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Emerging Trends in Safety and Efficacy

Emerging Trends in Safety and Efficacy. Venu Menon MD, FACC, FAHA Director Cardiac Intensive Care Unit, Director Cardiovascular Fellowship, Associate Director C5 Professor Of Medicine Cleveland Clinic Lerner College of Medicine. Emerging Trends in Safety and Efficacy.

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Emerging Trends in Safety and Efficacy

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  1. Emerging Trends in Safety and Efficacy Venu Menon MD, FACC, FAHA Director Cardiac Intensive Care Unit, Director Cardiovascular Fellowship, Associate Director C5 Professor Of Medicine Cleveland Clinic Lerner College of Medicine

  2. Emerging Trends in Safety and Efficacy

  3. Emerging Trends in Safety and Efficacy It was six men of Indostan to learning much inclined, Who went to see the Elephant (Though all of them were blind), That each by observation…might satisfy his mind. John Saxes (1816-1887)

  4. Emerging Trends in Safety and Efficacy JACC 2018;71:1021-4

  5. Expecting the Unexpected:

  6. Expecting the Unexpected: • Cast a broad net.

  7. "Pain is a more terrible lord of mankind than even death itself." -Albert Schweitzer, MD “Facial Expression of Pain,” Sir Charles Bell, 1865

  8. Trial Design and Duration Every 6 months Celecoxib 100-200 mg twice daily Established or at high risk for CVD Ibuprofen 600-800 mg three times daily Screen Naproxen 375-500 mg twice daily Diagnosis of symptomatic OA or RA -3 wks. Rand M1 M2 M4 M8 M12 M18 M24 M30 M36 M42 Visit 9 10 11 12 1 2 3 4 5 6 7 8 Minimum follow-up

  9. Primary Objective To assess the effects of celecoxib 100-200mg bid and ibuprofen 600-800mg tid compared to naproxen 375-500mg bid on the first occurrence of the Antiplatelet Trialists’ Collaboration (APTC) composite cardiovascular endpoint(CV death, non-fatal MI, non-fatal stroke)

  10. Secondary Objectives To compare and evaluate incidence: • MACE - Composite of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, revascularization, hospitalization for TIA • Clinically significant GI events (CSGIEs) • Effects on renal function and blood pressure • Arthritis efficacy: pain, global improvement, function

  11. Expecting the Unexpected: • Cast a broad net. • Set up Infrastructure.

  12. REG1: Pegnivacogin + Anivamersen Novel Anticoagulation System RNA aptamer Factor IXa inhibitor Controlling agent Active Specific Immediate Titratable Prior studies Phase 1a, 1b, 1c (n = 174) Phase 2a PCI (n = 26) Raises aPTT in relation to degree of FIX inhibition pegnivacogin (RB006) Factor IXa anivamersen (RB007) Rusconi CP et al., Nature 2002 Dyke C et al., Circulation 2006 Chan MY et al., J Thromb Haemost 2008 Cohen M et al., Circulation, 2010

  13. Phase 2B RADARAdaptive Design NSTE-ACS n=800 Planned catheterization < 24 h Povsic, AHJ 161:261(2011) Open Label Randomize Femoral Access Cardiac Catheterization / PCI Pegnivacogin 1mg/kg n = 600 Heparin n = 200 Sheath Removal < 6 h Blinded Anivamersen Reversal Immediate Sheath Removal Standard care n = 200 0.075 mg/kg Anivamersen (25%) n = 200 0.2 mg/kg Anivamersen (50%) n = 100 0.4 mg/kg Anivamersen (75%) n = 100 1 mg/kg Anivamersen (100%) n = 200 Open Label 100% Reversal for Persistent Bleeding or CABG Planned DSMB assessments at 100, 200 and 400 patients to consider termination of a reversal arm based upon excess bleeding c/w heparin and historical rates RADAR ACC11 LBCT: 13

  14. Expecting the Unexpected: • Cast a broad net. • Set up Infrastructure. • Consistency of definition and endpoint across a drug class

  15. Normal Kidney Glucose Handling Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion Glucose Filtration ~180g/day Wright EM.Am J Physiol Renal Physiol 2001; 280:F10–18; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Hummel CS, et al.Am J Physiol Cell Physiol 2011;300:C14–21

  16. Adverse Events with Canagliflozin CANVAS Program* Safety Results *Includes patients from CANVAS and CANVAS-R (N=10,142). †CANVAS-only population (n=4330). Neal B, et al. N Engl J Med. 2017 Jun 12 [epub ahead of print].

  17. Empagliflozin and Lower Limb Amputation Diabetes Care; 2018;41: e4-5

  18. Canagliflozin and Amputation • Is this a chance finding? • Is this finding specific to canagliflozin? • Is this a class- effect concern for SGLT-2 inhibitors? • Ongoing clinical trials with dapagliflozin and ertugliflozin. Researchers observed no evidence of increased risk of below-the-knee amputation with canagliflozin vs. dapagliflozin and empagliflozin in both the overall population (HR = 1.14; 95% CI, 0.67-1.93) and among patients with established CVD (HR = 1.08; 95% CI, 0.63-1.82). Similar results were observed when comparing canagliflozin with all non-SGLT2 therapies, with no increased risk in the overall type 2 diabetes population (HR = 0.75; 95% CI, 0.4-1.41) or among those with established CVD (HR = 0.72’ 95% CI, 0.34-1.51), JAMA Intern Med 2018;178: 1190-98 OBSERVE 4D

  19. Expecting the Unexpected: • Cast a broad net. • Set up Infrastructure. • Consistency of definition and endpoint across a drug class • Concurrent and Electronic Adjudication

  20. Advantages of the Electronic Record • Accurate and concurrent review of events. • Transparency in workflow status. • Immediate data accessibility via analytics. • Integration with EDC systems to minimize data entry. 

  21. Expecting the Unexpected: • Cast a broad net. • Set up Infrastructure. • Consistency of definition and endpoint across a drug class • Concurrent and Electronic Adjudication • Quality Control

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