of brain atrophy is a strong predictor of future disability in MS. Brain reserve is compensating for the clinically silent disease in RRMS through cortical remodeling and other mechanisms, and loss of brain reserve may explain progressive MS,” he said. To preserve brain volume, and thus brain reserve, early diagnosis and effec

—Brian G. Weinshenker, MD

Aggressive Treatment Only for Aggressive Disease

Although Dr Weinshenker did not oppose aggressive DMT induction in

some patients with MS, he encouraged a more individualized approach to treatment, given the disease’s variable prognosis. According to population studies, 20% to 40% of patients have a “benign” course and would not merit receiving aggressive treatment, Dr Weinshenker said. “Predicting disease course is imper fect, but a reasonable guess is possible at first presentation based on a combina tion of demographic, clinical, and radio logic findings. Observation and moni toring, even over the first few years, significantly refines prediction and facil itates selection of those requiring aggres sive treatment, allowing one to tailor treatment,” said Dr Weinshenker. A more nuanced, individualized ap proach that considers the combinations of relapse, relapse-related disability, and MRI activity is warranted, he argued. “We have to consider what treat ments have already been tried and the preferences and attitudes of our pa tients, especially for risk of complica tions. We must avoid escalation for progressive disability without attacks or MRI disability for which we have no evidence that we can influence,” said Dr Weinshenker, emphasizing that greater efficacy of treatment often comes with greater risks. Although the relative efficacy of treatments is based on limited head-tohead data, some alternative therapies, such as vitamin D, may have potent benefits, with minimal risk, Dr Wein shenker said. He reminded the audi ence that for the majority of patients with MS, no evidence of disease activi ty is not currently an attainable goal. “There’s no absolute ‘window of op portunity.’ I would say aggressive treat ment for aggressive disease…but not aggressive treatment for all patients,” Dr Weinshenker concluded. n

Natalizumab Shows Significant Benefit in Slowing Disability Progression in Multiple Sclerosis By Chase Doyle

n a phase 3, randomized clinical tri al, natalizumab (Tysabri) failed to slow the progression of ambulatory disability unrelated to relapses (primary end point) in patients with secondary progressive multiple sclerosis (MS). Al

though patients who received nataliz umab were less likely to have progres sion of ambulatory disability than those receiving placebo, the difference was not significant, according to the results presented at the 2016 American Acad

emy of Neurology annual meeting. Nevertheless, natalizumab was associ ated with a significant (44%) reduction of upper-extremity disability progression unrelated to relapses, as measured by the 9-Hole Peg Test (9HPT).

“The ASCEND study did not meet the primary end point, as natalizumab treatment did not delay progression of ambulatory disability. However, nataliz umab showed significant benefit in slowing sustained progression of up

Neurologic Disorders

Zika Virus Linked to Guillain-Barré Syndrome By Chase Doyle

ounting evidence led the Cen ters for Disease Control and Prevention (CDC) to deter mine in April 2016 that the Zika virus causes microcephaly and other congeni tal brain abnormalities. According to recent reports, however, the Zika virus may also be associated with Guillain-Bar ré syndrome, an autoimmune disorder that attacks the brain’s myelin sheath, as is the case with multiple sclerosis. “There is strong evidence of associa tion between Zika virus and Guil lain-Barré syndrome, and it’s likely that additional studies are going to substan tiate this. This is really a very concern ing finding,” said James J. Sejvar, MD, a neurologist and epidemiologist in the CDC’s Division of High-Consequence Pathogens and Pathology, Atlanta, GA, at the 2016 American Academy of Neurology meeting.

Causal Link Between Zika and Microcephaly Confirmed

Using information about known ex posures during pregnancy and fetal de velopment, the CDC has determined that infection with the Zika virus is in fact a cause of microcephaly and other congenital brain abnormalities, report ed Dr Sejvar. “The pattern of microcephaly in these children is consistent with fetal

brain disruption sequence,” said Dr Sej var, noting that the highest risk for con genital abnormalities is during the late first trimester or early second trimester. Despite this association, questions remain, such as the level of risk during the Zika virus infection, the spectrum of potential health effects, and possible cofactors for brain abnormalities. Recent brain abnormalities associat ed with the Zika virus have also been reported from Colombia, which has had the second highest number of Zika virus cases, after Brazil. “This is a very foreboding finding. If the pattern of congenital malforma tions that’s being seen in Brazil contin ues in other Zika-infected areas, this could present a public health and soci etal impact of unprecedented propor tions,” said Dr Sejvar. Guillain-Barré Syndrome and Other Neurologic Complications

According to Dr Sejvar, investiga tions in French Polynesia and Brazil suggest that increases in the incidence rates of Guillain-Barré syndrome after the introduction of the Zika virus are many times higher than expected. “There appear to be strong geograph ic and temporal correlations with Zika virus outbreak, with a significant pro portion of [Guillain-Barré syndrome]

cases reporting Zika-like symptoms compared to controls,” Dr Sejvar said. In French Polynesia, there is also lab oratory evidence of recent Zika virus infection that is greater in the Guil lain-Barré syndrome cases than in the

“There is strong evidence of association between Zika virus and GuillainBarré syndrome….The neurologic community will play a crucial role in the recognition of these emerging neurologic complications.” —James J. Sejvar, MD

controls; however, these data need to be interpreted with caution because of se rologic cross-reactivity, said Dr Sejvar. As of April 10, 2016, at least 12 Cen tral American, South American, and Caribbean countries reported possible increases in patients with Guillain-Bar ré syndrome after the introduction of the Zika virus, and some have laborato ry evidence of the infection.

In addition to congenital abnormali ties and Guillain-Barré syndrome, there have been anecdotal reports of other neurologic manifestations with the virus, including meningitis, encephali tis, myelitis, optic neuritis, and acute disseminated encephalomyelitis. “None [of these conditions] have been of the magnitude that we see with congenital abnormalities or Guil lain-Barré syndrome, but it does suggest the need for continued vigilance for these additional manifestations of Zika in the neurologic setting,” pointed out Dr Sejvar. Although the CDC guidelines focus on protection from mosquitoes, given the strong association with Guil lain-Barré syndrome and congenital ab normalities, women who are pregnant or plan to become pregnant have been advised not to travel to infected areas. “Everything we look at with Zika virus seems to be a little scarier than we initially thought,” said Anne Schuchat, MD, Principal Deputy Director at the CDC. “This is an evolving situation. We’re literally learning things about this virus day by day….The neurologic communi ty will play a crucial role in the recogni tion of these emerging neurologic com plications moving forward,” said Dr Sejvar. n

Natalizumab Shows Significant Benefit in Slowing... per-extremity disability, as measured by the 9HPT, and the meaningfulness of this finding was confirmed by ABIL HAND,” said Deborah Steiner, MD, MS, Medical Director, Biogen, Cam bridge, MA. Despite many clinical trials in pro gressive MS, no treatment has demon strated efficacy in reducing disability progression unrelated to relapses in pa tients with secondary progressive MS. Natalizumab, a recombinant human ized monoclonal antibody, reduces in flammation by inhibiting the transmi gration of leukocytes into the brain, and has been proved more effective than placebo in treating relapsingremitting MS.

cal relapses in the year before enroll ment, and had Expanded Disability Sta tus Scale scores ranging from 3 to 6.5. Patients were randomized to 300 mg intravenous natalizumab or to placebo every 4 weeks for up to 96 weeks. The proportion of patients who had progression of ambulatory disability (the study primary end point) was higher in the placebo group (48%) than in the na talizumab group (44%), but this differ ence was not significant, said Dr Steiner. Nevertheless, natalizumab was asso ciated with a significant 44% reduction of upper-extremity disability progres sion unrelated to relapses, as measured by 9HPT, a prespecified component of the primary end point. The ABILHAND questionnaire, a Study Details patient-reported outcome instrument The ASCEND clinical trial was an assessing upper-extremity impairment, international, multicenter, double- clearly differentiated patients who had blind, phase 3 study of patients with upper-extremity disability progression secondary progressive MS for at least 2 from patients who did not. years. Eligible patients had evidence of “The upper-extremity finding is nota disability progression unrelated to clini ble. If you consider the fact that these

“The upper-extremity finding is notable. If you consider the fact that these patients are using either unilateral or bilateral assistance, may be in wheelchairs, and may soon be confined to bed, being able to preserve upper-extremity function and still use one’s hands is extremely important.” —Deborah Steiner, MD, MS

patients are using either unilateral or bilateral assistance, may be in wheel chairs, and may soon be confined to bed, being able to preserve upper-extremity function and still use one’s hands is ex tremely important,” said Dr Steiner. Other secondary end points did not

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reach significance at the group level, al though point estimates were all in favor of natalizumab, Dr Steiner reported. In addition, exploratory efficacy end points of inflammatory activity demon strated strong treatment effects for na talizumab, with a 54.7% relative reduc tion in the annualized relapse rate. The relative reduction in the number of T1 Gd+ and T2 lesions was 95% and 89%, respectively, compared with placebo. Finally, natalizumab was well-tolerat ed. Adverse events, including urinary tract infection, headache, fatigue, and falls, were consistent with the known safety profile of natalizumab, although the use of natalizumab has been linked to progressive multifocal leukoencepha lopathy, a rare but potentially lethal adverse reaction, Dr Steiner said. Preserving upper-extremity mobility in patients with secondary progressive MS may be worthwhile, said Dr Steiner, adding that additional testing to con firm the positive finding for upper-ex tremity function may be warranted. n

Epilepsy/Seizures

New Indications for Novel Antiepileptic... tive treatment of seizures associated with the Lennox-Gastaut syndrome based on its significant reduction of atonic seizures in 2 multicenter con trolled clinical trials. But it has also been associated with serious adverse events and subsequent warnings from the FDA. In other countries, however, cloba zam is widely used as a broad-spectrum AED; one study of patients with refrac tory focal epilepsy had a seizure-free rate of 11% at 6 months, Dr Bazil said. “Clobazam differs from other benzo diazepines in that tolerance, especially to the anticonvulsant effect, seems much less common. It is also less sedat ing than other drugs in this class, al though this is the most common ad verse effect,” he emphasized. Clobazam’s half-life of 70 to 80 hours is relatively long, so once-daily dosing is typical, usually at bedtime. Of note, cannabidiol may alter the metabolism of clobazam, leading to higher concen trations of the active metabolite and possibly resulting in increased efficacy. Insurers may make this agent prohib itively difficult or expensive to obtain, Dr Bazil suggested.

suspension for the adjunctive treatment of patients with seizures, offering a new treatment option for patients who are unable to use oral tablets.

Perampanel

“Perampanel is a first-in-class AED that acts through noncompetitive AMPA receptor inhibition. It therefore likely has its anticonvulsant action through decreased excitation of overac tive neurons,” said Dr Bazil. The efficacy of perampanel in focal seizures was shown in 3 randomized, double-blind, placebo-controlled clini cal trials, demonstrating an effective

Initially approved by the FDA in 2012 for the treatment of patients with seizures, perampanel (Fycompa) tablets received a new indication from the FDA in 2015 for the adjunctive treat ment of primary generalized tonic-clon ic seizures in patients aged ≥12 years. And in May 2016, the FDA approved a new formulation of perampanel as oral

“The 4 newest AEDs have possible advantages over previously approved drugs. However, at this point, none is clearly better or considered suitable for firstline therapy.” —Carl W. Bazil, MD, PhD

dose of 4 mg to 12 mg daily. As with clobazam, perampanel has a very long half-life (70-100 hours) and is therefore suitable for once-daily dosing. The most common adverse effects associated with perampanel include diz ziness, somnolence, headache, and fa tigue, but there are also concerns for adverse psychiatric effects, including aggression, irritability, and homicidal ideation. The drug has a boxed warning about these psychiatric effects, although they are rare, said Dr Bazil. “Despite its distinct mechanism, per ampanel is not definitely more effective than other agents, and there are psychi atric concerns,” Dr Bazil concluded. Ezogabine

The FDA approved ezogabine (Poti ga) in 2011 as adjunctive therapy for the treatment of adults (aged ≥18 years) with partial-onset seizures that respond ed inadequately to several alternative treatments. Ezogabine is a first-in-class drug with a mechanism of action that activates voltage-gated potassium chan nels. The efficacy of ezogabine in focal seizures was demonstrated in 3 random ized, double-blind, placebo-controlled clinical trials. The effective dose is 600 mg to 1200 mg daily given in 3 doses. Urinary retention was a known and expected adverse effect of ezogabine, and occurred in approximately 2% of pa tients, said Dr Bazil. More concerning, however, was the “postmarketing recog nition of bluish discoloration caused by accumulation of a metabolite,” he said. “Discoloration is typically rather sub tle, but may be seen in the skin, espe

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cially fingers and lips. It can also occur in the retina, leading to the recommen dation for ophthalmological examina tions every 6 months on the drug,” Dr Bazil explained. Although reports suggest that discol oration will gradually resolve with time after the drug is stopped, this complica tion and the need for monitoring have greatly limited the use of ezogabine in clinical practice. Eslicarbazepine

Eslicarbazepine (Aptiom), which is structurally related to carbamazepine (Tegretol) and oxcarbazepine (Trilep tal), was initially approved by the FDA in 2013 as adjunctive therapy; in 2015 it received a new indication as mono therapy for the treatment of patients with partial-onset seizures. The initial approval of eslicarbaze pine for partial-onset seizures was based on 3 randomized, double-blind, place bo-controlled clinical trials in patients with refractory focal seizures. The effica cy of eslicarbazepine as monotherapy was subsequently established in 2 his torical control clinical trials and used for the FDA approval of the new indica tion as monotherapy. The adverse ef fects of the drug are qualitatively similar to the related compounds, Dr Bazil said. Eslicarbazepine is dosed at 400 mg to 800 mg daily, which can be increased to 1200 mg daily. “Eslicarbazepine is similar to oxcarba zepine, but with a longer half-life. Al though there are theoretical advantag es, no comparative clinical trials have been performed,” said Dr Bazil. n

Individualizing Antiepileptic Drug Therapy: Consider the Side Effects By Chase Doyle

ith approximately 20 antiepi leptic drugs (AEDs) ap proved in the United States, choosing the optimal agent for an indi vidual patient has become an increas ingly daunting task. “We have more approved drugs than ever before, yet for each indication there remains no specific drug that is more ef fective than another in populations of patients. We therefore still choose drugs based on other properties—ease of use, adverse effect profiles, efficacy in coexist ing conditions, and cost concerns,” said Jacqueline A. French, MD, FAAN, Di

rector of Translational Research and Clinical Trials for Epilepsy, New York

Neurology annual meeting. “There is no one-size-fits-all in epi

“There is no one-size-fits-all in epilepsy therapy, and there is no first-line therapy for everyone. You need to assess the needs of each individual patient.” —Jacqueline A. French, MD, FAAN

University Langone Medical Center, NY, at the 2016 American Academy of

lepsy therapy, and there is no first-line therapy for everyone. You need to assess

the needs of each individual patient,” Dr French added. Because many effective drugs are available, patients with newly diagnosed epilepsy should be prescribed a drug that is safe and well-tolerated. Although sev eral epilepsy drugs have been approved in the past few years, including lacos amide, ezogabine, and perampanel, their safety and efficacy in this patient popula tion have not yet been fully established. Consider the Side Effects

Recent studies indicate that 37% of patients with newly diagnosed epilepsy

Migraine Update

Poor Response to Acute Migraine Treatment May Lead to Headache Progression By Chase Doyle

hen it comes to migraine, the initial choice of therapy could mean the difference between episodic and chronic disease, according to a secondary analysis of the longitudi nal migraine study American Migraine Prevalence and Prevention (AMPP), presented at the 2016 American Acade my of Neurology annual meeting. The results showed that poor response to treatment is associated with a 3-fold increase in the risk for disease progres sion from episodic migraine to chronic migraine, said Richard B. Lipton, MD, Director of the Montefiore Headache Center, Bronx, NY, who presented the study. A better understanding of the re mediable risk factors for migraine pro gression may help to reduce the risk for progression, Dr Lipton said. “Episodic migraine is sometimes a progressive disease, and we have found that poor treatment optimization is a risk factor for progression,” he said. “In other words, if people take acute treatments and don’t get better, that may be associated with more pain, more

allodynia, and headache progression,” Dr Lipton added. The AMPP epidemiologic study in cluded >8000 patients with episodic migraines who were followed from 2005 to 2009. The 1-year results showed that 83% of patients with episodic migraines in 2005 continued to have them in

headache, including attack frequency and allodynia, progression is also related to comorbidities, particularly depres sion, anxiety, and pain disorders, said Dr Lipton. “Progression is related to a series of exogenous factors, and given that chronic migraine demonstrably aggre

“Episodic migraine is sometimes a progressive disease….If people take acute treatments and don’t get better, that may be associated with more pain, more allodynia, and headache progression.” —Richard B. Lipton, MD

2006. However, 2.5% of the patients had episodic migraines that progressed to chronic migraines (defined as a head ache on ≥15 days monthly). Although the risk factors for mi graine progression may be related to

gates within families, there may be a genetic foundation for pain progression, as well,” he said. Treatment-Related Risk Factors

The key is to discover what these risk

at a glance oor response to migraine P therapies was linked to a 3-fold increase in migraine progression risk Progression from episodic to chronic migraines may have a genetic component Poor response to treatment may be associated with prolonged activation of the trigeminovascular system Opioids and barbiturates are remediable and iatrogenic risk factors for migraine progression

factors may have in common, said Dr Lipton. It is possible that they all con verge to act on a single or a series of common pathways. Dr Lipton and colleagues theorized that poor response to the treatment of Continued on page 16

Epilepsy/Seizures

Individualizing Antiepileptic Drug Therapy... will become seizure-free while using an initial antiepileptic drug. Even in this cohort, however, changes to the treat ment regimen may be warranted. “I tell patients starting a new drug, ‘you’re not marrying it; you’re just dat

at a glance ll AEDs have similar efficacy, A so drug selection should be based on ease of use or cost The safety profiles of AEDs vary and should be considered when selecting the specific drug Evaluate the drug’s psychiatric adverse effects, as well as the potential impact on the patient’s weight Also consider patient factors when selecting an AED

ing it. You may date it for a while, or you may never want to have a second date, but you have some time to figure that out,’” said Dr French. She added that the majority of common dose-re lated side effects are the least concerning. “These side effects don’t occur often at lower doses, and if you take the drug away, the side effect will go away, as well. Dose-related side effects can happen during titration and get better, so clini cians have to wait a little before changing medications,” Dr French emphasized. Psychiatric and behavioral side ef fects should also factor into the choice of an AED. Levetiracetam, topiramate, zonis amide, tiagabine, phenobarbital, and perampanel may worsen psychiatric function, whereas carbamazepine, val proate, lamotrigine, and pregabalin may improve psychiatric function, al though there are cases where each can do the opposite, she said.

Furthermore, some AEDs may in crease or decrease weight in patients. It is important to avoid drugs that impact weight in patients with a history of eat ing disorder. “If patients are obsessed with their weight, clinicians shouldn’t prescribe a drug that’s going to [cause their weight to fluctuate], because it’s going to play into their obsession. What’s more, it actually drives their thinking about whether they want to take the drug or not,” Dr French said. “You have to remind your patient that it [weight gain] is not going to hap pen to everyone, but I struggle every day with patients I’ve had to put on val proate—watching them slowly gain 50 to 60 to 70 pounds,” Dr French added. In addition to valproate, other AEDs that may increase weight include ga bapentin, carbamazepine, pregabalin, ezogabine, and perampanel. Drugs that may decrease weight include topira mate, zonisamide, and felbamate.

Continued from page 14

“People usually have less of a prob lem with weight loss. In fact, they may actually want to go on a drug that helps them lose a few pounds,” said Dr French. For elderly patients or those taking diuretics, the risk for hyponatremia is another concern. Carbamazepine, ox carbazepine, and eslicarbazepine acetate should be avoided in this patient popu lation, she said. If a patient has existing cardiovascu lar risk factors, such as high cholesterol levels, carbamazepine and phenytoin may cause complications. Finally, clinicians should avoid pre scribing topiramate and zonisamide to patients with a history of kidney stones. “Someday, we will figure out an app for this: clinicians will be able to enter what they know about the patient that will drive treatment choice, and they will receive a manageable list of drugs to try. Until then, we must deal with this complexity,” Dr French concluded. n

Migraine Update

Monoclonal Antibodies: The Future of... growing awareness of this complex brain event through functional imaging studies, this is a hopeful time for pa tients with migraines and for neurolo gists alike. “These are particularly exciting times for migraine. For the first time, mi graine-specific targets are in develop ment,” said Andrew Charles, MD, Di rector, Goldberg Migraine Program, University of California, Los Angeles. Calcitonin Gene-Related Peptide a Prime Target for Migraine

A ubiquitous peptide that is produced in neural cells throughout the body, cal citonin gene-related peptide (CGRP) has multiple functions––it is involved in pain transmission, the dilation of blood vessels, inflammation, and regen eration of motor neurons. According to Dr Charles, the con nections between CGRP and migraines are manifold: 1. CGRP is released into the circulation in patients during a migraine attack 2. CGRP infusion in patients with mi graines evoked a migraine attack 2 to 3 hours later 3. Serum CGRP levels may be elevated in patients with chronic migraine

at a glance or the first time, migraineF specific targets are in clinical development CGRP is a migraine-specific target, with 4 anti-CGRP monoclonal antibodies currently in phase 2 or 3 clinical trials PACAP is another peptide implicated in migraines Migraine therapy may soon be individualized based on patients’ specific migraine mediators

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Table CGRP Monoclonal Antibodies in Migraine Clinical Trials Investigational agent

Completed studies

Phase 2 study: administration, frequency

Ongoing studies

AMG 334

Phase 2b: episodic migraine

Subcutaneous Once monthly

Phase 3: episodic migraine

ALD 403

Phase 2a: episodic migraine

Intravenous One time

Phase 3: episodic migraine Phase 2: chronic migraine

LY2951742

Phase 2a: episodic migraine

Subcutaneous Twice monthly

Phase 3: episodic migraine/cluster headache

LBR-101

Phase 2b: episodic/chronic migraine

Subcutaneous Once monthly

Phase 3: episodic/chronic migraine

CGRP indicates calcitonin gene-related peptide.

4. CGRP receptor antagonists as fast-acting agents effectively abort migraine attacks. Currently, 4 anti-CGRP monoclonal antibodies (humanized and human an tibodies) are in development for mi graine (Table). Overall, 5 phase 2 clinical trials with these monoclonal antibodies have been completed thus far in patients with epi sodic and chronic migraines. Phase 3 studies and other phase 2 studies are underway for chronic and episodic migraines, as well as for cluster headaches. “These are large, well-powered stud ies, with more than 1400 patients en rolled overall,” said Dr Charles, noting that each antibody met the primary end point of significant reduction in head ache days for at least 1 of the doses in the clinical trials. Furthermore, no pattern of serious ad verse events has emerged with these novel agents, and no effects on heart rate or blood pressure have been observed. “Importantly, there’s no evidence of elevation of liver enzymes, which was a concern because of prior studies with small molecules,” said Dr Charles. Of note, the responder analysis for some of the studies suggested subsets of patients for whom these therapies are very effective, with a 75% or 100% re duction in headache days. “Obviously, based on this kind of po

tential efficacy, these studies are gener ating a considerable amount of excite ment,” said Dr Charles.

“For the first time, migrainespecific targets are in development.” —Andrew Charles, MD

Finally, because CGRP receptors are found in multiple locations that may be involved in migraine, there are many potential sites of action, including the dural mast cells and the dural arterioles. There may also be >1 receptor that re sponds to CGRP, Dr Charles noted. Other Potential Targets and Precision Medicine

One of multiple potential therapeu

tic targets based on antibodies, pitu itary adenylate cyclase-activating poly peptide (PACAP) has also generated considerable interest for treating migraines. As with CGRP, a variety of evidence implicates this peptide in migraines. For example, the infusion of PACAP trig gers migraines in susceptible individu als, and PACAP levels are elevated in circulation during migraines and cluster headache attacks. In addition, PACAP is co-localized with CGRP in many an atomic regions, and shares an accessory protein with CGRP. PACAP may work synergistically or in parallel with CGRP, or with distinct sites of action, Dr Charles said. “The results of these studies have an enormous potential to teach us about the basic pathophysiology of migraine. We can begin to understand how a mi graine attack evolves, and how it evolves from an episodic into a chronic state,” said Dr Charles. Given the heterogeneous nature of this disorder, researchers are discussing the idea of tailoring fast-acting or pre ventive migraine therapy to individual patients based on their specific migraine mediators. “Perhaps most exciting of all, though, is that we’re able to offer new hope for patients who are suffering terribly from this extraordinarily common problem,” said Dr Charles. n

Poor Response to Acute Migraine Treatment... migraine attacks and medication over use may be associated with the pro longed or intense activation of the trigeminovascular system. Because mi graine progression was also associated with treatment-related factors, they re ferred back to the AMPP data. “We looked at how well people re sponded to acute treatment using the validated questionnaire, and we showed that in the group with an optimal re

sponse to acute treatment, 1.9% pro gressed from episodic to chronic mi graine over the course of the year. In the group that had the worst response to acute treatment, however, nearly 7% progressed,” said Dr Lipton. After adjusting for headache fre quency, headache-related disability, and symptom severity, the researchers found that poor response to treatment was associated with a 3-fold increase in

risk for migraine progression. “This provides at least some support for our hypothesis that prolonged activa tion [of the trigeminovascular system] may be associated with increased risk of headache,” said Dr Lipton, who empha sized that many of the risk factors uncov ered in the study are also remediable. The use of opioids and barbiturates, for example, not only is a remediable risk factor for migraine progression but

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also is an iatrogenic risk factor, he explained. “In headache medicine, we are per haps where our stroke colleagues were decades ago: we’ve identified a series of risk factors that allow us to identify a poor prognosis subgroup, but we’ve not yet conducted intervention studies to see if we can modify the natural progres sive history of migraine,” Dr Lipton concluded. n

Alzheimer’s Disease

Lifestyle Enrichment May Have Some Effect on Alzheimer’s Disease Biomarkers By Laura Morgan

ognitive enrichment, including intellectual and physical activi ties, has been shown to delay cognitive impairment; however, its role in the pathophysiology of Alzheimer’s disease has yielded contradictory results. A team of researchers from the Mayo Clinic in Rochester, MN, conducted a study on the impact of education on the pathophysiology of Alzheimer’s disease (Vemuri P, et al. Neurology. 2016;86: 1128-1135). Discrepancies in Alzheimer’s disease biomarker studies regarding lifestyle en richment can be partly explained by differences between cohorts, sample sizes, and paradigms of enrichment. More important, however, variations in patient education levels may contribute to the conflicting results; education oc curs during sensitive periods of brain development, and, therefore, may have a significant impact on Alzheimer’s dis ease biomarker trajectories. Prashanthi Vemuri, PhD, Assistant Professor of Radiology, Mayo Clinic, and colleagues, followed 393 individu

als (aged 70-89 years) with APOE ge notype and without dementia who had participated in the Mayo Clinic Study of Aging. They used 3 biomarkers to assess the pathophysiology of Alzhei mer’s disease, including (1) Pittsburgh compound B as an indicator of cerebral amyloidosis, (2) fluorodeoxyglucose (FDG) as an indicator of brain metabo lism, and (3) hippocampal volume as an indicator of neurodegeneration. All the participants completed ques tionnaires related to education level, primary occupation throughout life, midlife weekly cognitive activity, and physical activity. The results were ana lyzed in relation to the 3 biomarkers noted above. Amyloid deposition. Older age and APOE4 status were significantly asso ciated with higher levels of amyloid deposition. In addition, high midlife cognitive activity was associated with lower amyloid deposition in APOE4 carriers with high education, suggest ing a link between high cognitive en richment and low amyloid deposition,

especially in highly educated individu als. These results may be attributed to the link between education, APOE4 status, and amyloid deposition, the re searchers suggest. “Higher levels of education and high er levels of midlife cognitive activities somehow forestall amyloid deposition, which is evident in APOE4 carriers be cause APOE4 carriers are accumulating amyloid at an earlier age and at a faster rate than APOE4 noncarriers,” wrote Dr Vemuri and colleagues. FDG uptake. Older age and APOE4 gene status were also linked to lower glucose metabolism, a finding consis tent with previous studies. Furthermore, this study showed that APOE4 was not associated with lower FDG uptake in highly educated participants, suggesting that “high education in APOE4 carriers may be protective via nonimpaired glu cose metabolism,” the authors wrote. Hippocampal volume. Older age was further linked to lower hippocampal volume, but APOE4 status did not im pact hippocampal atrophy trajectories.

Overall, enrichment activities did not affect biomarkers of neurodegeneration. Although this finding is contradictory to some previous data, the effect of life style enrichment on neurodegeneration varies, depending on the biomarker used and the disease stage. Clinical implications. Taken to gether, these results suggest that life style enrichment variables, including education, occupation, midlife cogni tive activity, and midlife physical activ ity, have some, albeit minimal, impact on Alzheimer’s disease, especially on the rate of worsening. Overall, highly educated individuals with the APOE4 genotype and high midlife cognitive activity have lower amyloid deposition than APOE4 carriers with low midlife cognitive activity. Furthermore, age is associated with amyloid and neurode generation biomarker trajectories, and APOE4 status affected amyloid and FDG trajectories. Finally, APOE4 sta tus was linked to lower FDG uptake in the entire cohort and in the lower edu cation cohort. n

Parkinson’s Disease

Magnetic Stimulation Decreases “Freezing” Episodes in Parkinson’s Disease, Improves Patient Outcomes By Chase Doyle

lthough dopamine replacement therapy can improve many symptoms of Parkinson’s dis ease, in rare cases clinicians have ob served that gait worsens after the administration of medication, a phe nomenon known as “on freezing.” A new study showed that repetitive transcranial magnetic stimulation (rTMS) has a positive effect in patients with “on freezing” as well as unpredict ed “off freezing,” with a subsequent de crease in the number of falls. The treat ment also has a high safety profile, with no long-term effects, reported Hatem Samir M. Shehata, MD, Professor of Neurology, Cairo University, Egypt, at the 2016 American Academy of Neu rology annual meeting. “We saw a statistically significant de crease in unpredicted ‘offs’, number of falls, and turn time, and the improve

ment was maintained over the course of the study period. Apart from mild tran sient headaches, no adverse events were recorded,” said Dr Shehata. Freezing of gait is an independent feature of Parkinson’s disease that is re lated to motor and cognitive deficits and is characterized by a “sudden and brief interruption” or a “marked re duction of forward progression of the feet” despite the intention to walk, Dr Shehata explained. “Unfortunately, it’s not an uncom mon scenario. Approximately 30% of patients with Parkinson’s have freezing of gait within 5 years, and nearly 60% after 10 years....It’s a strong predictor of falls and can lead to depression and anxiety,” he said. Whereas the treatment of “off freez ing” is relatively straightforward, “on freezing” is a difficult-to-treat scenario,

requiring a multidisciplinary team ap proach, said Dr Shehata. Dr Shehata and colleagues enrolled 43 patients with advanced Parkinson’s dis ease. Patients were randomly assigned to 12 sessions of rTMS for 4 weeks, real or sham, every 3 months for 9 months. Treatments were synchronized with “on times” to facilitate training sessions, in which rTMS (20 trains of 50 stimuli each, at 5 Hz) was delivered over the leg motor area contralaterally to the more affected side. This was followed by a specific rehabilitation program lasting 60 minutes. Finally, all patients kept a daily diary to record “on times,” “offs,” “falls,” and “freezing episodes.” Doses of dopaminergic drugs were in dividualized and modified according to disease progression in both groups, said Dr Shehata. The final analysis included 34 patients

(20 men and 14 women) who completed the 9-month study. Freezing episodes and attacks of unpredicted “off freezing” significantly decreased in the active arm. There was also a significant reduction in the number of recorded falls, with an im provement in the turn time. Although motor scores (assessed by the Unified Parkinson’s Disease Rating Scale) improved, it was not a significant improvement, said Dr Shehata. Other gait variables, including cadence, stride length, and stride time, were not affect ed by the treatment. Other than mild transient headache, no adverse events were recorded. Discussing the long-term benefits of the intervention, Dr Shehata conclud ed, “The positive effects were main tained over the course of the study peri od, with more improvement noticed with further sessions.” n

Drug Update

Zinbryta (Daclizumab): First Once-Monthly, Self-Administered Treatment Approved for Patients with Multiple Sclerosis By Loretta Fala, Medical Writer

ultiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system (CNS) that causes demyelination and axonal damage in the brain, spinal cord, and optic nerves.1,2 The demyelination in MS is thought to be the result of ab normal immune response in which acti vated lymphocytes (T-cells and possibly B-cells) impact the CNS myelin.3 Although its incidence and preva lence are not well-established because of inconsistent reporting and tracking, MS affects 250,000 to 350,000 or more people in the United States, with as many as 200 new cases diagnosed week ly.4,5 Approximately 85% of people with MS are diagnosed with relaps ing-remitting MS (RRMS).6 As many as 60% to 70% of patients with relaps ing forms of MS gradually progress to secondary progressive MS.2 The symptoms of MS include muscle weakness, numbness, visual problems, fatigue, dizziness, tremor, pain, coordi nation and speech problems, bowel and bladder function problems, and in se vere cases, impaired mobility and dis ability.2 MS can have a profound im pact on patients, their families, and caregivers, particularly when the dis ease affects functionality, productivity, and quality of life.7 MS is associated with substantial healthcare costs.7-9 A recent study showed that the per-patient annual allcause healthcare costs for MS ranged from $8528 to $54,244, with direct costs accounting for 77% of the total.8 In an earlier study, intangible costs, including for health-related quality of life, account ed for 17.5% to 47.8% of the total costs of managing MS.9 Overall, evidence sug gests that the patient burden and health care costs increase with the severity of disease and its related disability.7,8 The main treatment goals for pa tients with MS are to manage symp toms and to prevent or delay relapse, disability progression, and disease ac tivity.10,11 In recent literature, no evi dent disease activity (NEDA), which is defined by clinical and magnetic reso nance imaging (MRI) criteria, has been suggested as a goal for MS treatment and clinical trial design.12 NEDA in volves a patient-individualized ap proach: active monitoring with a repeat baseline MRI once a specific dis Copyright © 2016 American Health & Drug Benefits. Used with permission.

Table 1 DECIDE Trial: Daclizumab versus Interferon Beta-1a in Patients with Relapsing Multiple Sclerosis Daclizumab 150-mg subcutaneous injection every 4 weeks (N = 919)

Interferon beta-1a 30-mcg intramuscular injection once weekly (N = 922)

0.216

0.393

Relative reduction, %

Proportion relapse-free, %

Proportion with 12-week confirmed disability progression, %

4.31

9.44

Efficacy parameter

P value

Clinical assessment resultsa Annualized relapse rate

<.001 .16

MRI results Mean new or newly enlarging T2 hyperintense lesions, N Relative reduction, %

<.001

Values refer to results up to 144 weeks. MRI indicates magnetic resonance imaging; NA, not available. Sources: Kappos L, et al. N Engl J Med. 2015;373:1418-1428; Zinbryta (daclizumab) prescribing information; May 2016.

ease-modifying therapy (DMT) has had time to work, and performing an annu al (or more frequent, if necessary) MRI for subclinical relapse.12 A recent study showed that relapsing MS therapies demonstrating the high est NEDA values in clinical trials were the most cost-effective.13 Treatment adherence, a key aspect of MS manage ment that improves clinical benefits for patients, is also associated with lower rates of emergency department visits, hospital stays, and work absences.14 Early diagnosis and treatment are crucial for achieving optimal patient outcomes: aggressive, early therapy with DMTs in the early stages of MS has been shown to reduce relapse rates and slow the formation of new lesions.15,16 DMTs are the cornerstone treatments for relapsing MS.11,15 These agents differ in their safety and efficacy profiles, mechanisms of action, formulation, mode of delivery, dose, and dosing fre quency. DMTs are associated with drug class– or agent-specific adverse events; therefore, the risks and benefits of each therapy must be considered. Until recently, DMTs for relapsing MS included alemtuzumab; the beta interferons interferon beta-1a subcuta neous injection, interferon beta-1a in tramuscular injection, interferon be ta-1b, and pegylated interferon beta; dimethyl fumarate; fingolimod; glatir amer acetate; natalizumab; and teri flunomide.11 In 2016, a novel oncemonthly DMT with a new mechanism of action became available for relapsing MS.17,18

Daclizumab: A New Once-Monthly Option for Multiple Sclerosis

On May 27, 2016, daclizumab (Zin bryta; Biogen/AbbVie), a long-acting, interleukin (IL)-2 receptor–blocking antibody, was approved by the US Food and Drug Administration (FDA) for the treatment of adults with relapsing forms of MS.17,19 Because of its safety profile, daclizumab should generally be used for patients who respond inade quately to ≥2 MS therapies.19 Dacliz umab is available only through restrict ed distribution via a Risk Evaluation and Mitigation Strategy (REMS) program.17 Jeffrey English, MD, Director of Clinical Research, Multiple Sclerosis Center of Atlanta, said, “MS affects each person differently, so it is critical that people have additional therapeutic options to address their needs through out the course of the disease. Zinbryta provides a meaningful new treatment option that demonstrates efficacy and offers once-monthly dosing.”18 Daclizumab is the first once-month ly, self-administered treatment for MS.18 One of the studies leading to its approval was the largest and longest head-to-head phase 3 trial conducted on a drug to treat MS, according to Biogen and AbbVie.18 Mechanism of Action

Daclizumab is a humanized monoclo nal antibody. Although the precise mechanism of exerting therapeutic ef fects in MS is unknown, daclizumab is presumed to modulate IL-2–mediated

activation of lymphocytes through bind ing to CD25, a subunit of the high-affin ity IL-2 receptor.19 These IL-2 receptors are expressed on lymphocytes, which are cells implicated in the pathogenesis of MS.19,20 Over a 52-week course of treat ment with daclizumab, the total lympho cyte/T-cell counts decreased by <10%.21 Dosing and Administration

The recommended dose of daclizu mab is 150 mg once monthly adminis tered subcutaneously. Patients must be trained in the proper technique for self-administration. Laboratory tests should be performed at baseline and at periodic intervals to monitor patients for early signs of potentially serious ad verse reactions.19 Daclizumab injection is available as a 150-mg/mL solution in a single-dose prefilled syringe.19

Clinical Trials

The FDA approval of daclizumab was based on 2 randomized, dou ble-blind, controlled studies (DECIDE and SELECT) in patients with relaps ing MS. In both studies, patients with progressive MS or an Expanded Dis ability Status Scale score of >5 were excluded.19 The DECIDE study compared the safety and efficacy of subcutaneous dac lizumab 150 mg every 4 weeks with in tramuscular interferon beta-1a 30 mcg weekly in 1841 patients with relapsing MS (Table 1).19,20 The primary end point was the annu alized relapse rate during 144 weeks.19,20

Drug Update The secondary end points included the proportion of patients whose disease relapsed, the proportion of patients who had confirmed disability progres sion, and the number of new or newly enlarging T2 hyperintense lesions. The patients were evaluated every 12 weeks and after a relapse event; MRI scans were performed at weeks 24 and 96.19,20 Daclizumab demonstrated a 45% re duction in the annualized relapse rate and a 54% reduction in the number of new or newly enlarging T2 hyperin tense lesions compared with interferon beta-1a. The effect of daclizumab on 12-week confirmed disability progres sion was not significantly better than with interferon beta-1a.19,20 The SELECT clinical trial was a 52week, randomized, double-blind, place bo-controlled study that compared the safety and efficacy of daclizumab with placebo in 412 patients (mean age, 36 years) with relapsing MS (Table 2).19,21 The primary end point was the annu alized relapse rate at week 52. Other end points included new T1 gadolinium (Gd)-enhancing lesions from week 8 to week 24 in a subset of patients, the pro portion of patients with disease relapse, the proportion of patients who had 12week confirmed disability progression, and the number of new or newly enlarg ing T2 hyperintense lesions. Daclizumab demonstrated a signifi cant 54% reduction in the annualized relapse rate compared with placebo. Significant reductions were also demon strated with daclizumab versus placebo in the proportion of relapse-free pa tients (81% vs 64%, respectively), the number of new T1 Gd-enhancing le sions (69% reduction), and the number of new or newly enlarging T2 hyperin tense lesions (70% reduction).19,21 Adverse Reactions

The safety data for daclizumab are based on 2235 patients with RRMS who received daclizumab for 5214 per son-years. Overall, 1576 were exposed to daclizumab for ≥1 years, 1259 for ≥2 years, and 888 for ≥3 years.19 The most common adverse events (incidence ≥5% and ≥2% higher than the comparator) reported with dacliz umab included nasopharyngitis (25%), upper respiratory tract infection (17%), rash (11%), influenza (9%), dermatitis (9%), oropharyngeal pain (8%), bron chitis (7%), eczema (5%), and lymph adenopathy (5%). The most common adverse reactions with daclizumab were upper respiratory tract infection (9%), depression (7%), rash (7%), pharyngitis (6%), and in creased alanine aminotransferase (ALT) levels (5%).19 Up to 5% of patients discontinued daclizumab treatment because of an ad verse event; hepatic events, including

elevated serum trans aminases and cutane ous events, were the most common reasons for discontinuation.19 Restricted Distribution Program

Because of the risk for hepatic injury, in cluding several im mune disorders, dacliz umab is only available through a restricted program—the Zinbry ta REMS Program. The drug is therefore only available to certi fied prescribers, phar macies, and patients enrolled in this program.19

Table 2 SELECT Trial: Daclizumab versus Placebo in Patients with Relapsing Multiple Sclerosis Daclizumab 150-mg subcutaneous injection every 4 weeks (N = 208)

Placebo (N = 204)

0.211

0.458

Relative reduction, %

Proportion relapse-free, %

Proportion with 12-week confirmed disability progression, %

Relative risk reduction, %

Mean new or newly enlarging T2 hyperintense lesions,a N

2.4

8.1

Relative reduction, %

1.46

4.79

Efficacy parameter Clinical assessment results

P value

Annualized relapse rate

<.001

MRI results

Mean new T1 Gd-enhancing lesions, N Relative reduction, %

<.001

Values refer to results at 52 weeks. Gd indicates gadolinium; MRI, magnetic resonance imaging, NA, not available. Sources: Gold R, et al. Lancet. 2013;381:2167-2175; Zinbryta (daclizumab) prescribing information; May 2016.

Contraindications

Daclizumab is contraindicated in pa tients with preexisting hepatic disease or hepatic impairment, including ALT or aspartate aminotransferase at least twice the upper limit of normal, in pa tients with a history of autoimmune hepatitis or other autoimmune condi tions involving the liver, and in pa tients with a history of hypersensitivity to daclizumab or any other component of its formulation.19

Drug Interactions

Caution should be exercised when hepatotoxic drugs, including nonpre scription products, are used concomi tantly with daclizumab. The patient’s need for the use of herbal products or dietary supplements that can cause hepatotoxicity should be carefully considered.19

Warnings and Precautions

Boxed warning. Daclizumab was ap proved with a boxed warning about the risk for severe liver injury, including life-threatening events, liver failure, and autoimmune hepatitis. The pa tient’s transaminase and bilirubin lev els should be obtained before initiating daclizumab treatment. Transaminase and bilirubin levels should be moni tored monthly and up to 6 months after the last dose. In addition, daclizumab can cause immune-mediated disorders, including skin reactions, lymphade nopathy, noninfectious colitis, and other immune-mediated disorders.19 Hypersensitivity reactions/infections. Daclizumab can cause anaphy laxis, angioedema, and urticaria, and can increase the risk for infections; withholding treatment should be con sidered for serious infections until the infection resolves.19 Depression/suicide. The discontinu

ation of daclizumab should be consid ered in patients who report symptoms of depression and/or suicidal thoughts.19 Use in Specific Populations

The developmental risk associated with the use of daclizumab in pregnant women has not been adequately stud ied. It is not known whether daclizu mab is present in human milk or wheth er it has an effect on the breastfed child or on milk production.19 Daclizumab has not been studied in children; dacliz umab should not be used in pediatric patients because of safety risks.19 Conclusion

With the FDA approval of daclizumab subcutaneous injection, a new dis ease-modifying therapeutic option be came available for patients with relaps ing forms of MS, in particular, those who have an inadequate response to ≥2 drugs. Daclizumab, a humanized IL-2 recep tor-blocking antibody, demonstrated su perior efficacy in annualized relapse rate compared with interferon beta-1a in the DECIDE trial and compared with place bo in the SELECT trial. Moreover, dac lizumab showed superior efficacy in re ducing the number of new or enlarging brain lesions compared with interferon beta-1a and placebo. Daclizumab provides patients with relapsing MS a convenient and effec tive once-monthly treatment option that is self-administered. n

References

1. National Multiple Sclerosis Society. Definition of MS. www.nationalmssociety.org/What-is-MS/Defini tion-of-MS. Accessed June 12, 2016. 2. Mayo Clinic staff. Multiple sclerosis: symptoms and causes. October 1, 2015. www.mayoclinic.org/diseas es-conditions/multiple-sclerosis/home/ovc-20131882. Accessed June 12, 2016. 3. National Multiple Sclerosis Society. T cells. www. nationalmssociety.org/What-is-MS/Definition-of-MS/ T-cells. Accessed June 19, 2016.

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