Figures for Draft Response to IMS III, MR RESCUE, and

SYNTHSESIS Trials

Figure 1: Lay Press Judgment May Belie a Deeper Examination of the Data. Truman ultimately defeated Dewey for the Presidency

All Subjects n=656

Baseline CTA/MRA n=306

No Baseline CTA/MRA

n=35047%292 Baseline CTAs and 14 baseline MRAs

Figure 2: Number of IMS III Patients who had pre-procedural imaging. This group represents the key subset analysis because of confirmed Large Vessel Occlusion (LVO)

Subject enrollment by CTA and treatment group

• 80 Subjects: No treatable occlusion by operator- 41: M3 and/or M4 at Angiography by Core Lab- 15 CTA

- 1 No Occlusion- 14 Occlusion- 1 ICA Terminus- 8 M1- 4 M2- 1 M3

IMS III: No Treatable Occlusion by CTA

Figure 3: Over 80 patients in IAT arm of IMS III had no treatable occlusion on angiography (Nearly 20%)

Reason Frequency

No treatable arterial occlusion (operator) 80*

Inability to access 3

Recanalization after baseline angiogram 2

Occlusion, but not responsible lesion 2

No reason 2

Figure 4: Over 20% of IAT cohort had no endovascular therapy administered

Endovascular therapy not administered n=89

NIHSS 8-19 NIHSS ≥ 20 All

EndovascularIV tPA only Endovascular

IV tPA only Endovascular

IV tPA only

MRS <=2 (%) 146 (48.3) 74 (49.3) 31 (23.5) 12 (16.7 177 (40.8)86

(38.7)

Risk Difference -0.01 (-0.11, 0.09) 0.07 (-0.04, 0.18) 0.02 (-0.06, 0.09)

CMH p-value 0.70

Breslow Day p-value 0.27

90-Day Modified Rankin Scale by Baseline NIHSS Strata and Treatment in IMS III

Figure 5: Higher NIHSS corresponded with much greater endovascular treatment likely due to the increased incidence of LVO in subjects with NIHSS > 20 and greater opportunity to realize benefit

7

A. Demchuk, IMS III: Comparison of Outcomes between IV and IV/IA Treatment in Baseline CTA Confirmed ICA, M1, M2 and Basilar Occlusions, slide 20, Presented at ISC 2013, Honolulu Hawaii

Endovascular confers a statistically significant benefit across the spectrum of mRS

With CTA-confirmed occlusion at baseline, representative of current practice, IMS III has a statistically significant positive outcome for endovascular

Figure 6: Recent High Quality Trials Demonstrate: Endovascular is Efficacious (pre-specified analysis)

Figure 7: Recent High Quality Trials Demonstrate: Endovascular is Safe.

In IMS III, despite reduced dose IV tPA and being subjected to angiography (with 20% of pts without occlusion), endovascular therapy had NO increase in death or symptomatic ICH

8

Figure 8: Recent High Quality Trials Demonstrate: Endovascular is Safe.

9

SYNTHESIS conclusion: Subjecting ALL potential IV tPA patients to IA therapy, including those with minimal deficit (NIHSS of 2 included) and without confirmation of occlusion, demonstrated EQUAL efficacy to IV tPA with NO significant safety concerns

Figure 9: Percentage of Patients who achieved a functional outcome in IMS III based on reperfusion result (p=0.001)

In IMS III, independent functional outcome (mRS 0-2) was strongly associated with TICI 2b-3 revascularization. Though TICI 2b-3 is the modern endovascular standard, a low percentage of patients in IMS III achieved this technical result due to older, inferior technologies. TICI 2a was considered a good outcome in IMS III but clearly does not translate into good clinical outcomes

N TICI 2-3 (%) TICI 2b-3 (%)

Internal Carotid Artery 65 65 38

M1 of Middle Cerebral Artery 135 81 44

M2 if Middle Cerebral Artery 61 70 44Multiple M2s 22 77 23Basilar 4 NA NA

Angiographic Reperfusion in IMS III

Figure 10: Few patients in IMS III met the clinically significant reperfusion standard due to use of first generation technologies. These TICI 2b and 3 rates fall well short of modern SWIFT and TREVO series

Primary Target Vessel Frequency

Percent with TICI 2-3 at

completion of procedure

Percent with TICI 2b-3 at completion

of procedure

All 328 74% 40%ICA extracranial occlusion 6 83% 33%ICA Intracranial 65 65% 38%

ICA-T (41) (63%) (36%)

Other Intracranial ICA (24) (67%) (42%)

M1 135 81% 44%

Figure 11: Low TICI 2b-3 rates due to first generation endovascular technologies persisted in IMS III independent of LVO location. Half of reperfusion successes in IMS III were only TICI 2a results.

IMS III TICI Reperfusion Primary Target Occlusion

Study OutcomesEmbolectomy,

penumbral (n=34)

Standard Case, penumbral

(n=34)

Embolectomy, nonpenumbral

(n=30)

Standard Case nonpenumbral

(n=20)p

Score on 90 day modified Rankin Score Unadjusted 0.23 Mean 3.9 3.4 4 4.4 Median 4 3 4 4 95% CI 3.3 to 4.4 2.8 to 4.0 3.4 to 4.6 3.6 to 5.2 Adjusted 0.3 Mean 3.3 3.4 4 4.2 Median 4 3 4 4 95% CI 3.2 to 4.4 2.9 to 3.9 3.8 to 4.7 1.7 to 4.8

Good Outcome at 90 days

# of patients (%) 7 (21) 9 (26) 5 (17) 2 (10) 0.48 Adjusted analysis (%) 14 23 9 10 0.39Death; number (%) 6 (18) 7 (21) 6 (20) 6 (30) 0.75Hemorrhage; number (%) Symptomatic 3 (9) 3 (6) 0 0 0.24 Asymptomatic 19 (56) 14 (41) 23 (77) 12 (60) 0.04Final infarct Volume

No. of patient evacuated 32 32 30 19

Median (interquartile range) - mL

58.1 (34.5 to 138.2)

37.3 (24.9 to 78.3)

172.6 (84.6 to 273.8)

217.1 (144.3 to 282.8) <0.001

Absolute infarct growth No of patients evacuated 32 32 10 19

Median - mL 27.1 6.7 55.1 83.8 0.009

Figure 12: Due to poor

technical performance of first

generation devices,

IAT patients in

MR RESCUE did

NOT achieve greater

reperfusion than

Standard Medical

Care Patients

Outcome and MeasurePatients with

Reperfusion or Recvascularization

Pationes without reperfusion or

RevascularizationP value

Reperfusion

# of Patients 43 43

Mean score on 90-day modified Rankin scale (95% CI) 3.2 (2.6 to 3.8) 4.1 (3.7 to 4.5) 0.04

Mean absolute infarct growth (interquartile range - mL) 9.0 (-13.7 to 50.3) 72.5 (5.6 to 120.7) <0.001

Partial or complete revascularization

# of Patients 79 22

Mean score on 90-day modified Rankin scale (95% CI) 3.4 (3.1 to 3.9) 4.4 (4.0 to 4.8) 0.04

Mean absolute infarct growth (interquartile range - mL) 17.7 (-8.8 to 89.2) 60.3 (19.9 to 93.3) 0.10

Figure 13: Those MR RESCUE patients that DID achieve reperfusion enjoyed better clinical outcomes

Figure 14: In IMS III, time from IV to IAT initiation was greater than 2 hours and greatly exceeds IMS I and II. Though likely secondary to decentralization of care secondary to development of PMSC’s, this diminishes the clinical benefit with endovascular therapy in the trial.

Figure 15: IMS III patients further suffered a significant lag between groin access and initiation of IAT at the lesion. Fourty-four minutes is far beyond reported standards with modern guide and distal access catheter technology.

bCTA No bCTAAge, median (min-max) 70 (23-83) 68 (23-89)Male (%) 163 (53.3) 177 (50.6)Baseline NIHSS median (min-max) 17 (7-40) 17 (9-40)ASPECTS 8-10 (%) 177 (57.8) 201 (57.4)Onset to iv tPA initiation, minutes; mean (SD) 123 (33.4) 123.1 (34)IV tPA to Groin Puncture, minutes: mean (SD) 80.7 (26.3)* 90.1 (35.5)*

Groin puncture to IA Therapy, minutes: mean (SD) 40.1 (22)** 49.9 (24.2)**

IMS III Baseline Characteristics

Figure 16: Time from puncture to START of IAT was 50 minutes for non cta centers; Centers that did baseline cta's were 20 min faster to IA intervention in IMS III

FIGURE 17FIGURE 17RCT for AIS Revascularization: Control arms of PROACT II and RCT for AIS Revascularization: Control arms of PROACT II and NINDS give some indication of LVO natural historyNINDS give some indication of LVO natural history

TrialTrial NINDSNINDS ECASS IIIECASS III PROACT IIPROACT II

Treatment TypeTreatment Type IVIV t-PA vs. t-PA vs. PlaceboPlacebo

IVIV t-PA vs. t-PA vs. PlaceboPlacebo

IAIA pUK + Hep pUK + Hep vs. Hepvs. Hep

PatientsPatients 333 (168 vs. 333 (168 vs. 165)165)

821 (418 vs. 821 (418 vs. 403)403) 180 (121 vs. 59)180 (121 vs. 59)

Time Window Time Window (hours)(hours) 0-30-3 3-4.53-4.5 0-60-6

Presentation Presentation NIHSSNIHSS 14 vs. 1514 vs. 15 10.7 vs. 11.610.7 vs. 11.6 17 vs. 1717 vs. 17

RecanalizationRecanalization NRNR NRNR 66 vs. 1866 vs. 18

Outcome (%) at Outcome (%) at 3 months3 months

mRS mRS << 1 1 39 vs. 39 vs. 2626

mRS mRS << 1 1 52.4 52.4 vs. 45.2vs. 45.2

mRS mRS << 2 2 40 vs. 40 vs. 2525

SICH Rates (%)SICH Rates (%) 6.4 vs. 0.66.4 vs. 0.6 2.4 vs. 0.22.4 vs. 0.2 10 vs. 210 vs. 2

FIGURE 18FIGURE 18Prospective Intervention Trials: Inferior Outcomes with First Prospective Intervention Trials: Inferior Outcomes with First Generation DevicesGeneration Devices

TrialTrial IMS- IIIMS- II MERCIMERCI Multi- MERCIMulti- MERCI PenumbraPenumbra

Treatment Treatment TypeType

IV t-PA + IA t-IV t-PA + IA t-PA + EKOS + PA + EKOS + low dose heplow dose hep

IA Merci + IATIA Merci + IAT IA Merci + IAT IA Merci + IAT + IVT+ IVT

IA Penumbra IA Penumbra + IAT+ IAT

PatientsPatients 81 (IAT-55)81 (IAT-55) 141141 164164 125125

Time Window Time Window (hours)(hours) 0-30-3 0-80-8 0-80-8 0-80-8

Presentation Presentation NIHSSNIHSS 1919 2020 1919 1717

Recanalization Recanalization (%)(%) 5858 60.3 (48 60.3 (48

device alone)device alone)68 (55 Merci 68 (55 Merci

alone)alone)81.6 (Device 81.6 (Device

alone)alone)

Outcome (%) Outcome (%) at 3 months at 3 months mRS mRS << 2 2

4646 3636 3636 2525

SICH Rates SICH Rates (%)(%) 9.99.9 7.87.8 9.89.8 11.211.2

FIGURE 19: Outcomes at 3 months better with ReperfusionFIGURE 19: Outcomes at 3 months better with Reperfusion

StudyStudy mRS mRS << 2 (%) 2 (%) Mortality (%)Mortality (%)

MERCIMERCI 46 vs. 10.4 46 vs. 10.4 (P<0.0001)(P<0.0001)

31.8 vs. 54.2 31.8 vs. 54.2 (P=0.001)(P=0.001)

Muti-MERCIMuti-MERCI 49.1 vs. 9.6 49.1 vs. 9.6 (P<0.001)(P<0.001)

24.8 vs. 51.9 24.8 vs. 51.9 (P<0.001)(P<0.001)

IMS I & II Pooled IMS I & II Pooled AnalysisAnalysis

45.6 vs. 6.945.6 vs. 6.9(P=0.004)(P=0.004)

10.9 vs. 34.5 10.9 vs. 34.5 (P=0.01)(P=0.01)