Follow-up of the CUPID Gene Therapy Trials

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1 Follow-up of the CUPID Gene Therapy Trials Roger J. Hajjar, MD Icahn School of Medicine at Mount Sinai New York, NY

2 Pathway to Heart Failure Injury / Damage Mature Dysfunctional Dying New Coronary Disease Myocardial Infarction Familial/Genetic Hypertension Pregnancy Valvular Alcohol Toxins Fibroblasts Extra-cellular Matrix Blood vessel Progenitors

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4 NE Ca 2+ Na + K + T-tubule SR Ca 2+ leak GRK2 PKA βar Ca 2+ NCX Na+/K+ Na + K + PKA Calstabin2 RyR Ca 2+ LTCC Ca 2+ LTCC CaMKII Ca 2+ Ca 2+ Ca 2+ I1 PKA PLB SR Ca 2+ content PLB SERCA2a Ca 2+ SR Ca 2+ uptake PP1 PP2 A TnI Ca 2+ Myofibrillar Responsiveness Contractile apparatus

5 Advanced Heart Failure Leads to a SERCA2a Deficiency Irrespective of the Underlying Cause of Heart Failure Coronary Heart Disease (Atherosclerosis, Leading to MI) Hypertension Advanced Heart Failure SERCA2a Deficiency Alcoholism and Drug Abuse Pregnancy Diabetes Familial Genetic Toxins, Infectious Agents, Congenital Mutations

6 Targeting by Gene Therapy Choice of Vectors Modes of Delivery Immune Response Clinical Trials

7 AAV Vectors Are Optimally Suited for Delivery to the Myocardium in Heart Failure Safety Nonpathogenic Low immune response Contains no viral genes and is non-integrating, non-mutagenic Glybera (AAV1 Genetic Enzyme Replacement Therapy) - received marketing approval from the EC in 11/2012 Delivery Able to be administered via coronary infusion (small size 20 nm) Results in long-term expression Broad distribution to the myocardium 7

8 Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID Trial) Phase 1: Open-Label, Sequential Dose Escalation 1.4x10 11, 6x10 11, 3x10 12, 1x10 13 drp N=12 (3:3:3:3) Phase 2: Double Blinded, Randomized, Placebo Controlled Trial 6x10 11, 3x10 12, 1x10 13 drp, & Placebo N=39 (8:8:9:14)

9 AAV1.SERCA2a Improved in a Number of Biological Parameters vs. Placebo Stable or Improved Declined Efficacy Domain AAV1.SERCA2a Placebo / Optimized Symptomatic Quality Of Life Questionnaire Functional 6Minute Walk Test = Improved = Stable = Worse VO 2 max Biomarker NT-proBNP Remodeling Ejection Fraction End-Systolic Volume * Circulation Jul 19;124(3): Double arrows indicate that change from baseline at 6 months (primary endpoint) reached prespecified criteria for a clinically meaningful change.

10 Time-to-Recurrent HF-Related Hospitalizations Adjusted for Competing Risk of Terminal Event (CV Death, Transplant, LVAD) 2.0 Cumulative Rate of Non-Terminal Events Placebo High Dose AAV1.SERCA2a Through 1 Year Through 3 Years Hazard Ratio (CI) 0.12 (0.03, 0.49) 0.18 (0.03, 0.99) Risk Reduction 88% 82% p-value p = p = Jessup M, et al. Circulation. 2011;124(3): ; Zsebo et al, Circ Res. 2014; 114:

11 CUPID 2: A Phase 2b/3 International Study Enrollment Conduct (12 Months on Study) Analysis 3 Months Study Population years of age Systolic HF Ischemic or non-ischemic EF 35% NYHA Class II to IV Maximal, optimized HF regimen & high risk for HF-related hospitalizations AAV NAb titer negative AAV1.SERCA2a 1x10 13 DRP, N=125 Placebo, N=125 Sample Size/Power: N=125 per treatment group with 186 recurrent events provides: 83% power, 0.05 two-sided significance level, to detect at least a 45% risk reduction (HR=0.55) All Subjects Followed Quarterly for Clinical Events Until: Last enrolled subject completes 12 months of observation AND 186 adjudicated HF-related hospitalizations have occurred PRIMARY ENDPOINT Time-to-recurrent HF-related hospitalizations in presence of terminal events (all-cause death, heart transplant, and LVAD implantation) SECONDARY ENDPOINT Time-to-first terminal event (all-cause death, heart transplant, LVAD implantation) ADDITIONAL ENDPOINTS Symptoms, Exercise Capacity and Quality of Life * 60 centers in US, Western and Eastern Europe ; 50% from US or US-like countries; on track for completion of enrollment 1H 2014

12 PRIMARY ENDPOINT Cumulative Number of Recurrent Events per Patient

13 Secondary Endpoint: Probability of Being Terminal Event Free

14 Subgroup Analyses

15 Potential Reasons for the Neutral Results of CUPID 2 The target: SERCA2a Different lots & formulation Myocardial uptake insufficient AAV concentration too low Large animal studies with AAV serotypes not predictive of human uptake T cell response Methods of gene transfer inadequate

16 SERCA2a In all preclinical studies, there has been a linear relationship between dose, % transduction of cardiomyocytes, and efficacy. Preclinical data from laboratories around the world support SERCA2a as an important target for the treatment of Heart Failure Cardiac: Increase in Contractility Decrease in Ventricular Arrhythmias Improvement in Energetic Profile Decrease in Cardiac Hypertrophy Vascular: Increase in Blood Flow - enos activation Decrease in Smooth Muscle Cell Proliferation Improvement in Pulmonary Hypertension SERCA2a Ca 2+ ATP ADP + P i ADP + P i Ca 2+

17 Study Subject Time Post- Infusion Heart Tissue AAV1/SERCA2a (ss copies/µg DNA) CUPID Month 18 Posterolateral wall <20 CUPID Month 11 Left ventricular apical core (LVAC) >20 to <200 Month 23 Anterior Septum Posterior Septum LVAC Right ventricular apical core (RVAC) Anterior Wall Posterolateral Wall >20 to <200 >20 to <200 CUPID Month 31 LVAC >20 to <200 CUPID Month 22 Posterolateral Wall Anterior Septum Posterior Septum Anterior Wall 223 >20 to <200 >20 to <200 >20 to <200 CUPID Month 12 LVAC CUPID Month 13 Anterior septum Posterior septum Anterior Wall Posterolateral Wall CUPID Month 1.5 Anterior Septum Posterior Septum Anterior Wall Posterolateral Wall LVAC RVAC CUPID Month 8 Anterior Wall Heart [1] CUPID Month 14 Anterior Septum Posterior Septum Anterior Wall Postolateral Wall CUPID Month 10 Anterior Septum Posterior Septum Anterior Wall Posterolateral Wall LVAC <10 < CUPID Month 20 Heart [2] 192 CUPID Month 16 LVAC <

18 Viral Uptake in Animal Models of Heart Failure where SERCA2a Gene Transfer was found to be Beneficial Animals Virus Delivery sscopies of viral DNA/µg DNA % Infected Cardiomyocytes Mice AAV9.SERCA2a Intravenous 42,000 ~75% Rats AAV9.SERCA2a Intravenous 30,000 ~70% Pigs AAV1.SERCA2a Intracoronary 8,000 ~30% Sheep AAV6.SERCA2a Intracoronary 9,000 ~33% AAV1.SERCA2a Surgical, MCARD 13,000 ~42% Humans AAV1.SERCA2a CUPID 1 Intracoronary CUPID 2 Intracoronary % <1%

19 Minimum of 20-30% Transduction Is Required for Improvements in vivo SERCA2a * Contractility (+dp/dt, mmhg/s) * * Control Phospholamban * 4000 < % Infected myocytes *P < 0.05 vs. Control 19

20 T Cell Reponse Safety data from CUPID 1 and CUPID 2 has not indicated any evidence of a T cell response against transduced cells (specific for AAV1 capsid proteins analyzed by ELISPOT), nor any other evidence of toxicity. Review of all safety data has provided a clean bill of health.

21 Modes of Gene Delivery Potential Modes of Delivery Surgical Technique: Antegrade Infusion during Bypass Retrograde Infusion during Bypass (MCARD TM ) Catheter Based Techniques: Extracoporeal Re- Circulating System (Osprey Medical) Retrograde Perfusion Antegrade Epicardial Coronary Artery Infusion (AECAI)

22 CUPID 2 Primary Analysis Summary No safety issues were noted. Primary endpoint, defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure did not meet the endpoint Secondary endpoint, defined as all-cause death, need for a mechanical circulatory support device, or heart transplant, likewise failed to show a significant treatment effect. All other exploratory efficacy endpoints (improvement in New York Heart Association classification, 6 Minute Walk Test, Quality of Life, and NT-proBNP) were also inconsistent with a treatment effect. Certain post-hoc analyses indicated a trend in favor of AAV1.SERCA2a

23 Other Trials with AAV1.SERCA2a Patients with pulmonary arterial hypertension

24 Distribution of Neutralizing Antibodies Against AAV1 in Europe & the US

25 Designer AAV Vectors Highly Tropic for Cardiac Muscle Highly Efficient in Primate & Human Cardiac Myocytes Has very little/no tropism to liver, lungs, spleen, kidneys Resistance to Antecedent Neutralizing Antibodies

26 HEART SPECIFIC AAV Mutant The Heart Specific BNP is a chimeric of several raav capids. It represents a heart targeted vector which is more resistant to neutralizing antibodies. Courtesy of R. Jude Samulski, UNC

27 Differential NAb Sensitivity of AAV2i8, AAV2 and AAV8 Serum AAV2i8 AAV2 AAV8 1 <1/2 1/64 1/16 2 <1/2 1/16 1/2 3 1/2 1/64 1/16 4 1/2 1/4 1/2 5 1/2 1/2 1/8 6 <1/2 1/4 1/8 7 <1/2 <1/2 1/8 8 1/2 1/4 1/ /2 1/4 <1/2 10 <1/2 1/4 1/8 11 <1/2 1/4 1/4 Average 1/2 ~1/15 ~1/18

28 AAV2i8.I-1c Program in Heart Failure Planned Start of Enrollment for Phase 1 in 2016 Phase 1: 12 patients 3x10 12 vg (n=3) 1x10 13 vg (n=3) 3x10 13 vg (n=3) 1x10 14 vg (n=3) Phase 2: 45 patients 3x10 13 vg (n=15) 1x10 14 vg (n=15) Placebo (n=15) 8 US medical centers

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30 Future of Gene Therapy in Cardiovascular Diseases AAV has proven to be a safe vector in CV Diseases Effective uptake of vector is necessary Antecedent neutralizing antibodies: Major obstacle to effective gene transfer Improved gene delivery systems need to be developed Modified AAV vectors with engineered capsids are new generation vectors Familial cardiomyopathies associated with specific mutations can now be targeted.

31 Thank you for your attention