Five Emerging Trends within Cardiovascular Research

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1 Five Emerging Trends within Cardiovasclar Research Michael F Mrphy MD, PhD Toni Bransford MD, FACC Eteri Tsetskhladze MD, PhD William L Slone PhD demari Mackie PhD

2 Over the past 50 years, dramatic changes in the treatment of cardiovasclar disease, accompanied by marked declines in morbidity and mortality have occrred. Nonetheless, cardiovasclar disease remains the leading case of death and disability in the world. With increasingly permissive science providing new insights into pathophysiology, innovative drg discovery methods now engage more specific targets of cardiopathophysiology and drg development occrs in a highly internationalized environment. 01 Five emerging trends within the drg discovery/drg development paradigm are highlighted in this review each reinforcing the need for therapetically focsed, methodologically rigoros, and highly efficient project teams for prodct evalation and commercialization. These trends are: Recognition of pleiotropic drg effects; Emergence of personalized/precision medicine; Impact of epigenetics and mirna antisense oligoncleotide therapetics; Development of innovative trial methods for innovative Interventions; and Academic, CRO, and pharmacetical collaboration as a natral extension of emerging science. 1 Therapetics and pharmacetical agreements: a natral

3 1 - in an Age of Pleiotropy Drgs treating metabolic aberrations sch as dyslipidemias and type 2 diabetes mellits are on the crrent wave of treatments which demonstrated mltiple effects freqently sbsmed nder the concept of pleiotropy. The impact of type II diabetic therapy on the cardiovasclar system specifically prompts scrtiny. The most recent target is the dipeptidyl peptidase 4 (DPP-4) enzyme. DPP- 4 inhibitors are crrently approved to lower glcose levels in Type 2 Diabetes Mellits throgh the incretin hormones, glcagon-like peptide-1 (GLP-1) and glcose-dependent inslinotropic peptide (GIP). Yet the sbstrates for DPP-4 inhibitors are varied and extensive with the potential to mediate a wide range of effects, independent of those mediated throgh GLP-1 modlation. For example, DPP-4 inhibitors exert cardiac effects throgh stromal cell derived factor-1 (SDF-1) potentiation. It s not clear if SDF-1 agmentation is de to the effects of GLP-1 increase or a direct effect of DPP-4 inhibition leading to improved circlating stem cell signaling throgh SDF-1. Yet, more research is nderway to nderstand these cardiac effects becase large scale trials have indicated conflicting information which is critically relevant clinically. As an example, both the SAVOR-TIMI 53 and the EXAMINE prospective cardiovasclar otcomes trials demonstrated a small bt statistically significant increase in heart failre hospitalizations. Several DPP-4 inhibitors are now approved for the treatment of hyperglycemia bt these agents can have variable selectivity for enzymes with DPP-4-like activity; i.e., off target effect. This wold spport the notion that the cardiovasclar effects, whether positive or negative, may not be a class-specific phenomenon of DPP-4 inhibitors. Indeed, a large, poplation-based stdy with data from the FDA-fnded mini Sentinel program failed to find an increase in heart failre hospitalizations relative to other diabetic agents contradicting the SAVOR and EXAMINE trials. Frther research into nderstanding the cardiovasclar effects of this diabetic drg based pon primary as well as secondary targets wold represent major progress that cold dramatically inflence the management of the cardiovasclar disease Therapetics and pharmacetical agreements: a natral

4 2 - Personalized/ Accelerating interest in personalized and precision medicine is changing the way the pharmacetical indstry, as well as physicians approach therapetic novelty in cardiovasclar disease. While personalized medicine has had sccess in oncology, it faces different challenges in cardiovasclar disease where complex genetics, the environment, and patient lifestyle combine to create a niqe clinical presentation for each patient. Mch more than simply genotype, it is the interplay of environmental factors with patient risk factors that dictate therapetic decisions, and hence factors which either confond or mediate beneficial therapetic effects. As an example, the prevalence of traditional therapies like angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and varios interventions to redce modifiable risk factors (e.g. exercise, smoking) means that many patients are receiving these and other therapies as a management stratagem which mst be acconted for in trial design, methods of exection and analysis. The complex interplay of genes and environmental inflences means that new therapies may work extremely well, bt only in a sbset of patients adding emphasis to a freqently voiced axiom that while researchers live at the mean, physicians live within the standard deviations. The challenge becomes defining the bondaries of that sbset. As an example, Regenerative therapies toted to repair and replace damage tisse and conditions as diverse as myocardial infarction, vasclogenesis, ventriclar fnction, and ischemic heart disease are still in their early stages, with allogeneic and atologos therapies nder development. In this case, medicine personalized by the se of a patient s own stem cells also can be a disadvantage commercially becase it reqires that the patient s cells be harvested and then converted into a therapetic agent, often by cltring and expanding donor cells into mesenchymal stem cells that can improve damaged heart tisse. In contrast, the se of allogeneic cells (e.g., derived from genetically non-identical donors) shortens the time to administration of a therapy for a specific patient and can be sed in an off-the-shelf manner, althogh with the potential for decreased compatibility with a patient s immne system Therapetics and pharmacetical agreements: a natral

5 Precision medicine sch as one-dose gene therapy treatments are also making their mark. In this stratagem, a vector is designed to introdce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. The application, which has recently been introdced for heart failre patients has profond implication for trial design and commercialization. For example, onedose gene therapy based interventions in heart failre cold reslt in a reevalation and ranking of the importance of otcomes with impact on milestones, timelines and expenditres for trials. Additionally, payer perspectives gain ascendancy becase gene therapy treatments have a disproportionate impact on formlary placement and reimbrsement decisions given the transformative benefit of the therapy, the nmber of patients possibly affected, and the interaction effects which will exist between this novel therapy, and existing pharmacotherapy as well as lifestyle modification mst also be considered. An integrated, a highly effective project team which can provide insights on medical diagnoses, measres, analysis, and otcomes all of which potentially inform vale as well as clinical tility provide a differentiated soltion in this setting. 1 Therapetics and pharmacetical agreements: a natral

6 3 - Epigenetics and MiRNA Antisense Oligoncleotide Therapetics The large amont of basic science research regarding epigenetics effects on RNA biology has greatly expand knowledge of their role in the progression and prevention of disease across therapetic areas. Scientific discoveries regarding epigenetic changes in DNA methylation, histone modification, and RNA biology affect the cardiovasclar system are opening p the potential for new therapetic avenes. For example, the methylation stats for certain genes has been linked to increased risk of cardiovasclar disease in discrete poplations, sch as F2RL3 in smokers, PLA2G7 in females, and locs 9p21 within the Chinese poplation. Promising antisense oligoncleotide technologies sggest that oligoncleotides themselves may soon emerge in the therapetic armamentarim as has been illstrated by mipomersen, an antisense oligoncleotide approved for treatment of hyperlipidemia. However promising these therapetic strategies appear, there are still encmbrances that mst be addressed before any clinical potential can be realized. For example, in antisense therapetic strategies, one challenge freqently addressed is how to specifically target antisense oligoncleotide prodcts to the organs of interest. Delivery mechanisms nder evalation inclde cell-penetrating peptides, nanoparticles, viral vectors, liposomes, polymers, dendrimers, micelle, and ltrasond-targeted microbbble destrction. Research and development implications ths are formidable. In addition to creating the antisense technology, a sponsor mst also co-develop or otherwise accont for differences in methods of delivery. Overall, these innovative disciplines have the potential to bring abot the next generation of cardiovasclar therapetics, and the design and exection of the trials that will evalate them mst also be eqally innovative. 1 Therapetics and pharmacetical agreements: a natral

7 4 - Innovative Trial Methods, Regional heterogeneity in treatment otcomes emphasizes the necessity of reevalating traditional trial designs and methods of exection. Even if trials may not differ in treatment intervention, eligibility criteria, or imaging assessments, it is commonly observed that patient response in different geographical regions can exhibit marked variation. These differences exist as a reflection of differences in standards of care, and either genotypic or phenotypic variation in patient presentation significantly impacting inferences which are possible based pon overall statistical analyses. Indeed, overall trial reslts may not generalize flly across the entire poplation of patients who might ltimately be eligible for treatment. Regional heterogeneity in treatment otcome therefore accentates the need to plan for examination of sbgrops in a fashion permitting valid analyses and clinical interpretation. For example, both qantitative and qalitatively different treatment effects across sbgrops are fraght with challenges in interpretation given that the otcome of one sbgrop may not be anticipated to be materially better or worse than the others in a new trial a priori. Nevertheless, these differences can be discerned particlarly in the larger clinical trial databases prodced in later phase clinical investigations. Becase assessments of the benefit: risk ratio for novel CV therapetics may vary by sbgrops, large international trials are a better way to assess potential new treatments across many contries verss the alternative of separate smaller trials in each region. Managing scale, process, staffing and dataflow in the context of mltiple contries and mltiple vendors demands the highest operational acmen. The combination of transformative therapetics in cardiovasclar disease and the international expansion of the clinical trial environment also mandates examination of different strategies in clinical trial design that extend across a program of research. For example, designing a program of research in which learning phase paradigms are maximally tilized prior to lanching confirmatory stdies become mandatory, and ths the entire panoply of adaptive stdy design methodology becomes a part of the clinical trial portfolio. Concepts 1 Therapetics and pharmacetical agreements: a natral

8 as diverse as sample size re-estimation procedres, adaptive randomization based on observed response, adaptive randomization based an acknowledged covariate, enrichment designs, adaptive treatment switching designs, and an adaptive seamless phase 2/3 program provide the basis for a 21st centry toolbox. And becase stdy reslts based pon adaptive trial methodology may not intitively translate into changes in clinical care, it becomes eqally important to evalate therapetic potential on the other end of the explanatory/pragmatic continm. Pragmatic clinical trials se inclsive rather than restrictive patient eligibility reqirements, approach sites delivering clinical care for research participation rather than centers specializing in clinical research, modify data ascertainment techniqes to be compatible with bsy practice environments and focs on otcomes impacting healthcare tilization with the objective of informing clinical and policy decisions to inflence real world practice. 1 Therapetics and pharmacetical agreements: a natral

9 5 - Academic, CRO, and pharmacetical agreements: a natral extension of the science Basic research (predominately academic), drg discovery (predominately indstry) and drg development (CRO dominated) are too often viewed as being at opposite ends of the research and development continm. However, within an increasingly complex scientific and medical environment these research cltres are complementary and heavily enmeshed. Serving as a mediator of process the contract research organization (CRO) mst exemplify an ability to facilitate, manage, and spport the interests of diverse stakeholders and in the process transform the way clinical trial research can be condcted. For example, large cardiovasclar trials provide an exemplary case stdy of the need for collaboration between research interests, althogh the relationship is applicable even within the earliest phases of translational research. These long, large, and complex programs reqire the financial spport and drg discovery expertise of indstry sponsors, the management acmen and efficiency of clinical trial operations within a CRO, and the oversight and expertise of academic specialists who inform patient diagnostics, assessments, and methods of analyses. Finally, there is an additional benefit. Academic/indstry/ CRO collaborations also create a niche environment for the next generation of trialists who have a pedigree in either basic or clinical research. Strong collaboration between these niqe grops, each with their own goals and expectations reqires clinicians and scientists who can navigate across environments, sing a common sbstrate of clinical trial methodology as a basis for reciprocal spport. Throgh a combination of didactic and experiential learning academic, CRO, and pharmacetical collaborative efforts provide an incbator for the next generation of investigators. 1 Therapetics and pharmacetical agreements: a natral

10 Conclsion Highly innovative science, increasingly nanced patient phenotypes, and a compelling nmet clinical need now converge to drive explosive growth in innovative technology and clinical research in diverse cardiovasclar indications. Althogh this selection of only a few potentialities reflect the arbitrary sentiments of athorship, the five emerging trends highlighted serve to illstrate the exciting era of therapetic possibilities developing within cardiovasclar research. 04 INTERNATIONAL: +44 (0) AMERICAS: V.1 - Feb 17 - USL

FIVE EMERGING TRENDS WITHIN CARDIOVASCULAR RESEARCH

FIVE EMERGING TRENDS WITHIN CARDIOVASCULAR RESEARCH MICHAEL F MURPHY, MD, PhD TONI BRANSFORD, MD, FACC ETERI TSETSKHLADZE, MD, PhD WILLIAM L SLONE, PhD demauri MACKIE, PhD Over the past 50 years, dramatic