PRE-HOSPITAL AND PERIPROCEDURE NEUROPROTECTION: THE FAST AND THE FURIOUS. William J. Mack, MD, MS, FAANS, FAHA

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1 PRE-HOSPITAL AND PERIPROCEDURE NEUROPROTECTION: THE FAST AND THE FURIOUS William J. Mack, MD, MS, FAANS, FAHA Associate Professor of Neurosurgery Neuroscience Graduate Program Zilkha Neurogenetic Institute University of Southern California ASNR MEETING April 23, 2017

2 DISCLOSURE STATEMENT OF FINANCIAL INTEREST Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Consulting Fees/Equity Consulting Fees/DSMB Consulting Fees/DSMB Consulting Fees/Core Lab Company Rebound Therapeutics Medtronic Penumbra Stryker

3 RESEARCH SUPPORT NIH/NIEHS 1R01ES Neurotoxicity of Airborne Particles: Role of Chronic Cerebral Hypoperfusion. NIH KL2 RR Complement Mediated Injury in a Translation Model of Chronic Cerebral Hypoperfusion NIH/NIEHS/SCEHSC 5P30ESO Airborne Particulate Matter from Vehicular Exhaust in the Setting of Acute Stroke NIH U01 MH Evaluation of Cellular Heterogeneity Using Patchclamp and RNA-Seq of Single Cells Knowles, Chow (Co-PIs)

4 DISCLOSURE STATEMENT OF FINANCIAL INTEREST I, William Mack DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

5 WHY NEUROPROTECTANT TRIAL HAVE FAILED Despite decades of active research for effective treatments of acute ischemic stroke, the only approved medication for use is recombinant tissue plasminogen activator (rtpa) Barriers: Preclinical Testing (STAIR Criteria) Time Window for Drug Administration Stroke Severity, Stroke Type Dosing Regimen Trial Design Combination Therapy Clinical Trial Design Heterogeneity of Clinical Administration

6 BARRIERS: TIME Only about a quarter to a third of patients with AIS arrived in the Emergency Department within 3 hours of symptom onset Faster onset to treatment times have been associated with reduced mortality, reduced symptomatic intracranial hemorrhage, and increased poststroke independence with endovascular therapy Khatri et al, Neurology, 2009; Branas et al. Health Serv Res 2000 ; Lichtman et al, Stroke, 2009

7 DOOR TO NEEDLE TIMES IN BEST PRACTICE Stroke Center Helsinki, Finland Erlangen, Germany Wash U, St. Louis Median Door to Needle Times 20 mins 25 mins 39 mins Meretojoa et al, Neurology, 2012; Korhman et al. Int J Stroke 2011 ; Ford et al, Stroke, 2012

8 STROKE: THE GOLDEN HOUR Narrow therapeutic time window Early intervention critical for stroke care Prehospital personnel 35-70% of stroke patients arrive by ambulance Unique position: first medical professional to come in contact with stroke patient

9 FAST-MAG: TRIAL CONSORTIUM Los Angeles and Orange Counties Population 13.3 million 40 EMS Provider Agencies 315 rescue ambulances 2988 paramedics 60 receiving hospitals 952 physician-investigators 715 Emergency Medicine (site PIs) 210 Neurologist 26 Nsurg/Intensive/Hosp 95 CCC coordinators and research assistants Supported by NIH-NINDS

10 FAST-MAG: TIME INTERVALS Placebo (n=843) Magnesium (n=857) Total (n=1700) p value Onset* to Drug (mins) 46 (36-62) 45 (35-60) 45 (35-62) 0.24 Onset to Drug (categorical) 0-1 hours 73.2% 75.3% 74.3% hours 25.7% 23.7% 24.7% >2 hours 1.1% 0.9% 1.0% On Scene to Drug 23 (19-28) 23 (18-27) 23 (18-27) 0.58 On Scene to Door** 33 (27-39) 32 (27-39) 33 (27-39) 0.91 Onset to on-scene: 23 min Onset to NP: 45 min Onset to ED arrival: 58 min NP to ED arrival: 13 min Onset to TPA: 137 min NP to TPA: 92 min Onset to Endovascular: 275 min *Onset = last known well time NP to Endovascular: 230 min **Historical **Historical comparator, comparator, pretrial pretrial LA LA scene scene to to door door times times = 35 = 35 minutes minutes (Stroke (Stroke 2004;35:e ) Supported by NIH-NINDS

11 FAST-MAG: OUTCOMES Primary Endpoint: Disability at 3 months: Modified Rankin

12 INTRAARTERIAL NEUROPROTECTION Endovascular Restorative Neurosurgery: A Novel Concept for Molecular and Cellular Therapy of the Nervous System Magnesium Sulfate delivered through intra-arterial access (Guide Catheter) during mechanical thrombectomy procedure Mg levels assessed distal to the thrombus and in the systemic circulation Mg Levels compared to those form FAST- MAG systemic administration Safety/ feasibility in a small sample cohort Mack, Liebeskind, Saver Amar, Zlokovic Apuzzo, Neurosurgery 2003

13 ACTIVATED PROTEIN C/ 3K3A-APC Endothelial Protein C Receptor Protease Activated Receptor Griffin, Zlokovic, Mosnier Blood, 2015

14 MULTIPLE TARGET/ MULTIPLE MECHANISM Targets: Neuron, Endothelial cells, Microglia Mechanisms: Antithrombotic Cytoprotective Regenerative Griffin, Zlokovic, Trends Neurosci, 2011

15 APC : PRECLINICAL MODELS Griffin, Zlokovic, Mosnier Blood, 2015

16 APC VARIANTS : PRECLINICAL MODELS Griffin, Zlokovic, Mosnier Blood, 2015

17 APC: STAIR QUALITY 3K3A-APC STAIR SCORE: 10 out of 10 3K3A-APC + tpa STAIR SCORE: 9 out of 10 tpa STAIR SCORE: 9 out of 10 Griffin, Zlokovic, Trends Neurosci, 2011

18 Murine transient ischemia tpa and 3K3A APC Administered 10 min before reperfusion and 20 min into reperfusion. APC also 3h post-reperfusion Hemoglobin levels at 24h Chen.. Zlokovic, Nature Med, 2006

19 EFFICACIOUS IN HYPERTENSIVE MICE 3K3A-APC + tpa combination demonstrated statistically significant improvement in efficacy compared with tpa alone 9 spontaneously hypertensive (HTN) rats per dose group Study recommended by STAIR tpa (10 mg/kg) and murine 3K3A-APC (0.2 mg/kg) dosed 4 hours after embolic stroke in spontaneously hypertensive rat Murine 3K3A-APC was additionally administered within 3 to 7 days post-stroke Vehicle 3K3A-APC tpa 3K3A-APC + tpa Wang.. Zlokovic, Stroke, 2013

20 Volume (mm 3 ) EFFICACIOUS IN HYPERTENSIVE MICE 3K3A-APC + tpa combination demonstrated statistically significant improvement in efficacy compared with tpa alone Infarct Volume, day 7 Neurological Severity Score: mnss * P<0.01 vs. vehicle P<0.01 vs. tpa * * * * * P<0.01 vs. vehicle P<0.01 vs. tpa * * vehicle tpa 3K3A-APC tpa + 3K3A- APC 0 1 day 7 days Vehicle tpa 3K3A-APC tpa + 3K3A-APC Wang.. Zlokovic, Stroke, 2013

21 3K3A-APC DECREASES tpa BLEEDING Bleeding in the brain is a major side-effect of tpa; 3K3A-APC helps make tpa safer tpa tpa + 3K3A-APC Wang.. Zlokovic, Stroke, 2013

22 EFFICACIOUS IN AGED FEMALE MICE 3K3A-APC + tpa combination demonstrated statistically significant improvement in efficacy compared with tpa alone Study Details 5 aged female mice per group Study recommended by STAIR tpa (10 mg/kg) and murine 3K3A- APC (0.2 mg/kg) dosed 4 hours after distal permanent MCAo Murine 3K3A-APC was additionally administered within 1, 3, 5, and 7 days post-stroke Results presented at 28 days poststroke Wang.. Zlokovic, Stroke, 2013

23 Hemorrhagic Area (mm 2 ) Hemoglobin (g/dl) ROBUST SAFETY IN AGED/ HTN MICE 3K3A-APC + tpa combination eliminated tpa s bleeding risk Hemorrhagic area in hypertensive rats, day 7 Hemoglobin concentration in aged female mouse brains, day * * P<0.01 vs. vehicle P<0.01 vs. tpa * * P<0.01 vs. vehicle P<0.01 vs. tpa Vehicle tpa 3K3A-APC tpa + 3K3A- APC 0 Vehicle tpa 3K3A-APC tpa + 3K3A- APC 3K3A-APC s elimination of tpa s bleeding risk persists in all animal models tested: mice and rats, male and female, young and old, healthy and hypertensive Wang.. Zlokovic, Stroke, 2013

24 3K3A-APC: PROMOTES NSC PRODUCTION Control 3K3A-APC Proliferation BrdU incorporation (FACS) Migration Neurospheres Migration Assays Cell Tracker Green Matrigel β3-tubulin Neuronal Differentiation 3-tubulin/Hoechst neuron-like cells NPCs 10 divisions Fetal human neural stem cells (SVC) Promotes neuronal production, inhibits astrocyte and oligodendrocyte lineages Guo et al. J Neuroscience 2013

25 3K3A-APC: PROMOTES NSC PRODUCTION 3K3A-APC promotes neuronal production from transplanted human NSCs and their structural and functional integration into the host neural circuits in mice treated 7 days after ischemic stroke Wang et al. Nature Medicine 2016 (In Press)

26 3K3A-APC: SAFETY IN HUMANS 3K3A-APC with reduced anticoagulant activity but normal cytoprotective activity is safe in humans when given as a high-dose bolus regimen Griffin, Zlokovic, Mosnier Blood, 2015

27 2. Effective in AD models (Sagare, Singh et al.) Murine and Rat AD models Vasculoprotection and BBB sealing effect Neuroprotection Anti-inflammatory Inhibits b-secretase 3K3A-APC: CLINICAL TRIAL/ APPLICATIONS THERAPIES: 3K3A-APC ZZ Biotech Phase 2 study: funded by the NINDS NeuroNext clinical trials.gov NCT Neuroprotectant - Ischemic Stroke Enrolled so far ~ 80 patients (goal ~100) Expected by the end of 2016 Phase 3 New applications for CNS disorders: 1. With stem cell (NSC) therapy for Stroke (Zhao Zlokovic, Nature Med 2016 in press) Integration of grafted NSCs into host neural circuitry

28 ADDITIONAL POTENTIAL TO BE UNLOCKED 3K3A-APC has the potential to impact the following areas, providing the opportunity to exploit further potential of this novel biologic agent beyond stroke Traumatic Brain Injury Alzheimer s & Parkinson s Diseases Sepsis 3K3A-APC Reperfusion Injury ALS Wound Healing

29 ACKNOWLEDGEMENTS NINDS grants R01NS and HL63290 to Zlokovic for preclinical proof of concept studies Berislav Zlokovic, MD, PhD Nerses Sanossian, MD Jeffrey Saver, MD David Liebeskind, MD Steven Giannotta, MD Arun Amar, MD Matthew Tenser, MD Nerses Sanossian, MD Qinghai Liu, MD Robin Babadjouni, BS Yaoming Wang, PhD Zhen Zhao, PhD

30 10/04/2017 Disclosures Intracranial Atherosclerotic Disease: The Frontier of Plaque Imaging Commercial Interests No relevant commercial interests Off Label / Investigational Use No off label / investigational use Daniel Mandell, MD PhD FRCPC Division of Neuroradiology Toronto Western Hospital University of Toronto Black Blood and CSF Routine contrast-enhanced T1-weighted gradient echo Sequence optimized for vessel wall imaging F 72 with acute weakness 52 M with vertigo for 1 month 52 M with vertigo for 1 month 1

31 10/04/2017 Plaque Enhancement Secondary Prevention of Ischemic Stroke Cardiac Source of Embolism Carotid Atherosclerotic Plaque Intracranial Atherosclerotic Disease Skarpathiotakis et al. AJNR 2013;34(2) CASE 1 T1 gad CASE 2 T1 no gad M 48 with left MCA territory infarct Acute symptoms onset 1 day earlier 2

32 10/04/2017 CASE 3 CASE 4 T1 no gad T1 T1 post gad M 81 with acute cerebellar infarct CASE 4 CASE 5 T1 T1 post gad M 81 with acute cerebellar infarct Ritman ET et al. Cardiovascular Research 2007;75:649. CASE 6 CASE 6 T1 gad F 34 previously well F 34 previously well 3

33 10/04/2017 CASE 7 CASE 7 Companion Case M 57 previously healthy presents to ER with severe headache and neck pain for a week. TO SUMMARIZE: danny.mandell@uhn.ca 4