Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction Results of the SOLSTICE Phase

1. Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction Results of the SOLSTICE Phase 2 Randomized Trial L. Kristin Newby, MD, MHS On behalf of the SOLSTICE Investigators and Steering Committee

2. Background and Primary Goal • Losmapimod is a novel p38 mitogen-activated protein kinase inhibitor that has been shown in preclinical and mechanistic studies to improve vascular function, reduce plaque inflammation and reduce infarct size • The goal of the SOLSTICE trial was to examine the safety of losmapimod and its effect on biomarkers of inflammation, infarct size and left ventricular function in patients with non-ST-segment elevation acute myocardial infarction

3. Study Organization Sponsor (GSK) D Sprecher, L Sarov-Blat, L Giancaterino, A Harter, D Litvan, G Cai, W Tao, C Baidoo, J Lepore Steering Committee C Granger (Chair), K Newby, P Aylward, C Hamm, J Heitner, A Lerman, M Marber, M Patel, J-F Tanguay, R deWinter Duke Clinical Research Institute C Granger, K Newby, C Melloni, L Aberle, H Al-Khalidi M Patel, C McLendon, J George CEC C Melloni, P Owens, R Mehta, R Lopes, M Roe, P Tricoci, S Leonardi, Z Eapen, J Vavalle Core LaboratoriesMRI:M Patel, R Kim, M Parker Central lab:Quest Diagnostics Data and Safety Monitoring Board P Armstrong (Chair), D Faxon, K Bailey

4. Study ParticipationInvestigators in 9 Countries at 84 Sites USA: 23 sites (n=112) Canada: 4 sites (n=26) Australia: 7 sites (n=46) Germany: 30 sites (n=228) The Netherlands: 5 sites (n=44) Spain: 4 sites (n=23) Poland: 3 sites (n=23) UK: 4 sites (n=23) India: 3 sites (n=11)

5. Top Enrolling Sites

6. Age ≥ 45 years • Sx w/i 24 h of presentation • No persistent ST  • Local lab Tn (T or I) > ULN • Randomization w/i 18 h of presentation • Early invasive strategy planned, with PCI > 2 h post first study drug SOLSTICE Study Design NSTE MI Patients N= 535 Randomization 3:3:2 Losmapimod 7.5 mg initial 7.5 mg bidN=199 Losmapimod 15 mg initial 7.5 mg bidN=192 PlaceboN=135 Early cath; PCI no sooner than 2 hours Treatment Period Week 2, 4, 8 and 12 visits on treatment Week 14 visit and 6-month phone contact Endpoints Safety: AEs, SAEs, LFTs, clinical (death, MI, stroke, RIUR, heart failure) Efficacy Co-Primary: hsCRP at 12 wks; Tn I AUC (through 72 h) Secondary: hsCRP, IL-6 time course; Peak Tn I (72 h / DC); BNP (DC / 12 wks)

7. Statistical Considerations • Primary comparisons: pooled losmapimod arms vs. placebo • Total of 150 patients per randomized losmapimod arm vs. 100 in placebo arm provides • 90% power to detect 36% relative reduction in hsCRP at 12 weeks for losmapimod vs. placebo • 90% power to detect 25% relative reduction in cTnI AUC through 72 hours (or discharge) for losmapimod vs. placebo • Of 535 patients randomized • 526 received at least one dose of study drug and composed the primary analysis population for both safety and efficacy • 329 (63%) completed 12 weeks of dosing • MRI substudy(n=93) • Scans at day 3-5 and week 12 • Primary endpoints: Infarct size as % of LV and LVEF • Comparisons at day 3-5, week 12, and difference (day 3-5 – week 12)

8. Baseline Demographics and Treatment Continuous variables are presented as medians with interquartile ranges.

9. Study Drug Discontinuation Data are preliminary.

10. Adverse Events *On and post-therapy. Data are preliminary.

11. Effect of Losmapimod on Inflammation Time course of hsCRP Time course of IL-6 *Last value carried forward

12. Losmapimod and Infarct Size Troponin I (ng/mL) Troponin I AUC Peak Troponin I

13. Losmapimod and Clinical Events Death, MI or Stroke Death, MI, Stroke, Recurrent ischemia or Heart failure Placebo = 15% All Losmapimod = 12.9% Placebo = 18.2% All Losmapimod = 16.4% All Losmapimod vs. Placebo HR 0.85 (95% CI 0.50-1.45; p=0.56) All Losmapimod vs. Placebo HR 0.88 (95% CI 0.54-1.42; p=0.59)

14. Effect of Losmapimod on BNP Time course of BNP Data are preliminary.

15. Effect of Losmapimod on MRI Measures Adjusted for: time from chest pain onset to blood draw, time from onset x MRI variable, log baseline Tn, log baseline Tn x time from chest pain onset, treatment, treatment x time from chest pain onset.

16. Summary and Conclusion • Summary • Losmapimodwas well tolerated in NSTEMI patients • No major liver or other safety signals • Numerically fewer cardiac events • Losmapimod was biologically active as evidenced by effects on hsCRP and IL-6 • Infarct size by Tn I AUC was not significantly reduced by losmapimod • Non-significant one third smaller infarct size by MRI at 12 weeks • Lower BNP and higher LVEF at 12 weeks with losmapimod suggest potential effects on remodeling • Conclusion • In aggregate, effects on biomarkers of inflammation, infarct size and cardiac function suggest promise for p38-MAPK inhibition as a worthwhile target for improving outcomes in acute coronary syndromes

18. Key Exclusion Criteria • Severe HF (NYHA class III or IV) or known severe LV dysfunction (EF< 30%) regardless of symptomatic status • Conditions known to be associated with active chronic or acute inflammation • History of myopathy or rhabdomyolysis • Current or chronic history of liver disease, known hepatic or biliary abnormalities, known Hepatitis B or Hepatitis C • Current or anticipated use of steroids (oral or intravenous)

19. Effect of Losmapimod on Clinical Events Death, MI or stroke KM rate at 180 days Placebo = 15% All Losmapimod = 12.9% All Losmapimod vs. Placebo HR = 0.95 (95% CI 0.80 – 1.13; log-rank p=0.56) 75 mg bid vs. Placebo HR = 0.69 (95% CI 0.37 – 1.29; log-rank p=0.24) Loading+75 mg bid vs. Placebo HR = 1.02 (95% CI 0.76 – 1.36; log-rank p=0.91) Death, MI, stroke, recurrent ischemia or heart failure KM rate at 180 days Placebo = 18.2% All Losmapimod vs. Placebo HR = 0.96 (95% CI 0.82 – 1.12; log-rank p=0.59) 75 mg bid (N=199) vs. Placebo (N=135) HR = 0.77 (95% CI 0.44 – 1.34; log-rank p=0.34) Loading+75 mg bid (N=192) vs. Placebo (N=135) HR = 1.00 (95% CI 0.77 – 1.30; log-rank p=0.99) All Losmapimod = 16.4%