First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure

Ward, Caroline L; Jamieson, Virginia; Nabata, Toshiya; Sharpe, John C.; Dozono, Koji; Suto, Fumitaka; Hashimoto, Yoshitaka; Gussak, Ihor

doi:10.1016/j.clinthera.2016.02.019

Cited by 16 publications

(7 citation statements)

References 19 publications

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“…Simultaneous stimulation with 100 nM ONO-0260164 significantly attenuated the TGF-β1-induced increase in Col1a1 and Col3a1 expression ( Figures 4A and 4B), suggesting that ONO-0260164 has inhibitory effects on TGF-β-mediated collagen expression in cardiac fibroblasts. ONO-4232, another EP4 agonist, 17) also showed inhibitory effects on TGF-β-mediated Col3a1 expression ( Figure 4C) and confirmed the inhibitory effects of EP4 agonist on TGF-β-mediated collagen expression in cardiac fibroblasts.…”

Section: Anti-fibrotic Effects Of Ep4 Agonistsupporting

confidence: 62%

“…At 5 weeks after TAC, the echocardiographic parameters, heart weight (HW, mg), lung weight (LW, mg), body weight (BW, g), and tibia length (TL, mm) were measured, and the mice were sacrificed for histological and molecular analyses. ONO-0260164 16) (US2005/0020686 A1) and ONO-4232 17) were provided by Ono Pharmaceutical Co., Ltd. (Osaka, Japan). BP measurement and echocardiography: Blood pressure (BP) and heart rate (HR) of conscious mice were measured by noninvasive recording using a BP-98A tail-cuff device (Softron, Tokyo).…”

Section: Methodsmentioning

confidence: 99%

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An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

et al. 2017

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SummaryCardiac fibrosis is a pathological feature of myocardium of failing heart and plays causative roles in arrhythmia and cardiac dysfunction, but its regulatory mechanisms remain largely elusive. In this study, we investigated the effects of the novel EP4 receptor agonist ONO-0260164 on cardiac fibrosis in hypertrophied heart and explored the regulatory mechanisms in cardiac fibroblasts.In a mouse model of cardiac hypertrophy generated by transverse aortic constriction (TAC), ONO-0260164 treatment significantly prevented systolic dysfunction and progression of myocardial fibrosis at 5 weeks after TAC. In cultured neonatal rat cardiac fibroblasts, transforming growth factor-β1 (TGF-β1) induced upregulation of collagen type 1, alpha 1 (Col1a1) and type 3, alpha 1 (Col3a1), which was inhibited by ONO-0260164 treatment. ONO-0260164 activated protein kinase A (PKA) in the presence of TGF-β1 in the cardiac fibroblasts. PKA activation suppressed an increase in collagen expression induced by TGF-β1, indicating the important inhibitory roles of PKA activation in TGF-β1-mediated collagen induction.We have demonstrated for the first time the antifibrotic effects of the novel EP4 agonist ONO-0260164 in vivo and in vitro, and the important role of PKA activation in the effects. (Int Heart J 2017; 58: 107-114)

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Section: Anti-fibrotic Effects Of Ep4 Agonistsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

et al. 2017

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“…Our results suggest that administration of a selective EP4 agonist might be a more promising option. Indeed, the first clinical report was very recently published showing that an EP4 agonist had a lucistropic and vasodilator effect in healthy volunteers 23 . This was followed with a concurrent publication showing that acute infusion of an EP4 agonist to normal anesthetized dogs increased ejection fraction and +dp/dt but decreased end systolic pressure 24 .…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Zhu

Bryson

et al. 2016

Circ: Heart Failure

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Background Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. Methods and Results The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM). Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10−6M) or sulp (10−6M) and compared to vehicle. Both PGE2 and sulprostone decreased +dp/dt (p<0.01) and left ventricular developed pressure, LVDP, (p<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. AVM contractility was also reduced after treatment with either PGE2 or sulprostone for 10 min. We then examined the acute effects of PGE2, sulprostone and the EP4 agonist on expression of phosphorylated phospholamban (PLN) and SERCA2a in AVM using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated PLN corrected to total PLN whereas treatment with the EP4 agonist had the opposite effect. SERCA2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure volume loops. Both PGE2 and sulprostone decreased +dp/dt while the EP4 agonist increased +dp/dt. Conclusions Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in PLN phosphorylation and has relevance to detrimental effects of inflammation.

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“…ONO-4232 is generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. This Phase I clinical study supported further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure [17]. However, Ono discontinued the development of ONO-4232 due to a strategic reason in January 2016 [18].…”

Section: Discontinued Drugsmentioning

confidence: 80%

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018

Jiang

et al. 2019

IJMS

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Cardiovascular drug research and development (R&D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I–III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.

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First Clinical Experience with ONO-4232: A Randomized, Double-blind, Placebo-controlled Healthy Volunteer Study of a Novel Lusitropic Agent for Acutely Decompensated Heart Failure

Cited by 16 publications

References 19 publications

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018

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