A more profound and longer-lasting reduction in IOP in normotensive monkeys can be observed with ONO-9054, which simultaneously stimulates both EP3 and FP receptors, compared with prostaglandin analogs.
1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .
PURPOSE. The use of a dual prostaglandin E3 (EP3) and prostaglandin F (FP) receptor agonist is a novel approach for the reduction of intraocular pressure (IOP) in open angle glaucoma and ocular hypertension and, as such, ONO-9054 may have benefits over existing therapies. The objectives of this phase I study were to assess the safety, tolerability, systemic pharmacokinetics (PK), and pharmacodynamics (PD) profiles of , the prodrug of ONO-AG-367, in healthy, normotensive adults. METHODS.In this randomized, double-masked, placebo-controlled, single-dose escalating study, 48 male and female healthy volunteers each received a single drop of ONO-9054 0.3, 1.0, 3.0, 10.0, 20.0, or 30.0 lg/mL, or matching placebo in each eye. Blood samples of PK were taken up to 24 hours post dose; ocular and systemic safety, tolerability, and PD assessments were conducted up to approximately 72 hours post dose, and on day 7 at the follow-up visit.RESULTS. We found ONO-9054 was safe and well tolerated and ONO-AG-367 exhibited dosedependent systemic PK with rapid elimination. The effect of PD was assessed by reduction in IOP, with the maximum change from baseline in IOP in these normotensive individuals of À28.23% achieved at the 30.0 lg/mL dose at 9 hours post administration. CONCLUSIONS.A single dose of the novel EP3 and FP receptor agonist ONO-9054 was safe and well tolerated in healthy volunteers at doses between 0.3 and 30.0 lg/mL and resulted in a significant reduction in intraocular IOP with maximum reduction at 9 hours post dose. This supports further evaluation of ONO-9054 for the treatment of ocular hypertension and open angle glaucoma. (ClinicalTrials.gov number, NCT01508988.)
ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [ C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [ C]PBR28 regional distribution volume (V ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to V (BP ) was derived as the difference between V in the ROI (V ROI) and V , normalized to V ; BP = (V ROI - V )/V . TSPO occupancy was calculated as the change in BP (ΔBP ) from individual's baseline scan to the on-medication scan to the baseline BP value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.
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