2020 July AANnews by American Academy of Neurology

VOLUME 33 · ISSUE 7 · July 2020

Visit AAN.com/Covid19 for the latest pandemic information and resources to support you and your crucial work.

AAN POSITION: SYSTEMIC RACISM AND INEQUITIES IN SOCIETY June 4, 2020 Dear Members, Earlier today, the American Academy of Neurology Board of Directors unanimously approved the following Position Statement on Systemic Racism and Inequities in Society: The American Academy of Neurology (AAN) condemns racism and deplores the impact that historic, deeply rooted, and systemic inequities have on our members, our patients, the communities we serve, and our nation. Throughout the COVID-19 pandemic, we have witnessed a disproportionate burden of illness and death on communities of color. This unacceptable reality is the result of centuries of systemic inequities in our society that have infected the health care system of which we are all a part. In the midst of this global crisis, we have seen violent deaths that also compel us to confront the legacy of race and racism in our society. George Floyd was an unarmed black man publicly killed on the street while in police custody. Breonna Taylor was an unarmed black woman killed in her own home after being shot at least eight times by police. Ahmaud Arbery was an unarmed black man who was jogging when he was chased, confronted, shot, and killed by two white men with a shotgun. These three shocking and senseless killings are part of a long legacy of society devaluing the lives of men, women, and children of color. The AAN’s Vision is to be indispensable to its members; our Mission is to promote the highest quality patient-centered neurologic care and enhance member career satisfaction. We cannot be indispensable if we remain silent in the face of an issue that so profoundly impacts so many of our members. We cannot promote the best care for our patients or enhance the careers of our members if we ignore the pervasive inequities that are often insurmountable barriers to both. In the face of these historic and systemic issues, it is not enough to not be a racist organization. We must speak out and lead in order to ensure change. To achieve our Vision and Mission, we must be an anti-racist organization. The AAN commits to enact sustained change for our members and patients. In this historic moment, we are resolved to pursue bold action beyond rhetoric and stand with the communities we serve to eliminate inequities that are antithetical to our values and the pursuit of our Vision and Mission. The AAN Board of Directors also approved the creation of an AAN Special Commission to recommend specific actions by July 15, 2020, to implement the position statement throughout the organization. The recommendations of the Special Commission will be reviewed by the AAN’s Equity, Diversity, and Inclusion Joint Coordinating Council and provided to the AAN Board of Directors. Many have contributed to the AAN’s efforts for equity, diversity, and inclusion. We are now calling on all members to take action to uphold our AAN core values of diversity and equity. Now more than ever, we are committed to lasting change. Sincerely, James C. Stevens, MD, FAAN President, American Academy of Neurology

Jeffrey C. McClean, II, MD, FAAN Chair, AAN Equity, Diversity, and Inclusion Joint Coordinating Council

Mary E. Post, MBA, CAE Chief Executive Officer, American Academy of Neurology

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18 Emerging Science Abstracts Announced

NEW & APPROVED

FOR RELAPSING FORMS OF MS 1

ZEPOSIA® (ozanimod) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsingremitting disease, and active secondary progressive disease, in adults.

DISCOVER THE FIRST AND ONLY S1P WITH NO FIRST-DOSE OBSERVATION REQUIRED1-3a FULL PRESCRIBING INFORMATION FOR ZEPOSIA HAS

NO FDO REQUIRED, NO GENETIC TESTING REQUIRED, AND NO OPHTHALMIC TESTING REQUIRED FOR MOST PATIENTS4b Start at ZEPOSIAhcp.com

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COMPARABLE

CONSISTENT 7f

Proven superior in reducing relapses vs Avonexd

Safety profile vs Avonex in overall incidence of adverse reactions1,5-7e

Proven superior in reducing GdE and T2 lesions vs Avonex

Consistently low discontinuation rates vs Avonex

ZEPOSIA consistently maintained ALC near the lower limit of normal across 2 large-scale pivotal trials

Comparable rates of serious infections and malignancies vs Avonex Indication

ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

IMPORTANT SAFETY INFORMATION

Contraindications: • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a presence of Mobitz type II second or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, unless the patient has a functioning pacemaker • Patients with severe untreated sleep apnea • Patients taking a monoamine oxidase (MAO) inhibitor Infections: ZEPOSIA may increase the susceptibility to infections. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is

resolved. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Please see Important Safety Information throughout and Brief Summary of Prescribing Information.

ZEPOSIA is commercially available in the US as of June 1, 2020, following FDA approval on March 25, 2020.

Before initiating treatment with ZEPOSIA, all patients require a recent CBC including lymphocyte count (within 6 months or after discontinuation of prior MS therapy), an ECG to check for preexisting conduction abnormalities, a recent liver function test (within 6 months), and consideration of current and prior medications, including vaccinations.1 Patients without a confirmed history of varicella (chickenpox), or without documented VZV vaccination should be tested for antibodies. If VZV or other live attenuated immunizations are required, administer at least 1 month prior to initiation.1 For patients with a history of uveitis or macular edema, an ophthalmic assessment is required.1 An up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA, as a transient decrease in heart rate and atrioventricular conduction delays may occur.1

Diabetes mellitus and uveitis increase the risk of macular edema; patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation. A prompt ophthalmic evaluation is recommended if there is any change in vision while taking ZEPOSIA.1

Study designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg vs weekly Avonex (interferon beta-1a), 30 μg intramuscular injection. Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.18 vs 0.35, respectively) and by 38% at 2 years (0.17 vs 0.28, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years. 9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.

A relapse was defined as the occurrence of new or worsening neurological symptoms persistent for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3

Adverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year were 59.8% and 75.5%, respectively, and at 2 years were 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of ≥2% for ZEPOSIA vs Avonex, respectively, were as follows: nasopharyngitis, 11.1% (vs 9.5%); alanine aminotransferase increased, 5.3% (vs 3.2%), gamma-glutamyl transferase increased, 4.5% (vs 1.2%); urinary tract infection, 4.1% (vs 3.1%); hypertension, 3.4% (vs 2.0%); pharyngitis, 3.2% (vs 2.3%); and respiratory tract infection viral, 2.4% (vs 1.2%). Overall discontinuation rates for ZEPOSIA vs Avonex at 1 year were 6% and 8%, respectively, and at 2 years were 10% and 15%, respectively. Discontinuation rates due to adverse reactions for ZEPOSIA vs Avonex at 1 year were 2.9% and 3.6%, respectively, and at 2 years were 3.0% and 4.1%, respectively. Serious infections: The rate of serious infections at 1 year for ZEPOSIA was 1.0% vs 0.6% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.9% for Avonex. Malignancy rates: The rate of malignancies at 1 year for ZEPOSIA was 0.2% vs 0% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.5% for Avonex.

ALC: ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible retention of lymphocytes in lymphoid tissues. ZEPOSIA may therefore increase the susceptibility to infections.1 Mean ALC was 0.75 × 10 9 cells/L for both SUNBEAM and RADIANCE (at 1 year and 2 years, respectively). ALC=absolute lymphocyte count; ARR=annualized relapse rate; CBC=complete blood count; ECG=electrocardiogram; FDO=first-dose observation; GdE=gadolinium enhancing; S1P=sphingosine-1-phosphate; VZV=varicella-zoster virus.

IMPORTANT SAFETY INFORMATION (CONTINUED) Infections (Continued): • Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued • In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, noncorticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • with significant QT prolongation • with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs • with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • with a history of Mobitz type II second-degree or higher AV block, sick-sinus syndrome, or sinoatrial heart block Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease

NEW & APPROVED

FOR RELAPSING FORMS OF MS 1

Start at ZEPOSIAhcp.com

IMPORTANT SAFETY INFORMATION (CONTINUED) Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA

Celgene/Ozanimod

Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated Macular edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued Unintended Additive Immunosuppressive Effects From Prior Immunosuppressive or Immune-Modulating Drugs: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended Severe Increase in Disability After Stopping ZEPOSIA: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment so patients should be monitored upon discontinuation Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA Most common Adverse Reactions (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

Please see Important Safety Information throughout and Brief Summary of Prescribing Information. References: 1. ZEPOSIA® (ozanimod) [package insert]. Summit, NJ: Bristol Myers Squibb Company; 2020. 2. Gilenya® (fingolimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. 3. Mayzent® (siponimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019. 4. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. 5. Comi G, Kappos L, Selmaj K, et al; for the SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020. 6. Cohen JA, Comi G, Selmaj K, et al; for the RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033. 7. Data on file, Bristol Myers Squibb Company. ZEPOSIA® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners. © 2020 Bristol-Myers Squibb Company. All rights reserved. Printed in the USA. 05/20 US-ZEP-19-0058

ZEPOSIA® (ozanimod) capsules, for oral use The following is a Brief Summary; refer to full Prescribing Information for complete product information. 1

• Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.2)]

INDICATIONS AND USAGE

DOSAGE AND ADMINISTRATION

2.1 Assessments Prior to First Dose of ZEPOSIA Before initiation of treatment with ZEPOSIA, assess the following: Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1)]. Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.2)]. Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.3)]. Ophthalmic Assessment In patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.7)]. Current or Prior Medications • If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

• Have severe untreated sleep apnea [see Warnings and Precautions (5.2)] • Are taking a monoamine oxidase (MAO) Inhibitor [see Drug Interactions (7.7)] 5

WARNINGS AND PRECAUTIONS

5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2)]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. In Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA was similar to that in patients who received interferon (IFN) beta-1a (35% vs 34% and 1% vs 0.8%, respectively). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes zoster [see Adverse Reactions (6.1)].

Celgene/Ozanimod

• Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]. Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7.3)]. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. 2.2 Dosing Information Maintenance Dosage After initial titration (see Treatment Initiation), the recommended maintenance dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. ZEPOSIA capsules should be swallowed whole and can be administered with or without food. Treatment Initiation Initiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions (5.2)]. Table 1: Dose Titration Regimen Days 1-4

0.23 mg once daily

Days 5-7

0.46 mg once daily

Day 8 and thereafter

0.92 mg once daily

2.3 Reinitiation of ZEPOSIA After Treatment Interruption If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimen [see Dosage and Administration (2.2)]. If a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned. 4

CONTRAINDICATIONS

ZEPOSIA is contraindicated in patients who: • In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.2)]

The proportion of patients who experienced lymphocyte counts less than 0.2 x 109/L was 3.3%. These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Herpes Viral Infection In Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below). Cryptococcal Infection Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, treatment with ZEPOSIA should be discontinued.

ZEPOSIA® (ozanimod) capsules, for oral use Prior and Concomitant Treatment with Anti-neoplastic, Immunosuppressive, or Immune-modulating Therapies In clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. Antineoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. 5.2 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)]. ZEPOSIA was not studied in patients who had: • A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months • New York Heart Association Class III / IV heart failure • Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient’s health • Other pre-existing stable cardiac conditions without clearance from a cardiologist • Severe untreated sleep apnea • A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. In Study 1 and Study 2, after the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate of 1.2 bpm occurred at Hour 5 on Day 1, returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2)]. In Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in Study 1 and Study 2 with dose titration, second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) • With arrhythmias requiring treatment with Class 1a or Class III anti-arrhythmic drugs

• With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4)] 5.3 Liver Injury Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. In Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2-4 weeks. In clinical trials, ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed. Individuals with an AST or ALT greater than 1.5 times ULN were excluded from Study 1 and Study 2. Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA, caution should be exercised when using ZEPOSIA in patients with a history of significant liver disease. 5.4 Fetal Risk There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1)]. Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.1)]. 5.5 Increased Blood Pressure In Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA. 5.6 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in patients treated with ZEPOSIA as early as 3 months after treatment initiation. In pooled analyses of Study 1 and Study 2, the decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a (60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)), though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation. One patient discontinued ZEPOSIA because of dyspnea. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.

ZEPOSIA® (ozanimod) capsules, for oral use 5.7 Macular Edema S1P modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. In Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is any change in vision while taking ZEPOSIA. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision on whether or not ZEPOSIA should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. 5.8 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued. 5.9 Unintended Additive Immunosuppressive Effects From Prior Treatment with Immunosuppressive or Immune-Modulating Drugs When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1)]. 5.10 Severe Increase in Disability After Stopping ZEPOSIA Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required. 5.11 Immune System Effects After Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2)]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7.1)]. 6

ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling: • Infections [see Warnings and Precautions (5.1)] • Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.2)] • Liver Injury [see Warnings and Precautions (5.3)] • Fetal Risk [see Warnings and Precautions (5.4)] • Increased Blood Pressure [see Warnings and Precautions (5.5)] • Respiratory Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)] • Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.9)] • Severe Increase in Disability After Stopping ZEPOSIA [see Warnings and Precautions (5.10)] • Immune System Effects After Stopping ZEPOSIA [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14)]. Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1aa (Pooled Study 1 and Study 2) Studies 1 and 2 ZEPOSIA IFN beta-1a 0.92 mg 30 mcg (n=882) Intramuscularly % Once Weekly (n=885) %

Adverse Reactions

Upper respiratory infectionb elevationc

Orthostatic hypotension

Urinary tract infection

Back pain

Hypertensiond

Abdominal pain upper

Hepatic transaminase

Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gammaglutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased. d Includes hypertension, essential hypertension, and orthostatic hypertension. Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate [see Warnings and Precautions (5.2)]. Respiratory Effects Dose-dependent reductions in absolute FEV1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.6)]. Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, and seminoma, were reported with ZEPOSIA in the active-controlled trials for ZEPOSIA. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator. Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials. 7

DRUG INTERACTIONS

7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies ZEPOSIA has not been studied in combination with anti-neoplastic, immunemodulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1)]. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.9)].

ZEPOSIAÂŽ (ozanimod) capsules, for oral use Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with ZEPOSIA after alemtuzumab is not recommended. ZEPOSIA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. 7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That may Decrease Heart Rate ZEPOSIA has not been studied in patients taking QT prolonging drugs. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought. Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties [see Warnings and Precautions (5.2)]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought. 7.3 Vaccination During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions (5.1)]. 7.4 Strong CYP2C8 Inhibitors Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. 7.5 Breast Cancer Resistance Protein (BCRP) Inhibitors Co-administration of ZEPOSIA with BCRP inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may increase the risk of ZEPOSIA adverse reactions. Therefore, co-administration of ZEPOSIA with inhibitors of BCRP (e.g., cyclosporine, eltrombopag) is not recommended. 7.6 Strong CYP2C8 Inducers Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3)], which may decrease the efficacy of ZEPOSIA. Therefore, co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided. 7.7 Monoamine Oxidase (MAO) Inhibitors Co-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the active metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see Clinical Pharmacology (12.3)]. The potential for a clinical interaction with MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibition may lead to a hypertensive crisis. Therefore, co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors. 7.8 Adrenergic and Serotonergic Drugs Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclics, tyramine] is not recommended. Monitor patients for hypertension with concomitant use. Opioid Drugs Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration. Serotonergic Drugs Although a small number of patients treated with ZEPOSIA were concomitantly exposed to serotonergic medications, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration.

Sympathomimetic Medications Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects on blood pressure [see Clinical Pharmacology (12.3)]. However, hypertensive crisis has occurred with administration of ZEPOSIA alone [see Warnings and Precautions (5.5)] and hypertensive crisis has been reported with co-administration of other selective and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic medications. 7.9 Tyramine MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramine reaction). Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of ZEPOSIA [see Warnings and Precautions (5.5)]. 8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine-1-phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and neural development. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformed blood vessels) and skeletal variations at the mid and high doses. Maternal toxicity was not observed. At the no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod exposure (AUC) was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects on pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the motherâ&#x20AC;&#x2122;s clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.

ZEPOSIA® (ozanimod) capsules, for oral use 8.3 Females and Males of Reproductive Potential Contraception Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific Populations (8.1)]. Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown [see Clinical Pharmacology (12.3)]. Use of ZEPOSIA in patients with hepatic impairment is not recommended. 13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors. At the highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximately 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Mutagenesis Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Metabolite CC1122273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays. Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay. Impairment of Fertility Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and during mating and continuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), plasma ozanimod exposure (AUC) was approximately 1600 times that in humans at the maximum recommended human dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273 and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD. 17

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions (5.1)].

Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. If immunizations are planned, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. Cardiac Effects Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment [see Dosage and Administration (2.2, 2.3) and Warnings and Precautions (5.2)]. Liver Injury Inform patients that ZEPOSIA may increase liver enzymes. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine [see Warnings and Precautions (5.3)]. Pregnancy and Fetal Risk Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions (5.4)]. Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea [see Warnings and Precautions (5.6)]. Macular Edema Advise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision. Inform patient with diabetes mellitus or a history of uveitis that their risk of macular edema maybe increased [see Warnings and Precautions (5.7)]. Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provide any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences [see Warnings and Precautions (5.8)]. Severe Increase in Disability After Stopping ZEPOSIA Inform patients that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA [see Warnings and Precautions (5.10)]. Immune System Effects After Stopping ZEPOSIA Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose [see Warnings and Precautions (5.11)]. Manufactured for: Celgene Corporation Summit, NJ 07901 Patent: www.celgene.com/therapies ZEPOSIA® is a trademark of Celgene, a Bristol-Myers Squibb Company. © 2020 Bristol-Myers Squibb Company. All rights reserved. ZEP_HCP_BSv.001.05 03/2020

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Nominations Sought for 2021–2023 Board Positions The AAN seeks nominations for a new president elect, vice president, secretary, treasurer, and director positions. Nominees must be Fellows of the American Academy of Neurology (FAAN). Members are encouraged to self-nominate or nominate a respected colleague by August 31, 2020.

Phone: (732) 778-2261 Email: Eileen.Henry@wolterskluwer.com

AAN Chief Executive Officer: Mary E. Post, MBA, CAE

Editor-in-Chief: Melissa W. Ko, MD, FAAN, CPE Managing Editor: Angela M. Babb, MS, CAE, APR Editor: Tim Streeter Writers: Ryan Knoke and Sarah Parsons Designer: Siu Lee Email: aannews@aan.com AANnews® is published monthly by the American Academy of Neurology for its 36,000 members worldwide. Access this magazine and other AAN publications online at AAN.com. The American Academy of Neurology ’ s registered trademarks and service marks are registered in the United States and various other countries around the world. “American Brain Foundation” is a registered service mark of the American Brain Foundation and is registered in the United States. The inclusion of advertisements and/or promotions of Sponsors and other Internet sites or resources that offer content, goods, or services on the Website does not imply endorsement of the advertised/promoted products or services by AAN.

Emerging Science Abstracts Announced

Twelve Emerging Science abstracts have been selected for having key aspects of research conducted after the original AAN abstract submission deadline. These abstracts represent new and sufficient scientific importance, warranting expedited presentation and publication.

News Briefs 2020 Research Program Recipients Congratulations to the recipients of the 2020 AAN Research Program, which has awarded more than $3 million toward neuroscience research and training. See the list of recipients at AAN.com/PressRoom/ Home/PressRelease/3791.

Member Survey on COVID-19 A total of 358 members responded to a pop-up survey on AAN.com in May on how they have been affected by

COVID-19. About half of the respondents have decreased their workload, especially advanced practice providers and neurologists who are not in academia. About one in five say their biggest concern is disruption to education/ teaching/training (especially for those in training) and increased personal health risks. About half say the AAN can best serve them by continuing to advocate for telemedicine reimbursement (especially for US neurologists and APPs, but less so for those in government and hospital practice settings). 

#NeurologyProud and proud to call the AAN my home. Share why you are #NeurologyProud on social media.

Pierre Fayad, MD, FAAN, FAHA

Conferences & Community

Our Popular Conferences Are Coming to You―Virtually! The AAN recognizes members may be reluctant or unable to travel during the COVID-19 pandemic, so your Academy has decided to bring our upcoming, always-popular conference events to you! The same excellence that you have come to expect in person can now be experienced in a virtual format—so look for more information on programming, faculty, and registration details to come your way soon.

AAN Sports Concussion Conference July 31–August 1, 2020 Get the latest science and education on the prevention, management, and treatment of concussion, as well as valuable CME and CE credits.

SPORTS CONCUSSION VIRTUAL CONFERENCE

AAN Advanced Practice Provider Neurology Education Series—A Virtual Experience Launching August 2020 A virtual education series designed especially for neurology advanced practice providers will offer overviews and updates of clinical topics and weekly resources.

AAN Fall Conference October 2020

Virtual 2020

AAN Advanced Practice Provider Neurology Education Series 2020

A Virtual Experience

Expect to receive timely clinical updates on the hottest topics in neurology in a virtual setting. As the end of year approaches, fulfill CME requirements, hear from noteworthy speakers, and engage with colleagues and industry professionals. 

Nominations of FAAN Members Sought for 2021–2023 Board Positions The AAN seeks nominations for a new president elect, vice president, secretary, treasurer, and director positions. Nominees must be Fellows of the American Academy of Neurology (FAAN). Members are encouraged to self-nominate or nominate a respected colleague by August 31, 2020. The AAN membership will vote on the proposed slate of officers at the 2021 Annual Meeting in San Francisco, CA. “The Academy has thrived due to the thoughtful and creative leadership of its members,” said AAN President James C. Stevens, MD, FAAN. “Our officers and boards over the years have successfully tackled numerous obstacles and threats to neurology, and now we face new challenges due to the COVID-19 pandemic and its impact on our services to our patients and how the Academy can support its membership. Mindful of this, we welcome nominations that reflect the rich diversity of our members. We seek leaders who have the capacity of vision, innovation, and collaboration that will strengthen and lift our organization to higher levels of value to our 36,000 members worldwide.” The AAN requests nominations for president elect, vice president, secretary, treasurer, and members of the Board of Directors for the 2021–2023 term of office. The role of president elect is a six-year commitment (two years each as president elect, president, and immediate past president).

AANnews • July 2020

The vice president, secretary, and treasurer are eligible for one additional two-year term, for a total of four years. A director is eligible for two additional two-year terms, for a total of six years. Descriptions of the roles and responsibilities of these officers are available at AAN.com/nominations. Learn more or submit your nomination now at AAN.com/nominations. 

Stevens Interviewing Inspiring Members in New Series of Videos The Academy is producing a new series of videos featuring President James C. Stevens, MD, FAAN, interviewing members who are living the values of the AAN in inspiring ways. The series is designed to highlight the real-life stories of members who, through their actions, clearly express the principles of the AAN. Stevens is virtually meeting with members to share their stories and learn more about their actions, motivations, and lessons learned.

Sisniega was pulled from rotation at a VA hospital and asked to go to the heavily affected ER at Elmhurst Hospital. She was asked to stay a few days, but she volunteered to stay the whole month. The experience affected her in other ways, as you can learn by viewing the video at YouTube.com/AANchannel.

The series kicked off with the story of Daniella Sisniega, MD, a PGY-2 neurology resident at Mount Sinai Hospital in New York City. With the hospital lacking enough personal protective equipment (PPE) for staff fighting COVID-19, Sisniega explained to Stevens how she had to use her ingenuity to design a mask with supplies from the ER department. It took her 25 minutes for the first working model, then others helped improve the design and got the temporary mask distributed to ER staff. PubPolicy: 19 NCP Adâ&#x20AC;&#x201D;Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

NEUROLOGY COMPENSATION AND PRODUCTIVITY SURVEY DATA AVAILABLE! Compare. Act. Improve. AAN.com/view/NCPSurvey

Conferences & Community

Congratulations 2020 AAN Scientific Award Winners! Congratulations to the winners of the 2020 AAN scientific awards. The AAN thanks the American Brain Foundation for its support through philanthropy of the American Academy of Neurology's awards program. A listing is available on the new 2020 AAN Science Highlights online platform, which is free to both AAN members and nonmembers at AAN.com/2020science. In addition to the awards, visitors can view up to 2,000 presentations, hear abstract presenters talk about their work, and engage in lively exchange with them via chat. The program is fully searchable on areas such as topic, institution, or presenter, and includes Emerging Science abstracts, abstracts on health care disparities, and abstracts of distinction. Alliance Awards Sponsored by the American Academy of Neurology and endowed by the former American Academy of Neurology Alliance.

Founders Award Recipient: Abhimanyu Mahajan, MD, MHS, Cincinnati, OH S. Weir Mitchell Award Recipient: Amir Hadi Maghzi, MD, Boston, MA Bruce S. Schoenberg International Award in Neuroepidemiology Sponsored by the American Academy of Neurology and endowed by GlaxoSmithKline, Inc.

Recipient: Jorge Llibre-Guerra, MD, MSc, Havana, Cuba Dreifuss-Penry Epilepsy Award Sponsored by the American Academy of Neurology and endowed by members of the American Academy of Neurology Epilepsy Section; Abbott Laboratories, Inc.; Cephalon, Inc.; Cyberonics, Inc.; Elan Corporation; GlaxoSmithKline, Inc.; Novartis; Ortho-McNeil Pharmaceutical, Inc.; Pfizer Inc; Shire Pharmaceuticals Group; and UCB Pharma.

Sponsored by the American Academy of Neurology.

Recipient: Elizabeth Coon, MD, Rochester, MN Medical Student Essay Awards Sponsored by the American Academy of Neurology.

Extended Neuroscience Award Recipient: Samuel Belfer, PhD, Philadelphia, PA G. Milton Shy Award Recipient: Christopher Tran, BMSc, Toronto, ON, Canada Roland P. Mackay Award Recipient: Jimmy Zheng, BS, Stanford, CA Saul R. Korey Award Recipient: Laura Lavette, BS, Winston-Salem, NC Michael S. Pessin Stroke Leadership Prize Sponsored by the American Academy of Neurology and endowed by Dr. Pessin’s family, friends, and colleagues.

Recipient: Vikram Rao, MD, San Francisco, CA

Recipient: Ashkan Shoamanesh, MD, BSc, Hamilton, ON, Canada

Harold Wolff-John Graham Award: An Award for Headache/Facial Research

Mitchell B. Max Neuropathic Pain Award

Sponsored by the American Academy of Neurology and endowed by GlaxoSmithKline, Inc.

Recipient: Mia Minen, MD, MPH, New York, NY Irwin Schatz Award for Autonomic Disorders

Sponsored by the American Academy of Neurology and endowed by Lundbeck, Inc.

Sponsored by the American Academy of Neurology and endowed by the United States Cancer Pain Relief Committee, the Mayday Fund, and friends of Dr. Mitchell Max.

Recipient: Anne Louise Oaklander, MD, PhD, FAAN, FANA, Boston, MA Movement Disorders Research Award

John Dystel Prize for Multiple Sclerosis Research

Sponsored by the American Academy of Neurology, the Parkinson’s Foundation, and the American Academy of Neurology Movement Disorders Section and endowed by the Parkinson’s Foundation.

Sponsored by the American Academy of Neurology and National Multiple Sclerosis Society and made possible through a special contribution from the John Dystel Multiple Sclerosis Research Fund at the National Multiple Sclerosis Society.

Neuroendocrine Research Award

Recipient: Horacio Kaufman, MD, FAAN, New York, NY

Recipient: Ian Duncan, BVMS, MRCVS, PhD, Madison, WI Jon Stolk Award in Movement Disorders for Young Investigators Sponsored by the American Academy of Neurology and endowed by Kyowa Pharmaceutical, Inc., Lineberry Research, Quintiles, Dr. Dennis Gillings, and VelaPharma.

Recipient: Aasef Shaikh, MD, PhD, Cleveland, OH

Lawrence C. McHenry: An Award for the History of Neurology

AANnews • July 2020

Recipient: Henry Paulson, MD, PhD, FAAN, Ann Arbor, MI Sponsored by the American Academy of Neurology and supported by friends of Dr. Andrew Herzog.

Recipient: This award was not given in 2020. Neuro-infectious Disease Award Sponsored by the American Academy of Neurology.

Recipient: Pria Anand, MD, Boston, MA

Neuro-oncology Investigator Award Sponsored by the American Academy of Neurology and supported by friends of Dr. Jerome Posner.

Recipient: Adrienne Boire, MD, PhD, New York, NY Neuro-oncology Scientific Award Sponsored by the American Academy of Neurology and supported by friends of Dr. WK Alfred Yung.

Recipient: David Gutmann, MD, PhD, St. Louis, MO, and Jaishri Blakeley, MD, Baltimore, MD Neuroscience Research Prize Sponsored by the American Academy of Neurology.

Recipients: Abe Baker-Butler, Rye Brook, NY; Bryan Dong, Baltimore, MD; Nikhil Boddu, Chesterfield, MO Neuroscience Research Prize in Child Neurology Sponsored by the American Academy of Neurology and the Child Neurology Society.

Recipient: Pratik Vangal, Portland, OR Norman Geschwind Prize in Behavioral Neurology Sponsored by the American Academy of Neurology and endowed through Dr. Geschwind’s family, friends, and colleagues; Pfizer Inc; and the Society for Behavioral and Cognitive Neurology.

Recipient: Richard Ryan Darby, MD, Nashville, TN Potamkin Prize for Research in Pick’s, Alzheimer’s, and Related Diseases Sponsored by the American Academy of Neurology and the American Brain Foundation and funded through the philanthropy of the Potamkin family.

Recipient: J. Paul Taylor, MD, PhD, Memphis, TN Sheila Essey Award: An Award for ALS Research Sponsored by the American Academy of Neurology, the American Brain Foundation, and the ALS Association and supported through the philanthropy of the Essey Family and the ALS Association.

Recipient: Guy Rouleau, MD, PhD, Montreal, QC, Canada Sleep Science Award Sponsored by the American Academy of Neurology and the American Academy of Neurology Sleep Section and endowed by Cephalon, Inc.

Recipient: Renée Shellhaas, MD, MS, Ann Arbor, MI Wayne A. Hening Sleep Medicine Investigator Award Sponsored by the American Academy of Neurology and endowed by UCB, Inc., Lilly USA, Elite Home Medical & Respiratory, Inc., Raleigh Neurology Associates, and friends of Dr. Wayne A. Hening.

Recipient: Mark Boulos, BSc, MD, FRCP(C), CSCN(EEG), MSc, Toronto, ON, Canada 

Trainees: It’s Time to Renew Your Membership for the 2020-2021 Academic Year Neurology trainees are an important part of our worldwide neurology community and staying connected to colleagues now during these unprecedented times is more important than ever. By renewing your valuable AAN memberships for the 2020–2021 academic year*, trainees can ensure continued connection to their community and access to essential training resources, education, and support to enhance professional development through these difficult times and beyond, including: Free access to Continuum® and Continuum® Audio Career guidance with job seeker tools including CV support, salary calculator, articles and webinars, and career coaching The latest scientific research and news affecting the neuroscience community Resources including online education and clinical practice guidelines Access to a network of more than 36,000 neurologists and neuroscience professionals worldwide Contact your program coordinator if your program typically renews your membership or visit AAN.com/dues to renew. If you have recently completed training, contact AAN Member Services prior to renewing to learn about special early career membership rates.  * Student, Intern, and Junior memberships run on an academic year (July 1 through June 30), regardless of join date.

Conferences & Community

Diversity Leadership Program Graduate Finds New Voice In her new role, Lewis actively works with admissions to develop innovative ways to recruit a diverse student body. “I lead several different pipeline programs that recruit underrepresented students ranging from high school to college,” she said. “In addition, I support the current student body through mentorship and promoting inclusive “Before the program started, I described myself as initiatives that build a community among the medical ‘conflict avoidant,'" explained Lewis. “But during the Lewis students. My new role has brought things full circle and program, I learned about the term ‘adaptive conflict.’ I am following a path that invigorates me and inspires With adaptive conflict, a leader has the ability to use a source me to build the next generation of physicians. Through my work of tension to their advantage. This may be as a lesson learned in admissions and in the Program for Diversity and Inclusion, on how to be a better negotiator, or it may reveal an alternative my daily tasks align with my internal desires.” way to view a project.” Like so many other AAN Leadership Program graduates before Another critical skill the program focused on was her, Lewis is quick to point out that her peers and mentors mindfulness—a philosophy Lewis has since found particularly are an integral part of the life-changing aspects of the overall useful in her position as associate professor of clinical experience. “I now have a nationwide pool of colleagues that neurology at Perelman School of Medicine at the University of have become valued mentors and friends—and also serve Pennsylvania in Philadelphia. “With all of the responsibilities as a source of encouragement,” she explained. “My mentor, of being in academic medicine, I was constantly taking on Rachel Salas, MD, FAAN, at Johns Hopkins University, provided tasks and moving from one project to the next without a clear me with guidance, accountability, and real-time advice as purpose,” she said, “but the program taught me the importance I was working through my promotion, and she taught me of thoughtful direction and taking a moment daily to reflect on about strength training. Her advice provided me with more my path. I gained clarity and was able to refuse opportunities self-awareness, which allowed me to lead with my strengths. that did not align with my purpose, which allowed me to clearly And I have to mention the invaluable guidance, resources, follow my own authentic path.” and advocacy that I received from Joanne Smikle, PhD, Armed with her newfound skills, Lewis found her own voice— who provided a gentle but invasive dive that was needed to and started using it. understand my true potential as a leader and unveil ways in which I could be limiting myself. The mentorship I “One of my many passions is mentorship and building pipelines experienced is multi-layered and specific and gave me a for underrepresented students in medicine,” she said. “Daily, deeper understanding of who I am as a leader.”  I am able to apply the leadership skills I learned as I direct When Sharon Lewis, MD, was selected for the 2019 Diversity Leadership class, she couldn’t anticipate its transforming effects, or the number of easily adoptable takeaways that would prove invaluable in the way she thinks about—and resolves—conflict.

teams, manage conflict, and advocate for students. I was already involved in much of the pipeline programming at the Perelman School of Medicine and with the skills taught to me through the Diversity Leadership Program, I used my voice to advocate for my new position as the assistant dean for diversity recruitment.”

AANnews • July 2020

Financially Distressed? New Neurology COVID-19 Relief Fund May Help Roundtable, our partners in providing care, to obtain additional funds. The goal is to secure $1,000,000 for the fund.

Because many neurology professionals in the US are struggling economically to provide services to their patients during the pandemic, the AAN Institute Board of Directors has established the Neurology COVID-19 Relief Fund.

Learn more about the Neurology COVID-19 Relief Fund and apply at AAN.com. 

The fund will provide grants to any neurology professional or neurology practice experiencing acute hardship and distress as an immediate result of this crisis, to enable neurologists and neurology practices to continue to provide needed health care services in communities that have become distressed as a result of the pandemic. Applications are reviewed by an impartial work group of volunteer physician leaders from various practice settings and locations. The Academy launched the Neurology COVID-19 Relief Fund in June with $100,000, and an additional $150,000 will be available through matched donations, for a total potential contribution of $250,000. The AAN Institute is collaborating with the Industry Fatigue Expert Manag Ways to e Tired ness Stroke Recove 5 Survivo ry Helped rs: What Get ThroThem ugh Cluste r New Tre Headache to Curb atments the Pain

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Tell your patients to join the Brain & Life® community. Delivered in print to AAN members in the US, with Spanish-language issues published quarterly.

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Education & Research

Emerging Science Abstracts Announced The following 12 Emerging Science abstracts have been selected for having key aspects of research conducted after the original AAN abstract submission deadline. These abstracts represent new and sufficient scientific importance, warranting expedited presentation and publication. Full abstract presentations from participating authors are available on the new 2020 AAN Science Highlights online platform, available free to both AAN members and nonmembers at AAN.com/2020science. In addition to the Emerging Science abstracts, visitors can view more than 1,500 presentations, hear abstract presenters talk about their work, and engage in lively exchange with them via chat. The program is fully searchable on areas such as topic, institution, or presenter, and includes 2020 scientific award winners, abstracts on health care disparities, and abstracts of distinction. Efficacy and Safety of AXS-07 for the Acute Treatment of Migraine: Results from the MOMENTUM (Maximizing Outcomes in Treating Acute Migraine) Phase 3 Randomized, Double-blind, Active- and Placebo-controlled Study Amanda Jones; Cedric O’Gorman, MD; Stewart J. Tepper, MD; Richard B. Lipton, MD, FAAN; Herriot Tabuteau Efficacy and Safety of 3 Different Dosages of IVIG (Panzyga®) in Patients with CIDP (ProCID Study) David R. Cornblath, MD; Pieter Van Doorn, MD; Hans-Peter Hartung, MD, FAAN; Ingemar S.J. Merkies, MD; Hans D. Katzberg, MD, FAAN; Doris Hinterberger; Elisabeth Clodi; and the ProCID Investigators Efficacy and Safety Results from Part 2 MOXIe: A Randomized, Doubleblind, Placebo-controlled Trial of Omaveloxolone in Friedreich Ataxia David R. Lynch, MD, PhD; Sylvia Boesch, MD; Melanie Chin; Martin Delatycki; Paola Giunti; Angie Goldsberry; Chad Hoyle, MD; Caterina Mariotti; Katherine D. Mathews, MD, FAAN; Megan O'Grady; Susan L. Perlman, MD; S. H. Subramony, MBBS, FAAN; George R. Wilmot, MD, PhD; Theresa A. Zesiewicz, MD, FAAN; Colin Meyer EMERGE and ENGAGE Topline Results: Phase 3 Studies of Aducanumab in Early Alzheimer's Disease Samantha Budd Haeberlein; Christian von Hehn; Ying Tian; Spyros Chalkias; Kumar Kandadi Muralidharan; Tianle Chen; Shuang Wu; Jie Li, LeAnne Skordos; Laura Nisenbaum;

AANnews • July 2020

Raj Rajagovindan; Gersham Dent; Katie Harrison; Ivan Nestorov; Ying Zhu; Craig Mallinckrodt; Alfred Sandrock Galcanezumab in Patients with Treatment-resistant Migraine: Results from the Open-label Phase of the CONQUER Phase 3 Trial Holland Detke; Uwe Reuter; Christian Lucas, MD; David Dolezil, MD; Austin L. Hand; Antje Tockhorn-Heidenreich; Chad Stroud; Sheena K. Aurora The HEALEY ALS Platform Trial Merit E. Cudkowicz, MD, MSC; Jinsy Andrews, MD, FAAN; James D. Berry, MD, MPH; Kristine Broglio; Michelle Detry; Eric A. Macklin, PhD; Melanie Quintana; Ben Saville; Jeremy M. Shefner, MD, PhD, FAAN; Sabrina Paganoni, MD, PhD Increased Amygdala Volume and Functional Connectivity with Largescale Brain Networks in Chronic Migraine: Associations with Clinical and Affective Measures Danielle D. DeSouza, PhD; Daniel Bissell; Bharati Sanjanwala; Samuel Krimmel; Addie M. Peretz, MD; Vinod Menon; David Seminowicz; Robert Cowan, MD, FAAN Longitudinal Dynamics of Mutant Huntingtin and Neurofilament Light in Huntington's Disease: The Prospective HD-CSF Study Filipe Andre Brogueira Rodrigues; Lauren M. Byrne; Rosanna Tortelli; Eileanoir Johnson; Peter Wijeratne; Marzena Arridge; Enrico de Vita; Daniel Alexander; Sarah J. Tabrizi, MD, PhD; Scott Schobel; Rachael Scahill;

Amanda Heslegrave; Henrik Zetterberg; Edward J. Wild, PhD, MBBS, MRCP NILO-PD: A Phase 2A Study of Nilotinib in Patients with Advanced Parkinson's Disease: Final Study Results NILO-PD Investigators The Parkinson Study Group; Tanya Simuni, MD, FAAN A Randomized, Double-blind Trial of Amantadine, Modafinil, and Methylphenidate for the Treatment of Multiple Sclerosis Fatigue Bardia Nourbakhsh, MD; Nisha Revirajan; Bridget Morris; Christian Cordano; Jennifer Creasman; Michael Manguinao; Kristen M. Krysko, MD; Alice Rutatangwa, DO; Salman Aljarallah, MD; Chengshi Jin; Ellen M. Mowry, MD, FAAN; Charles McCulloch; Emmanuelle Waubant, MD, PhD, FAAN Safety and Efficacy of Tilavonemab (ABBV-8E12), a Humanized Anti-Tau Monoclonal Antibody, for the Treatment of Progressive Supranuclear Palsy: Results From a Phase 2, Randomized, Placebo-Controlled, Multicenter Study Günter Höglinger; Michael Gold, MD; Nuno Mendonca; Beatrice RendenbachMueller; Deli Wang; Hana Florian TERIKIDS Study: Teriflunomide Efficacy and Safety in Pediatric Patients with Relapsing Forms of MS Tanuja Chitnis, MD, FAAN; Brenda Banwell, MD, FAAN; Ludwig Kappos; Douglas L Arnold; Kivilcim Gücüyener; Kumaran Deiva; Natalia Skripchenko; Wei Qiu; Stephane Saubadu; Wenruo Hu; Myriam Benamor; Annaig Le-Halpere; Philippe Truffinet; Marc Tardieu 

Education & Research

Feedback Sought for New Continuum Mobile Phone Experience The beta version of a new mobile phone experience for Continuum® readers is available to all subscribers. This Continuum prototype allows users to access Continuum and Continuum® Audio content quickly and easily on mobile phones and has been designed to serve the most common and critical needs of mobile users. It is an alternative to the full website mobile experience provided by ContinuumJournal.com. Using the beta mobile phone experience, users will be able to: Quickly find articles by issue topic or year Search specific terms to easily access needed information Easily navigate articles using outlines of major headings Swiftly access tables and figures within articles Seamlessly listen to Continuum Audio interviews To test the mobile phone experience and provide feedback, visit continpub.com/ConBeta and log in with your AAN ID and AAN password. Share your comments on your experience by taking a short survey using the “feedback” link on the home screen of the beta. Comments will be accepted through September 1 and the mobile experience will be adjusted to better meet members’ needs. 

Apply for Neuroimaging Certification Through UCNS Validate your expertise in neuroimaging through certification by the United Council for Neurologic Subspecialties (UCNS). For the 2021 examination dates, the early application deadline is August 3, with the extended deadline August 17. UCNS certification exams are administered online with virtual live proctoring, so exams can be completed from home. The five-hour exam includes 200 multiple-choice questions. For more information or to apply, visit UCNS.org. 

Neurology ® Podcast: PODCAST

20 Minutes Pack a Punch! Subscribe and download the latest podcast at Neurology.org/podcast

Education & Research

Complimentary Online Resources Offer Convenient Self-assessment Access to convenient online learning is now more critical than ever. Whether you have only a few minutes a day to spare, or longer, the AAN supports you with complimentary access to online self-assessment resources that can help you assess your knowledge, stay up-to-date, and help fulfill self-assessment CME requirements.

Neurology Question of the Day NeuroSAE®

Neurology Question of the Day App

Online and mobile friendly NeuroSAE exams can be taken on This new app promotes continuous learning and knowledge your own schedule, as a timed test or at your own pace, and retention with minimal effort. Using a monthly curriculum, the consist of 100-150 multiple-choice questions in 20 subject app serves up one new self-assessment question each day, areas to help you determine your strengths and areas for awarding two self-assessment CME for each 25 questions improvement and fulfill two Continuing Certification (CC) answered. Additional features include a leaderboard featuring requirements: self-assessment and CME. Exam results top performers across various categories and a separate compare your performance to other neurologists and include track of questions available for medical student members that feedback provided by subspecialty area and suggestions for focuses on foundational content. Visit AAN.com/QODapp to get further reading. While the exam is free to most AAN members, started.  Medical Student, Business Administrator, and Advanced 20 CHP Advocacy Awareness Ad: AANnews, NJ, NCP: Half Page Horizontal Provider at the lower duesJournal, rates or are not Clinical Practice USAGE: HighPractice Resolution PDF to bemembers placed in AANnews, Neurology Neurology for free access. Visit AAN.com/NeuroSAE to get started. SPECS: Trimeligible Size 8.25"x5.4375", Full Bleed +0.125", 4C (BW if in NJ)

BE INFORMED. GET ENGAGED. Read Capitol Hill Report

From the halls of Congress to the offices of regulatory agencies, AAN members and advocacy staff are working tirelessly to represent the needs of you and your patients. Stay up to date with Capitol Hill Report at AAN.com/view/HillReport. or on Twitter at #AANadvocacy.

Tools & Resources

AAN Publishes Neurology Outcome Quality Measurement Set The AAN published the neurology outcome quality measurement set for patients with neurologic conditions in the May 12, 2020, online issue of Neurology®. These measures capture patient outcomes for patient communication experience and quality of life for patients with neurologic conditions and EMG utilization for patients with isolated lower back pain. “This is the first time the AAN has created a measurement set solely focused on measuring health care outcomes for a wide range of patients with neurologic conditions,” said Jason J. Sico, MD, MHS, FAHA, FACP, FAAN, lead author of the Neurology article. “Measuring outcomes directly will provide physicians and treatment teams with needed data to drive quality improvement in practice. Neurologic outcomes are a challenge to measure given the long-term negative disease outcomes. The work group tried to strike a balance by identifying meaningful outcomes that would not pose a huge data collection burden. We hope over time that additional data will be available to develop meaningful risk adjustment models that would allow for greater monitoring of other neurologic outcomes. By releasing this first set, implementation can begin,

leading to monitoring for risk adjustment variables and unintended consequences while guiding potential quality improvement initiatives and informing payers of outcomes meaningful to neurology.”

Sico

The AAN will monitor the set for updates every three years. The measures will not be submitted for consideration in payer programs until testing is completed demonstrating measure feasibility, reliability, and validity. The AAN’s Axon Registry ® already has adopted the quality of life outcome measure. For more information on how to join the Axon Registry, contact registry@AAN.com. The neurology outcome quality measurement set is available for free at AAN.com/policy-andguidelines/quality. 

Registry Users Benefit from Quality Improvement Pioneer Program The Axon Registry is a tool that analyzes data for quality improvement. Participating Axon Registry practices may not be maximizing the power of the data for quality improvement because of limited staff time, limited resources, or inexperience leading quality improvement initiatives. To help close this gap, the Quality Measure Subcommittee, in partnership with the Axon Registry, launched the Quality Improvement (QI) Pioneer program to teach practices about quality improvement and help them improve performance on Axon Registry measures. Six practices were selected from across the nation to participate in the first cohort of the program in 2019 and are reporting success in driving improvement at their practices. “Participating in the AAN QI Pioneer Program helped the Minneapolis Clinic of Neurology to improve and sustain the rate of Dementia Functional Assessment over the course of 12 months,” said the clinic’s Quality Improvement Manager Kathy Vinson. “Using the Axon Registry to collect data, we saw a 44.59-percent improvement from December 2018 to December 2019.” The Axon Registry is currently recruiting practices to participate in the second cohort of this program. Participants will be given a one-day training on QI principles and return to their practices with a QI initiative to implement over the course of 12 months. Participants are provided ongoing monthly support by QI experts and AAN staff members to help ensure success. To enroll or learn more about the Axon Registry, visit AAN.com/axon or contact registry@aan.com. Visit the Axon Registry participants page for more information on the QI Pioneer program. 

Dementia: Caregiver Education and Support Falls: Querying About Falls for Patients Headache: Medication Prescribed for Acute Migraine Attack

Total

400

300

100

75%

400

250

150

62%

400

200

50%

400

100

300

25%

Parkinson's: Psychiatric Symptoms Assessment ALS: End of Life Planning Assistance

AANnews • July 2020 21

Policy & Guidelines

Capitol Hill Report Capitol Hill Report presents regular updates on legislative and regulatory actions and how the Academy ensures that the voice of neurology is heard on Capitol Hill. It is emailed to US members twice monthly and is posted at AAN.com/view/HillReport. Below are some recent highlights.

AAN Advocates for Future of Telehealth Regulations with CMS In response to the COVID-19 public health emergency (PHE) the Centers for Medicare & Medicaid Services (CMS) issued rulemaking that finalized a number of policies aimed at reducing regulatory burdens and improving access to care. Acknowledging the critical role of telehealth services during the PHE, CMS has made numerous temporary changes to the regulations and payment policies related to telehealth services. Key changes include: telehealth visits, including phone visits, are paid at the same rate as in-person visits; telehealth services can be furnished to beneficiaries in all areas of the country in all settings; frequency limitations for subsequent inpatient and nursing facility visits have been lifted; communication-based technology services can be furnished to new and established patients; and telehealth can be used to satisfy direct supervision requirements. Given the critical role that telehealth services have in ensuring that neurology patients can safely maintain access to high-quality neurology care during the PHE, the AAN submitted comments to CMS in support of many of the changes to telehealth services. In the comments, the AAN sets forth a forward-looking vision for changes to telehealth regulation and reimbursement both during and after the PHE. The AAN submitted numerous recommendations on how policy changes can be implemented or modified going forward. The AAN believes that telehealth will continue to play an essential role in the health care delivery system once the PHE has passed. The disruptions to the health care system stemming from the PHE have led to revolutionary changes as providers have quickly developed new telehealth capabilities and have gained experience delivering care via new modalities. The AAN believes it is critical that many of the temporary changes made to improve access to telehealth services during the PHE are made permanent. Improved access to telehealth services presents a unique opportunity to leverage new capabilities, promote access to care, advance chronic care management, and reduce disparities. In addition to the comments related to policy changes concerning telehealth services, the AAN also advocated for changes that would reduce administrative burdens during the PHE. Specifically, the AAN called on CMS to reduce burdens associated with prior authorization, modify Quality Payment Program requirements, suspend or delay the Appropriate Use Criteria program for advanced diagnostic imaging, and make needed reforms to the Medicare Shared Savings Program. The AAN also called on CMS to fully implement the new coding and payment structure for

AANnews • July 2020

evaluation and management services on January 1, 2021, without modification or delay, and to ensure that the decision as to the appropriateness of administering infusions at home during the PHE is made by the patient’s physician. For more information on the AAN’s advocacy throughout the COVID-19 PHE, please visit the “Advocacy in Action” at AAN.com.

AAN Members Speak Directly to Their Legislators and Staff The AAN advocacy team has been hard at work connecting AAN members with their senators and representatives to ensure that neurology remains a top priority as Congress continues its work to address the pandemic. To date, AAN staff have arranged more than 20 calls with senators, representatives, and their staff to speak with our members. This provides members valuable oneon-one time with their legislator to explain how their practice is affected by recently passed COVID-19 legislation. Lawmakers and their staff have taken an especial interest in how the expansion of telehealth has improved patient access to care, the interruption of life-saving research, and what regulatory barriers continue to impede the physician and patient relationship. Last week, AAN member James N. Goldenberg, MD, FAAN, CPI, had a very productive call with the health care staff in Sen. Marco Rubio’s (R-FL) office. The senator had recently sent a letter to the Centers for Disease Control (CDC) about his concerns with stroke and COVID-19, and Goldenberg was able to discuss this issue directly with the senator’s staff. They also discussed how his practice is adapting to the increased demand for telehealth services and the legislative changes that could help further support telehealth access. “Thanks to the AAN staff for engaging me in advocacy during these trying times,” said Goldenberg. “Previously we’ve relied on Neurology on the Hill in DC and Neurology off the Hill in our home districts to make contact with our legislators. I was so pleased to participate in a call with staff from Sen. Rubio’s office regarding the effect of the pandemic on the practice of neurology. The visit was efficient—as I took the call from my office—and hopefully as effective as an in-person visit. As the AAN leads the rapid implementation of telemedicine for our members we’ve also now implemented tele-advocacy. Let’s add Neurology Virtually on the Hill to our advocacy toolbox.”

These important conversations are ongoing and are critical to ensuring the voice of neurology is heard during these unprecedented times. If you would like to participate, please email us at advocacy@aan.com. 

American Brain Foundation

Remembering Philanthropist and Former American Brain Foundation Board Member Richard P. Essey Philanthropist, former American Brain Foundation Board member, and pioneer in the fight against ALS and other brain diseases, Richard P. Essey—known as Dick to family and friends—passed away on April 10 at his home in San Francisco at the age of 97. Essey, a business leader and innovator in the staffing industry, began a lifelong focus on curing ALS after his late wife, Sheila, was diagnosed with ALS in 1995. Essey was struck by the lack of research into discovering treatments, preventions, and cures for ALS. In his challenging role as caregiver for Sheila over the 10 years she suffered from the disease, Essey was equally concerned by the lack of available caregiver resources in the Bay Area. In response, Essey formed the Bay Area Chapter of the ALS Association. Now known as the Golden West Chapter, it is recognized as one of the largest in the ALS Association Chapter network. He also collaborated with the Caregivers Alliance in San Francisco to create an annual weekend retreat to provide replacement care to allow family caregivers a much needed and deserved hotel weekend getaway where they could be pampered with spa services and find support among other caregivers. In 1996, Essey established the memorial Sheila Essey Award: An Award for ALS Research, which he counted among his proudest accomplishments. The initial $25,000 award eventually grew to a $50,000 prize and stature as the veritable “Nobel Prize” in the field of ALS research internationally. In 2000, he joined the Board of Directors of the American Brain Foundation, known at the time as the American Academy of Neurology Foundation, making him the first non-neurologist to serve in that capacity. He leveraged this role to further promote the Sheila Essey Award which, to date, has awarded $825,000 to 27 recipients who have made critically important contributions towards discoveries into treatments and a cure, including:

Discovery of numerous genes responsible for causing familial ALS, including C9orf72, VCP, MATR3, FUS, TDP43, and SOD1 Essey Contributions to the first successful FDA-approved drug riluzole Identification of major environmental and genetic risk factors Development of ALS animal models that are key in understanding the disease Discovery of ALS biomarkers that can potentially help understand disease progression and aid in diagnosis Contributions to induced pluripotent stem cell (iPSC) technology and its use in clinical trials Uncovering of important ALS disease mechanisms such as oxidative stress, neuro-inflammation, excitotoxicity, and glial dysfunction Pioneering the use of antisense DNA oligonucleotides (ASOs) as a therapy for human neurodegenerative disease for the two most common genetic causes of ALS: C9orf72 and SOD1 Essey’s children are carrying his tireless commitment to cures forward. His son, Jim, currently serves proudly on the board of the American Brain Foundation. And the Essey family has generously selected the American Brain Foundation and the ALS Association’s Golden West Chapter as the two recipients of NCC: 20 Career Center Ad—Full Page> AANnews, NJ, NCP donations in Dick Essey’s memory. To make a gift to the American Placed in AANnews, Neurology Journal, or Neurology Clinical Practice 8.25 x 10.875 +0.125 bleed, 4C Brain Foundation, visit AmericanBrainFoundation.org. 

The American Academy of Neurology is proud to offer

THE #1 CAREER CENTER FOR NEUROLOGISTS AAN.com/careers

Visit the AAN’s Neurology Career Center to view hundreds of additional jobs and sign up for customized, confidential notifications when positions of interest are added. Stroke or epilepsy fellowship trained neurologist Brookdale University Hospital Brooklyn, New York Stroke or Epilepsy fellowship trained neurohospitalist position. Responsibilities are primarily for in-patient stroke or epilepsy care and respective program oversight, but also include inpatient critical care of general neurology patients and outpatient stroke/epilepsy/general neurology care. Competitive salary with full benefit package. Certified primary stroke center with thrombectomy capability. New, state of the art, 32 bed ICU slated to be completed by early 2021, including dedicated neuro ICU beds with bedside EEG monitoring. Join a team of 5 other full-time, fellowship trained neurologists with expertise in stroke, epilepsy, neuromuscular disease, dementia, movement disorders and neurorehabilitation Affiliated with nearby Downstate Medical School. Ample opportunity to teach IM and psychiatry residents who rotate through service, as well as medical students from programs in NYS and overseas. One Brooklyn Health is a consortium of three medical centers located in central Brooklyn, NY. We are convenient to the boroughs of Manhattan, Queens and Staten Island as well as Long Island. Email or fax CV. Email: akay@bhmcny.org. Fax: (718) 240-6546.

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The AAN offers a complete package of print, Learn more! Careers.AAN.com online, and in-person recruitment advertising opportunities. Visit careers.AAN.com for all AAN options, rates, and deadlines. Ad copy for the September 2020 print edition of AANnews must be submitted by August 1, 2020. The same deadline applies to changes/cancellations. The American Academy of Neurology reserves the right to decline, withdraw, or edit advertisements at its discretion. Every care is taken to avoid mistakes, but the responsibility for clerical or printer errors does not exceed the cost of the ad.

CONGRATULATIONS 2020 NEXT GENERATION RESEARCH GRANT RECIPIENTS

Alonso Zea Vera, MD Tourette Syndrome

Bryan Baxter, PhD

Cognitive Aging

Colin Ellis, MD

Collin Kreple, MD, PhD

Farinaz Safavi, MD, PhD

James Curtis, MS

Lawren VandeVrede, MD, PhD

Lenora Higginbotham, MD

Multiple Sclerosis

Epilepsy

Parkinson’s Disease

Paloma Gonzalez-Perez, MD, PhD Neuromuscular Disease

ALS

Alzheimer’s and Dementia

Sarah Berth, MD, PhD ALS

Lewy Body Diseases

Sarah Getz, PhD

Cognitive Aging

INVESTING IN THE NEXT GENERATION OF RESEARCHERS The American Brain Foundation funds a broad range of innovative research projects with the goal of identifying causes, improving treatments and discovering cures. Our Next Generation Research Grants elevate the best and brightest early-career scientific investigators. We are proud to support research across the whole spectrum of brain diseases and disorders with the knowledge that when we cure one, we will cure many. To apply for a Next Generation Research Grant, visit

AmericanBrainFoundation.org/For-Researchers