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

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

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

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 participation investigators in 9 countries at 84 sites

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

Top Enrolling Sites


Solstice study design

  • 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

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

Baseline Demographics and Treatment

Continuous variables are presented as medians with interquartile ranges.


Study drug discontinuation

Study Drug Discontinuation

Data are preliminary.


Adverse events

Adverse Events

*On and post-therapy. Data are preliminary.


Effect of losmapimod on inflammation

Effect of Losmapimod on Inflammation

Time course of hsCRP

Time course of IL-6

*Last value carried forward


Losmapimod and infarct size

Losmapimod and Infarct Size

Troponin I (ng/mL)

Troponin I AUC

Peak Troponin I


Losmapimod and clinical events

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

Effect of Losmapimod on BNP

Time course of BNP

Data are preliminary.


Effect of losmapimod on mri measures

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 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

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

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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