Cardioprotection and Plaque Regression with MEDI6012 in Acute ST Elevation Myocardial Infarction – Primary Results of the Phase 2B REAL-TIMI 63B Randomized Clinical Trial

Marc P. Bonaca1,2, David A. Morrow3,4, Brian A. Bergmark3,4, Joao A. C. Lima5, Udo Hoffmann6, Yoko Kato5, Michael T. Lu6, Julia Kuder3,4, Sabina A. Murphy3,4, Sami A. Omar7, Andrea L. Vavere7, Yi-Ting Chang7, Richard T. George7, Marc S. Sabatine3,4

1University of Colorado School of Medicine; 2CPC Clinical Research, Aurora, CO, 3Brigham and Women’s Hospital, Boston, MA, 4TIMI Study Group, 5Johns Hopkins University, 6Massachusetts General Hospital, 7AstraZeneca

BACKGROUND

Disclosures: REAL-TIMI 63B was funded through a grant to Brigham and Women’s Hospital from

AstraZeneca

M. Bonaca reports research grant support through CPC Clinical Research from Amgen, AstraZeneca,

Bayer, Janssen, Merck, Pfizer.

D. Morrow reports; B. Bergmark reports; J. Lima reports; U. Hoffman reports; Y. Kato reports; M. Lu

reports; J. Kuder reports; S. Murphy reports;

R. George, A Vavere, Y Chang and S. Omar are employees of AstraZeneca. R. George and A. Vavere own

AstraZeneca stock.

Dr. Sabatine reports Research grant support through Brigham and Women’s Hospital from Amgen; Anthos

Therapeutics; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; Intarcia; Medicines Company; MedImmune;

Merck; Novartis; Pfizer; Quark Pharmaceuticals; consulting for Althera; Amgen; Anthos Therapeutics;

AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dr. Reddy’s Laboratories; Dyrnamix; IFM

Therapeutics; Intarcia; Medicines Company; MedImmune; Merck.

DISCLOSURES

• High density lipoprotein (HDL) plays a key role in reverse

cholesterol transport (RCT) & Sphingolipids on HDL may be

cardioprotective: preclinical STEMI models → infusions of ApoA1 /

HDL particles ↓ infarct size.(Circulation 2006;114:1403 & ATVB 2019; 39:915)

• Enhanced HDL function may ↓ infarct size and plaque in STEMI

• Lecithin-cholesterol acyltransferase (LCAT) is a rate-limiting

enzyme in RCT. MEDI6012 is a recombinant human LCAT that

increases HDL cholesterol.

RESULTS RESULTS

• 593 patients were randomized (Figure 3) with 97%

receiving >1 treatment dose and 1 lost to follow up.

RESULTS & CONCLUSION

METHODS

• REAL-TIMI 63B (NCT03578809) was a Phase 2B multinational,

randomized, placebo-controlled trial designed to evaluate the

cardio- and atheroprotective effects of MEDI6012 IV in patients

with STEMI undergoing primary PCI (Figure 2).

• Patients with STEMI, sx ≤ 6 hrs, planned for PCI were randomized

2:1 to MEDI6012 or placebo. Pts with shock, prior MI or CABG,

suspected non-atherothrombotic etiology, or would be unable to get

MRI or CT were excluded. A 2- and 6-dose regimen was

investigated, Figure 2.

• The primary outcome for cardioprotection was infarct size (IS) by

cardiac MR (10-12 weeks post-MI) in pts with TIMI flow grade

(TFG) 0-1 who receive at least two doses; 2º outcome for

atheroprotection was change from baseline in non-calcified

coronary plaque volume (NCPV) by coronary CTA (10-12 weeks).

CONCLUSION

Bonaca MP…Sabatine MS et. al. Eur Heart J Cardiovasc Pharmacother. 2021 Jan 25

593 Patients Randomized

(2:1 MEDI6012 vs. PBO in each arm)

MEDI6012

Cohort A

N=185

MEDI6012

Cohort B

N=202

Placebo

(Pooled)

N=206

Received IP

N=179 (97%)

Received IP

N=195 (97%)

Received IP

N=201 (98%)

Premature Drug

Discontinuation

N=15 (8%)

Premature Drug

Discontinuation

N=36 (19%)

Premature Drug

Discontinuation

N=34 (17%)

Withdrew Consent

N=5 (3%)

Withdrew Consent

N=0 (0%)

Withdrew Consent

N=5 (2%)

Lost to Follow up

N=1 (0.5%)

Lost to Follow up

N=0 (0%)

Lost to Follow up

N=0 (0%)

Figure 3 – Patient Disposition

Table 1 – Baseline Characteristics

Characteristic

MEDI6012

Cohort A

N=179

%

Placebo

Cohort A

N=90

%

P-Value

MEDI6012

Cohort B

N=195

%

Placebo

Cohort B

N=111

%

P-Value

Any SAE 20 12 0.13 22 23 0.84

Treatment

Emergent SAE19 12 0.16 21 22 0.90

ADA Positive 7 1 0.069 53 1 <0.001

Neutralizing

antibody0 0 na 1 0 0.92

Patients receiving at least 1 dose of IP; SAE – serious adverse event, ADA – anti-drug antibody

Table 2 – Safety Outcomes

• Overall, there was no difference in infarct size with

MEDI6012 vs placebo in the primary efficacy analysis

population (TFG 0-1) or in the entire population (TFG

0-3) who received at least two doses (Figure 4).

• Median non-calcified plaque volume decreased from baseline to day

70-84 in both groups (Figure 5).

• There was no difference in change in global non-calcified plaque

volume in all Cohort B patients (geometric mean ratio 0.96, 90% CI

0.83 – 1.10, p=0.31) or in those who received all doses (geometric

mean ratio 0.96, 90% CI 0.83 – 1.10, p=0.30)

• There were no differences in serious adverse events

(SAEs) or treatment emergent SAEs (Table 2).

• However, anti-drug antibodies were more frequent with

MEDI6012 with the greatest number in Cohort B

(53% vs. 1%, p<0.001).

Figure 2 –

Design

Figure 4 – Infarct Size 10-12 weeks After Myocardial Infarction

• The majority of patients had an anterior MI (70%) and had an

occluded artery (TFG 0-1, 65%). Median time from MEDI6012

administration to PCI was 8 minutes.

• Prior to randomization 4% were on statins which increased to

92.5% at discharge with median LDL-C (mg/dL) decreasing

from 142 to 71 at 1 month and 50% with an LDL-C ≤ 70 mg/dL

Figure 5 –Change from baseline in NCPV in Cohort B

Figure 1 –

Role of LCAT

• In a statin-naïve acute STEMI population newly

initiated on statin therapy, compared with placebo,

MEDI6012 given as 2 or 6 doses did not reduce infarct

size or non-calcified plaque in those administered 6

doses over 30 days.

• Was well tolerated but led to more anti-drug antibodies

Adapted from George RT, et al. JAHA, in press.

MEDI6012 PLACEBO