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Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface
No full textAdvances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus™ with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented
Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications
No full textTargeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications
Systemic sclerostin antibody treatment increases osseointegration and biomechanical competence of zoledronic-acid-coated dental implants in a rat osteoporosis model
No full textOsseointegration of dental implants can be promoted by implant-surface modifications using bisphosphonate coatings. In addition, it is of clinical interest to promote peri-implant bone formation and to restore bony structure in low bone-mass patients. The present study evaluated a combination of an anti-resorptive zoledronic acid (ZOL) implant-coating and a systemically applied sclerostin antibody, a known bone anabolic treatment principle, versus sole sclerostin antibody treatment or ZOL implant-coating in a rat osteoporosis model. Uncoated reference surface implants or ZOL-coated implants (n = 64/group) were inserted into the proximal tibia of aged osteoporotic rats three months following ovariectomy. 32 animals of each group received once weekly sclerostin antibody therapy. Osseointegration was assessed 2 or 4 weeks post-implantation by ex vivo µCT, histology and biomechanical testing. Overall implant survival rate was 97 %. Histomorphology revealed pronounced bone formation along the entire implant length of ZOL-coated implants. At 4 weeks following implant insertion, bone-implant contact, cancellous bone mineral density and bone volume/tissue volume were significantly increased for the combination of ZOL and sclerostin antibody as compared to sclerostin antibody or ZOL implant-coating alone. Removal torque was also significantly increased in the combination therapy group relative to animals receiving only sclerostin antibody therapy or ZOL-coated implants. In an osteoporotic rat model, the combination of anti-resorptive ZOL implant-coating and systemically applied sclerostin antibody led to significantly increased peri-implant bone formation. Therefore, the combination of ZOL and the osteoanabolic sclerostin antibody was more effective than either agent alone
Tumor intrinsic efficacy by SHP2 and RTK inhibitors in KRAS mutant cancers
No full textKRAS, an oncogene mutated in nearly one-third of human cancers, remains a pharmacological challenge for direct inhibition except in the case of recent advances in selective inhibitors targeting the KRAS-G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, is effective in treating KRAS mutant cancer cell lines in vitro and in vivo. In vitro, sensitization of KRAS-driven cancers towards the allosteric SHP2-inhibitor, SHP099, is revealed when cells are grown as multicellular spheroids and correlates with activity in mouse models but is not apparent in standard 2D cell culture conditions. Interrogation of the MAPK pathway in SHP099 treated KRAS-mutant cancer models suggested relevance of both MAPK and non-MAPK pathway dependent mechanisms correlating with SHP099 sensitivity as phospho-ERK and DUSP6 modulation were equivalent in 2D, 3D and in vivo models despite differences in compound sensitivity. We demonstrate that efficacy is tumor-intrinsic due to the lack of anti-angiogenic activity of SHP099 and recapitulation of efficacy by genetic depletion of SHP2 in cancer cells, suggesting a dependence on RTK signaling upstream of RAS. Furthermore, KRAS mutants with low intrinsic GTP hydrolysis, e.g. KRAS-G13D and Q61H, also are sensitive to SHP099 in vivo. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic strategy for treating KRAS mutant cancers with SHP2 inhibitors
MAA868, a novel Factor XI antibody with a unique binding mode, shows long-lasting anticoagulation effects in humans
No full textA large unmet medical need exists for safer anti-thrombotic drugs since all currently approved anticoagulants interfere with hemostasis leading to an increased risk of bleeding. Genetic and pharmacological evidence in humans and animals suggest that reducing Factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with minimal risk of bleeding. We generated a fully human antibody—MAA868—that binds the catalytic domain of both FXI (zymogen) and the activated FXI (FXIa). Our structural studies show that MAA868 traps FXI and FXIa in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process revealing a particularly attractive anticoagulant profile of the antibody. MAA868 showed favorable anticoagulant activity in mice with a dose dependent protection from carotid occlusion in a FeCl3 induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys without any evidence of bleeding. Based on these preclinical findings, we conducted a first in human study in healthy subjects demonstrating that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose and time-dependent robust and sustained aPTT prolongation and FXI suppression for up to 4 weeks or longer, supporting further clinical development as once monthly subcutaneous anticoagulant therapy
Genetic toxicology in silico protocol
No full textIn silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches
Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors.
No full textCapmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). Primary objective was to determine maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics, and preliminary anti-tumor activity. Dose-escalation was guided by a Bayesian logistic regression model dependent on dose-limiting toxicities (DLTs) in cycle 1. Forty-four adult Japanese patients with confirmed advanced solid tumors were enrolled; 29 patients received capmatinib capsules (doses ranging from 100 mg once daily [qd] to 600 mg twice daily [bid]), and 15 patients received tablets (200 mg bid and 400 mg bid). DLTs occurred in 2 patients: grade 2 suicidal ideation (600 mg bid capsule) and grade 3 depression (400 mg bid tablet). MTD was not reached. The highest studied dose determined to be safe in tablets was 400 mg bid, while it was not yet determined with capsules. Most common adverse events suspected to be drug related were blood creatinine increased, nausea, decreased appetite, vomiting, and diarrhea. Following repeated daily dosing up to day 15 by qd or bid regimen using capsules, median Tmax ranged from 1.0 to 4.0 hours, while absorption was more rapid after dosing using tablet, with median Tmax of 1.0 hour on both day 1 and day 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib. (Trial registration no. NCT01546428
Drug-drug interaction (DDI) assessments of ruxolitinib, a dual substrate of CYP3A4 and CYP2C9, using a verified physiologically based pharmacokinetic (PBPK) model to support regulatory submissions
No full textRuxolitinib is mainly metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9 followed by minor contributions of other hepatic CYP enzymes in vitro. A physiologically based pharmacokinetic (PBPK) model was established to evaluate the changes in the ruxolitinib systemic exposures with co-administration of CYP3A4 and CYP2C9 perpetrators. The fractions metabolized in the liver via oxidation by CYP enzymes (fm,CYP3A4 = 0.75, fm,CYP2C9 = 0.19, and fm,CYPothers = 0.06) for an initial ruxolitinib model based on in vitro data were optimized (0.43, 0.56, and 0.01, respectively) using the observed exposure changes of ruxolitinib (10 mg) with co-administered ketoconazole (200 mg). The reduced amount of fm,CYP3A4 was distributed to fm,CYP2C9. For the initial ruxolitinib model with co-administration of ketoconazole, the area under the curve (AUC) increase of 2.60-fold was over-estimated compared with the respective observation (1.91-fold). With the optimized fm values, the predicted AUC ratio was 1.82. The estimated AUC ratios of ruxolitinib by co-administration of the moderate CYP3A4 inhibitor erythromycin (500 mg) and the strong CYP3A4 inducer rifampicin (600 mg) were within a 20% error compared with the clinically observed values. The PBPK modeling results may provide information on the labeling, i.e. supporting a dose reduction by half for co-administration of strong CYP3A4 inhibitors. Furthermore, an AUC increase of ruxolitinib in the absence or presence of the dual CYP3A4 and CYP2C9 inhibitor fluconazole (100-400 mg) was prospectively estimated to be 1.94-to 4.31-fold. Fluconazole simulation results were used as a basis for ruxolitinib dose adjustment when co-administering perpetrator drugs. A ruxolitinib PBPK model with optimized fm,CYP3A4 and fm,CYP2C9 was established to evaluate victim DDI risks. The previous minimal PBPK model was supported by the FDA for the dose reduction strategy, halving the dose with the concomitant use of strong CYP3A4 inhibitors and dual inhibitors on CYP2C9 and CYP3A4, such as fluconazole at ≤200 mg. Fluconazole simulation results were used as supportive evidence in discussions with the FDA and EMA about ruxolitinib dose adjustment when co-administering perpetrator drugs. Thus, this study demonstrated that PBPK modeling can support characterizing DDI liabilities to inform the drug label and might help reduce the number of clinical DDI studies by simulations of untested scenarios, when a robust PBPK model is established
Deciphering mechanisms of response and resistance in large-scale mouse cancer screens
No full textAcquired resistance is a major limitation for the successful treatment of cancer patients. Although numerous efficacious cancer therapeutics have been developed in the past decades, resistance arises due to a variety of reasons including tumoral genetic alterations, or modulation of factors in the tumor environment. Understanding the mechanistic reasons for tumor relapse supports the identification of novel combination therapies that could lead to more durable responses. Here, we will review large-scale in vivo screens in pre-clinical cancer models that employed genetic and pharmacological agents toward elucidating acquired drug resistance and informing on beneficial combinations to be tested in clinical trials
IID572: A New Potentially Best-In-Class β-Lactamase Inhibitor
No full textResistance in Gram-negative bacteria to β-lactam drugs is mediated primarily by the expression of β-lactamases, and co-dosing of β-lactams with a β-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New β-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of β-lactamases and the lack of intrinsic antibacterial activity