Developing New Treatments for Heart Failure

Abstract

Abstract-Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting. Morbidity and mortality for ambulatory patients with heart failure (HF) and reduced ejection fraction (HFrEF) have improved in recent decades through neurohormonal modulation using renin-angiotensin-aldosterone system blockade, β-adrenergic blockade, and most recently, neprilysin inhibition. 1,2 However, despite provision of all available therapies, ambulatory patients with HFrEF continue to have poor long-term outcomes, and with few notable exceptions, successful phase III clinical trials with this population during the past decade have been rare.

Mitochondrial function as a therapeutic target in heart failure

“…This unmet need is probably not going to be met by drugs that modulate neurohormonal abnormalities and lower heart rates, because further intervention along these axes is likely to be counterproductive as hypotension and bradycardia become limiting factors. The search for more effective and complementary therapy for this patient population must be focused on improving the intrinsic function of the viable, but dysfunctional, cardiac unit — the cardiomyocytes 3,9 . The novel therapy must be haemodynamically neutral (no decrease in blood pressure or heart rate) and must target the myocardium as the centrepiece of the therapeutic intervention 10 .…”

Reassessing Phase II Heart Failure Clinical Trials

“…4–8 To date, there has been no approved therapy that improves outcomes in patients with worsening heart failure (WHF) in spite of available therapies or those with heart failure and preserved ejection fraction (HFpEF) despite many clinical trials in these populations. 9 A disconnect between the results of phase II and phase III trials of drugs for heart failure is evident (e.g., levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide programs). 10 This experience with neutral or negative phase III trials for HF, despite enthusiasm from positive signals in phase II evaluation, brings into question the utility/role of phase II trials as they are currently designed, conducted and interpreted.…”

Advances in the pharmacotherapy of chronic heart failure with preserved ejection fraction: an ideal opportunity for precision medicine

“…The perception of poor HFpEF trial outcomes and explanations for their failures continue to be a hot topic of scientific commentary, and have even raised concerns about the role of multinational trials. 7–9 Lack of definitive results have led to innumerable HFpEF review articles that lament the failure of HFpEF trials, hopelessness, and lack of definitive therapy. 10–14 Here we seek to challenge this notion of lack of therapies for HFpEF via (1) a reexamination of large-scale multicenter HFpEF clinical trials; (2) discussion of the recent progress in the field, including the critical role of “matchmaking” of the right therapy to the right patient (i.e., making progress towards the goal of precision medicine in HFpEF); and (3) suggestions for appropriate available treatments for this complex condition.…”