Resverlogix Corp. · TSX:RVX
Resverlogix — ERA-EDTA 2020
25 slides from Resverlogix's conference presentation, Jun 9, 2020
Slide 1: Effects of the BET-Inhibitor Apabetalone on Cardiovascular Events in Type 2 Diabetes and ACS
TO001 - Free Communication Session S 38 Cardiovascular and renal protection - effects of SGLT2 inhibitors and GLP-1 receptor agonists in people with CKD and type 2 diabetes EFFECTS OF THE BET-INHIBITOR APABETALONE ON CARDIOVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND ACUTE CORONARY
Slide 2: BETonMACE Committees
BETonMACE Committees Clinical Steering Committee Contributions from 13 countries at 195 sites: K. K. Ray S. J. Nicholls H. Ginsberg K. Kalantar- Country National Lead (Chair) Zadeh Investigator(s) P. Toth K. Buhr (Independent Statistician) G. G. Schwartz Argentina A. Lorenzatti, M. Vico Non- Voting
Slide 3: BETonMACE Background & Rationale
BETonMACE Background & Rationale • Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Chromosome Chromatin Fiber Nucleosome Writers • Epigenetics refers to modifications to chromatin that regulate its activity Histone Tail • Transcription is regulated by Erasers
Slide 4: BET Inhibition by Apabetalone
BET Inhibition by Apabetalone BET Protein Recruits Apabetalone Apabetalone Gene Transcription Gene Binds Additional Inhibits Acetylated Transcription Transcription Treatment BET Protein Complex Transcription Activated Disrupted Inhibited Histone Factors Activity BET P-TEFb Protein Pol II TF Apabetal
Slide 5: BET Protein Inhibition with Apabetalone Favorably Impacts Pathways in Cardiovascular and Kidney Disease
BET Protein Inhibition with Apabetalone Favorably Impacts Pathways Implicated in Cardiovascular and Kidney Disease Apabetalone reduces the Treatment with apabetalone expression of multiple reduces mediators that drive components of the complement endothelial activation, monocyte cascade Complement V
Slide 6: Phase 2 Trials Suggest Potential CV Benefit with Apabetalone
Phase 2 Trials Suggest Potential CV Benefit with Apabetalone MACE Incidence in Total Patient Group MACE Incidence by Presence of Diabetes • MACE (major adverse cardiovascular events) including death, myocardial infarction, coronary revascularization, and hospitalization for cardiovascular causes). •
Slide 7: BETonMACE Inclusion and Exclusion Criteria
BETonMACE Inclusion and Exclusion Criteria Key Inclusion Criteria Key Exclusion Criteria • Type 2 Diabetes Mellitus • Planned further coronary revascularization at time of screening visit – HbA1c >6.5% or history of diabetes medication use • Previous or current diagnosis of severe heart failure (New
Slide 8: Study Endpoints
BETonMACE Study Endpoints • Primary Endpoint – Time to first occurrence of CV death or non-fatal MI or stroke • Pre-specified sensitivity analysis excluding deaths of undetermined cause from endpoint • Key Secondary Endpoints – Time to first 4-part MACE: primary endpoint + hospitalization for CV eve
Slide 9: Statistical Assumptions
Statistical Assumptions • A sample size of 2,400 randomized subjects was predicted to yield 80% power for the primary analysis under the following assumptions: – Total number of events: 250 – 2-sided type 1 error rate: α=5% – 10.5% event rate in the placebo arm at 18 months – 30% relative risk reduc
Slide 10: Study Design
BETonMACE Study Design Screening Follow-Up Period Treatment Period Period Placebo n = 1,206 Active Arm: apabetalone 100 mg b.i.d + standard of care 1:1 Randomization End of Treatment N=2425 Statin Run-in 40-80 mg Placebo Arm: atorvastatin or matching placebo 20-40 mg + rosuvastatin standard of care
Slide 11: Baseline Characteristics
BETonMACE Baseline Characteristics Apabetalone Placebo (n=1212) (n=1206) Median age, yrs 62.0 62.0 Male sex- % 74.8 74.0 Body mass index, kg/m2 30.2 30.3 Hypertension - % 89.4 87.8 eGFR Mean ± SD, mL/min/1.73m2 104.9 101.7 Duration of diabetes – yrs 8.4 8.7 Index acute coronary syndrome – % Myocardi
Slide 12: Primary Efficacy Endpoint
BETonMACE Primary Efficacy Endpoint • CV Death, Non-Fatal MI and Stroke (Total number of events = 274) Median follow-up of 26.5 months Primary Endpoint: Placebo = 12.4% Apabetalone = 10.3% Ray KK, Nicholls SJ, Buhr KA, Ginsberg HN, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Toth PP, Wong N, Sween
Slide 13: Prespecified Primary End Point Sensitivity Analysis Excluding Deaths of Undetermined Cause
Prespecified Primary End Point Sensitivity Analysis Excluding Deaths of Undetermined Cause CV Death (excluding death of undetermined cause), non-fatal MI, or stroke Ray KK, Nicholls SJ, Buhr KA, Ginsberg HN, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Toth PP, Wong N, Sweeney M, Schwartz GG, Inves
Slide 14: Primary Endpoint in Prespecified Subgroups
Primary Endpoint in Prespecified Subgroups Subgroup Apabetalone Placebo Hazard Ratio (95% CI) P Value no. of events/patients (%) Sex Female 23/305 (7.5%) 32/313 (10.2%) 0.79 [0.46, 1.36] 0.70 Male 102/907 (11.2%) 117/893 (13.1%) 0.84 [0.64, 1.10] Statin Rosuvastatin 62/591 (10.5%) 71/586 (12.1%) 0.8
Slide 15: BETonMACE Summary
BETonMACE Summary • Apabetalone did not have a significant effect on incidence of the primary endpoint (CV death, non-fatal MI or stroke) – Lower than anticipated event rate in placebo group (9.7% observed, 10.5% predicted at 18 months) – Study was powered on a 30% reduction in risk of primary endpo
Slide 16: Baseline Demographic Data of the CKD Subgroup
Baseline Demographic Data of the CKD Subgroup eGFR ≥ 60 eGFR < 60 P-value Placebo Apabetalone (CKD Stage 3-4) (eGFR <60) (eGFR <60) N N=2,125 N=288 N=164 N=124 Age (yr) 61 (54-67) 71 (65-76) <0.001 70.6 (7.9) 69.8 (7.9) Sex Male 1,628 (76.6) 168 (58.3) <0.001 91 (56%) 76 (63%) Race White 1,879 (88.4
Slide 17: CKD Group - Results
BETonMACE CKD Group - Results • CKD vs. non-CKD patients were older (71 vs. 61 years, P<0.001) with more females (42% vs. 23%, P<0.001) and self-identified non-white patients (18% vs. 12%, P<0.001). • CKD patients had a longer mean duration of diabetes (11.3 vs. 8.2 years, P<0.001) and were less lik
Slide 18: Hazard Ratios for Composite and Component Events by CKD Group
Hazard Ratios (HR) for Composite and Component Events by CKD Group eGFR < 60 eGFR ≥ 60 Placebo Apabetalone HR Placebo Apabetalone HR Evt/n (%) Evt/n (%) (95% CI) Evt/n (%) Evt/n (%) (95% CI) MACE 35/164 (21.3) 13/124 (10.5) 0.50 [0.26,0.96] 114/1041 (11.0) 112/1084 (10.3) 0.94 [0.73,1.22] MACE + HCH
Slide 19: BET on MACE CKD group - Results
BET on MACE CKD group - Results • Under placebo, CKD patients exhibited higher CVD prevalence, i.e. – 35/164 (21.3%) vs.114/1041 (11.0%) (HR=2.40, 95% CI [1.67, 3.44]) for ischemic CVD/MACE – 14/164 (8.5%) vs. 34/1041 (3.3%) (HR=3.19, 95% CI [1.66,6.12], P<0.001) for HCHF. • Under apabetalone, CKD g
Slide 20: Kaplan-Meier Estimates by CKD/Non-CKD for MACE
Kaplan-Meier Estimates by CKD/Non-CKD for MACE Apabetalone Compared to Placebo MACE: Composite of CV death, non-fatal MI and stroke CKD Group (eGFR < 60) Apabetalone CKD Group (eGFR<60) Placebo Placebo Events - 35/164 (21.3%) Apabetalone Events - 13/124 (10.5%) Hazard Ratio = 0.50 [95%CIs: 0.26,0.96
Slide 21: Kaplan-Meier Estimates: Hospitalizations for Congestive Heart Failure
Kaplan-Meier Estimates by CKD/Non-CKD for MACE Apabetalone Compared to Placebo Hospitalizations for Congestive Heart Failure (HCHF) CKD Group (eGFR < 60) Apabetalone CKD Group (eGFR<60) Placebo Non-CKD Group (eGFR ≥ 60) Placebo Events - 14/164 (8.5%) Apabetalone Placebo Apabetalone Events - 3/124 (2
Slide 22: Kaplan-Meier Estimates: Composite MACE and HCHF
Kaplan-Meier Estimates by CKD/Non-CKD for MACE Apabetalone Compared to Placebo Composite of CV death, non-fatal MI, stroke and hospitalizations for Congestive Heart Failure (HCHF) CKD Group (eGFR < 60) Apabetalone Placebo CKD Group (eGFR<60) Placebo Events - 41/164 (25.0%) Apabetalone Events - 3/124
Slide 23: Safety of Apabetalone in CKD Patients
Safety of Apabetalone in CKD Patients • Apabetalone was well tolerated with similar number a subjects in both groups experiencing AE’s [119 (72.6%) and 88 (71.0%) in the placebo and apabetalone groups, respectively]. • A significantly lower number of subjects in the apabetalone group had serious adv
Slide 24: Limitations of the CKD Study
Limitations of the CKD Study • Relatively small portion of the parent trial: 288 CKD patients out of 2,425 • Less balanced randomization among 288 CKD patients • Limited to CKD Stages 3a and 3b (given exclusion criteria of eGFR<30 ml/min/1.73) • Lack of urine data: No albuminuria data were collected
Slide 25: Conclusions
Conclusions • This is the first cardiovascular outcomes trial assessing the potential of epigenetic modification with BET protein inhibition “apabetalone” and shows promise • In this Phase III RCT, diabetic CKD patients with a recent acute coronary syndrome (ACS) exhibited a high prevalence of CVD (