Amgen and Bayer have announced two new therapies designed to treat chronic heart failure with reduced ejection fraction (HF-REF) are making positive strides after recent Phase II studies. Amgen’s cardiac myosin activator (omecamtiv mecarbil), being developed with Cytokinetics, was found to have improved cardiac function in patients with chronic HF-REF. Meanwhile, Bayer’s vericiguat, a cyclic GMP (cGMP) pathway-modulating drug, has made progress at higher doses in patients with deteriorating chronic HF-REF.
Both results were announced in November at the 2015 American Heart Association (AHA) meeting in Orlando, Florida.
Despite not having blockbuster potential, the two pipeline drugs could mark a shift from HF therapies that target the renin-angiotensin aldosterone system (RAAS) to therapies with novel mechanisms of action. With cases of HF on the rise, the demand for new drugs that do more than reduce symptoms is growing. Whether such therapies can break into the existing market of HF treatments, which is already saturated, is still cause for debate.
Amgen and Cytokinetics’ Phase II Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) trial investigated the pharmacokinetics, safety, and tolerability of orally-administered omecamtiv mecarbil in 448 patients with chronic HF-REF. The patients were randomized 1:1:1, receiving twice-daily doses of placebo, 25mg omecamtiv mecarbil, or the same drug with a starting dose of 25mg, but titrated up to 50mg after two weeks. After 20 weeks of treatment, statistically significant improvements in measures of cardiac function were observed in the dose-titration group compared with placebo, including increased systolic ejection time (p <0.001), increased stroke volume (p=0.022), and decreased heart rate (p=0.007), as well as statistically significant reductions in left ventricular end-systolic and end-diastolic volumes. A significant reduction in N-terminal pro-brain natriuretic peptide (NTproBNP) levels, a biomarker of HF, was also observed. By directly activating cardiac myosin, omecamtiv mecarbil represents a novel way to treat HF, with the potential to improve cardiac function. Further analysis of these results is being undertaken before a larger Phase III trial is conducted.
The results from the Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction (SOCRATES-REDUCED) trial were also announced at the AHA meeting. This Phase II study investigated the safety and efficacy of Bayer’s vericiguat, a soluble guanylate cyclase (sGC) stimulator, in patients with worsening chronic HF-REF. A cGMP deficit has been associated with worsening chronic HF; thus, vericiguat aims to counteract this deficit by directly stimulating sGC, even in conditions of nitric oxide (NO) deficiency. In this study, patients were randomized into five groups to receive either placebo or one of four daily target doses of vericiguat (1.25mg, 2.5mg, 5mg, or 10mg) for 12 weeks. Although the primary endpoint of a statistically significant reduction in NTproBNP levels after 12 weeks of treatment was not met, a secondary analysis revealed a potential dose-dependent response, with higher doses of vericiguat being associated with greater reductions in NTproBNP levels (p <0.02). Vericiguat was also well-tolerated, and therefore, the drug will likely be further investigated to determine whether higher doses will lead to greater reductions in NTproBNP levels.
A study of the safety and efficacy of vericiguat in the frequently overlooked cohort of HF patients with preserved ejection fraction (HF-PEF) was also conducted by the same group, called SOCRATES-PRESERVED. Although this study was completed, the results have yet to be announced. Treatments for patients with HF-PEF are scarce, so the results from the SOCRATES-PRESERVED trial are eagerly anticipated. However, based on the meager improvement observed in the HF-REF cohort and the notorious difficulty involved in treating HF-PEF patients, it is difficult to be optimistic about the effect of vericiguat in this group.
The current standard of care for patients with chronic HF-REF consists of a multitude of drugs predominantly targeting the RAAS pathway, including angiotensin II converting enzyme (ACE) inhibitors, beta-blockers, aldosterone receptor antagonists, angiotensin II receptor blockers (ARBs), and diuretics. These treatments are well-established, and cheap generic versions are widely available, making the HF treatment market a difficult one to break into. However, as the current treatments only relieve symptoms and slow the progression of HF, there is a huge gap in the market for drugs that restore heart function, with regenerative or curative potential. Both omecamtiv mecarbil and vericiguat represent exciting new therapies for HF, with novel mechanisms of action. Although there is a long way to go in the development of these two therapies, the results from these trials are a step in the right direction, away from the already exhausted RAAS pathway.
*This article first appeared on GlobalData on 12 November, 2015