PhaseBio Pharmaceuticals (United States)

Introduction: P2Y12 inhibitors (P2Y12i) reduce thrombotic risk in patients with acute coronary syndrome and in secondary prevention of atherothrombotic events, but dual antiplatelet therapy with a P2Y12i + aspirin increases bleeding risk. P2Y12i washout is recommended prior to procedures, but when procedures cannot be deferred, washout is precluded, thereby increasing periprocedural bleeding risk, with potential negative outcomes. Hypothesis: P2Y12i are associated with increased bleeding risk and poorer clinical and economic outcomes in invasive cardiovascular (CV) procedures. Methods: In a retrospective study of hospital chargemaster data (2017-2019), patients receiving P2Y12i (cangrelor, clopidogrel, prasugrel, ticagrelor, or ticlopidine) or aspirin without P2Y12i (control) prior to an invasive CV procedure were identified from hospital charge and ICD-10 codes. Inpatient bleeding, mortality, length of stay (LOS; days), and intensive care unit (ICU) LOS (days) were assessed. Results: Among 2,996,051 patients with invasive CT procedures, P2Y12i-treated patients had significantly higher bleeding rates versus control patients (4.2% vs 3.1% p<0.05). Coronary artery bypass graft (CABG) procedures were the most common. Heart valve procedures showed the highest bleeding rates. Both CABG and valve procedures showed significant increases in bleeding for patients with P2Y12i versus control patients (CABG 9.2% vs 5.7%; valve 17.2% vs 8.9%; both p<0.05). P2Y12i-treated patients with bleeding versus those without bleeding had significant increases in in-hospital mortality (CABG 5.0% vs 2.1%; valve 12.4% vs 4.8%), LOS (CABG 11.7 vs 10.7; valve 13.0 vs 11.6), and ICU LOS (CABG 8.4 vs 5.5; valve 11.2 vs 8.3) (all p<0.05). Similar findings were observed for other procedures. Conclusions: Invasive CV procedures in patients receiving P2Y12i were associated with increased bleeding rates. Patients with increased bleeding had poorer outcomes, including increased in-hospital mortality. Bleeding avoidance in P2Y12i-treated patients requires an adequate discontinuation period prior to invasive procedures. Delaying CV procedures, however, may result in suboptimal outcomes, highlighting the unmet need for a rapid reversal strategy for P2Y12i.

Duchenne muscular dystrophy (DMD) is a recessive X-linked neuromuscular disorder characterized by progressive muscle degeneration with DMD-associated cardiomyopathy being the primary mode of death. Vasoactive intestinal peptide (VIP) is a 28 amino acid neuropeptide with biological effects mediated by G protein-coupled receptors. Utilizing a genetically modified form of VIP (PB1046) targeting cardiomyocytes, we hypothesized that augmentation of VIP signaling prevents the development of DMD-associated cardiomyopathy through inhibition of NF-κB. Either PB1046 (1.5 mg/kg) or a Placebo (saline) was injected subcutaneously every other day in three mouse models: DMD mdx:Utr+/- , DMD mdx , and wild type mice starting at 4 weeks of age for a total of 8 weeks. Cardiac function was assessed by weekly echocardiography. The cardiac tissues were collected at 14 weeks of age for histological and molecular analyses. Drug-treated DMD mdx:Utr+/- mice showed preservation of cardiac function (fractional shortening 61%±0.4 vs 45%±1.3, p <0.01; n=8-12) and a marked reduction in myocardial fibrosis (2.92%±0.13 vs 6.42% ±0.39, p <0.01; n=3) compared with controls. Hydroxyproline levels within drug-treated DMD mdx:Utr+/- mice was decreased compared with controls (44.6±5.3 vs 64.3±6.9 nmol/100mg heart weight, p <0.05, n=6). RNA-Seq data revealed an upregulation of cAMP signaling with downregulation of NF-kB signaling in isolated cardiac myocytes from drug-treated DMD mdx:Utr+/- mice as compared to controls (n=3). Western blot analyses revealed increased phosphorylation of CREB (1.97±0.02 vs 1.00±0.06, p <0.05, n=5-9) with decreased phosphorylation of p65 in drug-treated DMD cardiac nuclei as compared to controls (0.62±0.06 vs 1.00±0.09, p <0.05, n=3). Collectively, the data revealed augmentation of VIP signaling prevents the development of DMD-associated cardiomyopathy in DMD mdx:Utr+/- mice. The molecular mechanism underlying the benefits of VIP signaling suggests an upregulation of cAMP-CREB signaling with downregulation of NF-kB signaling leading to inhibition of inflammation and fibrosis within drug-treated DMD hearts. VIP signaling in DMD may serve as a new therapeutic target for the treatment of DMD-associated cardiomyopathy.

Vasomera™ is a first-in-class stable long-acting vasoactive intestinal peptide (VIP) agonist, with preferential actions on the G-protein-coupled VPAC2-receptors; VIP mediates cardiopulmonary regulation and has been proposed as a therapeutic target for both hypertension and systolic dysfunction. Here, the acute effects of Vasomera in load-independent function and ventriculo-arterial coupling were in evaluated in a rats with chronic diastolic dysfunction, mimicking heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction, as demonstrated by altered E/A ratios via echocardiography, was induced by renoprival hypertension secondary to renal wrapping (RW). Conditioned rats (n = 5) were instrumented for the determination of left-ventricular (LV) hemodynamics as well as load-independent fnction and ventriculo-arterial coupling (via pressure-volume relationships); data were evaluated before/after a single-dose continuous IV infusion of Vasomera (7.5 μg/kg/min IV). Vasomera decreased the estimated arterial elastance (Ea: -20 ± 5%, P < 0.05) with negligible changes in heart rate (-4 ± 2%). Improved inotropy (Ees: +28 ± 8% and PRSW: +22 ± 3%, P < 0.05) was observed post-treatment, suggesting improved ventriculo-arterial coupling (Ea/Ees: -37 ± 5%, P < 0.05). Concomitantly, Vasomera reduced filling pressures (EDP: -30 ± 8%, P < 0.05), accelerated the time-constant of relaxation (tau: -24 ± 3%, P < 0.05) and improved compliance (EDPVR: -26 ± 5%, P < 0.05). Vasomera, a novel VPAC2 agonist, improved arterial elastance and ventriculo-arterial coupling, while improving indices of diastolic function (i.e., lusitropy) in animals with chronic renoprival hypertension mimicking HFpEF.