Disclosures Paul Walker MD PhD FRCSC

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2 Disclosures Paul Walker MD PhD FRCSC CEO Spectral Medical 2001-present Inaugural Critical Care Program Director - University of Toronto Chief of Surgery - University Health Network COO Toronto General Hospital

3 The EUPHRATES Trial A Canadian Story

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5 Measuring endotoxin - Endotoxin Activity Assay (EAA) LPS CR3 Zymosan A C 3 b Discovery Anti-LPS (IgM) CR1 Release of oxyradicals (HOCL) + lumiphor LPS-anti-LPS complex Chemiluminescence 5 - Romaschin, J.Immunol.Methods 212:169, 1998

6 Commercialize the discovery Keep the discovery as a research tool The only pathway that allows widespread clinical use of a discovery for patient care 6 Align with a commercial entity or develop it yourself?

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8 We went alone a 20 year project Developed the Endotoxin Activity Assay (EAA) with Dr. Alex Romaschin Filed patent (50K from us) First Industry funding 500K Second industry funding 1M Medic trial I became CEO Spectral October FDA panel meeting, EAA not approved 7-0 FDA approved EAA Spectral began working with Toray Spectral signed exclusive licensing deal with Toray for Toraymyxin Began FDA registration trial EUPHRATES Raised 60 Million EUPHRATES trial finished Oct 3 top line results made public

9 What was known Not all patients in septic shock have the same level of endotoxin present N= < > Reference: Marshall JID 2004.

10 Odds ratio for severe sepsis % Mortality High EAA Severe Sepsis Death [p=0.0003] Odds Ratio = 3.0 (C.I ) ICU Hospital < >0.6 0 < >0.6 EA range Admission Endotoxin Activity 10 Marshall, J. et al. JID 2004.

11 Percentage of Subjects Endotoxemia == Gram Negative Infection 100% No Growth 75% Gram Positive Gram Negative 50% 25% 0% < < 0.60 >= 0.60 Source: Klein et al. ATS EAA Level

12 Another failed sepsis trial... why? ACCESS: n=2000 EAA levels in ACCESS patients N=200 40% 37% < >0.6 28% 12 JAMA. 2013; 309(11):

13 PMX Cartridge: removes endotoxin Fabricated PMX-F Schematic Diagram of PMX-F Polymyxin B 13

14 EUPHRATES. The Story of a River Evaluating the Use of Polymyxin B Hemoperfusion in an RCT of Adults Treated for Endotoxemia and Septic shock 14 Principal Investigator: Dr. Phil Dellinger Steering Committee: M. Antonelli, J. Marshall, S. Trzeciak, C. Shorr, P. Palevsky, S. Bagshaw, D. Klein, P. Walker (sponsor), D. Foster (sponsor)

15 Protocol Design Phase 3, double-blinded, randomized, controlled study: Standard of care + PMX hemoperfusion vs. Standard of care Adaptive design with an Interim Analysis for sample size reassessment Designed to evaluate the safety and efficacy of the PMX Cartridge 15

16 Protocol Design Biomarker Driven Patient Selection Endotoxin Activity Assay (EAA) used to select endotoxemic patients for inclusion 16 16

17 Protocol Design Selection Criteria Septic Shock EAA>0.6 MODS > 9 EUPHRATES Patient 17 Centralized triage center confirmed patient eligibility prior to randomization

18 Protocol Design We performed a blinded device trial» Treatment allocation» Post randomization EAA results Blinded» Investigators & attending physicians» Steering Committee» Sponsor Unblinded» Attending ICU Nurses» Research Coordinator» Nephrology team (Performing treatment) Blinding was successfully maintained for 98% of all subjects 18

19 Endpoints Primary» Safety and efficacy, based on mortality at 28-days Secondary» Survival time from baseline to death within 28 days» Improvement of organ function from baseline to day 3» Change in MAP from baseline to day 3» Change in CVI* from baseline to day 3» Mechanical ventilation and RRT alive and free days 19 *CVI: Cumulative Vasopressor Index

20 Population screened, randomized and analyzed 921 Screened for Septic Shock + EAA 450 Randomized Screen fail: 471 EAA < 0.6 = 342 EAA 0.6 = 113 No EAA = 16 MODS < 9 = MODS>9 PMX =147 SHAM= PMX = SHAM=129 Died between runs Treatment time <90 mins Withdrew Did not receive 2 runs per protocol

21 21 Primary endpoint analysis The Primary endpoint for mortality was not met in full population ITT Population MODS>9 mortality : control arm = 44.3% PMX arm = 43.7% PMX control Per protocol population MODS >9 mortality: control arm = 36.9% PMX arm = 31.9% 5% in favor of PMX arm (p = 0.41)

22 22 Now what? Was the study under powered? Was the effect size overestimated? Did the treatment work? Were there other biological factors? EUPHRATES was a biomarker driven clinical trial. -we investigated endotoxin concentration as a potential factor the patient population was selected based on a Minimum endotoxin activity value Endotoxin (EAA 0.6) Septic Shock

23 Device adsorption capacity In-Vitro measurement The 15 lots used in the EUPHRATES trial were tested and demonstrated an average adsorption capability of ~12 µg of endotoxin per cartridge. 23

24 Does baseline EAA make a difference? Is the endotoxin burden too high in some patients? To measure accurately? To treat effectively? 24

25 Conversion of EAA to pg/ml of Endotoxin Concentration > 4000 pg/ml 25 Representative EAA dose response curve, modified from Romaschin et al. J of Blood purification 2017

26 Burden of Endotoxin: Calculated quantity of circulating endotoxin in an average size adult Burden of Endotoxin :Volume of blood + interstitial fluid ml 26

27 Examining the effect of endotoxin burden EAA < MODS>9 Per Protocol PMX =115 SHAM= mpp EAA >0.6 and <0.9 EAA > 0.9 = 48 PMX =88 SHAM=106 27

28 Demographics: Per Protocol, EAA < 0.9 & MODS>9 (n=194) PMX (N=88) SHAM (N=106) Variables N (%) N (%) Age [mean, (SD)] 58.7 (15.0) 57.5 (14.4) Age Groups Gender Race Less than (20.5) 21 (19.8) 45 to (30.7) 36 (34.0) 60 to (27.3) 26 (24.5) 70 and above 19 (21.6) 23 (21.7) Male 55 (62.5) 66 (62.3) Female 33 (37.5) 40 (37.7) Caucasian 72 (81.8) 81 (76.4) Black 8 (9.1) 8 (7.6) Hispanic 3 (3.4) 7 (6.6) Asian 2 (2.3) 6 (5.7) Other 3 (3.4) 4 (3.8) There were no significant between-group differences in the demographic characteristics at baseline. 28

29 29 Baseline characteristics Per Protocol, EAA < 0.9, MODS>9 PMX (N=88) SHAM (N=106) Variables N (%) N (%) APACHE [mean, (SD)] 30.6 (7.6) 29.2 (8.1) Mean Arterial Pressure [mean, (SD)] 71.7 (9.2) 73.5 (10.1) 0 to 5 41 (46.6) 38 (35.9) 6 to (34.1) 53 (50.0) CVI Levels 11 to (18.2) 13 (12.3) 16 to 20 1 (1.1) 2 (1.9) On Renal Replacement Therapy 19 (21.6) 27 (25.5) AKIN Stages Presumed Site of Infection Micro-Organisms 0 19 (21.6) 20 (18.9) 1 9 (10.2) 17 (16.0) 2 11 (12.5) 12 (11.3) 3 49 (55.7) 57 (53.8) Intra-abdominal 25 (29.1) 43 (40.6) Lung 29 (33.7) 38 (35.9) Mixed 4 (4.7) 6 (5.7) Other 28 (32.6) 19 (17.9) No Growth 28 (31.8) 31 (29.3) Gram Negative 22 (25.0) 13 (12.3) Gram Positive 20 (22.7) 33 (31.1) Other 5 (5.7) 7 (6.6) Mixed 13 (14.8) 22 (20.8) Presence of Bacteremia 26 (29.9) 33 (31.4)

30 Primary endpoint (mpp) EAA 0.6 and < 0.9, MODS >9 Mortality rate at 28 days Active N=88 n (%) Sham N=106 n (%) Difference 95% CI p-value* Number of subjects deceased 23/ 88 (26.1) 39/106 (36.8) ( ) 0.05 Absolute Reduction in Mortality Time Absolute Reduction % p-value* 14 Days Days Days Note: Subjects with unknown survival status are excluded from the analyses. * Results of Logistic Regression adjusted for baseline MAP and APACHE scores.

31 Survival analysis mpp EAA 0.6 and <0.9, MODS >9 (n=194) Time Risk Reduction % HR and p-value 14 Days 52 HR 0.48, p= Days 42 HR 0.58, p = Days 41 HR 0.594, p=0.04 PMX control 31

32 Effect of Endotoxin removal on MAP 10 Improvement of MAP at 72 hours PMX P=<0.05 for all comparisons SHAM MODS>9 MODS > 9, per protocol MODS > 9 & EAA 0.6- < 0.9

33 Impact of Refractory Shock on Mortality Stably Unstable = Slowly Dying 33 CHEST , DOI: ( /chest )

34 Mortality (%) Impact of vasopressors Patients with baseline dose of norepinephrine of > 0.1 mcg/kg/min (n=154) % PMX 40% Control 28 day Mortality P < 0.05

35 Where do we go now : Clinical trials are designed to control variability through detailed eligibility criteria and designed clinical protocols performed by specialized research personnel. They require intensive monitoring and data auditing to demonstrate that use of a device produces the expected results. Although useful in establishing a baseline for device performance, clinical trials may be narrow in scope due to practical challenges. 35 In contrast, studies leveraging RWD can potentially provide information on a wider patient population, thus providing information that cannot be obtained through a traditional clinical trial alone. Real World Evidence is important!

36 Real World Data for PMX >150,000 patients treated with safety data reported on all use >180 published papers on its use 9340 patients entered into trials 36

37 Effects of Polymyxin B Hemoperfusion on Mortality in Patients With Severe Sepsis and Septic Shock: A Systemic Review, Meta-Analysis Update, and Disease Severity Subgroup Meta-Analysis. Tzu Chang, MD, Yu-Kang Tu, PhD, et al Crit Care Med

38 Mortality benefit of PMX treatment Benefit of PMX on mortality 40% 35% 30% 25% 20% Nakamura 2003 (206) Cruz 2007 (523) Yaroustovski 2014 (40) Cruz 2009 (34) 15% 10% Dellinger 2017 (EAA 0.6 to 0.9 n=194) Iwagami 2015 (351 with 2 PMX) 5% 0% -5% -10% Iwagami 2013 Iwagami 2015 (654 with 1 PMX) Dellinger 2017 (450) Vincent 2005 (17 with 1 PMX) Payen 2015 (80 with 2 PMX) Payen 2015 (119 Intent-to-treat) -15% 0% 10% 20% 30% 40% 50% 60% 70% 80% Mortality of controls

39 39 Sepsis

40 Conclusions Endotoxemia occurs in many but not all patients with septic shock and high levels are associated with adverse outcomes PMX-HP removes endotoxin in sepsis, is safe, and improves blood pressure up to three days in all studies to date and shows improvement in organ dysfunction Targeted use of PMX-HP in patients with septic shock and EAA < 0.9 has the potential to save lives in the ICU 40