A phase I, randomized, ascending-dose study to assess safety, pharmacokinetics, and activity of GDC-8264, a RIP1 inhibitor, in healthy volunteers.

Receptor-interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)-α, Toll-like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1-mediated inflammation and cell death. GDC-8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo-controlled, double-blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single- (5-225 mg) and multiple- (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC-8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC-8264. All adverse events in GDC-8264-treated subjects in both stages were mild. GDC-8264 exhibited dose-proportional increases in systemic exposure; the mean terminal half-life ranged from 10-13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC-8264 had minimal renal excretion at all doses. A high-fat meal had no significant effect on the PKs of GDC-8264. In an ex vivo stimulation assay of whole blood, GDC-8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK-PD modeling, the GDC-8264 half-maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC-8264 support its further development for treatment of RIP1-driven diseases.

Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

BACKGROUND AND OBJECTIVES: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies. Lauriet is a phase 2 study of an anti-tau monoclonal antibody, semorinemab, in patients with mild-to-moderate AD. METHODS: The phase 2 Lauriet study included a randomized, placebo-controlled, double-blind period, during which participants with mild-to-moderate AD received 4,500 mg of IV semorinemab or placebo every 4 weeks for 48 or 60 weeks. Participants who chose to continue in the subsequent optional open-label extension received 4,500 mg of semorinemab every 4 weeks for up to 96 weeks. Coprimary efficacy endpoints were change from baseline to week 49 or 61 on the 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. Secondary efficacy endpoints included change from baseline on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety, pharmacokinetics, and pharmacodynamic effects were also evaluated. RESULTS: Between December 3, 2018, and February 27, 2020, 624 individuals were screened, 272 participants were randomized, and 238 were included in the modified intent-to-treat population (received ≥1 dose(s) of study medication and underwent baseline and ≥1 postbaseline assessment(s)). Baseline characteristics were well balanced. At week 49, the semorinemab arm demonstrated a 42.2% reduction (-2.89 points, 95% CI -4.56 to -1.21, p = 0.0008) in decline on the ADAS-Cog11 (coprimary endpoint) relative to the placebo arm. However, no treatment effects were observed on the ADCS-ADL scale (coprimary endpoint; absolute difference between the 2 treatment arms in the ADCS-ADL score change from baseline of -0.83 points, 95% CI -3.39 to 1.72, p = 0.52) or on the MMSE or CDR-SB (secondary endpoints). Semorinemab was safe and well tolerated. DISCUSSION: Based on the results of the prespecified coprimary endpoints, this study was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes. These results may warrant further exploration of semorinemab or other anti-tau therapies in mild-to-moderate AD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that semorinemab does not slow functional decline in patients with mild-to-moderate AD. TRIAL REGISTRATION INFORMATION: The Lauriet study is registered on ClinicalTrials.gov, NCT03828747, and EudraCT 2018-003398-87.

Modeling Alzheimer's disease progression utilizing clinical trial and ADNI data to predict longitudinal trajectory of CDR-SB.

There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression in Alzheimer's disease (AD). We have built upon previous longitudinal AD progression models, using a nonlinear, mixed-effect modeling approach to predict Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) progression. Data from the Alzheimer's Disease Neuroimaging Initiative (observational study) and placebo arms from four interventional trials (N = 1093) were used for model building. The placebo arms from two additional interventional trials (N = 805) were used for external model validation. In this modeling framework, CDR-SB progression over the disease trajectory timescale was obtained for each participant by estimating disease onset time (DOT). Disease progression following DOT was described by both global progression rate (RATE) and individual progression rate (α). Baseline Mini-Mental State Examination and CDR-SB scores described the interindividual variabilities in DOT and α well. This model successfully predicted outcomes in the external validation datasets, supporting its suitability for prospective prediction and use in design of future trials. By predicting individual participants' disease progression trajectories using baseline characteristics and comparing these against the observed responses to new agents, the model can help assess treatment effects and support decision making for future trials.

Quantitative systems pharmacology model of the amyloid pathway in Alzheimer's disease: Insights into the therapeutic mechanisms of clinical candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aß) pathophysiology in AD. The model included mechanisms of Aß monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti-Aß monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aß accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aß load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aß load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.

Hallmarks of neurodegenerative disease: A systems pharmacology perspective.

Age-related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease-modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial.

Importance: Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. Objective: To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. Design, Setting, and Participants: This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed ß-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. Interventions: During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter. Main Outcomes and Measures: The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. Results: In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and semorinemab (1500 mg: n = 86; Δ = 2.36 [95% CI, 1.83-2.89]; 4500 mg: n = 126; Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: n = 84; Δ = 2.41 [95% CI, 1.88-2.94]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. Conclusions and Relevance: In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach. Trial Registration: ClinicalTrials.gov Identifier: NCT03289143.

A quantitative systems pharmacological approach identified activation of JNK signaling pathway as a promising treatment strategy for refractory HER2 positive breast cancer.

HER2-positive breast cancer (BC) is a rapidly growing and aggressive BC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitative systems pharmacological (QSP) approach to evaluate the efficacy of lapatinib (LAP), abemaciclib (ABE) and 5-fluorouracil (5-FU) mono- and combination therapies in JIMT-1 cells, a HER2+ BC cell line exhibiting intrinsic resistance to trastuzumab. Concentration-response relationships and temporal profiles of cellular viability were assessed upon exposure to single agents and their combinations. To quantify the nature and intensity of drug-drug interactions, pharmacodynamic cellular response models were generated, to characterize single agent and combination time course data. Temporal changes in cell-cycle phase distributions, intracellular protein signaling, and JIMT-1 cellular viability were quantified, and a systems-based protein signaling network model was developed, integrating  protein dynamics to drive the observed changes in cell viability. Global sensitivity analyses for each treatment arm were performed, to identify the most influential parameters governing cellular responses. Our QSP model was able to adequately characterize protein dynamic and cellular viability trends following single and combination drug exposure. Moreover, the model and subsequent sensitivity analyses suggest that the  activation of the stress pathway, through pJNK, has the greatest impact over the observed declines of JIMT-1 cell viability in vitro. These findings suggest that dual HER2 and CDK 4/6 inhibition may be a promising novel treatment strategy for refractory HER2+ BC, however, proof-of-concept in vivo studies are needed to further evaluate the combined use of these therapies.

A Review on Drug-Induced Nephrotoxicity: Pathophysiological Mechanisms, Drug Classes, Clinical Management, and Recent Advances in Mathematical Modeling and Simulation Approaches.

A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited. Thus, drug-induced nephrotoxicity remains a major clinical challenge. Prior knowledge of risk factors associated with special patient populations and specific classes of drugs, combined with early diagnosis, therapeutic drug monitoring with dose adjustments, as well as timely prospective treatments are essential to prevent and manage them better. Most incident drug-induced renal toxicity is reversible only if diagnosed at an early stage and treated promptly. Hence, diagnosis at an early stage is the need of the hour to counter it. Significant recent advances in the identification of novel early biomarkers of nephrotoxicity are not beyond limitations. In such a scenario, mathematical modeling and simulation (M&S) approaches may help to better understand and predict toxicities in a clinical setting. This review summarizes pathophysiological mechanisms of drug-induced nephrotoxicity, classes of nephrotoxic drugs, management, prevention, and diagnosis in clinics. Finally, it also highlights some of the recent advancements in mathematical M&S approaches that could be used to better understand and predict drug-induced nephrotoxicity.

gQSPSim: A SimBiology-Based GUI for Standardized QSP Model Development and Application.

Quantitative systems pharmacology (QSP) models are often implemented using a wide variety of technical workflows and methodologies. To facilitate reproducibility, transparency, portability, and reuse for QSP models, we have developed gQSPSim, a graphical user interface-based MATLAB application that performs key steps in QSP model development and analyses. The capabilities of gQSPSim include (i) model calibration using global and local optimization methods, (ii) development of virtual subjects to explore variability and uncertainty in the represented biology, and (iii) simulations of virtual populations for different interventions. gQSPSim works with SimBiology-built models using components such as species, doses, variants, and rules. All functionalities are equipped with an interactive visualization interface and the ability to generate presentation-ready figures. In addition, standardized gQSPSim sessions can be shared and saved for future extension and reuse. In this work, we demonstrate gQSPSim's capabilities with a standard target-mediated drug disposition model and a published model of anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) treatment of hypercholesterolemia.

Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.

The heterogeneous polyclonal nature of multiple myeloma complicates the identification of protein biomarkers predictive of drug response. In this study, a pharmacodynamic systems modeling approach was used to link in vitro bortezomib exposure and myeloma cell death. The exposure-response was integrated through a network of important protein biomarker dynamics activated by bortezomib in four myeloma cell lines. The pharmacodynamic models reasonably characterized the protein and myeloma cell dynamics simultaneously following bortezomib (20 nM) treatment. The models were used to identify differences in pathway dynamics across cell lines from model-estimated protein biomarker turnover parameters and global sensitivity analyses. Additionally, a statistical correlation analysis between drug sensitivity and model-fitted protein activation profiles (i.e., cumulative area under the protein expression-time curves) supported the identification of shared biomarkers associated with sensitivity differences among the cell lines. Both types of analysis identified similar important proteins associated with bortezomib pharmacodynamics, such as phosphorylated Nuclear Factor kappa-light-chain-enhancer of activated B cells (pNFkappaB), phosphorylated protein kinase B (pAKT), and caspase-8 (Cas 8).

Network-Based Analysis of Bortezomib Pharmacodynamic Heterogeneity in Multiple Myeloma Cells.

The objective of this study is to evaluate the heterogeneity in pharmacodynamic response in four in vitro multiple myeloma cell lines to treatment with bortezomib, and to assess whether such differences are associated with drug-induced intracellular signaling protein dynamics identified via a logic-based network modeling approach. The in vitro pharmacodynamic-efficacy of bortezomib was evaluated through concentration-effect and cell proliferation dynamical studies in U266, RPMI8226, MM.1S, and NCI-H929 myeloma cell lines. A Boolean logic-based network model incorporating intracellular protein signaling pathways relevant to myeloma cell growth, proliferation, and apoptosis was developed based on information available in the literature and used to identify key proteins regulating bortezomib pharmacodynamics. The time-course of network-identified proteins was measured using the MAGPIX protein assay system. Traditional pharmacodynamic modeling endpoints revealed variable responses of the cell lines to bortezomib treatment, classifying cell lines as more sensitive (MM.1S and NCI-H929) and less sensitive (U266 and RPMI8226). Network centrality and model reduction identified key proteins (e.g., phosphorylated nuclear factor-κB, phosphorylated protein kinase B, phosphorylated mechanistic target of rapamycin, Bcl-2, phosphorylated c-Jun N-terminal kinase, phosphorylated p53, p21, phosphorylated Bcl-2-associated death promoter, caspase 8, and caspase 9) that govern bortezomib pharmacodynamics. The corresponding relative expression (normalized to 0-hour untreated-control cells) of proteins demonstrated a greater magnitude and earlier onset of stimulation/inhibition in cells more sensitive (MM.1S and NCI-H929) to bortezomib-induced cell death at 20 nM, relative to the less sensitive cells (U266 and RPMI8226). Overall, differences in intracellular signaling appear to be associated with bortezomib pharmacodynamic heterogeneity, and key proteins may be potential biomarkers to evaluate bortezomib responses.

Physiologically-Based Pharmacokinetic-Pharmacodynamic Modeling of 1α,25-Dihydroxyvitamin D3 in Mice.

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] concentrations are regulated by renal CYP27B1 for synthesis and CYP24A1 for degradation. Published plasma and tissue 1,25(OH)2D3 concentrations and mRNA fold change expression of Cyp24a1 and Cyp27b1 following repetitive i.p. injections to C57BL/6 mice (2.5 µg × kg(-1) every 2 days for 4 doses) were fitted with a minimal and full physiologically-based pharmacokinetic-pharmacodynamic models (PBPK-PD). The minimal physiologically-based pharmacokinetic-pharmacodynamic linked model (mPBPK-PD) related Cyp24a1 mRNA fold changes to linear changes in tissue/tissue baseline 1,25(OH)2D3 concentration ratios, whereas the full physiologically-based pharmacokinetic-pharmacodynamic model (PBPK-PD) related measured tissue Cyp24a1 and Cyp27b1 fold changes to tissue 1,25(OH)2D3 concentrations with indirect response, sigmoidal maximal stimulatory effect/maximal inhibitory effect functions. Moreover, the intestinal segregated flow model (SFM) that describes a low and partial intestinal (blood/plasma) flow to enterocytes was nested within both models for comparison with the traditional model for intestine (TM) where the entire flow perfuses the intestine. Both the mPBPK(SFM)-PD and full PBPK(SFM)-PD models described the i.p. plasma and tissue 1,25(OH)2D3 concentrations and fold changes in mRNA expression significantly better than the TM counterparts with F test comparisons. The full PBPK(SFM)-PD fits showed estimates with good precision (lower percentage of coefficient of variation), and the model was more robust in predicting data from escalating i.v. doses (2, 60, and 120 pmol) and the rebound in 1,25(OH)2D3 tissue concentrations after dosing termination. The full PBPK(SFM)-PD model performed the best among the tested models for describing the complex pharmacokinetic-pharmacodynamic interplay among Cyp27b1, Cyp24a1, and 1,25(OH)2D3.

Effect of salt on the hybridization of DNA by sequential immobilization of oligonucleotides at the air-water interface in the presence of ODA/DOTAP monolayers.

The effect of low ionic strength on the binding of preformed DNA duplexes and the hybridization of single-stranded oligonucleotides at the air-water interface in the presence of cationic Langmuir monolayers of octadecylamine (ODA), as well as 1,2-dioleoyloxytrimethylammonium propane (DOTAP), is investigated. The complexation of the single-stranded DNA molecules and preformed duplexes with NaCl in solution with ODA/DOTAP Langmuir monolayers was followed in time by monitoring the pressure-area isotherms, wherein a very large and rapid expansion of the ODA/DOTAP monolayer was observed. In the case of sequential immobilization of complementary oligonucleotides, after addition of the complementary strand and intercalator, there was not much expansion, indicative of the fact that equilibrium had been rapidly achieved. Langmuir-Blodgett (LB) films of the ODA/DOTAP-DNA complex were formed on different substrates and characterized using quartz-crystal microgravimetry (QCM), fluorescence spectroscopy, and thermal melting studies. These measurements clearly showed that the preformed duplexes retained their native form as double helices and further, hybridization of the complementary single-stranded DNA molecules had occurred at the air-water interface, leading to the characteristic double-helical structure.