Human Efficacious Dose Research Articles

Meeting report: DMPK optimisation strategies and quantitative translational PKPD frameworks to predict human PK and efficacious dose of targeted protein degraders

Meeting report: DMPK optimisation strategies and quantitative translational PKPD frameworks to predict human PK and efficacious dose of targeted protein degraders

Abstract 4525: Discovery of a highly potent and selective PARP1 inhibitor with superior PK and safety profiles

Abstract PARP inhibitors have been an effective treatment option for cancers deficient in homologous recombination repair, such as ovarian, breast, prostate, and pancreatic cancers, particularly those harboring BRCA mutations. However, their severe overlapping hematological and gastrointestinal toxicities have limited their clinical use, especially in the combination therapies with other anti-cancer agents. More recently, studies have shown that inhibiting PARP1 mainly drives anti-tumor activity while inhibiting PARP2 contributes to the hematological toxicity such as anemia due to its essential role in the survival of hematopoietic stem and progenitor cells. Thus, there is an urgent need for developing a selective PARP1 inhibitor. In this study, we report the discovery and characterization of a unique PARP1 inhibitor, ACE-86225106. This molecule is highly selective at inhibiting PARP1 over PARP2 as demonstrated in biochemical (72x) and DNA-trapping (131x) assays. It demonstrates potent anti-proliferative activities against BRCA mutant cancer cell lines (IC50 = 1-9 nM) but not against BRCA wild type cancer cells (IC50 >30,000 nM). As compared to the BRCA mutant cancer cells, this molecule is much less active at inhibiting the differentiation of CD34+ hematopoietic stem cells (IC50 ≈ 450-1,400 nM), i.e.: erythroid, myeloid and megakaryocyte. The results of these studies show that ACE-86225106 is a highly potent and selective PARP1 inhibitor. This molecule has a unique PK profile characterized by its long half-life and low volume of distribution. As such, it demonstrates robust efficacy at low dose (1 mg/kg) with a less frequent dosing schedule (once a week). Importantly, there was no significant body weight loss observed in the treatment group even at much higher doses (10 mg/kg), but there was a significant body weight gain. The GLP toxicology studies have confirmed its superior safety profile as the maximum recommended safe starting first-in-human dose was >5-fold higher than the predicted human efficacious dose. Taken together, ACE-86225106 is a highly potent, selective PARP1 inhibitor with excellent PK and safety profile and expected to have a better safety profile, deeper and more durable clinical responses, and broader utility in the clinic as a preferred combination partner with other anti-cancer therapies. A phase 1 clinical trial to evaluate its safety, PK, and clinical utility is to begin in early 2024. Citation Format: Yi Wei, Wenming Li, Zehui Li, Manhua Li, Kai Kang, Zhiming Wen, Tinggui Yin, Kuo-Long Yu, Genshi Zhao, Hongbin Yuan. Discovery of a highly potent and selective PARP1 inhibitor with superior PK and safety profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4525.

Abstract A139: Preclinical characterization and prediction of human pharmacokinetics and efficacious dose for VIP236, a novel alpha V beta 3 binding small molecule-drug conjugate (SMDC)

Abstract VIP236 is a small molecule drug conjugate (SMDC) consisting of an alpha v beta 3 (αvβ3) integrin binder linked to an optimized camptothecin (optCPT) payload via a protease sensitive peptide sequence. The overall drug design strategy for VIP236 is targeted delivery to the tumor microenvironment (TME) with extracellular release of the opCPT by neutrophil elastase (NE) present in the TME. VIP236 is anticipated to kill tumor cells while reducing effects to normal tissue. VIP236 was characterized in preclinical pharmacokinetic (PK) and efficacy studies to predict its human PK and efficacious dose. Briefly, VIP236 was administered intravenously (IV) to mice, rats, and dogs to characterize both its in vivo PK (1-2 mg/kg) and its routes of excretion (bile-duct cannulated [BDC] rat at 10 mg/kg). VIP236 was evaluated in vitro for its protein binding characteristics and as a substrate of human drug transporters. In addition, VIP236 was dosed to MX-1 (breast cancer) xenografted mice at doses ranging from 26-40 mg/kg IV on a 3 days on/4 days off regimen to characterize its antitumor activity. VIP236 had low plasma clearance in mice, rats, and dogs (CL=2.7-4.4 mL/min/kg) and low volume of distribution (Vss = 0.11 to 0.25 L/kg). Terminal half-life ranged from 0.93 hour in mice to 3.07 hours in dogs. In BDC rats, VIP236 was primarily excreted in bile with biliary clearance accounting for essentially all the total body CL. There was minimal to no metabolites in rat bile and urine. In vitro VIP236 exhibited low permeability in MDCKII cell monolayers and was identified as a substrate of BSEP and MRP2. VIP236 was highly protein bound to plasma protein with fraction unbound being <5% in all species tested. VIP236 showed robust tumor regression in MX-1 xenografted mice at all doses tested. Allometric methods were used to predict a low human VIP236 CL (0.87-2.68 mL/min/kg) and Vss (0.10 L/kg). Translational pharmacokinetic/pharmacodynamic modeling was used to predict human efficacious doses and exposures by benchmarking VIP236 against irinotecan antitumor activity in MX-1 xenograft mice after 5 cycles of dosing. Based on this analysis, predicted human doses ranged from 1-5 mg/kg IV on a 2 days on/5 days off regimen. VIP236 is currently being evaluated in a first-in-human study in patients with advanced or metastatic solid tumors (NCT05712889). Citation Format: Harvey Wong, Beatrix Stelte-Ludwig, Hans-Georg Lerchen, Amy J Johnson, Melanie M Frigault, Raquel Izumi, Ahmed Hamdy. Preclinical characterization and prediction of human pharmacokinetics and efficacious dose for VIP236, a novel alpha V beta 3 binding small molecule-drug conjugate (SMDC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A139.

Human Dose and Pharmacokinetic Predictions for Biologics at Boehringer Ingelheim: A Retrospective Analysis.

Accurate predictions of pharmacokinetics and efficacious doses for biologics in humans are critical for selecting appropriate first-in-human starting doses and dose ranges and for estimating clinical material needs and cost of goods. This also impacts clinical feasibility, particularly for subcutaneously administered biologics. We performed a comprehensive comparison between predicted and observed clearances and doses in humans for a set of 22 biologic drugs developed at Boehringer Ingelheim (BI) over the last 2decades. The analysis included biologics across three therapeutic areas comprising a wide variety of modalities: mono- and bispecific monoclonal antibodies (mAbs) and nanobodies and a Fab fragment. Our analysis showed that observed clearances in humans were within twofold of predicted clearances for 17 out of 20 biologics (85%). Six biologics had uncharacteristically high observed human clearances (range 32-280mL/h) for their respective molecular classes, impacting their clinical developability. For three molecules, molecular characteristics contributed to the high clearance. Clinically selected doses were within twofold of predicted for 58% of projects. With 42% and 25% of projects selecting clinical doses higher than two- or threefold the predicted value, respectively, the importance of better understanding not only the pharmacokinetic (PK) but also the predictivity of pharmacodynamic models is highlighted. We provide a clinical pharmacology perspective on the commonly accepted twofold range of human clearance predictions as well as the implications of higher than predicted targeted efficacious plasma concentration on clinical development. Finally, an analysis of key success factors for biologics at BI was conducted, which may be relevant for the entire pharmaceutical industry. This is one of the largest retrospective analyses for biologics and provides further evidence that successful predictions of human PK and efficacious dose will be further facilitated by gathering key translational data early in research.

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans.

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC50). As M3258 only weakly inhibits LMP7 in mouse cells, both in vitro and in vivo bridging studies were performed in rats, monkeys, and dogs for translational modeling. These data indicated that the PD response in human xenograft models was closely reflected in dog PBMCs. A PK/PD model was established, predicting a free IC50 value of 9 nM for M3258 in dogs in vivo, in close agreement with in vitro measurements. In parallel, the human PK parameters of M3258 were predicted by various approaches including in vitro extrapolation and allometric scaling. Using PK/PD/efficacy simulations, the efficacious dose range and corresponding PD response in human were predicted. Taken together, these efforts supported the design of a phase Ia study of M3258 in multiple myeloma patients (NCT04075721). At the lowest tested dose level, the predicted exposure matched well with the observed exposure while the duration of LMP7 inhibition was underpredicted by the model. SIGNIFICANCE STATEMENT: M3258 is a novel inhibitor of the immunoproteasome subunit LMP7. The human PK and human efficacious dose range of M3258 were predicted using in vitro-in vivo extrapolation and allometric scaling methods together with a fit-for-purpose PK/PD and efficacy model based on data from several species. A comparison with data from the Phase Ia clinical study showed that the human PK was accurately predicted, while the extent and duration of PD response were more pronounced than estimated.

A multi-model approach to predict efficacious clinical dose for an anti-TGF-β antibody (GC2008) in the treatment of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multidisciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-β) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of patients with OI. In this work, we have developed a multitiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-β antibody drug candidate (GC2008). This method aims to translate GC2008 pharmacokinetic/pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in patients with OI. Furthermore, a physiologically-based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the TGF-β level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection of GC2008 in humans. The different modeling efforts predicted a similar range of pharmacologically relevant doses in patients with OI providing an informed approach for an early clinical dose setting.

Abstract 3591: First in class drug ZB131 shows efficacy in cholangiocarcinoma models

Abstract Cholangiocarcinoma (CCA) is a lethal cancer with a high unmet need. The survival rate is low (5-year survival <20%), most non-palliative patients relapse within two years, and treatments in the advanced setting are limited. While FGFR2 and IDH1 inhibitors are effective in patients with select genomic alterations, they address only a small fraction (<20%) of biliary tract cancers. We now present the discovery and characterization of ZB131, a first in class humanized monoclonal antibody targeted to cancer specific plectin (CSP). CSP is a pro-tumorigenic protein exclusively expressed on the cancer cell surface. Previously, we demonstrated remarkable tumor regressions in preclinical murine models of pancreatic and ovarian cancer using a tool anti-CSP murine antibody. Here, we show that intra- and extra-hepatic CCA are 92% and 86% positive for membranous plectin staining by IHC, respectively, suggesting that anti-CSP therapy could be broadly effective against CCA. Indeed, in CCA cell lines in vitro, ZB131 (0.4nM binding affinity) arrests cell cycle, inhibits cell migration, and triggers intracellular ROS accumulation. In addition, both ZB131 and its murine version significantly suppressed tumor growth in 83% of the mice in a xenograft model and caused complete regression in the remaining 17%. Previous data from our group and others suggesting that CSP plays a role in chemoresistance led us to evaluate the efficacy of ZB131 in combination with gemcitabine. In vitro, we treated CSP-positive WITT cells with combinations of 0-500nM gemcitabine plus 0-1000nM ZB131 and found pockets of synergy or additivity. In a CCA xenograft model, the combination of 1mg/kg ZB131 and 100mg/kg gemcitabine showed 91% suppression in tumor growth compared with 74% in gemcitabine alone and 77% in huIgG plus gemcitabine at day 32. Collectively, our results suggest that ZB131 renders CCA tumors more chemosensitive and enhances the antitumor effects of gemcitabine. In contrast to the standard-of-care CCA treatment regimen, ZB131 showed remarkably low toxicity, likely because the antibody bypasses any non-malignant cells where plectin remains strictly cytoplasmic. Fc effector functional studies revealed a lack of antibody-dependent cell-mediated and complement-dependent cytotoxicity. Hemolysis and cytokine release studies suggested that ZB131 is compatible with human blood and unlikely to cause adverse cytokine release. Furthermore, in GLP toxicology studies, no signs of toxicity were observed at the highest dose evaluated of 100mg/kg/week, providing a >30-fold safety margin from the estimated human efficacious dose of 3mg/kg/week. In summary, ZB131 is an exciting new avenue for the treatment of CCA and other CSP-positive cancers with an excellent safety profile and strong antitumor activity in vitro and in murine models. Phase I clinical trials of ZB131 have been initiated. Citation Format: Samantha M. Perez, Randall Burton, Denise Krawitz, Christopher Sheth, Pina Cardarelli, Molly Owens, Brian Murphy, Matthew J. Reilley, Lindsey T. Brinton, Kimberly A. Kelly. First in class drug ZB131 shows efficacy in cholangiocarcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3591.

Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia

ObjectivesNew drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy. MethodsThree pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed. ResultsGood lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)ELF/AUCplasma = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (∼5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients. DiscussionApramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections.

Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV-1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs.

Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency in vitro against majority of the 124/125 variants. In vivo profiling of promising preclinical lead 29 showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of 29.

124-LB: Development of IDG-16177, a Selective and Safe GPR40 Agonist for the Treatment of Type 2 Diabetes

GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes. Disclosure J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.

Pivotal Role of Translation in Anti-Infective Development.

The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.

Model-Informed Drug Development for Antimicrobials: Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin.

Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model‐informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time‐kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One‐compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration‐time curve over MIC ratio) targets for stasis and 1‐log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain‐specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.

Preliminary Data on a Phase 1/2A First in Human Study of the Menin-KMT2A (MLL) Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Preliminary Data on a Phase 1/2A First in Human Study of the Menin-KMT2A (MLL) Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro.

A major impediment to eliminate lymphatic filariasis and onchocerciasis is the lack of effective short-course macrofilaricidal drugs or regimens that are proven to be safe for both infections. In this study we tested oxfendazole, an anthelmintic shown to be well tolerated in phase 1 clinical trials. In vitro, oxfendazole exhibited modest to marginal motility inhibition of adult worms of Onchocerca gutturosa, pre-adult worms of Onchocerca volvulus and Onchocerca lienalis microfilariae. In vivo, five days of oral treatments provided sterile cure with up to 100% macrofilaricidal efficacy in the murine Litomosoides sigmodontis model of filariasis. In addition, 10 days of oral treatments with oxfendazole inhibited filarial embryogenesis in patent L. sigmodontis-infected jirds and subsequently led to a protracted but complete clearance of microfilaremia. The macrofilaricidal effect observed in vivo was selective, as treatment with oxfendazole of microfilariae-injected naïve mice was ineffective. Based on pharmacokinetic analysis, the driver of efficacy is the maintenance of a minimal efficacious concentration of approximately 100 ng/ml (based on subcutaneous treatment at 25 mg/kg in mice). From animal models, the human efficacious dose is predicted to range from 1.5 to 4.1 mg/kg. Such a dose has already been proven to be safe in phase 1 clinical trials. Oxfendazole therefore has potential to be efficacious for treatment of human filariasis without causing adverse reactions due to drug-induced microfilariae killing.

In Vitro ADME, Preclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of RBx14255, a Novel Ketolide with Pharmacodynamics Against Multidrug-Resistant Bacterial Pathogens.

The preclinical pharmacokinetic and pharmacodynamic properties of a potent fluoroketolide RBx14255 against Streptococcus pneumoniae and Haemophilus influenzae was compared with telithromycin and human clinical dose was predicted for preclinical development. The in vitro pharmacokinetic characterization was performed for solubility, Caco-2 permeability, microsomal stability, CYP inhibition and plasma protein binding. In vivo pharmacokinetic studies were performed in Swiss albino mice, Sprague Dawley rats and Beagle dogs. The pharmacodynamic studies were carried out in mouse against S. pneumoniae in systemic infection and against S. pneumoniae and H. influenzae in rat lung infection models. RBx14255 showed superior potency and efficacy in mouse and rat infection models. RBx14255 showed pH dependent solubility (0.41 mg/mL at pH 6.8 and >1 mg/mL at pH 1.2), moderate Caco-2 permeability (A to B: 12 nm/s) with high efflux ratio. It showed high plasma protein binding (>97%) in mouse and low binding (45- 70%) in rat, dog and human. The compound is mainly metabolized through CYP3A4. Pharmacokinetic parameters and absolute bioavailability of both, RBx14255 and telithromycin are similar in mouse. Both the ketolides showed low plasma clearance (18% of the normal hepatic blood flow rate) in mouse, moderate to high clearance in rat and dog. Mean oral bioavailability was high in mouse (≥85%), moderate in rat (RBx14255: 15% and telithromycin: 51%) and high to moderate in dog (RBx14255: 98% and telithromycin: 56%). The predicted efficacious dose for a 70kg man ranges from 124 mg BID to 226 mg BID. RBx14255 displayed significantly better pharmacodynamics which correlates with the pharmacokinetic properties against S. pneumoniae and H. influenzae as compared to telithromycin. The predicted human efficacious doses are in the range of 124-226mg, making it amenable to oral dosage form drug in human. This could be a promising clinical candidate for future studies.

Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy.

Quantitative understanding about the dynamics of drug–target interactions in biological systems is essential, especially in rare disease programs with small patient populations. Follistatin, by antagonism of myostatin and activin, which are negative regulators of skeletal muscle and inflammatory response, is a promising therapeutic target for Duchenne Muscular Dystrophy. In this study, we constructed a quantitative systems pharmacology model for FS‐EEE‐Fc, a follistatin recombinant protein to investigate its efficacy from dual target binding, and, subsequently, to project its human efficacious dose. Based on model simulations, with an assumed efficacy threshold of 7–10% muscle volume increase, 3–5 mg/kg weekly dosing of FS‐EEE‐Fc is predicted to achieve meaningful clinical outcome. In conclusion, the study demonstrated an application of mechanism driven approach at early stage of a rare disease drug development to support lead compound optimization, enable human dose, pharmacokinetics, and efficacy predictions.

Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

Pharmacokinetic/Pharmacodynamic Modeling of the Anti-Cancer Effect of Dexamethasone in Pancreatic Cancer Xenografts and Anticipation of Human Efficacious Doses

Dexamethasone (DEX), a synthetic glucocorticoid, exhibited anti-cancer efficacy in pancreatic xenografts derived from patient tumor tissue or cancer cell lines. The aim of this study was to establish pharmacokinetic/pharmacodynamic (PK/PD) models to quantitatively characterize the inhibitory effect of DEX on tumor growth as well as its discrepancy among 3 xenograft models. Data of tumor growth profiles were collected from a patient-derived xenograft (PDX) model in NOD/SCID mice and 2 cell line–derived (PANC-1 and SW1990) xenograft models in BALB/c nude mice. Empirical PK/PD models were developed to establish mathematical relationships between plasma concentration of DEX and tumor growth dynamics after integrating PK parameters extracted from literature. Drug effect in each model was well described by a linear inhibitory function with a potency factor of 4.67, 3.14, and 2.35 L/mg for PDX, PANC-1, and SW1990 xenograft, respectively. Human efficacious doses of DEX were preliminarily predicted through model-based simulation, and 60% tumor growth inhibition at clinical exposure corresponded to a daily dose range of 26-52 mg intravenously. This modeling work quantified the preclinical anti-cancer effect of DEX and demonstrated the feasibility of its medication in pancreatic cancer, which would be conductive to future translational research.

751 Safety, Tolerability, and Pharmacokinetics of PTG-200, an Oral GI-Restricted Peptide Antagonist of IL-23 Receptor, in Normal Healthy Volunteers

INTRODUCTION: PTG-200 (JNJ-67864238) is an oral peptide that acts locally in intestinal tissues to block IL-23 signaling by selectively binding the IL-23 receptor (IL-23R). The gastrointestinal (GI)-restriction of PTG-200 is demonstrated in vivo by marked drug concentrations in GI tissues and feces and limited systemic blood exposure. PTG-200 therapeutic potential was established in a rat model of TNBS-induced colitis, where its threshold concentration in colonic tissue and luminal feces associated with efficacy was determined to inform the human efficacious dose. 1 The objectives of this Phase 1 study were to assess safety, tolerability, and pharmacokinetics (PK) of PTG-200. METHODS: This first-in-human (FIH) Phase 1 study was a single-center, randomized, double-blind, placebo-controlled trial comprising single and 14-day multiple ascending dose (SAD and MAD) arms in 82 healthy male volunteers. Oral doses ranged from 150 mg to 900 mg once daily (QD, fasted or fed) or twice daily (BID, fed). Subjects were monitored for safety and tolerability. PK in plasma, urine and feces was evaluated. RESULTS: Oral administration of PTG-200 was well-tolerated. There were no serious adverse events, dose-limiting toxicities, or clinically significant adverse events. PTG-200 plasma exposure was low (Table 1), below that expected to result in systemic biological activity. Following single-dose oral administration under fasted conditions, plasma PTG-200 concentrations exhibited dose-related increases with a median time to maximal concentration (Tmax) at 2 h. Administration of a high-fat meal prolonged the median Tmax to 4 h and had a modest effect on peak concentration (Cmax) and estimated overall exposure. Repeat dosing led to dose-related increases in plasma exposure. Consistent with a terminal half-life of ∼1.5 h in plasma, PTG-200 showed no evidence of accumulation except for the 900 mg BID group. Fecal concentrations in several cohorts met or exceeded the targeted threshold concentration associated with efficacy as established using the preclinical colitis model. CONCLUSION: Orally administered PTG-200 was well-tolerated in this FIH study. Systemic PK was consistent with the GI-restricted design of PTG-200. These safety and PK characteristics, combined with fulfillment of fecal drug threshold concentrations, support further clinical development of PTG-200 for the treatment of IBD. A Phase 2 study in patients with moderate-to-severe Crohn's disease is planned.