Modeling Disease Progression and Placebo Response in Huntington Disease: Insights From Enroll-HD and GENERATION HD1 Cohorts.

Background And Objectives: Huntington disease is a rare neurodegenerative disorder with no disease-modifying therapies. This study aimed to quantify longitudinal changes in Unified Huntington's Disease Rating Scale (UHDRS) scores and evaluate their susceptibility to placebo response, enhancing our understanding of disease progression and ability to optimize future trials.

Methods: We used data from the Enroll-HD natural history study (NCT01574053) and the GENERATION HD1 phase 3 clinical trial (NCT03761849) to model disease progression and placebo response for UHDRS scores, which are commonly used to evaluate disease progression in clinical trials.

Ocular Pharmacodynamics of Intravitreal Faricimab in Patients With Neovascular Age-Related Macular Degeneration or Diabetic Macular Edema.

Purpose: Evaluate the ocular pharmacodynamics (PD) of intravitreal faricimab, a bispecific inhibitor of angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME).

Methods: Aqueous humor (AH) samples (1025 free Ang-2 concentrations and 1345 free VEGF-A concentrations) were collected from approximately 300 faricimab-treated patients with nAMD or DME in phase 2/3 trials. A population pharmacokinetic pharmacodynamic (popPKPD) model was developed to describe the dynamic effect of faricimab on free AH Ang-2 and VEGF-A.

Ocular Pharmacokinetics of Faricimab Following Intravitreal Administration in Patients With Retinal Disease.

Purpose: To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints.

Methods: A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients.

Modeling of Parkinson's Disease Progression and Implications for Detection of Disease Modification in Treatment Trials.

Background: Objectively measuring Parkinson's disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD.

Objective: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD.

Methods: Data from the Parkinson's Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs).

A model-based approach for historical borrowing, with an application to neovascular age-related macular degeneration.

Bayesian historical borrowing has recently attracted growing interest due to the increasing availability of historical control data, as well as improved computational methodology and software. In this article, we argue that the statistical models used for borrowing may be suboptimal when they do not adjust for differing factors across historical studies such as covariates, dosing regimen, etc. We propose an alternative approach to address these shortcomings.

A Baseline Score to Predict Response to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration.

Purpose: What are the patient characteristics predictive of response to ranibizumab treatment?

Methods: Model-based characterization of best-corrected visual acuity (BCVA) time profiles of patients with neovascular age-related macular degeneration under ranibizumab or sham treatment based on 24-month observations of BCVA in 2419 patients from randomized multicenter phase 3 trials of ranibizumab: ANCHOR, MARINA, PIER, and HARBOR. Goodness-of-fit plots and precision of parameter estimates were used for measure of accuracy.

Results: The model incorporates a long-term effect on disease progression and an additive and more potent short-term effect of ranibizumab.

PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration.

Plasma drug concentration and electrocardiogram (ECG) data from a drug-drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both "therapeutic" and "supra-therapeutic" exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration.

Ocular Half-Life of Intravitreal Biologics in Humans and Other Species: Meta-Analysis and Model-Based Prediction.

Therapeutic antibodies administered intravitreally are the current standard of care to treat retinal diseases. The ocular half-life () is a key determinant of the duration of target suppression. To support the development of novel, longer-acting drugs, a reliable determination of is needed together with an improved understanding of the factors that influence it.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs.

Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.

Aims: This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR).

Methods: Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies.

Bayesian adaptive dose-escalation procedures for binary and continuous responses utilizing a gain function.

One of the main aims of early phase clinical trials is to identify a safe dose with an indication of therapeutic benefit to administer to subjects in further studies. Ideally therefore, dose-limiting events (DLEs) and responses indicative of efficacy should be considered in the dose-escalation procedure. Several methods have been suggested for incorporating both DLEs and efficacy responses in early phase dose-escalation trials.

Bayesian adaptive designs in single ascending dose trials in healthy volunteers.

Aim: Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach.

Methods: A trial simulation approach was used and seven different scenarios of dose-response were tested.

Pharmacokinetic-pharmacodynamic models for categorical toxicity data.

We propose a pharmacokinetic-pharmacodynamic (PK/PD) model (with possibly different choices for the PD link) for categorical toxicity data analysis. This is extension of the one-comportment model that applies to toxic endpoints categorised by grades (e.g.