New therapies for the treatment of heart failure: a summary of recent accomplishments

Figures & data

Table 1 An overview of the presented novel therapeutic methods with respect to their mechanism of action and latest stage of clinical development

Name	Mechanism of action	Stage of clinical trials
Omecamtiv mecarbil	Cardiac myosin activator; increases stroke power	Phase 3 (estimated completion date in 2021)
Ularitide	Urodilatin analog, promotes diuresis and natriuresis through binding with NPR-A receptor	Phase 3
Serelaxin	Member of relaxin family; stimulates NO production, increases cardiac output while decreasing vascular resistance via RXFP family receptors (G-protein coupled)	Phase 3b
Tolvaptan	Oral V2 receptors antagonist; promotes aquaresis without increasing electrolyte concentration in urine	Phase 3
CT-1	Promotes beneficial, reversible cardiac remodeling	–
SERCA2a	Improves Ca^2+ balance in the heart, which leads to recovery of cardiac contraction and relaxation	Phase 2

Note: “–” is not applicable.

Figure 1 Mechanism of the impact of OM on muscle contraction.(/p)(/p)Notes: OM binds to myosin filaments and shifts the equilibrium of ATP hydrolysis toward the ADP-P state. OM increases the number of myosin filaments ready to bind actin filaments, in turn increasing the stroke power.(/p)(/p)Abbreviations: OM, omecamtiv mecarbil; ATP, adenosine triphosphate; ADP, adenosine diphosphate; P, inorganic phosphate.

Figure 2 Mechanism of action of urodilatin.(/p)(/p)Note: The consequences of NPR-A receptor activation include increased cGMP production, resulting in lowered intracellular calcium level which reduces the smooth muscle tonus.(/p)(/p)Abbreviations: AVP, arginine vasopressin; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; NPR-A, natriuretic peptide receptor A.

Figure 3 Effect of relaxin binding with RXFP family receptor.(/p)(/p)Note: Mediated by G-proteins, the response involves activation of adenylate cyclase, increase in cAMP accumulation, as well as NO production.(/p)(/p)Abbreviations: RXFP, relaxin family peptide; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; Gαi3, Gαi subunit 3; GαoB, Gαo subunit B; GαS, Gα subunit S; β, Gβ subunit; γ, Gγ subunit; PI3K, Phosphatidylinositol-3 kinases; AKT, protein kinase B; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

Figure 4 Mechanism of action of SERCA2a.(/p)(/p)Note: This ATPase pump transfers calcium ions from the sarcolemma to the sarcoplasmic reticulum.

Table 2 A summary of the latest clinical trials with respect to their outcomes and observed adverse effects

Agent name	Trial name	Clinical trial registry number	Sample size	Outcomes	Observed adverse events
Omecamtiv mecarbil	ATOMIC-AHF	NCT01300013	614 AHF patients	– failed to meet the primary endpoint of dyspnea improvement – increased SET	– no difference in adverse effect rate compared to placebo
	COSMIC-HF	NCT01786512	544 HF patients	– increased SET and stroke volume – decreased heart rate and NT-proBNP level	– no difference in adverse effect rate compared to placebo
	GALACTIC-HF	NCT02929329	8,000 patients (recruiting)	Estimated completion date in 2021
Ularitide	TRUE-AHF	NCT01661634	2,157 AHF patients	– no significant differences in primary endpoints – significant dyspnea reduction in 83% of eligible patients	– adverse effect on dyspnea in 17% of ineligible patients (prohibited intravenous medications)
Serelaxin	RELAX-AHF	NCT00520806	1,161 patients hospitalized for AHF	– VAS AUC scale dyspnea improvement – fewer deaths at day 180	– infrequent hypotensive events
	RELAX-AHF-2	NCT01870778	6,600 AHF patients	– failed to meet primary endpoints (180-day cardiovascular death and worsening heart failure through day 5)	– no serious adverse events
	RELAX-AHF-ASIA	NCT02007720	1,520 patients with AHF	– terminated on the basis of RELAX-AHF-2 study results
Tolvaptan	QUEST-HF	NCT01651156	244 HF patients	– reduced heart failure symptoms such as: lower limb edema, pulmonary congestion or dyspnea	– thirst – hypernatremia
	EVEREST-HF	NCT00071331	4,133 HF patients	– no improvement in HRQOL score and mortality – dyspnea relief	– dry mouth and thirst – no serious adverse effects compared to placebo
SERCA2a	CUPID-2b	NCT01643330	250 HF patients	Lack of improvement of patients’ clinical course	Lack of differences between placebo and AAV/SERCA2a treated groups

Abbreviations: AHF, acute heart failure; HF, heart failure; HRQOL, health-related quality of life; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; SET, systolic ejection time; AAV/SERCA2a, adeno-associated virus / Sarco/endoplasmic reticulum Ca²⁺-ATPase 2a.