FRIDAY 5 DECEMBER 2014
BALLROOM
         
  8.00 am 1.00 pm  

STREAMLINING CLINICAL TRIALS
CVCT – NHLBI – EU joint session

         
    Moderators: Michael Lauer (NHLBI, USA), Aldo Maggioni (Florence, ITA)
     
   
  • Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Gaps may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. The problem of benefit–risk is to a considerable degree a problem of variability in drug response. Biological and behavioral variability as well as geographical and health care system variability contribute to the efficacy–effectiveness gap.
   
  • Wider use of electronic medical records generates big data that are being increasingly used in streamlined prospective clinical trials as well as in registry and observational studies. Results are offered as hypothesis generating or as assessments of effectiveness, occasionally challenging the results of clinical trials, and hopefully complementing these results.
   
  • Still, implementation is an issue. Industry sponsors seem reluctant to take advantage of innovative designs, even when regulators are endorsing innovative approaches, maybe because of valuing predictability more than cost saving. It is timely to discuss a way forward.
     
    Future of clinical research and the ripple effect of big data
  Robert Califf (Durham, USA)
     
    Embedding trials in existing longitudinal cohorts: pitfalls and challenges
  Denise Bonds (NHLBI, USA)
     
    Is it possible to randomize at point of care, have no study visits?
  Lou Fiore (Jamaica Plain, USA)
     
  Group randomized trials and other streamlined protocols
  présentation Speaker: Yves Rosenberg (NHLBI, USA)
  Discussant: Jerry Menikoff (FDA, USA)
     
    Methodological issues in analyzing big data
  Speaker: David Madigan (Columbia, USA)
  présentation Discussant: Nevine Zariffa (AstraZeneca, USA)
     
    Interaction between regulatory and DSMBs during the conduct of a trial
  présentation Jeffrey Borer (New York, USA)
     
    What are academic/government institutions doing to help with registries, streamlining clinical trials, using big data?
    • NIH’s perspective on streamlining trials -Catherine Meyers (NIH/NCCAM, USA)
  présentation • EU -Virginija Dambrauskaite (EC, BEL)
    • ESC -Aldo Maggioni (Florence, ITA)
  présentation • ACC -Deepak Bhatt (Boston, USA)
     
    How useful are registries, streamlined clinical trials and big data to regulatory bodies?
  présentation • FDA -Robert Temple (FDA, USA)
    • EMA -Gonzalo Calvo (Barcelona, ESP)
     
    Major journals’ editorial perspective:
    •The Lancet -Catherine Meyers (NIH/NCCAM, USA)
  • NEJM -John Jarcho (Boston, USA)
  présentation • JAMA -Robert Golub (Chicago, USA)
  présentation • Circulation -Marc Pfeffer (Boston, USA)
     
Moderated discussion with audience participation
     
    Panellists: Deepak Bhatt (Boston, USA), Denise Bonds (NHLBI, NIH, Bethesda, USA), Jeffrey Borer (New York, USA), Robert Califf (Durham, USA), Gonzalo Calvo (Barcelona, ESP), Virginija Dambrauskaite (EC, BEL), Lou Fiore (Jamaica Plain, USA), Robert Golub (Chicago, USA), John Jarcho (Boston, USA), Michael Lauer (NHLBI, USA), Lars H Lund (Stockholm, SWE), David Madigan (Columbia, USA), Aldo Maggioni (Florence, ITA), Jerry Menikoff (FDA, USA), Catherine Meyers (NIH/NCCAM, USA), Marc Pfeffer (Boston, USA), Yves Rosenberg (NHLBI, USA), Tabassome Simon (Paris, FRA), Stuart Spencer (London, UK), Robert Temple (FDA, USA), Andrew Zalewski (GSK, USA), Nevine Zarifa (AstraZeneca, USA)
     
THEATRE
     
8.30 am - 1.00 pm
THE THROMBOSIS TRIALISTS WORKSHOP
     
    Moderators: Roxana Mehran (New York, USA), Lars Wallentin (Uppsala, SWE)
     
   
  • New antiplatelets and new anticoagulants are at the helm of a golden age. NOAC trials have accumulated a sizeable level of evidence with 73,000 patients in the 4 AF trials alone, and around 20,000 in the VTE trials and are life-saving therapies after ACS.
   
  • Among big issues is how to get physicians and patients to do the right thing--keep taking the drugs and at doses that optimize clinical outcomes.
   
  • Whether optimizing therapy should generally involve monitoring, even if you can beat standard therapy without it, is another issue that may merit specific trial designs.
   
  • Although prasugrel is an effective and relatively safe agent in the invasive management of ACS, will comparative effectiveness and/or registry data better inform on whether we should refrain from giving it upfront before the cathlab, or from giving it late in patients on clopidogrel? Or is ticagrelor the better choice for all options in ACS?
   
  • Duration of therapy, combination strategies and where new therapy might fit within the current antiplatelet armamentarium is a new matter of debate.
   
  • Approvability issues were raised recently with occasionally divergent decisions among major agencies. Is the bleeding not too heavy? Regulatory agencies across the Atlantic differ in their interpretation of the available data. Are more trials needed?
   
  • Antidotes are the big challenge, how to study a rare event, but even more challenging is how to get regulatory approval of a rare event.
   
  • But do we need an antidote, since all trials show a reduction in fatal bleeding when compared to warfarin, where we do have adequate antidote and bridging therapies?
     
    Prasugrel or Ticagrelor in ACS? A case study on how trial, comparative effectiveness and registry data may be used in conjunction, short of a head-to-head comparison.
  présentation Lars Wallentin (Uppsala, SWE)
     
    Cangrelor: how to use it? Why was it not approved?
  présentation Speaker: Michael Gibson (Boston, USA)
  Discussant: Freek Verheugt (Amsterdam, NED)
     
    Bivaluridin trials in PPCI: has the dust settled?
  présentation Speaker: Roxana Mehran (New York, USA)
  Discussant: Efthymios Deliargyris (MedCo, USA)
     
    A glimpse into the future: what space is left for new anti Xas and for the actively controllable IXa blocker aptamer?
  présentation Freek Verheugt (Amsterdam, NED)
     
    Evaluating rare events: how to get regulatory approval for target-specific oral anticoagulants antidotes
  Speaker: Robert Califf (Durham, USA)
  présentation Discussant: James Costin (Perosphere, USA)
     
    Approvability issues: FDA–EMA divergence explained?
  Speaker: Thomas Marciniak (FDA, USA)
  présentation Discussant: Angeles Alonso (EMA, UK)
     
Moderated discussion with audience participation
     
    Panellists: Angeles Alonso (EMA, UK), Robert Califf (Durham, USA), James Costin (Perosphere, USA), Efthymios Deliargyris (MedCo, USA), Pete diBattiste (Janssen, USA), Marc Ditmarsch (AstraZeneca, UK), Amani El-Gazayerly (EMA, NED), Michael Gibson (Boston, USA), Thomas Marciniak (FDA, USA), Roxana Mehran (New York, USA), Martin Rose (FDA, USA), David Rutledge (Abbott, USA), Martin Unverdorben (Daiichi-Sankyo, USA), Freek Verheugt (Amsterdam, NED), Lars Wallentin (Uppsala, SWE)
     
1.00 pm – 1.30 pm - LUNCH BREAK
     
BALLROOM
     
1.30 pm - 6.00 pm
NEW DRUGS AND FUTURE TRIALS IN HEART FAILURE:
OPTIMIZING TRIAL DESIGN TO PUTATIVE MECHANISM OF ACTION

CVCT – HFSA joint session
     
    Moderators: JoAnn Lindenfeld (Denver, USA), Christopher O’Connor (Durham, USA)
     
    Recent trials are adopting different strategies attempting to better define patient populations enrolled in the trials.
     
   
  • Is it possible to target homogenous trial populations within the heterogeneous HF population?
   
  • What approaches are most promising (e.g. biomarkers, hemodynamics, echo parameters, omics, other?)
   
  • How to better target a primary pathophysiology?
   
  • How to deal with the confounding role of concomitant comorbidity?
   
  • What are the implications for industry?.
     
    On another hand, many new drug entities are being tested and novel trials are being designed or are being enrolling in HFREF and HFPEF. Targeting these to individual patient populations most likely to benefit from each respective new class of agents is a challenging issue and will be the focus of this session.
     
    Also, failure to improve outcome in patients with worsening heart failure and the increasing burden of heart failure hospitalization are the main drivers for a shift from chronic to worsening heart failure trials.
     
    Ongoing trials: therapies on the horizon?
  présentation • Ivabradine -Jeffrey Borer (New York, USA)
  présentation • Serelaxin -John Teerlink (San Francisco, USA)
  présentation • Finerenone -Faiez Zannad (Nancy, FRA)
    • Natriuretic peptides -Alexandre Mebazaa (Paris, FRA)
    • Vericiguat -Lothar Roessig (Bayer, GER)
  présentation • Omecamtiv mecarbil -Fady Malik (Cytokinetics, USA)
  présentation • Targeting the mitochondria -James Carr (Stealth Peptides, USA)
  présentation • NOACS -Faiez Zannad (Nancy, FRA)
  présentation • Biased ligand (Trevena) -Javed Butler (Atlanta, USA)
    • Myocardial matrices: cell therapies to reverse/delay progression? -Marc Penn (Akron, USA)
  présentation • Auto Servo Ventilation in sleep disordered breathing -Faiez Zannad (Nancy, FRA)
     
    Shifting from chronic to worsening heart failure
  présentation Javed Butler (Atlanta, USA)
     
    Remote monitoring trials
  présentation Speaker: William Abraham (Columbus, USA)
  présentation Discussant: Steven Ruble (BSCI, USA)
  Discussant: Ileana Piña (New York, USA)
     
    Biomarker guided trials
  présentation Speaker: James Januzzi (Boston, USA)
  Discussant: Kirkwood Adams (Chapel Hill, USA)
     
Moderated discussion with audience participation:
Time to change approach? Mechanism-based therapy and personalized HF therapy
     
    Panellists: William Abraham (Columbus, USA), Kirkwood Adams (Chapel Hill, USA), Jeffrey Borer (New York, USA), Javed Butler (Atlanta, USA), James Carr (Stealth Peptides, USA), Robert Cody (Janssen, USA), Pete diBattiste (Janssen, USA), Amany El-Gazayerly (EMA,NED), Mona Fiuzat (Durham, USA), Karen Hicks (FDA, USA), Johannes Holzmeister (Cardiorentis, CHE), James Januzzi (Boston, USA), Marty Lefkowitz (Novartis, USA), JoAnn Lindenfeld (Denver, USA), Lars H Lund (Stockholm, SWE), Aldo Maggioni (Florence, ITA), Fady Malik (Cytokinetics, USA), Alexandre Mebazaa (Paris, FRA), Christopher O’Connor (Durham, USA), Milton Packer (Dallas, USA), Marc Penn (Akron, USA), Ileana Piña (New York, USA), Marc Pfeffer (Boston, USA), Francis Plat (Juventas Therapeutics, USA), Ricardo Rochas (Novartis, USA), Lothar Roessig (Bayer, GER), Steve Ruble (BSCI, USA), Luis Ruilope (Madrid, ESP), Dan Schaber (Medtronic, USA), Martin Unverdorben (Daiichi-Sankyo, USA), Holger Woehrle (ResMed, GER), Faiez Zannad (Nancy, FRA)
     
THEATRE
     
1.30 pm - 4.30 pm
MANAGING HYPERKALEMIA FOR OPTIMAL RAAS INHIBITOR THERAPY AND OTHER
INDICATION FOR POTASSIUM BINDERS: TRIAL DESIGN AND APPROVABILITY ISSUES

CVCT - INI CardioRenal Clinical Trialists joint session
     
    Moderators: Murray Epstein (Miami, USA), Patrick Rossignol (Nancy, FRA)
     
   
  • The use of renin-angiotensin-aldosterone inhibitors or blockers may lead to hyperkalemia, particularly in patients with heart failure and concomitant chronic kidney disease. Interventions to control serum potassium reliably during renin-angiotensin-aldosterone inhibition, which have not been available to date, would be of particular value with the use of mineralocorticoid receptor antagonists that have been shown to lower mortality in patients with heart failure and reduced left ventricular ejection fraction.
   
  • Adoption of optimal therapy including mineralocorticoid receptor antagonists (MRAs) is slow and hindered by concerns over the risk of hyperkalemia, especially in the elderly and in patients with concomitant CKD and diabetes
   
  • Whether potassium-binding polymers may lower the incidence of hyperkalemia and allow a higher proportion of heart failure patients to receive life-saving multiple renin-angiotensin-aldosterone inhibitors is an attractive solution being currently tested in several clinical trials.
   
  • Two novel potassium binders (patiromer and ZS-9) under development may open the field for new indications beyond the classical hyperkalemia in CKD and hemodialysis patients.
     
    Therapeutic options to manage hyperkalemia: update on recent and ongoing trials
  Speaker: Bertram Pitt (Ann Arbor, USA)
  Discussant: Mikhail Kosiborod (Kansas City, USA)
     
    New therapeutic options development programs: live examples
    • Industry viewpoint
  présentation Speaker: Lance Berman (Relypsa, USA)
  Discussant: Henrik Rasmussen (ZS Pharma, USA)
     
    What should the indication be for a drug that lowers serum potassium?
Treatment vs. prevention vs. a broad treatment/prevention of hyperkalemia
     
    • Target populations’ issues: what are the unmet needs?
  présentation Nephrology indications: George Bakris (Chicago, USA)
  Cardiology indications: Patrick Rossignol (Nancy, FRA)
     
    • Acute critical care indications
  Alexandre Mebazaa (Paris, FRA)
    • How to adapt trial design to the clinical indication: methodological issues
  présentation Janet Wittes (Washington, DC, USA)
    • What indications are approvable?
  présentation Speaker: Luis Ruilope (Madrid, ESP)
  présentation Discussant: Aliza Thompson (FDA, USA)
     
Moderated discussion with audience participation:
Would safe and effective therapy for hyperkalemia impact prescribing RAAS inhibitors?
Could this be an approvable claim for novel potassium binders?
     
    Panellists: Angeles Alonso (EMA, UK), Georges Bakris (Chicago, USA), Lance Berman (Relypsa, USA), Murray Epstein (Miami, USA), Mikhail Kosiborod (Kansas City, USA), Alexandre Mebazaa (Paris, FRA), Bertram Pitt (Ann Arbor, USA), Patrick Rossignol (Nancy, FRA), Luis Ruilope (Madrid, ESP), Henrik Sandvad Rasmussen (ZS Pharma, USA), Norman Stockbridge (FDA, USA), Aliza Thompson (FDA, USA), Janet Wittes (Washington, DC, USA)
     
4.30 pm – 5.00 pm - COFFEE BREAK
     
THEATRE
     
5.00 pm - 6.00 pm
KEYNOTE DEBATE: DO CURRENT TRIALS MEET SOCIETY’S NEEDS?
A REVIEW OF RECENT EVIDENCE
     
  présentation Moderators: Stuart Pocock (London, UK), Roxana Mehran (New York, USA)
     
présentation 6.00 pm – 6.30 pm- KEY NOTE LECTURE
Gary Gibbons, Director (NHLBI, USA) ;
   
 
 
 
 
       
     
SATURDAY 6 DECEMBER 2014
     
BALLROOM

8.00 am - 11.30 am
WORKING WITH REGULATORY PARTNERS ON EXPEDITED PROGRAMS FOR SERIOUS
CONDITIONS: HOW DOES THIS APPLY TO CARDIOVASCULAR CLINICAL RESEARCH?

     
    Moderators: Robert Califf (Durham, USA), Pieter de Graeff (Amsterdam, NED)
     
    The FDA has released a draft guidance entitled ‘Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics’ (June 2013). This guidance outlines the four FDA programs intended to expedite the development and review of new drugs that address an unmet medical need in the treatment of a serious or life-threatening condition. In addition to clarifying the established programs, it adds the new ‘Breakthrough Therapy’ designation that may help to facilitate early approval of treatments for serious or life threatening diseases.y
   
  • Fast Track: designation granted to a drug that is intended to treat a serious condition and nonclinical/clinical data demonstrate the potential to address an unmet medical need.
   
  • Priority Review: designation granted to an application for a drug that treats a serious condition and if approved, would provide a significant improvement in safety or effectiveness..
   
  • Accelerated Approval: is a pathway for a drug that treats a serious condition and provides meaningful advantages over available therapies and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.
   
  • Breakthrough Therapy: this designation was instituted under the 2012 FDA Safety and Innovation Act (FDASIA) and is a designation for a drug that treats a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. A drug that qualifies for breakthrough therapy designation would also qualify for the fast-track designation features. It would receive intensive guidance from the FDA for an efficient drug development program and organizational commitment from senior management at the FDA.
     
    The guidance has stimulated a lot of excitement within the drug development community. How much elements of the guidance may apply to CV diseases is an issue that may benefit from discussion among the various stakeholders usually attending CVCT meetings.
     
    To which CV disease is the ‘serious conditions’ track applicable?
  Robert Temple (FDA, USA)
     
    What are ‘breakthrough’, ‘fast track’ and ‘priority’?
  présentation Fortunato Senatore (FDA, USA)
     
    Novartis experience with expedited programs
  Patricia Kay-Mugford (Novartis, USA)
     
    European Medical Agency position
  présentation Pieter de Graeff (Amsterdam, NED)
     
    Unmet clinical needs in cardiovascular disease
    • Investigator viewpoint:Robert Califf (Durham, USA)
    • Industry viewpoint:Joerg Koglin (Merck, USA)
  présentation • Analyst viewpoint:Eric Dimise (GlobalData, USA)
     
    Panellists: Angeles Alonso (EMA, UK), Robert Califf (Durham, USA), Luther Clark (Merck, USA), Pieter de Graeff (Amsterdam, NED), Eric Dimise (GlobalData, USA), Patricia Kay-Mugford (Novartis, USA), Joerg Koglin (Merck, USA), Ricardo Rochas (Novartis, USA), Fortunato Senatore (FDA, USA), Robert Temple (FDA, USA)
     
THEATRE
     
  8.00 am 11.30 am  

DIABETES CV SAFETY TRIALS

     
    Moderators: Gonzalo Calvo (Barcelona, ESP), Deepak Bhatt (Boston, USA)
     
   
  • Obesity epidemic and diabetes are increasing throughout the world, and will have major impact on CV disease worldwide.
   
  • The FDA guidance outlines a new approach to CV safety requirements, designed to gather sufficient data during a development program to show that new anti-diabetic or weight loss therapies are not associated with an unacceptable increase in CV risk. A large number of trials have since been initiated, adhering to the new guidance.
   
  • The SAVOR and EXAMINE trials represent the first studies in the post-FDA new guidance that have reported results. TECOS is to deliver results short after CVCT, likely early in 2015. While Saxaglitin and Alogliptin proved to be non-inferior to placebo on the primary outcome of MACE, the results of the two trials diverged regarding effects on heart failure events. SAVOR, EXAMINE and TECOS trial data will be great case-studies for discussing the appropriateness and challenges of FDA Guidance trials to establish the effect of diabetes on CV outcomes, and discuss the likely important consequences on clinical practice.
   
  • A recent FDA Advisory Committee meeting completely repudiated the findings that led to doing CV safety studies for DM drugs. Oddly, FDA responded by leaving its guidance in place. With calls for CV safety, studies are springing up in many other places – not just the weight loss drugs. An overarching guidance on when there is enough evidence to merit asking for studies is much needed.
   
  • How to design/conduct prevention studies? Should CV safety trials detract from seeking efficacy (CV prevention) as an endpoint?
   
  • How big are the challenges of large sample size, long follow-up? How to overcome? Where will resources come from (i.e., may not be attractive for industry due to need for long trial)? Will the regulatory environment adapt to facilitate/promote research in this area?
     
    Why assess CV efficacy/safety in diabetes? Surrogacy challenged
  présentation Faiez Zannad (Nancy, FRA)
     
    Methodological issues: non-inferiority, using interim data in regulatory decisions, composite endpoints, comparisons across trials
  présentation Speaker: Stuart Pocock (London, UK)
  présentation Discussant: Nancy Geller (NHLBI, USA)
     
    CV safety endpoints: the heart failure issue
    • Trial data
  présentation EXAMINE: Faiez Zannad (Nancy, FRA)
  présentation SAVOR: Deepak Bhatt (Boston, USA)
  AleCardio Jean Claude Tardiff (Montreal, CAN)
     
    Mechanistic insights in DPP4 heart physiology and neurohormonal interactions
  présentation Speaker: Nancy Brown (Nashville, USA)
  Discussant: John Burnett (Rochester, USA)
     
    Regulatory issues:Gonzalo Calvo (Barcelona, ESP), Ray Lipicky (North Potomac, USA)
     
Moderated discussion with audience participation:
Shouldn’t we be aiming at CV prevention, rather than simple CV safety?
     
    Panellists: Deepak Bhatt (Boston, USA), Nancy Brown (Nashville, USA), John Burnett (Rochester, USA), Gonzalo Calvo (Barcelona, ESP), Luther Clark (Merck, USA), Mads Engelmann (Novo Nordisk, DEN), Nancy Geller (NHLBI, USA), Boaz Hirshberg (AstraZeneca, DEN), Stuart Kupfer (Takeda, USA), Ray Lipicky (North Potomac, USA), Shamik Parikh (AstraZeneca, USA), Stuart Pocock (London, UK), Arantxa Sancho (EMA, ESP), Norman Stockbridge (FDA, USA), Jean Claude Tardiff (Montreal, CAN), Faiez Zannad (Nancy, FRA)
     
10.00 am – 10.30 am - COFFEE BREAK
     
BALLROOM
     
11.30 am - 3.00 pm
THE SPECIFIC FRAMEWORK OF CELL AND GENE THERAPY TRIALS
     
    Moderators: Ileana Piña (New York, USA), Steve Winitsky (FDA, USA)
     
   
  • There are an increasing number of patients with significant morbidity despite optimal medical management. Researchers are studying whether cellular and gene therapies may be capable of repairing a diseased heart through mechanisms such as modulation of paracrine pathways or regeneration of cardiac tissues. Preclinical data that provide an enhanced understanding of cardiac repair mechanisms are critical for the field to progress, as preclinical knowledge can be used to inform the design of efficient clinical programs for development of biologic products.
   
  • Cellular therapies for the treatment of cardiac disease generally meet the definition of “biological product” in section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)), and are regulated by the Center for Biologics Evaluation and Research (CBER).
   
  • The aims of this session are to:
   
Familiarize clinical trialists with specific issues related to development of cell and gene therapies, with a focus on considerations for Phase 1 and Phase 2 clinical trials (which collectively may be referred to as “early phase clinical trials”), including:
   
A brief overview of the main categories of cell and gene therapies that are being developed to treat cardiac disease, with a focus on stem cell derived products (autologous and allogeneic cell therapies, iPSC and ESC derived product, gene therapies)
   
Discuss what needs to be done before a product can be used in a Phase I trial (safety of manufactured product, lot release specs, initial stability and shipping tests, manufacturing issues, i.e. donor testing, reagent quality, cell banking, lot release testing requirements, i.e. sterility, purity, identity, potency)
   
Identify challenges – the end product often is a complex mixture and there may be very limited time material to test the final product
   
Discuss preclinical considerations (animal species/model selection, preclinical study design, data submission to support an IND for a Phase 1 study)
   
Overview of FDA Guidance Document, ‘Cellular Therapy for Cardiac Disease’
   
Discuss study design elements
     
    An introduction to CBER and its function
    • Chemistry, Manufacturing, and Controls (CMC) considerations for early-phase cardiovascular cell and gene therapy studies
  présentation Brenton McCright, (FDA, USA)
    • Preclinical considerations for early-phase cardiovascular cell and gene therapy studies
  présentation Wei Liang (FDA, USA)
    • Clinical considerations for early-phase cardiovascular cell and gene therapy studies
  présentation Steve Winitsky (FDA, USA)
     
    Trial design issues
    • Heart failure trials: clinically meaningful endpoints
  présentation Carl Pepine (Miami, USA)
    • Discrepancies in design, methods, or results
  présentation Graham Cole (London, UK)
    • Industry viewpoint
  présentation Janice Pogoda (Celladon, USA)
  présentation Francis Plat (Juventas Therapeutics, USA)
     
Moderated discussion with audience participation:
Guidance for future trials of cellular therapy for cardiac disease
     
    Panellists: Graham Cole (London, UK), Wei Liang (OCTGT Preclinical Reviewer FDA, USA), Brenton McCright, (OCTGT CMC Reviewer, FDA, USA), Marc Penn (Akron, USA), Carl Pepine (Miami, USA), Ileana Piña (New York, USA), Francis Plat (Juventas Therapeutics, USA), Janice Pogoda (Celladon, USA), Steve Winitsky (FDA, USA)
     
THEATRE
     
11.30 am - 3.00 pm
RENAL DENERVATION/MODULATION TRIALS
     
    Moderators: Cecilia Linde (Stockholm, SWE), Henry Black (New York, USA)
     
   
  • Rigorous evaluation of safety and efficacy is required for neural modulation device therapy that involves invasive procedures, which are costly in comparison to generic drug therapy (i.e., for hypertension), and have an unknown benefit versus risk profile.
   
  • Designing pivotal trials to test these devices is challenging because of complexities related to blinding, patient selection, choice of control group, and selecting appropriate endpoints. SIMPLICITY-HTN3 testing catheter-based renal denervation for the treatment of resistant hypertension failed to achieve its primary efficacy end point, which was a sustained reduction in systolic blood pressure at six months.
   
  • Based on positive results from registry data, a sizable group of investigators are challenging the design of SIMPLICITY-HTN3. Many more sham-controlled trials will soon deliver. Reassessing the evidence is extremely timely.
   
  • For other, neural modulation therapies in cardiovascular medicine, clinical experience is limited from which to base assumptions about effect size, sustainability of treatment effect, and long-term safety. Several pivotal trials are ongoing that, once complete, will begin to provide the data necessary to evaluate these treatment approaches and inform future clinical trial design with these or similar devices.
     
    Hypertension
    • Gaps in hypertension trials and management post JNC 8
  présentation Henry Black (New York, USA)
    • Renal denervation: how to reconcile trial results with registry data
   
  • Evidence from trials and registries
  présentation Darrel Francis (London, UK)
   
  • Methodological commentary
  présentation Speaker: Stuart Pocock (London, UK)
  présentation Discussant: Nancy Geller (NHLBI, USA)
     
    Barostimulation: how to leverage enough evidence to become standard of care?
  présentation Speaker: John Bisognano (Rochester, USA)
  Discussant: Patrick Rossignol (Nancy, FRA)
     
    Heart failure
    • Lessons learnt post NECTAR-HF
  présentation Faiez Zannad (Nancy, FRA)
     
    Industry perspective:
  présentation Steve Ruble (BSCI, USA)
  présentation Nadim Yared (CVRx, USA)
     
    Regulatory perspective:
  présentation Angeles Alonso (EMA, UK)
  présentation Bram Zuckerman (FDA, USA)
     
Moderated discussion with audience participation:
What level of evidence? Effectiveness and cost-effectiveness issues
     
    Panellists: Angeles Alonso (EMA, UK), William Abraham (Columbus, USA), Georges Bakris (Chicago, USA), John Bisognano (Rochester, USA), Darrel Francis (London, UK), Nancy Geller (NHLBI, USA), Cecilia Linde (Stockholm, SWE), Stuart Pocock (London, UK), Patrick Rossignol (Nancy, FRA), Steve Ruble (BSCI, USA), Luis Ruilope (Madrid, ESP), Philippe Wanstok (CVRx, USA), Nadim Yared (CVRx, USA), Faiez Zannad (Nancy, FRA), Bram Zuckerman (FDA, USA)
     
3.00 pm – 3.30 pm - COFFEE BREAK
     
BALLROOM
     
3.30 pm - 6.30 pm
THE ATHEROSCLEROSIS TRIALISTS WORKSHOP
     
  présentation Moderators: Wolfgang Koenig (Ulm, GER), Robert Rosenson (New York, USA).
     
    On the way to personalized medicine: what are promising future strategies to deal with the high standard of care in today`s clinical trials to identify those patients that might have an additional benefit?
     
    Widespread early intervention in acute coronary syndromes (ACS) and complete revascularization of stenotic lesions complemented by aggressive polypharmacy has considerably reduced early mortality and improved prognosis in patients after ACS. Still, there are a fairly high percentage of patients who develop secondary fatal or non-fatal events. The challenge for today`s clinical practice is to adequately identify and treat those subjects rather than providing additional therapy to all patients after an event. Thus, despite all our current efforts there is room for improvement.
     
   
  • A very active clinical research program is delivering an important number of new potential therapeutic targets that may be ready for trial testing. These may be lipid or lipid-associated targets or complementary anti-inflammatory strategies.
   
  • There is a strong need for better markers to identify high-risk subjects after an ACS. Can OMICS technology help in terms of new specific biomarkers for improved risk stratification? Could there be a role for genetic testing to identify the population at risk for additional thera py?
   
  • One major question relates to the value of biomarker-guided and/or risk guided therapy and how to design appropriate trials to test these therapeutic strategies. Should therapy be targeted to patients with specific biomarkers profiles? e.g. dysfunctional HDL, high inflammatory burden (elevated CRP), high Lp-PLA2 activity etc.?
   
  • In summary, a fairly large number of lipid-associated new targets or targets reflecting other pathways of the complex atherosclerotic process are being evaluated in mechanistic imaging studies but also in large randomized controlled clinical trials looking for major cardiovascular endpoints. In all of these trials the standard of care is much better than seen in the real world situation. Thus, the question arises, whether these additional compounds will lead to a clinically significant reduction in cardiovascular events on top of optimal standard care.
   
  • Finally, results of IMPROVE-IT, soon to be known, can affect the acceptability of upcoming new drugs for treating hyperlipidemia.
     
    MRI imaging in clinical trials
  présentation Speaker: Robin Choudhury (Oxford, UK)
  Discussant: Ahmad Tawakol (Boston, USA)
     
    IMPROVE-IT: insight and consequences on the lower is better strategy and ongoing PCSK9 trials
    Robert Califf (Durham, USA)
    Identifying new risk markers and potential targets: the value of the proteome, metabolome, microRNAs or the transcriptome?
  présentation Manuel Mayr (London, UK)
    STABILITY and SOLID: could targeted intervention with an Lp-PLA2 inhibitor work?
  présentation Wolfgang Koenig (Ulm, GER)
    Do negative Mendelian randomization studies rule out a relevant therapeutic effect of an intervention?
  présentation Robert Rosenson (New York, USA)
    Clinical trials with antisense therapy targeting triglycerides and Lp(a): geared for the big picture
  présentation Sam Tsimikas (ISIS Pharmaceuticals, USA)
     
    Industry perspective:Sam Tsimikas (ISIS Pharmaceuticals, USA)
     
  présentation Regulatory perspective:Arantxa Sancho (EMA, ESP)
     
Moderated discussion with audience participation:
How to design new trials for approval of new anti-atherosclerosis agents
     
  présentation Panellists: Angeles Alonso (EMA, UK), Denise Bonds (NHLBI, USA), Robert Califf (Durham, USA), Gonzalo Calvo (Barcelona ESP), Luther Clark (Merck, USA), Robin Choudhury (Oxford, UK), Efthymios Deliargyris (MedCo, USA), David Gordon (NHLBI, USA), Dave Kallend (MedCo, USA), Armin Koch (EMA, GER), Wolfgang Koenig (Ulm, GER), Joerg Koglin (Merck, USA), Michael Lauer (NHLBI, USA), John Lawrence (BMS, USA), Manuel Mayr (London, UK), Carl Pepine (Miami, USA), Yves Rosenberg (NHLBI, USA), Robert Rosenson (New York, USA), David Rutledge (Abbott, USA), Arantxa Sancho (EMA, ESP), Walter Singleton (ISIS Pharmaceuticals, USA), Jean Claude Tardiff (Montreal, CAN), Ahmad Tawakol (Boston, USA), Sam Tsimikas (ISIS Pharmaceuticals, USA)
     
THEATRE
     
3.30 pm - 6.00 pm
ASSESSING THE ‘PARADIGM’ TRIAL IN HEART FAILURE THERAPY?
     
    Moderators: Bertram Pitt (Ann Arbor, USA), Faiez Zannad (Nancy, FRA)
     
   
  • The PARADIGM trial is unique among HF trials.
   
  • It has been stopped prematurely for an excess of benefit. Although, in HF, such early termination is not uncommon (CIBIS II, BEAUTIFUL, RALES, EMPHASIS-HF all went through this process), there are issues with this, since stopping a trial prematurely tends to overstate benefits and understate safety observations.
   
  • This phase 3 trial was planned without a prior phase 2 study. However, it came after OVERTURE, a trial that tested another neprelysine inhibitor. The trial offers a great opportunity to discuss when and how skipping phase 2 might be occasionally advisable.
   
  • The trial wasn’t placebo-controlled. It evaluated LCZ696, a novel potential treatment for chronic heart failure combining in a single molecule an ARB and a NEP inhibitor, instead of – not on top of – an old-standby ACE inhibitor. Whether this trial may open up the minds to head-to-head comparison trials, rather than on-top-of trials, is an interesting case for discussion.
   
  • PARADIGM is the largest-ever drug trial in chronic HF. Was it overpowered? Still, the trial shows that in very well treated patients with systolic heart failure (mostly mild to moderate), there is room for improvement. How much further improvement is possible?
   
  • The trial enrolled mainly mild to moderate Caucasian patients. How many results may apply to asymptomatic or more severe patients? Are we prepared to initiate patients on LCZ696, rather than on ACE inhibitors? How about patients on ACE inhibitors? Should we switch them to LCZ696? Is safety secured enough, especially in African Americans who did not tolerate omapatrilat, a not so different compound?
     
    PARADIGM: the main findings and application for patient type?
  présentation Milton Packer (Dallas, USA)
     
    PARADIGM trial design: when and how could phase 2 be skipped?
  présentation Speaker: Christopher O’Connor (Durham, USA)
  Discussant: Marty Lefkowitz (Novartis, USA)
     
    Challenges, interpretation and generalizability issues relative to stopping the trial early
  présentation Speaker: Stuart Pocock (London, UK)
  présentation Discussant: Marc Pfeffer (Boston, USA)
     
    Moving to HFPEF: PARAGON, the ultimate design?
  présentation Speaker: Scott Solomon (Boston, USA)
  présentation Discussant: Javed Butler (Atlanta, USA)
     
Moderated discussion with audience participation:
What’s next – when to substitute from ACE inhibitor therapy to LCZ696?
     
    Panellists: Javed Butler (Atlanta, USA), Nancy Geller (NHLBI, USA), Marty Lefkowitz (Novartis, USA), Felipe Martinez (Cordoba, ARG), Milton Packer (Dallas, USA), Marc Pfeffer (Boston, USA), Bertram Pitt (Ann Arbor, USA), Stuart Pocock (London, UK), Luis Ruilope (Madrid, ESP), Scott Solomon (Boston, USA), Janet Wittes (Washington,USA), Faiez Zannad (Nancy, FRA)
     
         
SUNDAY 7 DECEMBER 2014
     
BALLROOM
     
8.30 am - 12.00 noon
TOWARD A NEW STANDARD OF CLINICAL TRIALS
IN PRIMARY PULMONARY ARTERIAL HYPERTENSION?
     
    Moderators: Ileana Piña (New York, USA), Steve Winitsky (FDA, USA)
     
   
  • Pulmonary arterial hypertension (PAH) includes a series of clinical conditions characterized by progressive increase of pulmonary vascular resistance leading to right heart failure and premature death. Randomized controlled studies so far resulted in the regulatory approval of 8 drugs of three pharmacological classes: endothelin receptor antagonists, phosphodiesterase type-5 inhibitors and prostanoids. These therapies improve symptoms, exercise capacity, haemodynamics, and outcome but the clinical relevance of these effects have been recently challenged and, despite important progresses on medical therapy, many patients with PAH remain with relevant symptoms and poor outcome.
   
  • Meta-analyses of trials with approved drugs, utilized either as monotherapy or in combination, have shown improvements on all-cause mortality or clinical worsening, respectively. Therefore, the effect on survival of these compounds has not been appropriately assessed in individual trials because limited improvements observed on the exercise capacity and the short duration and the small sample size of the individual studies.
   
  • A new standard of clinical trials in PAH is being set with larger outcome trials, such as the completed SERAPHIN trial with macitentan, using the composite endpoint of symptomatic worsening and death and the ongoing lagest trial in the area, GRIPHON with the prostacyclin (PGI2) Receptor agonist Selexipag, using a morbiditymortality endpoint is just terminated and is positive, setting new standards of morbidity-mortality trials in PAH.
   
  • Discussion on the optimal design of future PAH trials is ongoing, including the selection of patient populations (representativity, geographical variations, severity, etc), endpoint related issues (relevance of soft endpoints, need for M&M trials), sample size and duration of follow up with the challenges related to a rare disease and approvability.
   
  • A number of treatments for PAH will lose patent protection in the coming years including treprostinil, iloprost, sildenafil, tadalafil. Riociguat was approved recently and is one of the many first-in-class entrants, such as Actelion’s oral prostacyclin receptor antagonist selexipag, as well as ambrisentan and macitentan. Oral treprostinil has also been recently finally approved by the FDA after 2 initial rejections.
     
    Critical appraisal of randomized clinical trials and meta-analyses in PAH
  Nazzareno Galié (Bologna, ITA)
     
    Imaging in pulmonary hypertension
  Ahmad Tawakol (Boston, USA)
     
    Individual experiences and lessons learnt from recent trials: will outcome trials prevail? Macitentan (SERAPHIN) Selexipag (GRIPHON)
  Speaker: Gérald Simonneau (Bicêtre, FRA)
  Discussant: Sebastien Roux (Actelion, CHE)
     
    Ambrisentan, from ARTEMIS, ARIES to AMBITION
  prĂ©sentation Speaker: Olivier Sitbon (Paris, FRA)
     
    The 6-minute walk test trials: Riociguat (PATENT, CHEST), Treprostinil (FREEDOM), Imatinib (IMPRES), Tadalafil (PHIRST)
  prĂ©sentation Speaker: Stuart Rich (Chicago, USA)
     
    Industry perspective:
  prĂ©sentation Neil Davie (Bayer, GER)
  Sebastien Roux (Actelion, CHE)
     
    Regulatory perspective:
  prĂ©sentation Amani El-Gazayerly (EMA, NED)
  Kaori Shinagawa (PMDA, JAP)
  prĂ©sentation Martin Rose (FDA, USA)
     
Moderated discussion with audience participation:
How should evolve the new standard of clinical trials in pulmonary arterial hypertension?
     
    Panellists: Angeles Alonso (EMA, UK), Neil Davie (Bayer, GER), Amani El-Gazayerly (EMA, NED), Nazzareno Galié (Bologna, ITA), Hunter Gillies (Gilead, USA), Stuart Rich (Chicago, USA), Martin Rose (FDA, USA), Sebastien Roux (Actelion, CHE), Kaori Shinagawa (PMDA, JAP), Gérald Simonneau (Bicêtre, FRA), Olivier Sitbon (Paris, FRA), Mary Ross Southworth (FDA, USA), Ahmad Tawakol (Boston, USA), Robert Temple (FDA, USA)
     
THEATRE
     
8.30 am - 12.00 noon
WORKSHOP TO ADDRESS POLYPILL CLINICAL TRIALS AND REGULATORY APPROVAL
Wellcome Trust – CVCT – ISCP joint session
     
    Moderators: Gheorghe-Andrei Dan (Bucharest, ROM), Anthony Rodgers (Sydney, AUS)
     
   
  • A fixed-dose combination of blood pressure, cholesterol lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of CVD given its potential for better adherence, lower costs and improved treatment affordability.
   
  • Polypill formulations have now been approved in almost a dozen countries in Europe, South America, Central America, Europe and India (e.g. Trinomia®, Polycap) and applications are underway or planned for other products.
   
  • Potential patient populations can be divided into three target groups:
   
  • Patients recommended to receive all the components (e.g. established coronary disease) who are currently being treated with the same medications as separate pills i.e. straight substitution.
   
  • Patients recommended to receive all the components who are not currently being treated with all medications i.e. step-up substitution.
   
  • Patients without current indications to all components who are nevertheless at raised cardiovascular risk and could benefit from all components e.g. high-risk primary prevention with non-optimal BP and lipid levels but without hypertension or dyslipidaemia.
     
    Regulatory approvals have focused on the first of these three groups, while polypill clinical trialists have focused on the last two groups.
   
  • More than half of all new cardiovascular products in Europe are combinations (defined as products containing two or more agents from the classes of blood pressure lowering, cholesterol lowering, antiplatelet and glucose lowering).
   
  • Some have noted that fixed dose combination therapy contradicts a key principle of clinical pharmacology of individualization of therapy and the paradigm of precision and personalized medicine. Dosing is a significant issue, and one area of debate is whether different polypills with different doses of medication should be developed, and if so how many. Concern has been expressed that lack of dose versions will lead to deterioration in risk factor control.
   
  • Many have expressed concern that use of a polypill would lead to patients neglecting diet, exercise and other lifestyle measures.
   
  • Results from several large, long-term polypill clinical trials have become available in the last year that will help address these issues. Several trials are due to complete in the next few years.
   
  • Given the results to date, and the type of evidence that will soon be emerging, what are the challenges and opportunities for regulatory approvals?
   
  • What are the regulatory issues for under-treated patient population?
   
  • When can approval be made on surrogate outcomes and when are event trials needed?
   
  • How can there be a rational approach to the number of dose versions?
   
  • What post-approval pharmacovigilance studies are required?
     
    Clinician perspective:
    • The problem of CV drug adherence worldwide
  prĂ©sentation José M. Castellano (Madrid, ESP)
     
    • Fixed dose combinations in cardiovascular disease. Opportunities and challenges
  prĂ©sentation Anthony Rodgers (Sydney, AUS)
    • Focusing on polypills in CV secondary prevention: the FOCUS trial and beyond
  prĂ©sentation Felipe Martinez (Cordoba, ARG)
     
    Industry perspective:Fabiana d’Aniello (Ferrer Grupo, ESP)
     
    Regulatory perspective:
    • EMAPieter de Graeff (EMA, NED), Armin Koch (EMA, GER)
    • FDANorman Stockbridge (FDA, USA)
     
    Payers’ perspective:Deneen Vojta (United Health, USA))
     
Moderated discussion with audience participation:
Regulatory approval routes for cardiovascular combination pills
     
    Panellists: José M. Castellano (Madrid, ESP), Gheorghe-Andrei Dan (Bucharest, ROM), Fabiana d’Aniello (Ferrer Grupo, ESP), Pieter De Graef (EMA, NED), David Guez (Servier, FRA), Armin Koch (EMA, GER), Felipe Martinez (Cordoba, ARG), Anthony Rodgers (Sydney, AUS), Natalia París Sotes (Ferrer Grupo, ESP), Norman Stockbridge (FDA, USA), Koon Teo (Hamilton, CAN), Deneen Vojta (United Health, USA)
     
10.30 am – 11.30 am - COFFEE BREAK