RVX-208 Update, October 6 th , 2014 WWW.RESVERLOGIX.COM Todays - - PowerPoint PPT Presentation

WWW.RESVERLOGIX.COM

RVX-208 Update, October 6th, 2014

Todays Presentation Points

• 1. Annual Milestone Review
• 2. Ongoing Biomarker & Genetic

Pathway Analysis

• Step 1: Analysis of all clinical data
• Step 2: Further delineate mechanisms
• Step 3: Design & launch next clinical trial
• 3. BET Bromodomain Opportunities
• 4. Milestones & Inflection Points

Safe Harbor Statement. This presentation contains forward-looking statements that involve risks and uncertainties,

which may cause actual results to differ materially from the statements made. For this purpose, any statements that are contained herein that are not statements of historical fact may be deemed to be forward- looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "plans," "intends," "will," "should," "expects," "projects," and similar expressions are intended to identify forward- looking statements. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause actual results, future circumstances, or events to differ materially from those projected in the forward-looking statements. These risks include, but are not limited to, those associated with the success of research and development programs, the regulatory approval process, competition, securing and maintaining corporate alliances, market acceptance of the Company's products, the availability of government and insurance reimbursements for the Company's products, the strength of intellectual property, financing capability, the potential dilutive effects of any financing, reliance on subcontractors and key personnel. The forward- looking statements are made as of the date hereof, and the Company disclaims any intention and has no obligation or responsibility, except as required by law, to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise. CONTACT: Donald J. McCaffrey

300, 4820 Richard Road SW, Calgary, Alberta T3E-6L1 Tel: (403) 254-9252, Fax:(403) 256-8495, http://www.resverlogix.com/

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2013

Oct Dec Feb 2014 Apr Jun Aug Oct

2014

Today Annual General Meeting 2014

Oct 8

European Society of Cardiology presentation reports 77% MACE reduction in Diabetes Mellitus patients

Sep 2

RVX secures $30MM financing

Jul 3

RVX closes a $2.3MM insider led private placement

Jun 11

Nature Publishing Group's SciBex reports RVX-208 is an emerging first-in-class BET inhibitor

May 21

RVX-208 completes Australian Diabetes trial

Mar 31

RVX-208 gets European Patent approval

Mar 17

Combined trial data confirm MACE reduction

Jan 15

PLOS-ONE Journal publishes RVX-208 ApoA-I enhancer & BET Bromodomain Antagonist

Jan 2

Australia Diabetes Trial fully enrolled

Dec 23

RVX-208 annouced as effective in Atheroma regression in High Risk CVD patients.

Nov 4

Structural Genome Consortium reports RVX-208, 1st Selective BET inhibitor

Oct 8

Annual General Meeting - 2013

Oct 3

Annual Milestone Review

Recent RVX-208 Publications

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Ongoing Biomarker & Genetic Pathway Analysis

RVX Internal Analysis 6

“I’m searching for my keys here because this is where the light is located.”

Thinking Outside the Box to Expand Our World Leading Knowledge in Reader Epigenetics

• Step 1 – Analyze all clinical data

– Australia Diabetes Trial – ongoing, publication & oral presentations expected mid 2015 – SUSTAIN & ASSURE combined data analysis

• Step 2 – Further delineate mechanisms driving MACE reduction

– Microarray analysis of relevant cell types – Analysis of blood biomarker data to develop algorithms for identification of patients likely to respond to treatment – Proteomic analysis of archived clinical samples (from multiple trials) to investigate and possibly identify novel RVX-208 responsive biomarkers

• Step 3 –Design and launch the next clinical trial

– Utilize knowledge gained in steps 1 & 2 to enhance enrollment criteria – Hire a high caliber Chief Medical Officer – Plan additional smaller, less expensive trials for value creation purposes – Confirm clinical sites and PI’s

Critical steps required to maximize probability of success of future trials

RVX Internal Analysis 7

Step 1: Determined that RVX-208 lowered MACE by 77% in CVD patients with diabetes mellitus

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Source: RVX data on file – ASSURE and SUSTAIN Safety Population. Log-Rank test for between group comparison

77% RRR p = 0.01 diabetes mellitus 0.0% 3.0% 6.0% 9.0% 12.0% 15.0% 18.0% 21.0% 30 60 90 120 150 180 210 Cummulative Event Rate (%) Days Since Randomization RVX-208 (N=127) Placebo (N=65) 55% RRR p = 0.02

RVX-208, DM pts (n=127) Placebo, DM pts (n=65) RVX-208 (n=331) Placebo (n=168)

Additional knowledge gained from clinical data analysis

Biomarker

Placebo (n=166) RVX-208 (n=331)

Percent Change p value vs. baseline Percent Change p value vs. baseline

HDL Cholesterol, (mg/dL)

0.0 0.59 +7.69 <0.0001

ApoA-I, (mg/dL)

+3.8 0.0003 +10.3 <0.0001

Total HDL particles, (mol/L)

+0.40 0.61 +6.51 <0.0001

HDL particle size, (nm)

0.0 0.30 +1.16 <0.0001

Large HDL particles, (mol/L)

+4.11 0.02 +30.71 <0.0001

hsCRP, (mg/L)

• 22.4

0.0002

• 28.4

<0.0001

Alkaline phosphatase, (U/L)

• 3.23

0.03

• 11.0

<0.0001

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Results expressed as median percentage change from baseline

Source: RVX data on file – ASSURE and SUSTAIN mITT Population. 2-sided Van Elteren test of RVX-208 vs placebo, stratified by study

RVX Internal Analysis

• Reverse Cholesterol transport markers measured: ApoA-I, ApoB, cholesterol, HDLc, HDLc (total), HDL

particles (total), HDL size, IDL particles, large HDL particles, large LDL particles, large VLDL & chylomicron

• particles. LDLc, LDL particles (total), LDL size, medium HDL particles, medium VLDL particles, non-HDL

cholesterol, small HDL particles, small LDL particles, small VLDL particles, triglycerides, triglycerides (total), VLDL & chylomicron particles, VLDL & chylomicron triglyceride, VLDL size

• Inflammatory markers measured: hsCRP, IL-6
• Metabolic markers measured: glucose, HbA1c
• Chemistry markers measured: albumin, alkaline phosphatase blood urea nitrogen, calcium, chloride,

creatinine, creatine kinase, lactate dehydrogenase, phosphate, potassium, total protein, sodium, granular casts‡, hyaline casts‡, ketones‡, specific gravity‡, pH‡, waxy casts‡, triphosphate crystals‡

• Liver safety markers measured: ALT, AST, total bilirubin, direct bilirubin, GGT
• Atheroma markers measured: PAV†, TAV†, 10MTAVMX†
• Hematology markers measured: hematocrit, hemoglobin, mean corpuscular volume, percent basophils,

percent eosinophils, percent lymphocytes, percent monocytes, percent neutrophils, platelets, RBCs, WBCs, RBC casts ‡

• Vital Signs measured: diastolic BP, systolic BP, weight

SUSTAIN & ASSURE: Pooled Analysis of Biomarkers

RVX 10

ASSURE only† SUSTAIN only‡

ASSURE & SUSTAIN: Biomarker Rank

Rank

Biomarker RVX-208 (n=331) Placebo (n=166)

p value vs placebo Change from baseline (%▲) p value vs. baseline Change from baseline (%▲) p value vs. baseline 1

Alkaline phosphatase (U/L)

• 8.0 (-11.0)

<0.0001

• 2.0 (-3.2)

0.03

<0.0001

2

HDL-C (mg/dL)

+3.0 (+7.69) <0.0001 0.0 (0.0) 0.59

0.0003

3

ApoA-I (mg/dL)

+12.3 (+10.3) <0.0001 +4.8 (+3.8) 0.0003

0.005

4

Glucose† (mmol/L)

• 0.3 (-4.69)

0.25 +0.9 (+10.3) 0.06

0.008

5

Large HDL particles (mol/L)

+0.8 (+30.7) <0.0001 +0.1 (+4.11) 0.02

0.03

6

HDL particle size (nm)

+0.1 (+1.16) <0.0001 0.0 (0.0) 0.30

0.049

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Total HDL particles (mol/L)

+1.9 (+6.51) <0.0001 +0.1 (+0.40) 0.61

0.07

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hsCRP (mg/L)

• 0.36 (-28.4)

<0.0001

• 0.33 (-22.4)

0.0002

0.67

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Results expressed as median percentage change from baseline † Significance vs placebo observed in diabetes population with baseline HDL<40 mg/dL

Source: RVX data on file – ASSURE and SUSTAIN mITT Population. 2-sided Van Elteren test of RVX-208 vs placebo, stratified by study

Ranking based on statistical significance vs placebo

RVX Internal Analysis

• Recent studies have shown higher levels of serum ALP associate with increased mortality

in the general population and in survivors of myocardial infarction, Tonelli M, et al. 2009 Circulation 2009;120(18):1784-1792

• More compelling data in those with chronic kidney disease, Beddhu S, et al., 2009. Clin J

Am Soc Nephrol. 2009;4(11)1805-1810, Blayney MJ, et al 2008 Kidney Int. 2008;75(5):655-663, Kalantar-Zadeh K, et al., 2006 Am J Kidney Dis.2006;48(1):59-68. Lee GH et al., 2007 J Ren Nutr. 2007;17(1):38-44, Regidor DL, et al 2008 J Am Soc

• Nephrol. 2008;19(11):2193-2203.
• The highest quartile of serum ALP associate with higher prevalence of M.I., stroke, CHF,

and DM. High serum ALP levels strongly associate with increased prevalence of metabolic syndrome and subsequent increase in all-cause mortality (retrospective observational study of 15,234 adult participants in the NHANES III. Krishnamurthy VR et al., 2011 The American Journal of Medicine (2011) 124, 566.e1-566.e7)

• Serum ALP may have a critical role in calcification and has been used as a marker and

therapeutic target of vascular calcification, BAP (bone derived ALP) has been proposed to link insulin resistance with vascular calcification, cardiovascular diseases, or even mortality Cheung CL et al., 2013 J Clin Endocrinol Metab. 2013 Sep;98(9):3856-63.

ALP a Novel Biomarker Linked to Mortality, CVD and DM.

12 RVX

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Step 2 - Delineating the Mechanisms RVX-208 affects gene pathways & networks

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Purple- interaction with Asn140 deep in the pocket Red – interaction with the WPF shelf Green – interactions in the ZA channel Blue – interaction in the “peptide” channel

WPF shelf

I-BET726 (GSK)

Further elucidating mechanisms driving MACE reduction using co-crystallography

Abbvi e RVX-208 MS417 I-BET762 (GSK) JQ1 3,5-dimethylisoxazole analogues (SGC) I-BET151 (GSK) PFI- 1(Pfizer)

ZA channel

BET Bromodomain acts as a Master Regulator of important gene networks.

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Red: High signal intensity; White: Medium signal intensity; Blue: Low signal intensity

Down regulation observed at 48 hours A replica example of what a gene pathway cascade may look like for demonstrative purposes.

• 3

+3 Fold Change

Each line of 6 above represents a single gene

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BET Inhibition can now explain why MACE attained a 77% reduction.

• 1. Alkaline phosphatase
• 2. Lipid parameters
• 3. Glucose
• 4. Weight loss
• 5. Renal function
• 6. Thrombosis

BET Inhibition

Reverse Cholesterol Transport

Vascular Inflammation Thrombosis

Metabolic Increased ApoA-I is only part of the rationale underlying the observed 77% reduction in MACE. Recently identified BET-inhibition mechanisms also confirm contribution to the MACE reduction.

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Step 3 - Clinical Planning

Re-MACE Trial Planning in Progress

RVX Internal Analysis 18

1. Main objective: To confirm MACE reduction by RVX-208 as seen in SUSTAIN and ASSURE and expand safety assessment in a phase 2-3 study. 2. Patient population: Those with diabetes mellitus (DM), established CAD, HDL-c < 40 mg/dL who are 15 days - 6 months post event. 3. Treatment: RVX-208 100mg b.i.d. vs. placebo added to standard of care therapy including any standard of care rosuvastatin randomized 1:1 to an average of 18 months. 4. Location and Size: 40+ European sites, adaptive trial with 800 patient minimum. 5. Primary endpoint: Lowering of serum ALP of RVX-208 vs. placebo. 6. Main secondary endpoint: A reduction in MACE as defined by;

• Death, including suddenly with no other reasonable explanation,
• Ischemic stroke,
• Non-fatal MI,
• Hospitalization for worsening of angina,
• Revascularization with evidence of progressive anatomy or symptoms
• Congestive heart failure (ischemic etiology)

• Re-MACE, a phase 2/3 Study?

– If significant effects on MACE are shown in Re-MACE a single phase 3 study showing MACE reduction by p<0.05 will suffice for registration – Faster and less expensive route

• Acceptable MACE definition important:

– Death - including sudden death with no other reasonable explanation, non-fatal Myocardial Infarction, ischemic stroke, hospitalization for CVD events including angina, Revascularization procedures, congestive heart failure, – A third party adjudication committee has been planned

• First registration goal in the US or Europe?
• Existing FDA Guidance allows for such a program

Re-MACE Regulatory Considerations - Ongoing

RVX Internal Analysis 19

RVX Internal Analysis 20

2012

2012 2013 2014 2015 2016 2017 2018 2019 2020

2020

Today

Estimated Drug Approval

2020

NDA - FDA or EMA submission

2018

Phase 3 Diabetes MACE trial - 2,500 patients - $45MM

2016

Phase 2/3 Diabetes MACE trial - 800 patients- $15MM

2015

ASSURE Phase 2b trial results

2013 2015 - 2017

Phase 2/3 Trial

2016 - 2018

Phase 3 Trial

2018 - 2020

FDA/NDA

Re-MACE Phase 2/3 Design Model

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Examples of Expanded BET Bromodomain Opportunities

RVX-208 Additional Clinical Plan Potentials

Source: RVX Internal Estimates

• 100-140 Patients $3-4MM

Chronic Kidney Disease Phase 2b

• 150-200 Patients $3-4MM

Phase 2 PAD

• 60 patients $5.6MM – NIH funding pending

Phase 2 Alzheimer’s

Kidney Disease Progression - EXAMPLE

Type 2 Diabetes Diabetic Nephropathy Chronic Kidney Disease Dialysis End Stage Renal disease

Risk of CVD and Death Type 2 diabetes mellitus patients are at an increased risk for path of kidney failure

Existing RVX-208 Chronic Kidney Disease Data

• In patients with eGFR < 60mL/min/1.73m2, there is a significant increase in eGFR

compared to baseline (P<0.02) from pooled SUSTAIN and ASSURE data (n=48)

• 8
• 6
• 4
• 2

2 4 6 RVX208 Placebo Percent Change in eGFR vs baseline

*

N= 35 N= 13

77.8 55.9 45.4 30.4 8.55 19.5

30 60 90 RVX-208 (N=280) Placebo (N=152) Cincalcet (N=507) Proportion of Patients (%) Patients with any reduction (%) Patients with a ≥ 20% reduction (%)

Reductions in ALP; Comparison to Cinacalcet Phase III post-hoc data

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Week 12/14

Source: RVX data on file – ASSURE and SUSTAIN mITT Population; Belozeroff et al. 2009

• Patients with baseline serum calcium ≥ 8.4mg/dL (2.1mmol/L)
• Median Baseline measurements: RVX-208 = 71.0 U/L Placebo = 77.5 U/L Cinacalcet = 111 U/L

RVX Internal Analysis 26

Future Inflection Points and Milestones.

2014

Oct Nov Dec Jan 2015 Feb Mar Apr May Jun Jul Aug Sep

2015

Today

RVX-208 Data presented at the European Society of Cardiology American Diabetes Association Australia Trial data presentation RVX-208 data presentation at the American College of Cardiologists Publication

• f the

SUSTAIN and ASSURE studies Targeted first patient in Re- MACE trial NIH Alzheimer's funding requests made public NIH Alzheimer's review scores Announcement

• f Top Notch

Chief Medical Officer REMACE Trial Commence RVX-208 Alzheimer’s Trial - If NIH funded Second BET trial

RVX-208

• 1. RVX-208 is now well positioned to

move forward on an expedited and more affordable registration path.

• 2. Genetic and clinical data have cleared

the path for full development of this first-in-class selective BET Bromodomain inhibitor in several indications.

• 3. Clinical planning and execution is in

full swing.

• 4. Business development licensing and

partnering discussions have commenced.

Summary

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