Baloxavir acid (baloxavir), the active metabolite of the prodrug baloxavir marboxil, is a selective inhibitor of the influenza virus cap-dependent endonuclease. The population pharmacokinetic (popPK) profile of baloxavir in adults/adolescents has been described previously. To characterize the PK of baloxavir in patients aged ≥1 year, a popPK model was developed using data from 1,795 patients across six studies, including miniSTONE-2 (NCT03629184) in which children aged 1 to <12 years received a bodyweight-based single oral dose of baloxavir marboxil (2 mg/kg, <20 kg; 40 mg, ≥20 kg) for treatment of influenza. The final popPK model was a 2-compartment model with first-order absorption and elimination processes and an absorption lag time; the most influential covariates affecting baloxavir exposure were bodyweight and race (Asian versus non-Asian). Pediatric-to-adult exposure matching for PK parameters relevant for treatment and post-exposure prophylaxis (PEP) indications were used to support pediatric label extensions. Adequate exposure matching was demonstrated between non-Asian pediatric patients using the miniSTONE-2 dose and non-Asian adult patients. After dosing optimization, predicted baloxavir exposures in Asian pediatric patients using the miniSTONE-2 dose were similar to exposures in Asian adults. To bridge PEP efficacy data from the BLOCKSTONE study in Japanese pediatric patients (JapicCTI-184,180) to non-Asian patients aged ≥1 year, an exposure-matching approach between Japanese pediatric patients receiving the lower BLOCKSTONE dose and non-Asian pediatric patients receiving the miniSTONE-2 dose was employed. Together, these observations indicate that the recommended miniSTONE-2 dosing regimen is likely to be efficacious for treatment and PEP in children aged 1-<12 years, regardless of race.

Pharmacokinetic profile of anti-TF mAb 25A3 with zovodotin linker-payload (XB002) or vedotin linker-payload

Internalization of fluorescently tagged XB002

Binding affinity of 25A3 to TF-expressing cell lines

Cleavage of XB002 with cathepsin B – release of ZD02044 payload

Effect of XB002 on neutrophil levels

Factor VII binding to TF in presence of 25A3

Purpose: To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints. Methods: A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients. Results: Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was similar to 6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t 1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens. Conclusions: Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen. Translational Relevance: The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t 1/2 alone.

PURPOSE To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Abstract Anti‐neutrophil cytoplasmic antibody‐associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ‐ and life‐threatening autoimmune conditions affecting adult and pediatric patients. An open‐label phase II study was conducted to determine safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA. To determine the selection of an appropriate dose regimen in children for induction and maintenance, a population pharmacokinetic approach was used (nonlinear mixed‐effect modeling), combining pediatric data with data from adults with GPA/MPA. The time course of B‐cell depletion was assessed in both populations. The exposure‐effect relationship was assessed by logistic regression. Twenty‐five pediatric patients (80% female patients; age range, 6–17 years) were enrolled in the trial and received the induction regimen of intravenous rituximab 375 mg/m2 weekly for 4 weeks, which resulted in a similar exposure to that of adults. Based on pharmacokinetic modeling, a maintenance dosing regimen of 250 mg/m2 administered twice over 14 days followed by 250 mg/m2 every 6 months is expected to result in similar rituximab exposure as that of adults receiving the approved maintenance dose of 500 mg administered twice over 14 days followed by 500 mg every 6 months. The time course of B‐cell depletion was similar between the pediatric and adult populations, supporting the similarities in response in both populations and allowing extrapolation to patients less than 6 years old. Using a partial extrapolation approach helped identify safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA and lead to regulatory approval.

ObjectiveTo assess the safety, tolerability, pharmacokinetics, and efficacy of rituximab (RTX) in pediatric patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).MethodsThe Pediatric Polyangiitis Rituximab Study was a phase IIa, international, open‐label, single‐arm study. During the initial 6‐month remission‐induction phase, patients received intravenous infusions of RTX (375 mg/m2 body surface area) and glucocorticoids once per week for 4 weeks. During the follow‐up period, patients could receive further treatment, including RTX, for GPA or MPA. The safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy outcomes with RTX were evaluated.ResultsTwenty‐five pediatric patients with new‐onset or relapsing disease were enrolled at 11 centers (19 with GPA [76%] and 6 with MPA [24%]). The median age was 14 years (range 6–17 years). All patients completed the remission‐induction phase. During the overall study period (≤4.5 years), patients received between 4 and 28 infusions of RTX. All patients experienced ≥1 adverse event (AE), mostly grade 1 or grade 2 primarily infusion‐related reactions. Seven patients experienced 10 serious AEs, and 17 patients experienced 31 infection‐related AEs. No deaths were reported. RTX clearance correlated with body surface area. The body surface area–adjusted RTX dosing regimen resulted in similar exposure in both pediatric and adult patients with GPA or MPA. Remission, according to the Pediatric Vasculitis Activity Score, was achieved in 56%, 92%, and 100% of patients by months 6, 12, and 18, respectively.ConclusionIn pediatric patients with GPA or MPA, RTX is well tolerated and effective, with an overall safety profile comparable to that observed in adult patients with GPA or MPA who receive treatment with RTX. RTX is associated with a positive risk/benefit profile in pediatric patients with active GPA or MPA.

Background: L1 cell adhesion molecule (L1CAM) is a ∼200kDa transmembrane protein which is overexpressed in several tumor types. Its expression has been shown to be a predictor of poor outcome in several independent publications. Anti-L1CAM antibody therapy, is expected to lead to tumor regression through inhibition of tumor growth, inhibition of migration/cell adhesion, reversal of chemoresistance and cell killing via ADCC. In addition to tumors, L1CAM is expressed in a restricted set of healthy tissues, including the nervous system and kidney tubules.

Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03-20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet-leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet-leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study.

Inclacumab is a novel monoclonal antibody directed against P-selectin in development for the prevention and treatment of atherosclerotic cardiovascular diseases. It is likely to be used concomitantly with heparin in patients undergoing percutaneous coronary intervention. Coadministration of both drugs may potentially increase the bleeding risk associated with heparin. This crossover study evaluated the potential pharmacodynamic interaction between inclacumab and unfractionated heparin in 18 healthy smokers. Owing to the long elimination of inclacumab (half-life of approximately 18 days), a 2-period, one-sequence study design was used. Subjects received an intravenous bolus injection of unfractionated heparin (5000 IU) on days 1 and 8 and an intravenous infusion of inclacumab (20 mg/kg) on day 8. Blood samples were collected on days 1 and 8 for pharmacodynamic effects of unfractionated heparin (anti-FXa and anti-FIIa activities, activated partial thromboplastin time and tissue factor pathway inhibitor) and over 6 months for pharmacokinetics of inclacumab. Sixteen subjects were eligible for pharmacodynamic analysis. Inclacumab had no clinically significant pharmacodynamic interaction with unfractionated heparin. With the exception of the minor but statistically significant increase of the maximum effect [Emax] of anti-FIIa activity, pharmacodynamic parameters (areas under the effect curve [AUElast] and Emax of anti-FXa) were almost similar on days 1 and 8. The 90% confidence intervals of geometric mean ratios of day 8 to day 1 for AUElast and Emax were however all contained within bioequivalence boundaries. The data demonstrate that the anticoagulant effect of unfractionated heparin was not affected by the administration of inclacumab.

BACKGROUND AND OBJECTIVE:Elevated levels of platelet-leukocyte aggregates (PLAs) have been reported in several cardiovascular diseases and suggested to contribute to disease pathology. Our aim was to characterize the effects of inclacumab, a novel human anti-P-selectin antibody, on the interactions between leukocytes and platelets in preclinical and clinical studies.EXPERIMENTAL APPROACHES:Dual-label flow cytometry was used to detect the effect of inclacumab on agonist-induced platelet-leukocyte/platelet-monocyte aggregates in cynomolgus monkeys and humans, following ex vivo and in vivo administration. Platelet-dependent leukocyte activation and leukocyte adhesion to a platelet monolayer were also investigated after ex vivo administration of inclacumab to human blood.RESULTS:Treatment of cynomolgus monkeys with inclacumab profoundly inhibited thrombin receptor-activating peptide (TRAP) or adenosine diphosphate (ADP)-induced PLAs with an IC50 (<2 μg/mL) similar to the in vitro spiking experiments. Maximal inhibition of PLAs persisted for ≥28 days following single dose of inclacumab. In human blood, inclacumab was about 2-fold more potent in inhibiting TRAP-induced PLAs (IC50: 0.7 μg/mL) compared to monkeys. PLA formation was suppressed independently of the inducing platelet agonist. Inclacumab also inhibited the activation of the leukocyte integrin Mac-1 and leukocyte adhesion to a platelet monolayer under flow conditions. In clinical studies, inclacumab inhibited TRAP-induced PLA formation in a dose-dependent manner following single and multiple dose administration to healthy volunteers. It also reduced elevated circulating PLA levels in patients with peripheral arterial disease.CONCLUSION:By inhibiting platelet-leukocyte interactions, demonstrated in multiple preclinical and clinical studies, inclacumab may provide an effective treatment for cardiovascular diseases.

14570 Background: Bevacizumab (BEV) is an antibody targeting vascular endothelial growth factor (VEGF), and is approved in the EU and other countries for the treatment of breast, renal cell, colorectal, and non small cell lung carcinoma. Simultaneous characterization of BEV pharmacokinetics (PK) in ∼770 patients with different underlying disease was performed using a population (popPK) approach in order to improve the factors which may impact on BEV disposition. Methods: Patients with several carcinoma type received multiple intravenous (IV) infusions of BEV (either single agent or with chemotherapies) ranging from 1 to 20 mg/kg with administration ranging from weekly to every 3 weeks. Multiple samples were collected from each patient, and BEV serum concentrations were determined by ELISA. BEV PK was characterized by a 2- compartment model with first order elimination. The data were analyzed using non linear mixed effects modeling (NONMEM). Results: 6108 BEV samples from 773 patients (52% male, median body weight [BW] =73 kg) were included in the analyses. For a typical subject, clearance (CL) was 9.2 mL/hr, central volume of distribution (Vc) was 3280 mL, intercompartmental clearance (Q) was 15 mL/hr and the peripheral volume (Vp) was 3850 mL. The parameters were well estimated with relative standard error from 1.4 to 33% and the between subject variability ranged from 15 to 43%. The significant covariates, in order of decreasing influence on the variability of the parameters were 1) CL: baseline body weight (BW), albumin, tumor burden (TB) and sex 2) Vc: BW, sex, TB and protein 3) Vp: sex and chemotherapies. Conclusions: The final popPK model adequately described BEV PK profiles across all disease types. BEV has moderately variable PK and demographic/disease factors were identified to be correlated with PK parameters. BW was the covariate with impact on variability of both CL and Vc and supports the current dosing scheme based on body weight, while the clinical impact of other covariates do not warrant dose adjustments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Genentech™ BioOncology Genentech™ BioOncology, Hoffman-La Roche Roche