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

Q2 · MEDICINE

Article

Author: Marchand, Line ; Gotteland, Jean‐Pierre ; Lorch, Ulrike ; Coates, Simon ; Pohl, Oliver ; Täubel, Jörg

AimsTo investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard‐of‐care medicines for preterm labour, enabling coadministration and further clinical development.MethodsPart A: open‐label, randomized, 3‐period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO4. Part B: open‐label, single‐sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty‐five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13).ResultsOBE022, alone or in combination with standard‐of‐care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4. Co‐administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax] 22%, area under the concentration–time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax + 18%, AUC +27%) and OBE002 exposure (Cmax + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax + 29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2‐fold and AUC by 2‐fold), which may be clinically significant.ConclusionsThe use of OBE022, a PGF2α antagonist prodrug, in combination with standard‐of‐care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.

01 Nov 2018·Clinical Pharmacology in Drug Development

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

Article

Author: Fernandes, Sara ; Foley, Paul ; Täubel, Jörg ; Coates, Simon ; Pohl, Oliver ; Ferber, Georg ; Gotteland, Jean‐Pierre ; Lorch, Ulrike

AbstractOBE022, 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.

01 Aug 2018·British Journal of Clinical PharmacologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Marchand, Line ; Gotteland, Jean‐Pierre ; Lorch, Ulrike ; Coates, Simon ; Pohl, Oliver ; Täubel, Jörg

AimsPreterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F2α receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F2α receptor antagonists under development for treating preterm labour.MethodsWe performed a prospective, first in human, Phase I, dose escalation, placebo‐controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day–1; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated.ResultsSubjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half‐life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22–29 h after multiple doses.ConclusionsAdministration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients.

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Preclinical	CH	ObsEva SA	01 Aug 2018

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