Confirmation of the Cardiac Safety of PGF_2αReceptor Antagonist OBE022 in a First‐in‐Human Study in Healthy Subjects, Using Intensive ECG Assessments

Abstract

OBE022, a new orally active prostaglandin F2α receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first‐in‐human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration–effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration–response analysis showed the absence of QTc prolongation at all doses tested. Two‐sided 90% confidence intervals of the geometric mean Cmax for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

“…The QTc shortening after a meal was previously proposed to be a result of the net effect of the antagonistic effects exerted by C‐peptide and glucose . This and other published studies confirm that the QT interval shortening in response to standardized meals is reproducible and independent of time of day . The marked effect on HR and the inverse relation between HR and QTcF has been previously reported after food intake …”

“…43 This and other published studies confirm that the QT interval shortening in response to standardized meals is reproducible and independent of time of day. 44 The marked effect on HR and the inverse relation between HR and QTcF has been previously reported after food intake. 13 Of note was the short-lasting peak in HR values during the 3 to 4 hours after dose, which corresponds to the end of bed rest required for after-dose study assessments ( Figure 3B) and most volunteers would have left their beds for physical mobilization.…”

Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first‐in‐human trial in healthy postmenopausal women

“…All subjects fasted for at least 10 h predose and 4 h postdose. Venous blood samples were collected for PK analysis predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6,7,8,12,16,24,36,48,72,96,120 and 144 h postdose.…”

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone

“…OBE022 is a potent, small molecule PGF2α receptor antagonist being developed to inhibit preterm labour . Ongoing clinical investigations are testing twice daily administrations of OBE022 during up to 7 days in preterm labour patients.…”

“…It was important to first conduct trials in healthy nonpregnant female volunteers rather than preterm labour patients as it was important to determine the safety and tolerability of OBE022 when coadministered with various standard of care medications. Data from the FIH trial demonstrated that OBE022 would not expose them to an increased risk …”