Slide 1: Detailed Preliminary Results of BETonMACE
TSX: RVX Detailed Preliminary Results of BETonMACE Strengthening Opportunities Through Positive Findings & Synergy November 18th, 2019
Slide 2: Forward Looking Statement
Forward Looking Statement This presentation may contain certain forward-looking information as defined under applicable Canadian securities legislation, that are not based on historical fact, including without limitation statements containing the words "believes", "anticipates", "plans", "intends",
Slide 3: Executive Summary (1)
Executive Summary (1) • Very Encouraging Cardiovascular Disease Efficacy Results – Narrow Miss on Primary: 18% Hazard Reduction (95% CI; 0.65-1.04) p=0.11 • 21% Hazard Reduction (95% CI; 0.62-1.01) p=0.06, excluding undetermined cause of death – Trending MACE Improvements on Multiple Endpoints (see
Slide 4: Executive Summary (2)
Executive Summary (2) • Early December Release of Cognitive Impairment Data – Embargoed until Clinical Trials on Alzheimer’s Disease conference (CTAD: Dec. 4 – 7, 2019) – Additional BETonMACE results to be presented; details to come • Significantly Enhanced Intellectual Property Position from Additi
Slide 5: Cardiovascular Disease Efficacy Results
Cardiovascular Disease Efficacy Results 5
Slide 6: Primary Endpoint
Cc ™™ RESVERLOGIX ™——__ Primary Endpoint
Slide 7: Primary Outcome Measure and Components
Primary Outcome Measure and Components Apabetalone Placebo Endpoint, n(%) HR (95% CI) Log-rank p-value (N=1212) (N=1206) MACE 125 149 0.82 (0.65-1.04) 0.11 Non-fatal MI 77 94 0.80 (0.59,1.08) 0.15* Stroke 17 17 1.01 (0.52, 1.98) 0.99* CV Death 45 55 0.81 (0.54, 1.19) 0.29* *Nominal p value 7
Slide 8: Primary Endpoint: Narrowly Defined MACE
Primary Endpoint: Narrowly Defined MACE Sustained throughout the duration of the trial 18% Hazard Reduction Early separation of curves No. at Risk Placebo 1206 1135 1102 937 641 383 108 Apabetalone 1212 1151 1114 950 672 397 107 8
Slide 9: Primary Endpoint Excluding Undetermined Deaths
Primary Endpoint Excluding Undetermined Deaths Sensitivity Analysis MACE defined as CV Death, non-fatal MI, stroke (excluding undetermined cause of death patients) 21% Hazard Reduction No. at Risk Placebo 1206 1135 1102 937 641 383 108 Apabetalone 1212 1151 1114 950 672 397 107 9 *excludes undetermi
Slide 10: Secondary and Other Prespecified Endpoints
Secondary and Other Prespecified Endpoints
Slide 11: Forest Plot Primer – Presented at AGM
Forest Plot Primer – Presented at AGM Hazard Ratio (95% CI) Primary End Point First occurrence of primary end point – Announced September 30th, 2019 – Marginal miss Key Secondary End Points Hazard ratios are First occurrence of primary end point or hospitalization for unstable indicative of the effe
Slide 12: Cardiovascular Endpoints
Cardiovascular Endpoints Apabetalone Placebo Primary End Point Hazard Ratio (95% CI) P Value no. of events (%) First occurrence of primary end point 125 (10.3%) 149 (12.4%) 0.82 [0.65, 1.04] 0.11 Key Secondary End Points First occurrence of primary end point or hospitalization for unstable 144 (11.9
Slide 13: Alternative Primary Outcome Measure and Components
Alternative Primary Outcome Measure and Components Apabetalone Placebo Endpoint, n(%) HR (95% CI) Log-rank p-value (N=1212) (N=1206) Non- MACE 126 163 0.76 (0.60, 0.95) 0.02* QC’d Non-fatal MI 77 94 0.80 (0.59,1.08) 0.15* CV Death 45 55 0.81 (0.54, 1.19) 0.29* Hosp. for CHF 29 48 0.59 (0.38, 0.94) 0
Slide 14: Alternative Primary Outcome Measure – Survival Curve
Alternative Primary Outcome Measure – Survival Curve 24% Hazard Reduction No. at Risk Placebo 1206 1135 1102 937 641 383 108 Apabetalone 1212 1151 1114 950 672 397 107 Source: RVX Internal Analysis – Non-QC’d 14
Slide 15: Hospitalization for Congestive Heart Failure (CHF)
Hospitalization for Congestive Heart Failure (CHF)
Slide 16: Key Secondary Endpoint – First Hospitalizations for CHF
Key Secondary Endpoint – First Hospitalizations for CHF 41% Hazard Reduction No. at Risk Placebo 1206 1135 1102 937 641 383 108 Apabetalone 1212 1151 1114 950 672 397 107 16
Slide 17: Exploratory Endpoint – First Hospitalizations for CHF or CV Death
Exploratory Endpoint – First Hospitalizations for CHF or CV Death 27% Hazard Reduction No. at Risk Placebo 1206 1135 1102 937 641 383 108 Apabetalone 1212 1151 1114 950 672 397 107 Source: RVX Internal Analysis – Non-QC’d 17
Slide 18: Prespecified Subgroups
Prespecified Subgroups 18
Slide 19: Endpoint Significance Reached in Prespecified Subgroups
Endpoint Significance Reached in Prespecified Subgroups 0.25 0.5 1 2 19 Apabetalone Better Placebo Better
Slide 20: Apabetalone Overperforms in Patients with Renal Impairment
Apabetalone Overperforms in Patients with Renal Impairment (Baseline eGFR Below 60 mL/min)
Slide 21: Apabetalone Improved CVD Outcomes in Impaired Renal Subgroup
Apabetalone Improved CVD Outcomes in Impaired Renal Subgroup Baseline eGFR Below 60 mL/min Endpoint Hazard Ratio (95% CI) P Value Narrowly Defined MACE eGFR < 60 mL/min 0.50 [0.26, 0.96] 0.03 eGFR ≥ 60 mL/min 0.94 [0.73, 1.22] Narrowly Defined MACE (Excl. Undetermined Death) eGFR < 60 mL/min* 0.47 [
Slide 22: Apabetalone Improved CVD Outcomes in Impaired Renal Subgroup
Apabetalone Improved CVD Outcomes in Impaired Renal Subgroup Baseline eGFR Below 60 mL/min Apabetalone Placebo Endpoint Subgroup No. of Patients No. of Events No. of Patients No. of Events Hazard Ratio p-value Narrowly Defined MACE 13 33 0.50 0.03 Narrowly Defined MACE (excluding undetermined cause
Slide 23: Renal Subgroup – Narrowly Defined MACE
Renal Subgroup – Narrowly Defined MACE MACE defined as CV death, non-fatal MI, and stroke Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 50% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 23
Slide 24: Renal Subgroup – Narrowly Defined MACE
Renal Subgroup – Narrowly Defined MACE MACE defined as CV death, non-fatal MI, and stroke excluding undetermined cause of death Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 53% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 24
Slide 25: Renal Subgroup – Broadly Defined MACE
Renal Subgroup – Broadly Defined MACE Broad MACE defined as CV death, non-fatal MI, stroke, and hospitalizations for CVD events Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 47% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 25
Slide 26: Renal Subgroup – CV Death or Non Fatal MI
Renal Subgroup – CV Death or Non Fatal MI Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 47% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 26
Slide 27: Renal Subgroup – Hospitalization for CHF
Renal Subgroup – Hospitalization for CHF Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 64% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 27
Slide 28: Renal Subgroup – Hospitalization for CVD Events
Renal Subgroup – Hospitalization for CVD Events Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 72% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 28
Slide 29: Renal Subgroup – Hospitalization for CHF or CV Death
Renal Subgroup – Hospitalization for CHF or CV Death Patients with eGFR < 60 at Baseline Patients with eGFR ≥ 60 at Baseline 50% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 29
Slide 30: Apabetalone Significantly Reduced MACE Risk in Low LDL Subgroup
Apabetalone Significantly Reduced MACE Risk in Low LDL Subgroup (Baseline LDL Below Median)
Slide 31: Apabetalone Reduced MACE Risk in Low LDL Subgroup
Apabetalone Reduced MACE Risk in Low LDL Subgroup Baseline LDL Below Median Endpoint Hazard Ratio (95% CI) P Value Narrowly Defined MACE LDL < Median 0.60 [0.42, 0.86] 0.02 LDL ≥ Median 1.06 [0.77, 1.46] Narrowly Defined MACE (Excl. Undetermined Death) LDL < Median* 0.60 [0.42, 0.87] 0.01 LDL ≥ Medi
Slide 32: Apabetalone Reduced MACE Risk in Low LDL Subgroup
Apabetalone Reduced MACE Risk in Low LDL Subgroup Baseline LDL Below Median Apabetalone Placebo Endpoint Subgroup No. of Patients No. of Events No. of Patients No. of Events Hazard Ratio p-value Narrowly Defined MACE 48 78 0.60 0.02 Narrowly Defined MACE (excluding undertermined cause of death) 44 7
Slide 33: LDL Subgroup – Narrowly Defined MACE
LDL Subgroup – Narrowly Defined MACE MACE defined as CV death, non-fatal MI, and stroke Patients with LDL < Median Patients with LDL ≥ Median 40% Hazard Reduction Source: RVX Internal Analysis – Non-QC’d 33
Slide 34: Surprise Finding! Potential Synergy with New Generation of Diabetes Drugs
Surprise Finding! Potential Synergy with New Generation of Diabetes Drugs 34
Slide 35: Baseline Characteristics: Cardiovascular and Diabetes Medications
Baseline Characteristics: Cardiovascular and Diabetes Medications Cardiovascular and Diabetes Medications Apabetalone (N=1212) Placebo (N=1206) Atorvastatin 621 (51.2) 620 (51.4) Rosuvastatin 591 (48.8) 586 (48.6) High intensity statin 1089 (89.9) 1092 (90.5) ACE inhibitors/ angiotensin II blockers
Slide 36: Comparison to Other Major Therapeutic Classes
Comparison to Other Major Therapeutic Classes Impact on MACE in Patients with Type 2 Diabetes Therapeutic Trial Name # Patients Effect on MACE Apabetalone BETonMACE 2,425 -18%* Apabetalone + SGLT2i BETonMACE 298 -60%** DDP-4 inhibitors1,2 CAROLINA 6,042 no effect Insulin3 ORIGIN 12,537 no effect SGL
Slide 37: Apabetalone Reduces MACE Beyond Benefit of New Diabetes Drugs
Apabetalone Reduces MACE Beyond Benefit of New Diabetes Drugs p = 0.05 59% RRR p = 0.04 Event Rate in Patients Taking SGLT2i (%) 66% RRR 12% 10% 10% 8% 8% Apabetalone 6% Placebo + Top Standard of Care 4% 4% 3% 2% 0% Primary MACE Broad MACE Patent Filed, No. of Events 4 12 6 15 Additional Patents Pat
Slide 38: Apabetalone and Empagliflozin (Jardiance)
Apabetalone and Empagliflozin (Jardiance) 66% Hazard Reduction Note: Based on Patients who were taking Empagliflozin for at least 30 days during the trial, and prior to their MACE No. at Risk Narrowly Defined MACE: Apabetalone 113 108 67 13 - CV Death - Non Fatal MI Placebo 115 104 59 18 - Stroke So
Slide 39: Market Growth of SGLT2 Inhibitors
Market Growth of SGLT2 Inhibitors Global Market Growth Jardiance Market Growth >USD 7.5Bn* USD 12.7Bn 2019-2024 CAGR: 15.78% USD 2.5Bn Source: *RVX Internal Estimate 39
Slide 40: New Findings Presented at CtAD Symposium – December 5th, 2019
New Findings Presented at CtAD Symposium – December 5th, 2019 Epigenetics and the BET-system in vascular dementia, Alzheimer’s disease and mixed dementia – the problem and potential remedies Chairman: Bengt Winblad, Karolinska Institutet, Sweden • Dementias, who and how to treat and by what specialt
Slide 41: Summary
Summary • The first approach at confirming a Primary endpoint was narrowly missed with consistent positive trend in key secondary endpoints – Clinically relevant MACE reductions – Lower than anticipated placebo event rate (5.8/100 pt yrs) due to new drugs entering today’s market – Apabetalone furthe
Slide 42: Near Term Commercialization Steps
Near Term Commercialization Steps In the near term we will continue our five point approach to progressing our corporate commercial value. This approach involves aggressive exploratory development of the following: • Breakthrough Therapy status filings, both FDA and EMA, over the next 90-120 days •
Slide 43: Detailed Preliminary Results of BETonMACE
TSX: RVX Detailed Preliminary Results of BETonMACE Strengthening Opportunities Through Positive Findings & Synergy November 18th, 2019
Slide 44: Appendix
Appendix 44
Slide 45: Study Design
Cc ™™ RESVERLOGIX ™——__ Study Design
Slide 46: BETonMACE Study Parameters
BETonMACE Study Parameters Primary Objective Primary Endpoint • To evaluate if treatment with apabetalone as • Time to first occurrence of adjudication-confirmed triple compared to placebo increases time to the first MACE occurrence of triple MACE. Triple MACE is defined as a single composite endpoi
Slide 47: BETonMACE a Global, Multi-centered Clinical Trial
BETonMACE a Global, Multi-centered Clinical Trial GERMANY NETHERLANDS POLAND RUSSIA BELGIUM SLOVAKIA UNITED STATES CROATIA BULGARIA TAIWAN SERBIA ISRAEL MEXICO HUNGARY ARGENTINA With 14 approved countries around the world, BETonMACE included patients randomized at 220 different sites 47
Slide 48: BETonMACE Study Design
BETonMACE Study Design Screening Follow-Up Treatment Period Period Period 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 atorvastatin or Placebo Arm: 20-40 mg matching placebo rosuvastatin + standard of care 1-2 weeks Median 1
Slide 49: BETonMACE: Patient Disposition
BETonMACE: Patient Disposition Completed n = 1,083 Placebo (89.8%) n = 1,206 Reason for non-completion Randomized in error: 4 Adverse Event 3 Withdrew Consent 24 Screened Randomized Lost to Follow-up 13 n = 3,937 n = 2,425 Died 72 Other 15 Screen Failures n=1,512 HDL-C 998 Bilirubin 136 Apabetalone
Slide 50: Baseline Characteristics
Cc ™™ RESVERLOGIX ™——__ Baseline Characteristics
Slide 51: Baseline Characteristics, Prior Medical and Index ACS History
Baseline Characteristics, Prior Medical and Index ACS History 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 cor
Slide 52: Baseline Characteristics: Cardiovascular and Diabetes Medications
Baseline Characteristics: Cardiovascular and Diabetes Medications Cardiovascular and Diabetes Medications Apabetalone Placebo (%) (N=1212) (N=1206) Atorvastatin 51.2 51.4 Rosuvastatin 48.8 48.6 High intensity statin 89.9 90.5 ACE inhibitors/ angiotensin II blockers 92.3 92.0 Beta blockers 91.0 90.2
Slide 53: BETonMACE: Baseline Laboratory Parameters
BETonMACE: Baseline Laboratory Parameters Apabetalone Placebo Baseline Laboratory Parameters (n=1212) (n=1206) Serum glucose, mg/dL 152.2 ± 60.7 150.7 ± 62.5 eGFR, ml/min/1.73m2 † 104.9 ± 39.3 101.7 ± 38.6 Total cholesterol, mg/dL 134.8 ± 35.3 136.8 ± 38.2 LDL cholesterol, mg/dL 69.7 ± 29.8 70.9 ± 3
Slide 54: Biochemical Parameters at 100 weeks and changes from baseline
Biochemical Parameters at 100 weeks and changes from baseline Biochemical parameters Apabetalone (N=1212) Placebo (N=1206) P value HDL cholesterol, mg/dL 38.1 (+16.4%) 36.4 (+10.4%) 0.001 LDL cholesterol, mg/dL 69.6 (+11.5%) 72 (+14.9%) 0.35 eGFR, ml/min/1.73m2 104.3 (-0.4) 105.2 (+2.1) 0.03 Alkalin
Slide 55: Safety Results
Cc ™™ RESVERLOGIX ™——__ Safety Results
Slide 56: Top Line Data: Safety
Top Line Data: Safety Variable Apabetalone (N=1212) Placebo (N= 1207) Adverse events - n (%) Patients with at least one adverse event 830 (68.5) 820 (67.9) Adverse event leading to discontinuation 114 (9.4) 69 (5.7) Serious adverse events – n (%) Patients with at least one SAE 354 (29.2) 339 (28.1)
Slide 57: Top Line Data: Safety
Top Line Data: Safety Adverse Events, System Organ Classes with at least one AE > 2% incidence either group* System Organ Class, Adverse Event Apabetalone (N=1212) Placebo (N= 1207) Infections and Infestations 291 (20.6) 296 (19.3) Nasopharyngitis 46 (3.8) 56 (4.6) Urinary tract infection 58 (4.8) 4
Slide 58: Background Slides
Cc ™™ RESVERLOGIX ™——__ Background Slides
Slide 59: Apabetalone Mechanism of Action: Transcriptional Regulation
BETonMACE: Background & Rationale Apabetalone Mechanism of Action DNA Genome Editing Altering the sequence of DNA itself and then reintroducing modified genes into the body There are currently no FDA-approved Transcription therapies based on gene editing Transcriptional Regulation RNA Adjusting the
Slide 60: BETonMACE: Background & Rationale
BETonMACE: Background & Rationale Epigenetics Regulate Gene Activity Chromosome Chromatin Fiber Nucleosome Writers • Epigenetics refers to modifications to chromatin that regulate it’s activity Histone Tail • Transcription is regulated by addition, removal, or Erasers recognition of these modificati
Slide 61: Apabetalone Mechanism of Action
Apabetalone Mechanism of Action BET P-TEFb Protein TF Pol II Transcription Activated Apabetalone Treatment TF Transcription 61 Inhibited
Slide 62: BETi Impacts the Pathways that Drive CV and Kidney Disease
BETi Impacts the Pathways that Drive CV 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 Vascular recruitment and plaque destabilization Wasiak et
Slide 63: Addressing Critical Unmet Needs
Addressing Critical Unmet Needs Cardiovascular Disease Diabetes Epidemic Still the number one killer of both males and females and costs the US healthcare system over $500B per year Current CVD Therapies - 30% Statins are the top medication used to treat CVD 60% Despite maximized use, Opportunity cu