CSRC Introduction:Mitchell Krucoff, MD, Duke University Medical Center
Overview of Key Concepts: Peter Kowey, MD, LankenauHeart Institute
Session I: How should the benefits of anticoagulants to reduce strokes and other CV events be balanced against bleeding risks?
Session Chair: Jonathan Seltzer, MD,MBA, ACI Clinical
· How big is the problem? What do we know about bleeding from clinical trials or registries with NOACs and how does this compare with warfarin/other agents? Christopher Granger, MD, Duke University Medical Center
· What are the current strategies for bleeding management and what can be learned from our experience with warfarin? Jeffrey Weitz, MD, McMaster University
o Definition of types of strategies: antidotes vs. reversal
o What are the current issues in bleeding with warfarin/other existent therapies?
– Are they being used appropriately; how large a problem is this?
– What are the barriers to appropriate use?
· What current treatment approaches are used to manage serious bleeding with NOACs? Are they the same for each agent? How effective are they? Jerrold Levy, MD, Duke University Medical Center
o What available hemostatic agents are used (e.g., PCC, aPCC, rFVIIa, tranexamic acid)?
– What are the mechanisms of action (very brief)?
– How effective are they? What are the risks and benefits? What preclinical and clinical data are there?
· What is the unmet medical need? How should the risks and benefits be appropriately balanced? Daniel Singer, MD, Massachusetts General Hospital
Lead Discussant: What is the unmet medical need? Peter Kowey, MD, Lankenau Heart Institute
Session II: What are the newer approaches to managing bleeding with NOACs?
Session Chair: Troy Sarich, PhD, Janssen Research and Development
· The subsequent talks should cover these issues:
o Rationale for development and MOA (1-2 mins)
o Key Issues that impact pre-clinical and clinical development (e.g.)
– “Measurement” of reversal and potential for off-target effects
§ Duration of effect, elimination pathway, drug interactions
§ Potential for re-administration
o Andexanet Alfa – A Factor Xa inhibitor reversal agent John Curnutte, MD, PhD, Portola Pharmaceuticals
o Highly specific and selective reversal agent for dabigatran Paul Reilly, PhD, Boehringer Ingelheim Pharmaceuticals
o PER-977 – A non-specific anticoagulant reversal agent – James Costin, MD, Perosphere Inc
Lead Discussant: General concepts in NOAC development. What differentiates the various NOAC antidotes and how does that influence potential development strategies Mitchell Krucoff, MD, Duke University Medical Center
Session III: What are the most viable development strategies for NOAC reversal agents?
Session Chair: Jeffrey Weitz, MD, McMaster University
· Considerations for evidentiary standards for approval of NOAC reversal agents. Stephen Grant, MD, FDA
· What clinical endpoints would be acceptable (e.g., clinically meaningful, reliable and practical) for Phase 3 or 3b studies of reversal agents for NOACs? How would the benefit:risk relationship be defined? Is it NOAC indication-specific? What data would be needed to support reversal agent use in practice?
· What would a well-designed study with a reversal agent look like? What patients would be most appropriate to study? What are the practical limitations for conducting Phase 3/3b with NOAC reversal agents? How should bleeding be attributed to NOACs vs underlying disease or clinical condition?
o Clinical/Academic Perspective – Stuart Connolly, MD, McMaster University and Michael Gibson, MD, Harvard Medical School
o Industry Perspective- Scott Berkowitz, MD, Bayer HealthCare and Jack Lawrence, MD, Bristol-Myers Squibb, Inc (combined presentation)
· What are the regulatory requirements and pathways for approval of a novel reversal agent with NOACs? How much clinical research must be done pre-marketing vs the use of post-marketing clinical trials and/or surveillance
o CBER speaker—Nisha Jain, MD
o Health Canada- Timao Li, PhD
Lead Discussant: How do we assess Risk vs. Benefit for NOAC reversal agent development? Norman Stockbridge MD, PhD, FDA
Conclusions – Remarks
· Summarize the available approaches for managing bleeding with NOACs, potential clinical trial designs for development of reversal agents and potential regulatory paths for development of reversal agents (new or old) for managing bleeding with NOACs