Despite multiple efforts from pharmaceutical companies at developing drugs to improve the survival and well-being of patients suffering from acute heart failure (AHF), none of the emerging therapies investigated for the treatment of this condition in the past decade has managed to succeed in reaching the market. Following the recent Phase 3 trial failures of Cardiorentis’s ularitide and Novartis’s serelaxin, previously heralded as the two most promising emerging AHF therapies, increasing number of key opinion leaders in cardiology question the potential of any AHF therapy to be able to prolong patient survival. The resulting absence of promising emerging therapies in late-phase development for AHF makes the current treatment options for AHF all the more important.
AHF is a life-threatening condition, with nearly one-fifth of patients admitted to hospital with AHF not surviving past one year.1,2 These statistics have not improved significantly in the recent years, largely because no currently approved AHF drugs have been able to prolong patient life. Nevertheless, reduction in mortality is the clinical end point that physicians regard as the most influential in the treatment of AHF3, clearly showing that any therapy capable of improving this outcome will make a significant impact in this indication. Many drug developers have pursued this opportunity and a number of emerging therapies have been evaluated against mortality end point in late-stage clinical trials. However, so far, this has only led to disappointment with negative results. The most recent high-profile failures were those of ularitide and serelaxin. In its Phase 3 TRUE-AHF trial the natriuretic peptide receptor agonist ularitide failed to lead to a significant improvement in clinical outcomes.4 Similarly, serelaxin, a recombinant form of human relaxin-2, did not reduce mortality or worsening heart failure in AHF patients in its Phase 3 RELAX-AHF-2 trial.5
Some cardiologists have long questioned whether a short-term (typically 24 - 48 hour-long) treatment with an AHF therapy could result in long-term reductions in mortality and morbidity outcomes. Following the clinical trial failures of serelaxin and ularitide, this view became even more prominent among key opinion leaders.
“Conceptually, it’s quite difficult to think about why a treatment given for 24 or 48 hours might lead to benefit over 30 days or 60 days or 90 days or even a year.” - Cardiologist, United Kingdom
In the absence of therapies able to improve long-term outcomes, what treatment options do cardiologists have at hand for their AHF patients? Decision Resources Group’s CurrentTreatment® Acute Heart Failure 2017 (US) provides in-depth insights into current physician prescribing practices, as well as key drivers of treatment selection for AHF in the United States.1 According to findings from the survey of 101 U.S. cardiologists, current treatment approaches in AHF focus mainly on relieving symptoms. Over 80% of AHF patients treated by surveyed cardiologists receive loop diuretics, which remains the cornerstone of AHF treatment due to their effectiveness in improving symptoms of AHF such as breathlessness and fluid overload.1 Addition of other drug classes is typically dictated by patient characteristics, which, due to the heterogeneous nature of AHF, can vary significantly.
With effectiveness of current therapies limited to symptomatic relief, is it the end of the road for AHF therapies aimed at improving survival? Potentially. However, some cardiologists believe that the recent AHF trial failures only reflect our lack of understanding of the etiology and pathophysiology of AHF, and there is still a possibility that future emerging therapies will be able to improve long-term outcomes, provided they target the right patient subpopulation with the right molecule. It is also conceivable that an AHF therapy administered during patient in-hospital stay, could continue to be used in patients when they transition to chronic heart failure (CHF), and would be able to prove successful in improving outcomes, overcoming the concerns associated with short administration time. Omecamtiv mecarbil was once a candidate to become one such drug, previously investigated for the treatment of AHF and CHF. However, Amgen and Cytokinetics, its developers, have since decided to focus their efforts only on development in CHF.
The future of AHF treatment landscape may not be as bleak as the picture painted by the recent trial failures makes out, but AHF will likely remain the indication, for which development of new effective therapies is associated with higher than average risk of failure. Notwithstanding all challenges associated with developing effective AHF therapies, a label for improving outcomes would likely secure a drug's place as a first-line therapy.
For more insights and analysis on the cardiovascular and metabolic markets follow @drudnicka_DRG.
1 Decision Resources Group’s Current Treatment Acute Heart Failure 2017 (US). https://decisionresourcesgroup.com/acute-heart-failure-u-s-current-treatment/
2 Roger VL, et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012;125 :e2-e220.
3 Decision Resources Group’s Unmet Need Acute Heart Failure 2017 (US/EU).
4 Packer M, et al. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med. 2017 18;376(20):1956-1964.
5 Novartis, press release, March 22, 2017. https://www.novartis.com/news/media-releases/novartis-provides-update-phase-iii-study-rlx030-serelaxin-patients-acute-heart