Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer.

OBJECTIVES: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. MATERIALS AND METHODS: Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. RESULTS: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. CONCLUSION: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer.

PURPOSE: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles. Four dose cohorts of NUC-1031 (500, 625, and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was recommended phase II combination dose (RP2CD). Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetics. RESULTS: A total of 25 women with recurrent ovarian cancer, a mean of 3.8 prior lines of chemotherapy, and a median platinum-free interval of 5 months (range: 7-451 days) were enrolled; 15 of 25 (60%) were platinum resistant, 9 (36%) were partially platinum sensitive, and 1 (4%) was platinum sensitive. Of the 23 who were response evaluable, there was 1 confirmed complete response (4%), 5 partial responses (17%), and 8 (35%) stable disease. The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin. CONCLUSIONS: NUC-1031 combined with carboplatin is well tolerated in recurrent ovarian cancer. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 and 8 with AUC5 carboplatin day 1, every 3 weeks for six cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.

Open innovation and external sources of innovation. An opportunity to fuel the R&D pipeline and enhance decision making?

Historically, research and development (R&D) in the pharmaceutical sector has predominantly been an in-house activity. To enable investments for game changing late-stage assets and to enable better and less costly go/no-go decisions, most companies have employed a fail early paradigm through the implementation of clinical proof-of-concept organizations. To fuel their pipelines, some pioneers started to complement their internal R&D efforts through collaborations as early as the 1990s. In recent years, multiple extrinsic and intrinsic factors induced an opening for external sources of innovation and resulted in new models for open innovation, such as open sourcing, crowdsourcing, public-private partnerships, innovations centres, and the virtualization of R&D. Three factors seem to determine the breadth and depth regarding how companies approach external innovation: (1) the company's legacy, (2) the company's willingness and ability to take risks and (3) the company's need to control IP and competitors. In addition, these factors often constitute the major hurdles to effectively leveraging external opportunities and assets. Conscious and differential choices of the R&D and business models for different companies and different divisions in the same company seem to best allow a company to fully exploit the potential of both internal and external innovations.

Population pharmacokinetic modelling of roflumilast and roflumilast N-oxide by total phosphodiesterase-4 inhibitory activity and development of a population pharmacodynamic-adverse event model.

BACKGROUND: Roflumilast is an oral, selective phosphodiesterase (PDE)-4 inhibitor in development for the treatment of chronic obstructive pulmonary disease (COPD). Both roflumilast and its metabolite roflumilast N-oxide have anti-inflammatory properties that contribute to overall pharmacological activity. OBJECTIVES: To model the pharmacokinetics of roflumilast and roflumilast N-oxide, evaluate the influence of potential covariates, use the total PDE4 inhibitory activity (tPDE4i) concept to estimate the combined inhibition of PDE4 by roflumilast and roflumilast N-oxide, and use individual estimates of tPDE4i to predict the occurrence of adverse events (AEs) in patients with moderate-to-severe COPD. METHODS: We modelled exposure to roflumilast and roflumilast N-oxide (21 studies provided the index dataset and five separate studies provided the validation dataset), extended the models to COPD (using data from two studies) and assessed the robustness of the parameter estimates. A parametric bootstrap estimation was used to quantify tPDE4i in subpopulations. We established logistic regression models for each AE occurring in >2% of patients in a placebo-controlled trial that achieved a p-value of <0.2 in a permutation test. The exposure variables were the area under the plasma concentration-time curve (AUC) of roflumilast, the AUC of roflumilast N-oxide and tPDE4i. Individual AUC values were estimated from population models. RESULTS: Roflumilast pharmacokinetics were modelled with a two-compartment model with first-order absorption including a lag time. A one-compartment model with zero-order absorption was used for roflumilast N-oxide. The final models displayed good descriptive and predictive performance with no appreciable systematic trends versus time, dose or study. Posterior predictive checks and robustness analysis showed that the models adequately described the pharmacokinetic parameters and the covariate effects on disposition. For roflumilast, the covariates of sex, smoking and race influenced clearance; and food influenced the absorption rate constant and lag time. For roflumilast N-oxide, age, sex and smoking influenced clearance; age, sex and race influenced the fraction metabolized; bodyweight influenced the apparent volume of distribution; and food influenced the apparent duration of formation. The COPD covariate increased the central volume of distribution of roflumilast by 184% and reduced its clearance by 39%; it also reduced the estimated volume of distribution of roflumilast N-oxide by 21% and reduced its clearance by 7.9%. Compared with the reference population (male, non-smoking, White, healthy, 40-year-old subjects), the relative geometric mean [95% CI] tPDE4i was higher in patients with COPD (12.6% [-6.6, 35.6]), women (19.3% [8.2, 31.6]), Black subjects (42.1% [16.4, 73.4]), Hispanic subjects (28.2% [4.1, 57.9]) and older subjects (e.g. 8.3% [-11.2, 32.2] in 60-year-olds), and was lower in smokers (-19.1% [-34.0, -0.7]). Among all possible subgroups in this analysis, the subgroup with maximal tPDE4i comprised elderly, Black, female, non-smoking, COPD patients (tPDE4i 217% [95% CI 107, 437] compared with the value in the reference population). The probability of a patient with tPDE4i at the population geometric mean [95% CI] was 13.0% [7.5, 18.5] for developing diarrhoea, 6.0% [2.6, 9.4] for nausea and 5.1% [1.9, 8.6] for headache. CONCLUSIONS: Covariate effects have a limited impact on tPDE4i. There was a general association between tPDE4i and the occurrence of common AEs in patients with COPD.

Effect of single and repeated doses of ketoconazole on the pharmacokinetics of roflumilast and roflumilast N-oxide.

Effects of single and multiple doses of oral ketoconazole on roflumilast and its active metabolite, roflumilast N-oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral roflumilast 500 microg once daily for 11 days and a concomitant 200-mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral roflumilast 500 microg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single-dose ketoconazole with steady-state roflumilast increased the AUC of roflumilast by 34%; C(max) was unchanged. For roflumilast N-oxide, AUC and C(max) decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C(max) of roflumilast by 99% and 23%, respectively; for roflumilast N-oxide, AUC was unchanged, and C(max) decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.

Metabolism of ciclesonide in the upper and lower airways: review of available data.

Ciclesonide is a novel corticosteroid (CS) for the treatment of asthma and allergic rhinitis. After administration, the parent compound ciclesonide is converted by intracellular airway esterases to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). We investigated the in vitro activation of ciclesonide and further esterification of des-CIC to (mainly) des-CIC oleate in several human target organ test systems. Human precision-cut lung slices, alveolar type II epithelial cells (A549), normal bronchial epithelial cells (NHBE), and nasal epithelial cells (HNEC) were incubated with ciclesonide. Enzymes characterization and the determination of the reversibility of fatty acid esterification was investigated in HNEC and NHBE. Ciclesonide was taken up and converted to des-CIC in all cellular test systems. Intracellular concentrations of des-CIC were maintained for up to 24 h. Formation of des-CIC oleate increased over time in HNEC, A549 cells, and lung slices. The formed des-CIC fatty acid conjugates were reconverted to des-CIC. Increasing concentrations of carboxylesterase and cholinesterase inhibitors progressively reduced the formation of metabolites. The results derived from these studies demonstrate the activation of ciclesonide to des-CIC in the upper and lower airways. The reversible formation of des-CIC fatty acid conjugates may prolong the anti-inflammatory activity of des-CIC and may allow for once-daily dosing.

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices.

BACKGROUND: The therapeutic effect of inhaled corticosteroids (ICS) may be affected by the metabolism of the drug in the target organ. We investigated the in vitro metabolism of beclomethasone dipropionate (BDP), budesonide (BUD), ciclesonide (CIC), and fluticasone propionate (FP) in human lung precision-cut tissue slices. CIC, a new generation ICS, is hydrolyzed by esterases in the upper and lower airways to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). METHODS: Lung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 microM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection. RESULTS: BDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP. CONCLUSION: The in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.

Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549).

BACKGROUND: Ciclesonide is a novel inhaled corticosteroid for the treatment of airway inflammation. In this study we investigated uptake and in vitro metabolism of ciclesonide in human alveolar type II epithelial cells (A549). Ciclesonide uptake was compared with fluticasone propionate, an inhaled corticosteroid that is not metabolized in lung tissue. A549 cells were incubated with 2 x 10(-8) M ciclesonide or fluticasone propionate for 3 to 30 min to determine uptake; or with 2 x 10(-8) M ciclesonide for 1 h, followed by incubation with drug-free buffer for 3, 6, and 24 h to analyze in vitro metabolism. High performance liquid chromatography with tandem mass spectrometry was used to measure the concentrations of both corticosteroids and metabolites. RESULTS: At all time points the mean intracellular concentration was higher for ciclesonide when compared with fluticasone propionate. Activation of ciclesonide to desisobutyryl-ciclesonide (des-CIC) was confirmed and conjugates of des-CIC with fatty acids were detected. The intracellular concentration of ciclesonide decreased over time, whereas the concentration of des-CIC remained relatively stable: 2.27 to 3.19 pmol/dish between 3 and 24 h. The concentration of des-CIC fatty acid conjugates increased over time, with des-CIC-oleate being the main metabolite. CONCLUSION: Uptake of ciclesonide into A549 cells was more efficient than that of the less lipophilic fluticasone propionate. Intracellular concentrations of the pharmacologically active metabolite des-CIC were maintained for up to 24 h. The local anti-inflammatory activity of ciclesonide in the lung may be prolonged by the slow release of active drug from the depot of fatty acid esters.

The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue.

Ciclesonide (CIC) is an inhaled glucocorticosteroid. This study aimed to identify esterases involved in the metabolism of CIC to the active metabolite desisobutyryl-ciclesonide (des-CIC), and to measure hydrolysis rates in human liver, lung and plasma and normal human bronchial epithelial (NHBE) cells in vitro. Ciclesonide (5 microM and 500 microM) was incubated with microsomal or cytosolic fractions from liver, lung and plasma (n=4 for each) and des-CIC formation was determined by reverse-phase high-performance liquid chromatography with U.V. detection. The roles of carboxylesterase, cholinesterase and A-esterase in CIC hydrolysis were determined using a range of inhibitors. Inhibitor concentrations for liver and NHBE cells were 100 microM and 5 microM, respectively. Liver tissue had a higher activity for 500 microM CIC hydrolysis (microsomes: 25.4; cytosol: 62.9 nmol/g tissue/min) than peripheral lung (microsomes: 0.089; cytosol: 0.915 nmol/g tissue/min) or plasma (0.001 nmol/mL plasma/min), corresponding with high levels of carboxylesterase and cholinesterase in the liver compared with the lung. CIC (5 microM) was rapidly hydrolyzed by NHBE cells (approximately 30% conversion at 4h), with almost complete conversion by 24h. In liver and NHBE cells, major involvement of cytosolic carboxylesterases, with some contribution by cholinesterases, was indicated. The highest level of conversion was found in the liver, the site of inactivation of des-CIC through rapid oxidation by cytochrome P450. Carboxylesterases in bronchial epithelial cells probably contribute significantly to the conversion to des-CIC in the target organ, whereas low systemic levels of des-CIC are a result of the high metabolic clearance by the liver following CIC inhalation.