Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction
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Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction Results of the SOLSTICE Phase 2 Randomized Trial PowerPoint PPT Presentation


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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 O n behalf of the SOLSTICE Investigators and Steering Committee. Background and Primary Goal.

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Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction Results of the SOLSTICE Phase 2 Randomized Trial

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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


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


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


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)


Top Enrolling Sites


  • 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)


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)


Baseline Demographics and Treatment

Continuous variables are presented as medians with interquartile ranges.


Study Drug Discontinuation

Data are preliminary.


Adverse Events

*On and post-therapy. Data are preliminary.


Effect of Losmapimod on Inflammation

Time course of hsCRP

Time course of IL-6

*Last value carried forward


Losmapimod and Infarct Size

Troponin I (ng/mL)

Troponin I AUC

Peak Troponin I


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)


Effect of Losmapimod on BNP

Time course of BNP

Data are preliminary.


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.


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


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)


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%


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