AbbVie (Germany)

Psoriasis is a chronic inflammatory disease associated with multiple systemic comorbidities and reduced quality of life. Risankizumab, an interleukin (IL)-23 inhibitor, has demonstrated efficacy in achieving rapid and sustained skin clearance in moderate-to-severe psoriasis. However, its impact on chronic subclinical inflammation is less understood. Conventional clinical assessments like Psoriasis Area and Severity Index (PASI), Investigator's Global Assessment (IGA), and Body Surface Area (BSA) focus on evaluating visible symptoms and are limited in capturing underlying disease activity. Optical coherence tomography (OCT), a non-invasive imaging modality, offers real-time assessment of structural and vascular changes, providing valuable insights beyond the skin surface. This sub-analysis of a prospective, single-center exploratory study included 22 patients with moderate-to-severe psoriasis treated with risankizumab. Clinical assessments (PASI, IGA, BSA) were conducted at baseline and weeks2, 4, 16, 28, 40, and 52. OCT imaging performed at baseline and weeks4, 16, and 52 evaluated epidermal thickness and vascular parameters (e.g., vessel density and diameter) in lesional and perilesional skin. By week16, mean (95% confidence interval [CI]) PASI score decreased from 16.3 (11.6-21.1) at baseline to 3.5 (1.8-5.2), and BSA involvement from 24.7% (16.1-33.3) to 5.2% (1.9-8.4) (both p < 0.001). By week52, 86.7%, 73.3%, and 40.0% of patients achieved PASI75, 90, and 100, respectively, and 93.3% achieved IGA0/1. OCT showed lesional reductions in epidermal thickness (- 37.4%), vessel density (- 26.6% Δ area under the curve [AUC]), and vessel diameter (- 59.5% ΔAUC) over the 52-week period. Notably, vascular changes also occurred in uninvolved perilesional skin. Risankizumab improved both clinical and OCT parameters over 52weeks, emphasizing the importance of long-term therapy with benefits extending beyond visible improvement. OCT emerged as a valuable tool for assessing deep (vascular) treatment response, thereby supporting a more comprehensive understanding of therapeutic outcomes in psoriasis.

Accurately measuring compound binding affinities is key to driving the pharmaceutical development process. Rigorous physics-based in silico approaches, particularly alchemical free energy methods, have become a gold standard tool for estimating compound affinity changes. Here we present the results of a large-scale pre-competitive collaborative assessment of relative binding free energy (RBFE) calculations generated by 15 pharmaceutical companies. We evaluate an open-source and MIT licensed RBFE Protocol from the Open Free Energy (OpenFE) ecosystem across both public and blinded private datasets, encompassing over 1,700 ligands in total. For the public dataset, the weighted RMSE across the 58 systems was 1.73 [1.53, 1.96] kcal/mol, with 10 of the systems reaching sub-kcal/mol accuracy. For the private dataset, the weighted RMSE across the 37 systems was 2.44 [1.94, 3.06] kcal/mol, with only 2 of the systems reaching sub-kcal/mol accuracy, reflecting the increased complexity of real-world drug discovery. The protocols performance was system-dependent, with no single dominant error source, indicating that accuracy is primarily influenced by input quality and transformation type. Overall, these benchmark results are encouraging and indicate that OpenFE is ready for large-scale industrial applications, with an "out-of-the-box" accuracy that approaches that of commercial solutions. While comparison against published FEP+ results, which were obtained after manual parameter optimization, shows comparable ranking statistics, a gap remains in error statistics, for which we outline possible paths toward improvement. The protocol meets key criteria required for production use in an industrial setting: it shows robust performance, generates reproducible results, and achieves both sufficient throughput and rapid convergence.

IntroductionWe evaluated continuous subcutaneously administered foslevodopa/foscarbidopa (LDp/CDp) in younger patients earlier within advanced Parkinson’s disease (aPD).MethodsThis phase 3 trial included patients aged ≥ 30 years with levodopa-responsive PD, Mini-Mental State Examination score ≥ 24, and levodopa equivalent dose ≥ 400 mg/day. Patients were considered by the investigator as inadequately controlled on current oral/transdermal therapy and experienced ≥ 2.5 h/day “Off” time, with recognizable “On”/“Off” states. Patients were randomized (1:1) to LDp/CDp plus placebo capsules or orally administered immediate-release levodopa/carbidopa plus placebo infusion. This post hoc exploratory analysis focused on younger patients (≤ 65 years) earlier within aPD (Hoehn and Yahr stage ≤ 2 [“On” state], ≤ 5 years since motor fluctuations started). Outcomes included change from baseline (CFB) to week 12 in “Off” and “On” time, Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) II, 39-item PD Questionnaire (PDQ-39), and PD Sleep Scale-2 (PDSS-2).ResultsTwenty-six patients met subgroup criteria (LDp/CDp, n = 13; orally administered levodopa/carbidopa, n = 13). Despite small sample sizes, at week 12, LDp/CDp was associated with significantly greater improvements in “Off” time (mean [SD] CFB − 3.7 [3.1] vs − 1.6 [2.9] h; P = 0.0011), “On” time without troublesome dyskinesia (+ 3.9 [3.3] vs + 1.4 [3.8] h; P = 0.0011), and PDSS-2 (− 6.4 [4.6] vs − 1.8 [3.1]; P = 0.0220) vs orally administered levodopa/carbidopa. Mean (SD) CFB to week 12 (LDp/CDp vs orally administered levodopa/carbidopa) was + 4.2 (2.8) vs + 1.9 (4.6) h for “On” time without dyskinesia (P = 0.0878), − 3.0 (6.4) vs − 0.9 (3.5) for MDS-UPDRS II (P = 0.3539), and − 9.9 (7.4) vs − 1.9 (9.4) for PDQ-39 (P = 0.0534). For most assessments, treatment differences were numerically larger in the subgroup vs the overall population. Safety findings were consistent with the overall population.ConclusionsLDp/CDp was associated with significantly greater improvements in motor function and sleep vs orally administered levodopa/carbidopa in younger patients earlier within aPD whose symptoms were inadequately controlled by oral/transdermal therapies. Larger real-world studies are needed to confirm findings.Trial RegistrationClinicalTrials.gov identifier, NCT04380142.

Background and ObjectiveAtogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model to support dosage regimen selection during the clinical development of atogepant in patients with episodic migraine (EM) or chronic migraine (CM) and to guide the dosing recommendations for regulatory approval.MethodsPharmacokinetic data collected from 12 phase 1 studies, 1 phase 2b/3 study, and 1 phase 3 study in healthy participants and patients with EM were used to develop a popPK model that was externally validated with data from a CM phase 3 study and a phase 3 study in patients with EM for whom two to four classes of conventional oral preventive treatments have failed. The model was built and evaluated using nonlinear mixed-effect modeling and diagnostic assessments.ResultsThe final model featured three disposition compartments, with linear elimination from the central compartment and a sequential zero-/first-order lagged absorption process. Formulation, dose, food status, liver function, concomitant medication, and body weight were each found to have a statistically significant influence on atogepant’s pharmacokinetics. Absorption was affected by dose and formulation, the apparent central volume of distribution (V1/F) increased with body weight, relative bioavailability (Frel) modestly increased with dose, and a high-fat meal lengthened absorption lag time. Severe hepatic impairment and coadministration of itraconazole, quinidine, or a single rifampin dose decreased apparent clearance (CL/F) by ~37% and ~66%, ~29%, and ~13%, respectively, while coadministration of multiple rifampin doses increased CL/F by 1.82-fold. Frel increased by 1.95 and 2.4 fold with coadministration of itraconazole and a single rifampin dose, respectively, and decreased by ~25% with multiple rifampin doses. Mild/moderate renal impairment, coadministration of breast cancer resistance protein (BCRP) inhibitors, BCRP substrates and statins, age, and sex had no clinically relevant effect on atogepant pharmacokinetics. No statistically significant differences were observed in atogepant’s pharmacokinetics between healthy participants and patients with migraine.ConclusionsThe pharmacokinetics of atogepant are similar in healthy participants and patients with CM or EM. Dose adjustments owing to intrinsic factors of age, sex, race, and body weight, or owing to concomitant medications consisting of P-glycoprotein (P-gp) inhibitors, BCRP inhibitors, oral contraceptive components (ethinyl estradiol and levonorgestrel), famotidine, esomeprazole, sumatriptan, acetaminophen, and naproxen are not necessary. Atogepant’s popPK model provides a valuable tool for evaluating specific questions for patients, healthcare providers, and regulatory agencies. Integration into other modeling approaches has also aided in model-informed drug development decisions.Clinical Trial RegistrationNCT03855137 (EudraCT number: 2018-004337-32).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-025-01566-5.

Reliable prediction and prevention of adverse drug reactions (ADRs) remains a key challenge in the development of new medicines. Advanced mathematical and computational modelling approaches, which incorporate cutting-edge mechanistic understanding of ADRs in concert with systematically collected data addressing knowledge gaps, are integral components of model-informed drug discovery and development (MID3). These approaches provide a precise, quantitative framework for predicting and mitigating safety risks in the earliest phases of drug development. Here, we highlight recent developments in the burgeoning field of quantitative systems toxicology (QST), including insights into the current state-of-the-art, as well as outcomes from the Innovative Medicines Initiative (IMI) 2 TransQST project. QST models that describe the disruption of cardiovascular, gastrointestinal, hepatic and renal physiological functions following drug exposure are presented, along with recommendations for their application in drug discovery and development.

Proteolysis targeting chimeras (PROTACs) exhibit a unique and promising pharmacology. However, this comes with molecular properties exceeding the 'drug-like' rule of five chemical space, which often limits gastrointestinal absorption. This in vivo study aimed to investigate the contribution of luminal and plasma stability, intestinal effective permeability, P-glycoprotein (P-gp) efflux, and bile excretion, on the rat intestinal absorption and systemic exposure of two PROTACs, ARV-110 (812Da, LogD7.4 4.8) and ARV-471 (724Da, LogD7.4 4.6). Luminal stability and effective intestinal permeability were determined directly from luminal disappearance using single-pass intestinal perfusion, with and without a protease inhibitor, or a P-gp/Cytochrome P450 CYP3A inhibitor (ketoconazole) in rats. Plasma stability was tested by in vitro incubations. Intestinal absorption, systemic exposure, and biliary excretion were examined after intraduodenal and intravenous dosing with ketoconazole or the P-gp selective inhibitor (encequidar). Both PROTACs were degraded in the intestinal lumen and in plasma by peptidases. The intestinal effective permeability in rats was moderate for ARV-110 (0.62×10-4 cm/s) and low for ARV-471 (0.23×10-4 cm/s). P-gp inhibition increased the permeability 1.6- and 2.3-fold for ARV-110 and ARV-471, respectively. After intraduodenal dosing with the P-gp inhibitors a corresponding increase in systemic exposure was observed for both PROTACs. There was only a minor difference in the increased systemic exposure induced by the two inhibitors, suggesting that the mechanisms were primarily P-gp inhibition, rather than gut-wall and hepatic extraction. Biliary excretion was a minor pathway and did not affect the absorption and systemic exposure of the PROTACs to a large extent. In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux.

Neuronal loss is the ultimate driver of neural system dysfunction in Alzheimer's disease (AD). We used single-nucleus RNA sequencing and neuropathological phenotyping to elucidate mechanisms of neurodegeneration in AD by identifying vulnerable neuronal populations and probing for their differentially expressed genes. Evidenced by transcriptomic analyses and quantitative tau immunoassays of human AD and non-AD brain tissue, we identified a neuronal population especially vulnerable to tau pathology. Multiplexed immunohistochemistry and in situ hybridization (CBLN2 and LINC00507) validated the presence of the tau-vulnerable neuronal population and revealed a propensity of this population to bear tau pathology. Differentially expressed genes associated with phospho-tau pathology in these neurons revealed genes involved in apoptosis, cell-component dissociation (e.g., autophagosome maturation and actin filament depolymerization), and regulation of vesicle-mediated transport.

BackgroundIn Germany, the approach to treatment optimization for patients with advanced Parkinson's disease (PD) is considered somewhat conservative. The MANAGE-PD tool (www.managepd.eu) was developed to help identify patients with advanced PD and to facilitate treatment decision making and appropriate allocation of patients to device-aided therapies (DAT). This prospective, non-interventional study aimed to investigate the real-world disease burden of PD and treatment optimization after MANAGE-PD implementation.MethodsAdult PD patients (N = 278) visited specialist clinics and neurologist’s practices in Germany in 2022. Disease burden was assessed using the Unified PD rating scale (UPDRS parts II-IV), the non-motor symptoms scale (NMSS) and the 8-item Parkinson’s disease Questionnaire (PDQ-8). Data on planned treatment changes were collected. Data were analyzed by disease control categories according to the MANAGE-PD tool.ResultsMean scores for motor and non-motor symptoms, quality of life, and comorbidity burden were worse in patients with lower disease control measured by MANAGE-PD. For 52.8% of patients in Category 2 (inadequately controlled—might benefit from oral optimization), no change in oral treatment was planned. No change in oral treatment and no DAT initiation was planned for 37.9% and 65.0% of patients in Category 3 (inadequately controlled—might benefit from DAT). Patient refusal and needing more time to decide were the most common reasons for not making treatment changes.ConclusionsThis study supports the validity of MANAGE-PD by showing its high association with disease burden and emphasizes the importance of timely provision of necessary information to enable informed decisions about treatment optimization.