2/15/2018

UCSF Movement Disorders

Neurology Research /Support Staff Jill Ostrem, MD Sarah Wang, PhD Nicholas Galifianakis, MD Kristen Dodenhoff, BA Caroline Tanner, MD, PhD Farah Kauser Marta San Luciano, MD Joncarmen Mergenthaler Maya Katz, MD Janet Allen Ian Bledsoe, MD,MS Shatara Blackmon James Maas, MD, PHD Yasmeen Gonzalez Chadwick Christine, MD Jeverly Calaunan New Directions in Movement Disorders Michael Aminoff, MD Kathleen Comyns, MPH Robert Edwards, MD Samantha Betheil, BA Caroline Tanner, MD, PHD Ken Nakamura, MD, PhD Cheryl Meng, MPH Alexandra Nelson, MD, PhD Danilo Romero Jill Ostrem, MD Michael Geschwind, MD Kanchi Mehta Amy Viehoever, MD, PhD Nijee Luthra, MD, PhD Psychiatry UCSF Movement Disorder and Neuromodulation Center Cameron Dietiker, MD Andrea Seritan, MD Recent Advances in Neurology 2018 Neurosurgery Neuropsychology Social Work Philip Starr, MD, PhD Caroline Racine Belkoura, PhD Fellows Monica Eisenhardt, LCSW Paul S. Larson, MD Jessica Weinstein, MD Edward F. Chang, MD Nursing Kyle Mitchell, MD Chaplin Daniel Lim, MD, PhD Monica Volz, FNP, MS Jennifer Choi, MD Judith Long Krzysztof Bankiewicz, MD, PhD Karen Merchant, MSN Ethan Brown, MD Coralie De Hemptinne, PhD Physical Therapy Susan Heath, MS, RN Mitra Afshari, MD Whitney Chen, PhD Nancy Byl, PT, PhD UCSF Weill Gina Bringas-Cinco, RN Melissa Heiry, MD Doris Wang, MD, PhD Heather Bhide, PT Institute of Annie Li Wong, NP Idit Tamir, MD, PhD Neurosciences

Disclosures New Direction #1

Caroline Tanner, MD, PHD • Parkinson’s Disease is not one disease • An employee of the San Francisco Veterans Affairs Medical Center and the University of California – San Francisco. and will be better managed with an • Receives grants: the Michael J. Fox Foundation, the Parkinson’s Disease Foundation, the Department of Defense, BioElectron, Roche/Genentech and the National individual treatment approach Institutes of Health, • Compensation for serving on Data Monitoring Committees: Biotie Therapeutics, Voyager Therapeutics and Intec Pharma • Personal fees for consulting: Neurocrine Biosciences, Adamas Therapeutics, PhotoPharmics , 23andMe and Alexza

Jill Ostrem, MD • Consultant and speaker: Allergan Inc., Medtronic Inc. • Educational grant support: Medtronic Inc, Allergan Inc, AbbVie Inc, Boston Scientific Inc. • Clinical trial support: Ceregene Inc., St. Jude Medical, Inc, Boston Scientific Inc, Cala Health Inc, Google Inc 2/15/2018

One Disease or Many? PD Subtypes

5 jamanetwork.com

PD Genetics PD Genetics– Targeted Therapies

Gene Mutations Protein/Enzyme Function Age at Phenotype Pathology Genetic influence increasingly recognized onset Dominantly inherited last-onset PD Monogenic forms (Mendelian inheritance)= mutation in single gene sufficient to SNCA Missense Alpha synuclein- structural 60 yr Levodopa responsive Diffuse lewybodies cause PD brain protein (30-80) SNCA Locus duplication (and 31-71 yr Levodopa responsive, younger age, rapid Diffuse lewy bodies, 30% of all familial cases triplication) progression, autonomic dysfunction, dementia, prominent nigral and wide spread Lewy Bodies hippocampal loss ~5% of sporadic cases LRRK2 Missense: Arg Leucine-rich repeat kinase 60 yrs Levodopa responsive, Like sporadic PD, slow Brain Stem LB, 1441Cys/Gyl/His; 2- enzyme when mutated (32-79) progression, abduction-addition lower limb neurofibrillary tangle or Try1688Cys, Gly2019Ser, causes Lewy-body tremor, little dementia TDP-43 pathology and/or Six regions contain genes that conclusively cause PD IIe2020Thr phenotype –increased nigral neuronal loss Polymorphisms, protective kinase activity haplotypes The cause of PD is multifactorial VPS35 Missense: ASP620Asn 53 yrs Levodopa responsive tremor-dominant, Inconclusive- ? No LB (40-68) dyskinesia and dystonia, occasionally dementia

• Several genes Juvenile and early-onset recessively inherited PD • Modifying effects of susceptibility factors PARK2 Numerous missence, exon Parkin- a ubiquitin-protein <45yr Levodopa responsive, early dystonia, slow Predominantly nigral deletion and duplication ligase involved in protein (12-58) progression, hyperreflexia, dyskinesia, early neuronal loss 15-50% • Environmental exposures mutations degradation gait and balance issues, less non-motor Occasionally with synuclein or tau pathology • Gene-environment interactions Parkin ~5% PINK1 Misssence: many PTEN-induces putative <45yr (18- Levodopa responsive, akinetic/ridgid postural One case with lewy bodies Penetrance/ kinase 56) instability, gait, slow progression, sleep benefit DJ-1 LRRK2 Rare: locus and exon Effect Size deletion PINK1 SNCA SNCA VPS35 DJ-1 Misense: Glu163lys, Leu Positive regulator of <40 yr Like PINK-1, rare Unknown 166Pro Exon 1-5 deletion, androgen- receptor (24-39) Young-onsetAge at onset of PD Late-onset g.168-185 dup dependent transcription

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PD Mechanisms of Disease LRRK2 Mutation

Protein trafficking • Mutation in the leucine rich repeat kinase 2 (LRRK2) gene (G2019S) is • ubiquitin/protease system the greatest known genetic cause of PD • Most common monogenic cause of PD in Europe and North America • alpha-synuclein • 30% penetrance Calcium-channel • Mutations seem to heighten the activity of LRRK2 kinase • apoptosis Inflammation Oxidative stress Phenotype Mitochondrial dysfunction • Like sporadic PD (later onset) • Variable clinical and pathological phenotype • Levodopa responsive • Slow progression • Abduction-addition lower limb tremor • Little dementia Video Courtesy of Dr. San Luciano and Darel Ogbonna

Trinh J and Farrer M Nature Review, 2013.

LRRK2 Treatment Approaches PD and GBA Mutation

GBA mutations cause dysfunction in the LRRK2 based treatment glucocerebrosidase (Gcase) protein- leading • Inhibitors of LRRK2 kinase activity could potentially be used to to build-up of alpha-synuclein prevent or treat PD More common in Ashkenazi Jewish descent /Gaucher or relative with Gaucher (lipids Denali Therapeutics build up and enlarge organs) • Completed phase I study in control volunteers in 12/2017. • Reported 90% inhibition of LRRK2 activity (target engagement) Video Courtesy of Dr. San Luciano and Darel Ogbonna Phenotype • Well tolerated • Slightly earlier age of onset • Also testing a second compound in Phase I study. • Initial symptom often • Likely these drugs will move into phase II trial in LRRK2 PD bradykinesia • 5-10 % of PD patients carry this mutation More rapid motor disease patients next. progression, more dyskinesia GBA mutation - 20X increased risk of PD • More cognitive dysfunction GBA mutations are common but overall • Less tremor chance of PD is still low • More depression 2/15/2018

GBA Treatment Approaches Mitochondrial Dysfunction in Genetic PD

• Overwhelming evidence implicates Sanofi / Genzyme mitochondrial function being compromised • Small molecule (GZ/SAR402671) in Parkinson’s disease Venglustat -targeting cellular • Oxidative stress is found in PD tissue dysfunction in PD patients with a GBA mutation (also for Gaucher Type III Especially for genetic subtypes: disease and Fabry disease) • Parkin • • Glucosylceramide synthesis inhibitor Video Courtesy of Dr. Ian Bledsoe PINK1 Heterozygous carrier of N370S mutation • DJ-1 • LRKK2 • Pre-clinical GBS mutation PD models treated with similar compound had fewer alpha-synuclein aggregation and did better on memory tests • Energy failure leads to neuronal cell death • Phase II international trial enrolling PD patients with GBA mutations (N=230) • Nigral dopaminergic neurons seem to be • First industry – sponsored Phase II clinical trial in genetically defined PD selectively vulnerable to energy failure population • Energy-based therapies have generally failed in their application in PD

Mitochondrial Based Therapies Bioelectron – EPI-589

A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype and Idiopathic Parkinson’s Disease Subjects Phenotype: Parkin- a ubiquitin-protein ligase • (R)-troloxamide quinone (EPI-589) is a vitamin E involved in protein degradation derivative and ORALLY available drug Numerous missense, exon deletion • Aids in the catalysis of glutathione, an important and duplication mutations, No LB? antioxidant that aids in reducing oxidative stress

Phenotype: • Glutathione depletion has been linked to mitochondrial dysfunction Levodopa responsive, dystonia, Video Courtesy of Dr. Nick Galifianakis akinetic/ridged, postural instability, Parkin Mutation PD • Being developed for treatment of neurological gait, slow progression, sleep benefit diseases characterized by high levels of oxidative Caldwell, 2008 stress and mitochondrial pathology (i.e. ALS, PD, HD, mitochondrial diseases) DJ-1: Mitochondrial regulation, antioxidative stress, chaperone PARKIN: Mitochondrial autophagy, ubiquitin-protease system • Focus on safety and quantifying glutathione cycle PINK1: Mitochondrial serine/threonine-protein kinase, protects against biomarkers mitochondrial dysregulation LRRK2: modulates mitochondrial dynamics and function 2/15/2018

New Direction #2 Levodopa

• Newer formulations of carbidopa/levodopa • Most effective and widely used treatment in PD • Dopa decarboxylase (carbidopa) inhibits peripheral LD are on the market or in development metabolism- more levodopa CNS availability (improves tolerability reducing nausea) • Early PD simple dosing schedules, becomes more complex in advanced PD • Short half-life (1.5 hours) • As PD progresses, conversion of LD to dopamine, storage, release, becomes unpredictable • Intermittent/pulsatile release of dopamine in the striatum, produces changes in the postsynaptic receptors leading to motor complications and dyskinesia (70% after 5 years)

Motor Fluctuations Extended Release Carbidopa/Levodopa (Rytary- IPX066) (Impax)

• New oral formulation of CD-LD (contains both IR and CR “Wearing off” period levodopa) • Each Rytary capsule contains CD- Symptoms Symptoms controlled adequately time”) (“on LD (1:4) microbeads designed to dissolve at various rates allowing for release and absorption of LD Time over a longer timeframe

PD Medication PD Medication PD Medication Symptoms not not Symptoms controlledadequately (“offtime”)

Typical Clinical Pattern of Wearing Off

Adapted from Hauser RA. Geriatrics. 2006;61:14-20. 2/15/2018

Conversion to Rytary Carbidopa/Levodopa Enteral Suspension Duopa (AbbVie)

• Continuous intraintestinal infusion of C/L gel • Programmable pump to adjust dose • Prospective, double-blind, double dummy, double titration study showed reduction in off time without increase in dyskinesia • High complication rate, Costly

Practical Considerations PD Drugs in Development

Dose titration: New Drug: Other DOPAMINE AGONISTS • Outpatient, but at least ½ day in office to initiate Other LEVODOPA Formulations • Apomorphine infusion (Ago-Go) • Calculate based on current c\l dose • CVT-301 (Acorda) • Apomorphine sublingual film (APL- • Infusion usually 16 hours • Accordion Pill (Intec Pharma) 130277) (Sunovion) • Morning dose a bolus • Dopafuse (SynAgile) • Continuous dose thereafter with option for extra doses • ND0612L “Pump Patch” (Neuroderm) Others Return in one week for re-adjustment of dose • ADX48621-201 (Dipraglurant-IR) (Addex Monitor B12, B6 (peripheral neuropathy) Therapeutics) Neuroprotective agents? • AVP-923 (dextromethorphan/quinidine) • Costs: Est.~ $6000/month • Inosine (Avanir Pharmaceuticals) • Patient and caregiver understanding key to • Isradipine • Eltoprazine (Amarantus Bioscience) success • Nicotine • AQW051 (alpha7 nicotinic receptor) • Care of site • NAC (Novartis) • Handling of cassette • Nilotinib • Nicotinic receptor agonists in PD • Pump program can be fixed or adjustable • Monoclonal antibodies to (AstraZeneca) misfolded alpha-synulean • Adjustable often better efficacy • Preclinical stage of development • Affitope PD01A vaccine (Medical Letter 2015) • Candidate drug is already tested for safety and tolerability in humans 2/15/2018

Carbidopa /Levodopa Inhaled Formulation Carbidopa/Levodopa Gastro Retentive Formulation CVT-301 (AcordaTherapeutics) Accordion Pill (Intec Pharma delivery system)

• Inhaled formulation of levodopa • New levodopa formulation which surface area • Developed for rapid/reliable relief from debilitating off periods expands over time in the stomach to achieve • Fine powder delivered via a small, plastic inhaler similar to an asthma longer half-life inhaler • Used biodegradable polymeric films • Phase III showed safety and efficacy to improve motor function in PD • Allows for maximum absorption before leaving experiencing OFF periods the stomach • Filed new drug application with FDA 2017 • Promising Phase II study results • Phase II study enrolled and study to be completed in 2018

Continuous Oral Carbidopa Levodopa Liquid Levodopa Subcutaneous Continuous Delivery (Neuroderm) DopaFuse / OroFuse (SynAgile) “Pump-patch” (ND0612L, ND0612H, ND06080)

• Continuous delivery of • Levodopa/carbidopa formulation continuously administered subcutaneously carbidopa/levopdopa via the mouth “Pump-patch” • Device that uses a customized • May reduce or prevent motor complications reusable retainer fitted to the top of • Small device (as big as a credit card) made up of a drug reservoir and a series of the mouth/teeth with a miniature micro-needles (painless) pump the therapy under the skin and into the blood disposable propellant-driven drug stream pump • Phase II study- Significant reduction on off time and well tolerated* • Fresh drug pump each week – • Phase III study planned remove to eat • Phase IIa study showed improved “off” time compared to regular C/L*

Stocchi F, et al. Abstract Movement Disorders Congress 2016 * Olanow W, et al. Abstract Movement Disorders Congress 2017 2/15/2018

Amantadine ER New Direction #3 Gocovri (Adamas)

• FDA approved for levodopa induced dyskinesia (first drug) • The field of DBS is about to get more • Also some reduction in off time • Special concentration profile with time: initial complicated! slow rise overnight, highest concentration achieved in the morning and daytime when most useful • Once-a-day dosing, 137mg QHS for one week then increase to 274mg QHS • SE: Hallucinations/ Peripheral Edema

Oertel et al Movement Disorders, 2017.

Historical DBS Considerations – Medtronic Devices St Jude Medical/Abbott Infinity DBS System •Which device? Single Channel Dual Channel now FDA approved

• FDA approved 2016 for PD and ET • Constant current device • BluetoothTM wireless communication • Upgradeable software option •Which location? • Bilateral frequency control • Communicates with Apple digital devices (iPad mini/iPod touch) • Directional lead to allow for current “steering” • Not MRI compatible • Non-rechargable

Vim Thalamus Subthalamic Nucleus Globus Pallidus 2/15/2018

Boston Scientific Vercise™ DBS System New DBS directional leads now FDA approved

New leads Traditional Medtronic Lead (Four concentric ring electrodes)

• Soon to have Non-rechargeable and rechargeable neurostimulators • Tablet based programmer • Current steering and 8 electrode DBS leads Two concentric ring electrodes (outer) • Directional leads Six non-concentric directional electrodes (middle) • Fractional current delivery • Not MRI Compatible- may change soon?

New software to localization and visualize shape New Direction #4 of electrical stimulation field • Computational modeling / volume of tissue activation (VTA) and • Therapeutics for PD directly target individualized direct programming pathological alpha synuclein are now in clinical trails

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Immunotherapeutic Approach in PD- Roche – PRX002 Anti Alpha-Synuclein A Phase 2 Study of Anti-α-Synuclein Antibody in Early ParkiNson’s DiseAse

Prevent and promote the clearance of misfolded alpha- • PRX002 is an INFUSION of a humanized synuclein targeting the underlying disease mechanism and monoclonal antibody against an epitope on the slow and ultimately halt the disease process. C-terminus of human α-synuclein • Aggregated and phosphorylated α-synuclein is the major component of pathological hallmark Monoclonal Antibody Infusion against alpha-synuclein - lesions in… blocks cell to cell transmission by blocking uptake of - PD: Lewy bodies, Lewy neurites misfolded endogenous alpha synuclein - MSA: glial cytoplasmic inclusions • Antibody has a high affinity for pathologic forms of α-synuclein consisting of oligomers Synaptic/Neuronal and fibrils, ultimately preventing propagation Loss and Pathological Spread Antibodies and neuronal cell death neutralize and clear pathogenic • ENROLLING EARLY-PD PATIENTS (within 2 -synuclein years from dx, H&Y <= 2, MAO-I-treated only, not anticipated to start a new dopaminergic rx F. Hoffman-La Roche, Ltd. for 1 year) Aggregated, extracellular Syn

Immunotherapeutic Approach in PD- Biogen – BIIB054 Anti Alpha-Synuclein A Phase 2a Study of the Safety, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Subjects with Parkinson’s Disease Vaccine development against alpha-synuclein • BIIB054 is an INFUSION of a humanized • AFFiRiS First in human trial to assess the safety and tolerability monoclonal antibody against an epitope (Europe) - Phase IA study showed positive safety and toxicity profile on the N-terminus of human α-synuclein (N=32) • Multiple (4) subcutaneous vaccinations with two doses were tested/ • Antibody has a high affinity for Patients developed intended alpha-synuclein- antibodies aggregated pathological forms of α- • Multiple phase Ib trials ongoing/ Randomized to low or high booster synuclein as well, to ultimately prevent immunizations propagation and neuronal cell death Preventing Toxic Protein Aggregation • Adopted by the Parkinson’s Study Group • Neuropore/UCB – NPT200-11 – Binds to alpha-synuclein and blocks accumulation. Planning Phase Ib study in Europe • ENROLLING EARLY-PD PATIENTS (within • Proclara/Neurophage – NPT088 – Binds to alpha-synuclein and 3 years from dx, H&Y <= 2.5, UNTREATED amyloid- beta and tau. ALZ 1st and next would be PD for at least 12 weeks and not anticipated to start a dopaminergic rx for 6 months) 2/15/2018

New Direction #5 Falls in the Elderly

• Evaluate for Falls in PD. Very common and multifactorial in many patients.

Simon Fraser University Video Footage of Falls https://www.youtube.com/watch?v=Z3e1Xvnj8Wo

PD Postural Instability Consequences of Falls Falls  Fractures • Reduced mobility • Prolonged hospital stay • Prolonged recovery after surgical repair • Increased placement outside of home • Increased mortality Falls  Head injuries • Concussion, subdural, etc.  CNS injury • Reduced cognitive function, reduced mobility, seizures • Prolonged hospital stay • Increased placement outside of home • Increased mortality 2/15/2018

Osteoporosis & Parkinson’s Disease Prevention Falls Prevention • Environmental modification - remove obstacles, correct footwear & eyeglasses, improve lighting, etc. • Avoid hypnosedatives • Physical therapy • Tai chi, dance • Monitor & treat Orthostatic Hypotension

Fracture Prevention - Reduce osteoporosis/osteopenia (vit.D, Calcium, bis- phosphonates) - Reduce falls - “Learn how to fall” Torsney et al, 2012

New Direction #6 Northera (Droxidopa capsules) • Treatment for neurogenic orthostatic hypotension associated • It can be helpful to obtain a DatScan in with PD, MSA, and pure autonomic failure • Converted to norepinephrine and causes vasoconstriction these clinical situations: • Recently FDA approved (Chelsea Therapeutics)

• Dose 100mg TID (am, midday, late afternoon, >3hr before bedtime) • Titrate up by 100mg every other day –max dose 600mg TID • Box warning for risk of supine hypertension 2/15/2018

DatScan Mechanism & Indications Case 1 INDICATIONS AND USAGE* DaTscan is a radiopharmaceutical indicated for striatal dopamine • 68 yr old retired left handed pharmacist transporter visualization using single • History of GERD with increasing severity in recent months  photon emission computed tomography taking metoclopramide , recently increased from 10 mg. TID (SPECT) brain imaging to assist in the to 15 mg. QID with good control of symptoms evaluation of adult patients with • Has noticed sense of muscular stiffness, increased fatigue, suspected Parkinsonian syndromes (PS). occasionally a tremor at rest, affecting both upper extremities, more bothersome on the left side In these patients, DaTscan may be used • Referred to neurologist to help differentiate essential tremor • Exam: Mild bilateral bradykinesia, intermittent resting tremor from tremor due to PS (idiopathic left > right, slightly stooped posture, small steps, reduced arm Parkinson’s disease, multiple system swing bilaterally atrophy and progressive supranuclear • Gastroenterologist reluctant to discontinue metoclopramide palsy). given increased symptoms DaTscan is an adjunct to other diagnostic • Referred for a SPECT scan evaluations.

*Bajal, 2013; FDA Product Label

Case 1 SPECT with DatSCAN (123I-Ioflupane) Case 2 • 78 year old retired high school English teacher • Brought to office by daughter • Recent history of fearfulness, believing there are intruders in his home; called exterminator 4 times in 2 months to remove rats; loss of interest in reading, golfing; fell 2 weeks ago • Lifelong history of “shakiness” on and off throughout adult life, particularly bothersome during public speaking; never treated Normal scan • Exam: Oriented to person, 2 years off on date, difficulty copying figures and generating lists of words; Mild postural COMMENT: Metoclopramide blocks striatal dopamine tremor bilaterally; mild right hand resting tremor, reduced right arm swing, stooped posture, pull test: retropulsion 4- receptors and can produce drug-induced parkinsonism. 5 steps Symptoms resolve gradually after stopping drug treatment. 2/15/2018

Case 2 SPECT with Case 2 Comment: 123 Diagnostic accuracy of 123I-FP-CIT SPECT in possible DaTSCAN ( I-Ioflupane) dementia with Lewy bodies O’Brien, British J Psychiatry 2009

• Dopamine transporter imaging can distinguish Dementia with Lewy Bodies from Alzheimer’s Disease: 100% of clinical AD at 12 months had normal scans at baseline

Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy WalkerJ Neurol Neurosurg Psychiatry 2007

• 20 patients with a clinical diagnosis of DLB or other dementia & Datscan at diagnosis • Follow-up with detailed neuropathological autopsy • 8 DLB, 9 AD, 3 other diagnoses • Sensitivity initial clinical diagnosis of DLB was 75%, specificity was 42% • DatSCAN sensitivity was 88% and specificity was 100% Abnormal scan • Conclusion: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone

Dopamine Transporter Imaging in Autopsy-Confirmed Parkinson’s Disease and Multiple System Atrophy Case 3- ET Laura D. Perju-Dumbrava, Movement Disorders, 2012 • A 55 year old right handed woman, works as a jewelry artist • Abnormal imaging in • Recent sense of slight loss of fine movement dexterity, both PD and MSA especially in right hand • Asymmetry possibly • Fatigue and tremor of right hand more than the left hand greater in MSA • Neurologist examination: • DATSCAN cannot – ? right upper extremity rigidity, possible cogwheel differentiate phenomenon – mild bradykinesia throughout – fine tremor in the hands (right>left) – tremor at rest and with posture – normal gait • Referred to observational trial in early PD • Referred for baseline DatScan 2/15/2018

Case 4 : SPECT with New Direction #7 DATscan (123I-Ioflupane) • Toxicant Exposure and Parkinson’s Disease • Ask about military service!

Normal Scan

Vietnam Veteran Agent Orange & Parkinson’s Disease Risk Operation Ranch Hand: 1962-1971 20 x 106 gallons Agent Orange

2,4-D 2,4,5-T 2,3,7,8 tetrachlorodibenzodioxin

• 2009: Agent Orange Linked to Parkinson's Disease established service-connection:

Used defoliant • Certain Vietnam Veterans may be eligible for: agent orange disability compensation and health care benefits. 2/15/2018

History: 1953-1985 - Water contaminated with New Direction #8 Camp Lejeune N.C. TCE & PCE (i.e., PERC) 1980 – Contaminants discovered 1987- Wells closed 1989 - EPA Superfund • There are new treatments for tardive dyskinesia 500,000 – 1 million exposed Military: Marines, National Guard, • Tardive dyskinesia is an uncontrolled movement reservists Civilian: Family members, employees that is associated with prolonged use of dopamine receptor blocking agents (DRBAs) Sources of exposure: Drinking water, bathing, for at least a few months Inhalation, swimming, recreation Exposure levels: Est. monthly median (max. mean) ug/L: PCE: 85 (158); TCE: 366 (783) vs. US max. contaminant level: 5 ug/l Dept. of Veterans Affairs 2017 • 30 or more days of service • Entitled to benefits

Tardive Dyskinesia Treatment of TD: American Psychiatric Association (APA)

American Psychiatric Association (APA)1 APA Guideline Watch2

•TD treatment recommendations from •Updated 2009 Schizophrenia Practice Guideline (last •No specific TD recommendations published in 2004): •“The distinction between first- and second- – Use second-generation antipsychotics generation antipsychotics appears to have due to “decreased risk of extrapyramidal limited clinical utility” side effects and TD” – For TD, switch to a second-generation antipsychotic or reduce first-generation dose – Perform a baseline assessment of abnormal involuntary movements with ongoing monitoring: • First-generation antipsychotics: Every 6 months (3 months for high-risk patients) • Second-generation antipsychotics: Every 12 months (6 months for high-risk patients)

1. Lehman AF, et al. Am J Psychiatry. 2004;161(2 Suppl):1-56. 2. American Psychiatric Association (APA), et al. Guideline Watch (September 2009). http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia-watch.pdf. Accessed August 2017. 2/15/2018

Prospective Survey of TD in Psychiatric Outpatients - Preliminary Findings 20% Schizophrenia Dopamine-Depleting Drugs 18% Schizoaffective disorder 61% Mood disorder (Anxiety 37%, Bipolar 29%, Major depressive disorder 22%) Reserpine and Tetrabenazine (TBZ) 1% Other 

First and second Inhibit vesicular monoamine transporter (VMAT) at the presynaptic generation membrane of the nerve terminals antipsychotics associated with  TD Expose monoamines to monoamine oxidase  Incidence rates in Depletion of synaptic pool of monoamines patients over age 55 • 25% after 1 year Reserpine: TBZ: • 34% after 2 years • Slower onset and prolonged duration of • Quicker onset and shorter duration • 53% after 3 years effect of effect • Inhibits both VMAT1 and VMAT2 • Inhibits only VMAT2 • Side effects of depression, orthostatic • Side effects of depression, lethargy, hypotension and GI side effects parkinsonism, akathisia

Valbenazine and Deutetrabenazine UCSF Movement Disorders and Neuromodulation Center

Valbenazine Deutetrabenazine UCSF Mt Zion Campus Dosing Dosed once a day Dosed multiple times a day and with 1635 Divisadero Street, Suite 520, San Francisco, CA 94115 multiple tablets Titration Requires no titration and 1 week to Typically requires titration, often over Referrals: reach the recommended dose the course of several weeks • Clinical Consultations: 415-353-2311 (phone); 415-353-9060 (fax) Food Can be taken with or without food Needs to be taken with food • Clinical Trials: 415-353-8328; (Danilo Romero) Selectivity A selective VMAT2 inhibitor with no Not a selective VMAT2 inhibitor [email protected] appreciable binding affinity for dopaminergic (including D2) or serotonergic receptors EKG • Doesn't require an EKG to start • For patients at risk for QT treatment prolongation, assess the QT • For patients at increased risk of a interval before and after increasing prolonged QT interval, assess the total deutetrabenazine dosage QT interval before increasing the above 24 mg per day dosage • Assess the QTc interval before and after increasing the dose of other meds known to prolong QTc