CVKD 8-K
Cadrenal Therapeutics, Inc. (CVKD)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
Date of Report (date of earliest event reported):
(Exact name of registrant as specified in charter)
| (State or other jurisdiction of incorporation) |
(Commission File Number) | (IRS Employer Identification No.) |
(Address of principal executive offices and zip code)
(
(Registrant’s telephone number including area code)
N/A
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of registrant under any of the following provisions (see General Instruction A.2. below):
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| Soliciting material pursuant to Rule 14a-12(b) under the Exchange Act (17 CFR 240.14a-12) |
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class | Trading Symbols | Name of each exchange on which registered | ||
| The (Nasdaq Capital Market) |
Indicate by check mark whether the registrant is an emerging growth company as defined in in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by checkmark
if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards
provided pursuant to Section 13(a) of the Exchange Act.
Item 7.01 Regulation FD Disclosure
On September 25, 2024, Cadrenal Therapeutics, Inc. (the “Company”) posted an updated corporate presentation within the Investor Relations section of the Company’s website, which is furnished as Exhibit 99.1 to this Current Report on Form 8-K. The updated corporate presentation includes information regarding the Company’s plans for its Phase 3 trial in its lead targeted indication, patients with an approved left-ventricular assist device (LVAD), as well as two other targeted indications: patients with end stage kidney disease with atrial fibrillation, and mechanical heart valve patients with difficult-to-control time in therapeutic range or genetic resistance to warfarin. Representatives of the Company may use the updated presentation in various meetings with investors from time to time.
The information contained in this Item 7.01 (including Exhibit 99.1) is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Exchange Act, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section and shall not be deemed to be incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such filing.
The investor presentation furnished as Exhibit 99.1 to this Current Report on Form 8-K includes “safe harbor” language pursuant to the Private Securities Litigation Reform Act of 1995, as amended, indicating that certain statements contained therein are “forward-looking” rather than historical.
Item 8.01. Other Events.
The updated corporate presentation includes information regarding the Company’s plans for its Phase 3 trial in its lead targeted indication, patients with an approved left-ventricular assist device (LVAD), as well as two other targeted indications: patients with end stage kidney disease with atrial fibrillation and mechanical heart valve patients with difficult-to-control time in therapeutic range or genetic resistance to warfarin.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
The following exhibits are furnished with this Current Report on Form 8-K:
| Exhibit Number |
Exhibit Description | |
| 99.1 | Investor Presentation of Cadrenal Therapeutics, Inc. dated September 2024 | |
| 104 | Cover Page Interactive Data File (the cover page XBRL tags are embedded within in the inline XBRL document) |
1
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Dated: September 25, 2024 | CADRENAL THERAPEUTICS, INC. | |
| By: | /s/ Quang Pham | |
| Name: | Quang Pham | |
| Title: | Chairman and Chief Executive Officer | |
2
Exhibit 99.1
Cadrenal Therapeutics, Inc. NASDAQ: CVKD September 2024
2 Caution Concerning Forward - looking Statements This document contains forward - looking statements . In addition, from time to time, we or our representatives may make forward - looking statements orally or in writing . We base these forward - looking statements on our expectations and projections about future events, which we derive from the information currently available to us . Such forward - looking statements relate to future events or our future performance, including : our financial performance and projections ; our growth in revenue and earnings ; and our business prospects and opportunities . You can identify forward - looking statements by those that are not historical in nature, particularly those that use terminology such as “may,” “should,” “expects,” “anticipates,” “contemplates,” “estimates,” “believes,” “plans,” “projected,” “predicts,” “potential,” or “hopes” or the negative of these or similar terms . In evaluating these forward - looking statements, you should consider various factors, including : our ability to successfully develop and commercialize product candidates, our ability to raise capital when needed, and the competitive environment of our business . These and other factors may cause our actual results to differ materially from any forward - looking statement, including those risk factors disclosed in our Annual Report on Form 10 - K for the year ended December 31 , 2023 filed with the Securities and Exchange Commission on March 11 , 2024 and our Quarterly Reports for the quarters ended March 31 , 2024 and June 30 , 2024 . Forward - looking statements are only predictions . The forward - looking events discussed in this document and other statements made from time to time by us or our representatives may not occur, and actual events and results may differ materially and are subject to risks, uncertainties, and assumptions about us . We are not obligated to publicly update or revise any forward - looking statement, whether as a result of uncertainties and assumptions, the forward - looking events discussed in this document, and other statements made from time to time by us or our representatives might not occur .
3 Cadrenal Therapeutics Overview Our Phase 3 - ready drug candidate, tecarfarin, is a new vitamin K antagonist (VKA) anticoagulant expected to be superior and safer than warfarin Striving to overcome the many challenges of warfarin and result in improved outcomes and fewer major events such as heart attacks, strokes, bleeds and deaths and lower cost of care by avoiding costly hospitalizations Late - stage Biopharma Developing a New Anticoagulant to Improve Care for Underserved Warfarin - dependent Patients 3
4 Three Top Potential Indications of Tecarfarin Two Orphan Drug and One Fast Track Designations Left Ventricular Assist Devices (LVAD) for advanced heart failure patients End - stage Kidney Disease (ESKD) + Atrial Fibrillation (AFib) Mechanical Heart Valve (MHV) patients with difficult - to - control TTR* or genetic resistance to warfarin *Time in therapeutic range (TTR) as measured by the international normalized ratio (INR) Orphan Drug Designation (ODD) Orphan Drug Designation + Fast Track Focused on patients with implanted cardiac devices or rare cardiovascular (CV) conditions that require chronic anticoagulation
5 Key Investment Highlights for Cadrenal Opportunity Experienced m a n a g e m e nt team with a late - stage drug candidate NO anticoagulation drugs are indicated for those with LVADs or many rare CV conditions requiring chronic anticoagulation Extensive safety data from 11 clinical trials demonstrates fewer major events such as strokes, heart attacks, bleeding and death Pursuing fastest path to market and partnerships for pivotal clinical trials, including collaboration with LVAD maker Abbott Tecarfarin was granted ODD by FDA for LVADs and ESKD + AFib; intend to pursue ODD for MHV subset Costly warfarin complications should drive premium tecarfarin orphan pricing and rapid market adoption Large Market of Underserved Patients 1 Data Shows Safety and Efficacy Superiority to Warfarin 2 Opportunist i c Strategy & Bus Dev Potential 3 Accelerated Regulatory Path 4 Strong Projected Adoption & Pricing 5
6 Gaps in Modern Heart Failure and Chronic Kidney Disease Research 1 Damman K, Valente MAE, Voors AA, et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta - analysis. Eur Heart J 2014;35:455 – 69. Interdependence of the Heart and Kidney in Chronic Kidney Disease (CKD) and Heart Failure (HF) 49% of HF patients also have CKD, and an estimated 17 – 21% of CKD patients develop de novo HF 1
7 Tecarfarin Clinical Development Pipeline Development Phase Program P r i o r iti z e d T a r ge t I nd i ca ti ons Regulatory Strategy/Status Discovery Preclinical Phase I Phase II Phase III Tecarfarin L e f t V e nt ri c u l a r A ss i s t D e v i ce s ( L V A D s) • F D A Orph a n D ru g D es ign a t io n Gr a n t e d • Fin a lizin g T ri a l Pro t o c ol • D e v e lopin g E M A Orph a n D ru g A pp l i ca t i o n End - s t a g e K idn e y D i seas e w i t h A Fi b • F D A Orph a n D ru g D es ign a t io n Gr a n t e d • F D A F as t T r ac k D es ign a t io n Gr a nt ed • D e v e lopin g E M A Orph a n D ru g A pp l i ca t i o n Mechanical Heart Valve (MHV) patients with difficult - to - control TTR or genetic resistance to warfarin • D e v e lopin g F D A a n d E M A Orph a n D rug Applications Potential 2024 catalysts for future milestones to build enterprise value Future milestones may include Ph 3 trial enrollment, anticipated data readouts and progress with strategic partnerships
8 A Review of Tecarfarin HOW TECARFARIN COMPARES Tecarfarin is metabolized via a different pathway than warfarin, thus its efficacy is not affected by drug - drug interactions or kidney impairment, which are common in these patients Based on data from Phase 2/3 trials, tecarfarin performed better than warfarin and provided more stable anticoagulation with a higher TTR, fewer major events Extensive safety data (n=1000) Potential solution for patients with genetic variants, estimated at 18 percent of all CV patients* Direct Oral Anticoagulants (DOACs) such as Eliquis not indicated for LVADs and many rare CV conditions, provide little or negative data with these patients Tecarfarin is the ONLY anticoagulant in development for patients with LVADs Being championed by LVAD and ESKD KOLs and clinicians *Source: https://www.nature.com/articles/jhg201073 8
9 The Problem: Patients with Implanted Cardiac Devices and Rare CV Conditions Lack Effective Anticoagulation Warfarin DOACs (Pradaxa, Xarelto, Eliquis & Savaysa) LVAD • High frequency of bleeding events, with LVAD patients being hospitalized more than twice on average within six months of implant* • Unstable metabolism due to drug - drug interactions, genetic variability of pathway • Late - stage heart failure and kidney dysfunction are often seen in conjunction. Chronic kidney disease (CKD) inhibits the metabolism of warfarin. • Cost and time of reversal compared to VKA is not acceptable for patients at high risk of bleeding o r in t er v en t ion • LV A D pa t i en t s w e r e e x c l ude d f r o m a ll app r o v a l st udie s, leaving void or negative data from earlier clinical trials • D OA C s no t appro v e d f o r o r i n gu i de li ne s f o r LV A D pa t i en t s * Source: Annals of Trans Medicine Antiplatelet and anticoagulation strategies for left ventricular assist devices - PubMed (nih.gov) ESKD+AFib • Higher risk of bleeding in dialysis patients with AFib c o m pa r e d t o D OA Cs • M ul t ipl e do s e ad j u st m e n t s t o k ee p pa t i en t s w i t hin International Normalized Ratio (INR) range • Drug interaction in patients with multiple comorbidities • Limited head - to - head evidence; existing data fails t o de m on st ra t e bene f i t i n t h r o m bo e m b o li s m an d r e v ea l s stroke risk • Not approved or included in ESKD treatment guidelines Ambiguity in dosing recommendations Both warfarin and DOACs are not FDA - approved for patients with LVADs or many rare CV conditions SIGNIFICANT ISSUES WITH ONLY CHOICES FOR THESE PATIENTS
10 • Rate of severe bleeding significantly increased when TTR falls below 56% • Mean TTR in LVAD patients treated with warfarin is <50% (Martinez et al 2018) ARIES - HM3 Study (Sponsored by Abbott) Documents the Impact of Poor Anticoagulation Quality of Adverse Events in LVAD patients Source: Mehra et al; Impact Of Vitamin K Antagonist Therapy On Outcomes In a Randomized Controlled Trial of Aspirin Removal In Left Ventricular Assist Device Patients - A Pre - specified Analysis From the ARIES - HM3 Trial; Presented April 2024 at the ISHLT Annual Meeting 0 60 40 20 7. 4 2 11. 7 6 20. 2 4 26. 4 3 49. 1 5 Event per patients per year M edia n TT R +10% +20% ≥56% <56% +30% Linear regression p - value=0.007 Events are Hemocompatibility Related Adverse Events (HRAE) = Any Stroke, Pump Thrombosis, Major Bleeding, and Arterial Peripheral Thromboembolism 0.49 0.26 0.20 0.12 0.07 0 .2 0 .4 0 .6
11 Bleeding Rate in LVAD Patients is a Major Problem Poor quality anticoagulation, manifest as sub - target TTR, is the cause Recent clinical evidence from the ARIES - HM3 (Abbott) study documents the consequences of suboptimal anticoagulation with warfarin in LVAD patients • Time in Therapeutic Range (TTR) 1,2 o Well - established marker used to evaluate anticoagulation quality (safety and efficacy) o Higher TTR levels correlate directly with improved clinical outcomes including rates of death, bleeding, myocardial infarction, stroke, and systemic embolism • TTR predictive of clinical outcomes o Quality of VKA management as measured by TTR correlates strongly with the occurrence of non - surgical bleeding risk in patients with the HM3 LVAD3 o TTR measurements correlate linearly with bleeding risk (Linear regression p - value=0.007) 3 1) 2) White et al. 2007; 2) Currie et al. 2006; 3) Jones et al. 2005 TTR quantifies the percentage of time a patient is at the desired level of anticoagulation Estimated event rate decreases as a function of increasing TTR 4 3) Meh ra et al; Impact Of Vitamin K Antagonist Therapy On Outcomes In a Randomized Controlled Trial of Aspirin Removal In Left Ventricular Assist Device Patients - A Pre - specified Analysis From the ARIES - HM3 Trial; Presented April 2024 at the ISHLT Annual Meeting
12 Phase 2/3 Trial Shows Tecarfarin results in improved TTR, with Fewer Thrombotic and Hemorrhagic Events 1 0 0 0 2 2 1 Is c h e m i c Stroke Deep Venous Pulmonary Thrombosis Embolis Teca f a r in Warfarin T e c a r f a ri n - t r e a t e d s ub j e ct s experienced numerically fewer major hemorrhages than the warfarin - treated patients and had numerically fewer thrombotic events Tecarfarin had fewer thrombotic events compared to warfarin Randomized, double - blind clinical trial N=607 Patients with indications for chronic anticoagulation Tecarfarin (n = 304) Warfarin (n = 303) 1) Whitlock RP, Fordyce CB, Midei MG, et al. A randomised, double - blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin, which was a subsequently corrected and more - in - depth analysis of EmbraceAC Trial. Thromb Haemost. 2016;116(2):241 - 250. doi:10.1160/TH15 - 11 - 0910 64 65 66 67 68 69 70 71 On treatment (excluding medication interruptions) Warfarin T e c ar f a rin p=0.04 Time in Therapeutic Range (TTR) using Observed Values
13 44 15 0 5 10 15 20 25 30 35 40 45 50 W a r f a r in T e c a r f a r in Percent Increase 20 - 8 - 10 - 5 0 5 10 15 20 25 W a r f a r in T e c a r f a r in Percent Increase/Decrease AUC t 1/2 Percent Increase in Exposure for Chronic Kidney Disease Subjects vs Healthy subjects for Warfarin and Tecarfarin (n =23) Albrecht D, Turakhia MP, Ries D, et al. Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease. Thromb Haemost. 2017;117(11):2026 - 2033. doi:10.1160/TH16 - 10 - 0815 Tecarfarin Phase 1 PK Trial in Stage 4 CKD Patients Provides Evidence that CKD Does Not Alter Tecarfarin Exposure While Warfarin Exposure is Increased Tecarfarin metabolism not as impacted by kidney failure
1 4 14 The Solution: Tecarfarin Aims to Solve Warfarin’s Major Problems and Be the Superior, Safer Choice Metabolized via an alternate pathway to avoid effects of common drug interactions Reliable, stable PK profile . Tecarfarin is not impacted by kidney impairment. STABLE ANTICOAGULATION with longer TTR and extensive safety data Warfarin: High risk for bleeding and other major events Significant variability with frequent dosing adjustments MAJOR PROBLEM for implanted CV devices or rare CV patients Challenging to control Drug - drug interactions Variable PK profile due to genetic variants and interference from other drugs X ✓ SOLUTION: Tecarfarin designed to solve warfarin challenges DECREASING MAJOR EVENTS SUCH AS STROKE & BLEEDING
1 5 LVADs are a Double - digit Growth Market Source: LVADS Market Size, Share, Growth, Trends Industry Analysis Forecast 2025 Technavio LVAD Market by Application and Geography – Forecast and Analysis 2021 - 2025 Market growth will ACCELERATE at a CAGR of 12 . 2 3 % 46% of the growth will originate from N o r th A m e r i c a
16 Proposed Tecarfarin Pivotal Trial Design for LVAD Patients Randomization Tecarfarin (n = 220) Warfarin (n = 220) Primary Endpoint: Hierarchical composite of clinical events and assessment of anticoagulation quality as measured by TTR R 1:1 Patients newly implanted with an approved LVAD and older than 18 years of age Planned E n r o ll me nt N = 440 Treatment for 26 weeks A randomized, blinded, phase 3, multicenter study to evaluate the efficacy and safety of tecarfarin compared to warfarin in patients with an approved left - ventricular assist device (LVAD) Tecarfarin Anticoagulation and Hemocompatibility in LVAD Patients
1 7 Attractive Addressable Market Opportunities * Based on management’s assumptions such as market analysis studies and expected adoption rates. 17 End - stage K i dn e y D is e a se with AFib Mechanical Heart Valves with D i f f ic u l t - t o - co n t r ol TTR Approximately >$2 Billion Combined Peak Annual Market Potential* US market potential estimated @ $2 billion+ for three targeted implanted CV device and rare CV conditions Left Ventricular Assist Devices
18 Cap Table (reflects August ‘24 reverse split) Cash $5.0 million Debt NONE Common Shares Outstanding 1,182,225 Warrants – Investors (avg. $26.25) 285,714 Warrants - Underwriter & Place Agt. Warrants (avg. $40.20) 25,938 Stock Options Outstanding (avg. $13.20) 156,333 Financial Summary Market Capitalization As of 9/18/24 $14.2 million Insider Ownership (Common Stock) Insider Ownership as Percent of Shares Outstanding 42% 2024 Financial Results – 6 Months ended June 30th Operating Expenses (excluding non - cash items) $3.9 million Cash used in operating activities $3.4 million
19 Leadership Team: Clinical to Commercial Expertise Quang Pham CEO & Founder, Chairman Matthew Szot, CPA Chief Financial Officer John R. Murphy Board Member Steven Zelenkofske, DO Board Member Glynn Wilson, PhD Board Member Robert Lisicki Board Member Douglas Losordo, MD Chief Medical Officer Jeff Cole Chief Operating Officer
20 Scientific Advisors with Deep Experience in CV and Beyond Christopher Granger, MD Professor of Medicine in the Division of Cardiology, Duke University Member, Duke Clinical Research Institute (DCRI) Sean Pokorney, MD, MBA Electrophysiologist and Assistant Professor of Medicine, Duke University Elaine M. Hylek, MD, MPH Professor of Medicine, Boston University School of Medicine Director of the Thrombosis and Anticoagulation Service at Boston Medical Center (BMC) Richard Whitlock, MD Cardiac Surgeon and Professor of Surgery, McMaster University Medical Center Investigator, Population Health Research Institute Michael Lincoff, MD Vice Chairman, Dept. of Cardiovascular Medicine, Cleveland Clinic Director of Clinical Research, Lerner Research Institute Wolfgang C. Winkelmayer, MD, MPH Chief, Section of Nephrology, Professor of Medicine, Baylor University Director, Selzman Institute for Kidney Health C. Michael Gibson, MD Professor of Medicine, Harvard Medical School Interventional Cardiologist, Beth Israel Deaconess Medical Center President & CEO, Baim Institute for Clinical Research Mandeep, Mehra MD, MSc, FRCP Medical Director of the Brigham Heart and Vascular Center, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine
2 1 Data Shows Superior Efficacy and Safety Phase 1 and 2/3 clinical data shows that tecarfarin is an effective, stable and safe anticoagulant and expected to be superior to warfarin in these underserved patients. 21 Why Cadrenal Now? CLEAR FROM RECENT DATA that tecarfarin has attractive, defined opportunity in patients where warfarin CHALLENGES ARE HUGE BURDEN and DOACs, with little or negative relevant data, are not the solution Bus Dev Progress and O ppo r tun is t ic Approach Pursuing business development strategies to help fund pivotal clinical trials; Multiple potential indications provides optionality. Orphan R e gu la to ry Pathway Tecarfarin has been granted two Orphan Drug Designations and a Fast - track designation by FDA providing potential seven - year marketing exclusivity post - approval. Attractive Market with Orphan Drug Pricing Drugs for rare CV conditions that save money and lives command price premiums that value the tecarfarin addressable market @ $2B+; Experienced team to deliver results. Phase 3 - ready Candidate Tecarfarin is advancing toward pivotal trials in patients with implanted CV devices or rare CV conditions. KOLs express need and support for a new VKA that is superior, safer and saves the healthcare system hospitalization costs.
22 Contact Us Quang Pham CEO & Founder [email protected] Matthew Szot CFO [email protected]
23 A PPE ND IX
24 Bleeding Rate by TTR Increments 0 20 40 60 Event per patients per year Incremental improvement of 10% above the median of 56% trends in a significant reduction in bleeding rate M ed i a n TT R Linear regression p - value=0.007 Connors/Netuka/Mehra. ARIES VKA Analysis (ISHLT Thursday April 11, 2024) Placebo Median (Q1, Q3) Aspirin Median (Q1, Q3) P - value INR Distribution 2.3 (2.1, 2.4) 2.3 (2.0, 2.5) 0.8227 E li g i b l e Fo ll o w - up Days 344.0 (247.0, 364.0) 336.0 (213.0, 365.0) 0.4620 Days in TR (%) 55.8 (41.2, 73.9) 57.3 (38.3, 68.0) 0.4127 Days Above TR (%) Days Below TR (%) 8.4 (0.8, 17.4) 26.2 (13.2, 44.5) 9.5 (2.2, 19.3) 27.4 (14.4, 47.6) 0.2206 0.3653 Non - Standard TR * 14.4% (40/277) 16.6% (46/277) 0.5576 * TR=Therapeutic Range (INR from 2 to 3 ) 49.15 26.43 20.24 11.76 7.42 <56% ≥56% +10% +20% +30%
25 0% 0 3 6 9 12 No. at Risk: Months After Implant TTR < 56% 272 211 184 163 133 TTR ≥ 56% 282 256 233 211 170 10% 20% 30% 40% 50% Bleeding Components of the Secondary End Point Rate of Bleeding TTR < 56% TTR ≥ 56% 30.3 21.4 22.1 10 . 3 HR: 1.381 (0.978,1.951); p=0.004 TTR < 56% TTR ≥ 56% 0 20 40 60 26. 4 3 49. 1 5 Event per 100 patient year Bleeding p - value <0.0001 The Impact of TTR on Bleeding in ARIES - HM3 Analysis from ARIES - HM3 presented at ISHLT 2024 ( Mehra et al)
26 Cikes M, Yuzefpolskaya M, Gustafsson F, Mehra MR . J Card Fail . 2024; S1071 - 9164(24)00318 - X. Strategies to Mitigate Bleeding Complications with HM3 LVAD A Bleeding Paradox?
27 Tecarfarin’s Metabolic Advantage C Y P 2 C 19 C Y P1A2 CYP2C8 CYP1A2 CYP2C18 CYP1A1 CYP3A4 CYP1A1 CYP2C9 CYP2C9 CYP2C9 CYP2C9 6 - hydroxywarfarin 8 - hydroxywarfarin 10 - hydroxywarfarin 7 - hydroxywarfarin 4 - hydroxywarfarin 7 - hydroxywarfarin 6 - hydroxywarfarin dehydroxywarfarin 7 Different CYP450 Isoenzymes involved in Warfarin M etabo lis m ! Warfarin CYP450 R - W a r f a ri n S - W a r f a ri n E limi na t io n via kidney E li m ination via bile AB C B1 Tecarfarin Human Carboxylesterase 2 (CES2) Tecarfarin C ES2 ~30 % of population CYP2C9 genetic v a ri at i ons Drug interactions G ene t i c v a r i a t i ons E li m i nat i o n via bile Tecarfarin is metabolized via an alternate pathway that is abundant and essentially insaturable, thereby avoiding the bottleneck in the CYP450 pathway where warfarin in metabolized.
28 Warfarin Metabolism via CYP450 is Complicated by Known Competitors, Inhibitors and Inducers and the Established Impact of Genetic Variants Enzymes Substrates Inhibitors Inducers CYP 3A4 amlodipine, simvastatin, warfarin , amiodarone, sildenafil, midazolam, fluoxetine, haloperidol, codeine, oxycodone, methadone, fentanyl ciprofloxacin, ketoconazole, ritonavir, methylprednisone, imatinib, tamoxifen, cimetidine, grapefruit juice simvastatin, efavirenz, pentobarbital, carbamazepine, phenobarbital, phenytoin, valproic acid, caffeine CYP IA2 alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, tizanidine ciprofloxacin, enoxacin, fluvoxamine, oral contraceptives, phenylpropanolamine montelukast, phenytoin, smoking components of cigarettes CYP 2C8 repaglinide, paclitaxel, methadone gemfibrozil, fluvoxamine, ketoconazole, trimethoprim rifampin CYP 2C9 celecoxib, warfarin , phenytoin amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, etravirine, fluvastatin, metronidazole, Sulfinpyrazone, tigecycline carbamazepine, rifampin, aprepitant, bosentan, phenobarbital, St. John's wort CYP 2D6 lidocaine, metoprolol, haloperidol, fluoxetine, amitriptyline, metoclopramide, codeine, oxycosone, tramadol amiodarone, c hlo r p r o m a z ine , c i t alop r a m , bupropion rifampin, dexamethasone Tecarfarin was specifically designed to avoid metabolism via the CYP450 Pathway, thus improving safety and efficacy over warfarin
29 Tecarfarin is Metabolized via the Human Carboxyl Esterase 2 Pathway (CES2) Provides More Effective, Safe, and More Consistent Anti - coagulation Enzymes Substrates Inhibitors Inducers CYP 3A4 amlodipine, simvastatin, warfarin , amiodarone, sildenafil, midazolam, fluoxetine, haloperidol, codeine, oxycodone, methadone, fentanyl ciprofloxacin, ketoconazole, ritonavir, methylprednisone, imatinib, tamoxifen, cimetidine, grapefruit juice simvastatin, efavirenz, pentobarbital, carbamazepine, phenobarbital, phenytoin, valproic acid, caffeine CYP IA2 alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, tizanidine ciprofloxacin, enoxacin, fluvoxamine, oral contraceptives, phenylpropanolamine montelukast, phenytoin, smoking components of cigarettes CYP 2C8 repaglinide, paclitaxel, methadone gemfibrozil, fluvoxamine, ketoconazole, trimethoprim rifampin CYP 2C9 celecoxib, warfarin , phenytoin amiodarone, fluconazole, miconazole, oxandrolone, capecitabine, etravirine, fluvastatin, metronidazole, Sulfinpyrazone, tigecycline carbamazepine, rifampin, aprepitant, bosentan, phenobarbital, St. John's wort CYP 2D6 lidocaine, metoprolol, haloperidol, fluoxetine, amitriptyline, metoclopramide, codeine, oxycosone, tramadol amiodarone, c hlo r p r o m a z ine , c i t alop r a m , bupropion rifampin, dexamethasone Antiplatelet/Anticoagulants • Acetylsalicylic acid • Prasugrel • Dabigatran etexilate Angiotensin receptor blockers • Candesartan cilexetil • O l m esa r t a n m edo x o m i l • Azilsartan medoxomil Antivitral agents • Tenofovir disoproxil • Adefovir dipivoxil • Valacyclovir CNS agents • Cocaine • Heroin • 6 - monoacetylmorphine Immunosuppressive agents • Methylprednisolone sodium succinate • Deflazacort Oncology agents • Irinotecan • Capecitabine Anesthetic drug • Procaine CES2 Substrate Drugs Limited Substrates Identified Genetic variation exists, but limited evidence of clinical impact
30 Vitamin K Antagonism Inhibits Multiple Factors (II, VII, IX, X, Proteins C & S) in the Clotting Cascade vs. Single Targets of Newer Agents ANTI - Fxa Apixaban Edoxaban Ri v a r o x aban ANTI - FIIa Dabigatran TISSUE FACTOR (TF) PATHWAY CONTACT ACTIVATION PATHWAY C O MM ON PATHWAY F IXa FXIIa FVIIa TF - FVIIa complex T F F XI a FV IIIa Tenase complex (FIXa + FVllla) P r o t h r omb in ase complex ( FIXa + FVllla + FXa) F Xa F IIa CL O TT I NG MULTI - TARGETS VKA MULTI - TARGETS VKA MULTI - TARGETS VKA MULTI - TARGETS VKA c l o t ti ng SINGLE - TARGET DOACs SINGLE - TARGET DOACs Proven mechanism of action resulting in clinically meaningful anticoagulation in certain conditions where DOACs have failed
31 Tecarfarin vs. Placebo in Patients with ESKD and AFib Randomized, Double - Blind, Placebo - Controlled Tecarfarin Phase 3 Trial Design for ESKD and AFib Randomization stratified according to VKORC1 status Tecarfarin (n = 246) Placebo (n = 246) 12 - month follow - up for Primary Endpoint of time to combined endpoint of ischemic stroke or systemic embolism (80% power to detect a 25% treatment benefit) R 1:1 ES K D (eGFR < 15 mL/min/1.73 mm 2 ) documented chronic paroxysmal, pe r s i st e n t o r pe r m anen t A F ib Trial Sites: U.S. and Canada, ROW TBD Planned E n r o ll me nt N = 492
3 2 32 Significant Underserved Patient Populations 1. Yoon CY, Noh J, Jhee JH, et al. Warfarin Use in Patients With Atrial Fibrillation Undergoing Hemodialysis: A Nationwide Population - Based Study. Stroke . 2017;48(9):2472 - 2479. doi:10.1161/STROKEAHA.117.017114 2. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End - Stage Renal Disease: A Systematic Review and Meta - analysis. JAMA Netw Open. 2020;3(4):e202175. doi:10.1001/jamanetworkopen.2020.2175 70 . 7% 29 . 3% 0% 2 0% 4 0% 6 0% 8 0% 1 0 0% Warfarin Non - us er 7,053 W a r f a rin User 2,921 n= 78.0% 22.0% Warfarin Non - us er 37,035 W a r f a rin User 10,445 n= Most patients with ESKD + AFib are not prescribed ANY ant i coagu l at i on to reduce their risk of stroke Despite the significantly increased risk of stroke in ESKD patients with AFib, most patients are not anticoagulated due to the lack of evidence of benefit Use of warfarin in ESKD + AFib Patients 1 (N=9,974) 1 (N=47,480) 2
33 TTR Decreases with CKD Severity for AFib Patients on Warfarin AFib Patients with ESKD on Warfarin are Poorly Controlled with TTR of 42 - 51%, compared to the TTR goal of 70% or greater □ Time in Therapeutic Range (TTR) 1,2,5 o Well - established FDA metric used to evaluate quality of anticoagulation control (safety and efficacy) o Higher TTR levels correlate directly with improved clinical outcomes including rates of death, bleeding, myocardial infarction, stroke, and systemic embolism □ TTR predictive of clinical outcomes o Stage 4 and 5 CKD with AFib: Similar TTR cutoffs predictive of mortality and cardiovascular outcomes 3,4 □ Overall TTR for AFib Patients with ESKD on warfarin is 42 - 51% 6 □ Only 21% of ESKD patients on dialysis using warfarin achieve TTR ≥60% 6 1) White et al. 2007; 2) Currie et al. 2006; 3) Szumer et al., 2017; 4) Inoue et al., 2018; 5) Jones et al. 2005 6) Yang et al. Heart (2017 June) Figure 2. Warfarin Utilization and Anticoagulation Control in Patients with Atrial Fibrillation and Chronic Kidney Disease 6 TTR of AFib patients with CKD on Warfarin by eGFR Group ESKD Patients (eGFR <15) TTR of 70% or greater is generally accepted as the goal for stable anticoagulation with a VKA
34 Trial terminated prematurely due to an excess of thromboembolic and bleeding events among patients in the dabigatran group Dabigatran Versus Warfarin in Patients with Mechanical Heart Valves EXCESS RISK AND NO BENEFIT Eikelboom, JW. et al. New England Journal of Medicine. 2013. DOI: 10.1056/NEJMoa1300615 Dabigatran N =168 N (%) Warfarin N =84 n (%) Ischemic or unspecified stroke 9 (5.4) 0 Major bleeding 7 (4.2) 2 (2%) Dose adjustment or discontinuation of dabigatran (as - treated analysis) 32% 1 . 0 0 . 9 0 . 8 0 . 7 0 . 6 0 . 5 0 . 4 0 . 3 0 . 2 0 . 1 0 . 0 0 50 1 0 0 1 5 0 200 D a y s 2 5 0 3 0 0 3 5 0 4 0 0 First Bleeding Event W a r f a ri n Da b i g a t r an W a r f a ri n Da b i g a t r an First Thromboembolic Event 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 200 D a y s 50 1 0 0 1 5 0 2 5 0 3 0 0 3 5 0 4 0 0 Probability of Event Free Survival Probability of Event Free Survival Freedom from First Thromboembolic Event Freedom from First Bleeding Event