Boehringer Ingelheim (United States)

Borderline personality disorder (BPD) is a significant cause of morbidity with no approved pharmacological treatment. We assessed treatment trajectories of patients with BPD in real-world clinical practice to help identify treatment gaps. This retrospective, observational, cohort study used de-identified MindLinc electronic health records data from the Holmusk NeuroBlu database (Version 21R2) to analyse the treatment journey of patients with BPD (aged ≥ 12 years with ≥1 diagnosis of BPD) that were prescribed pharmacological treatment within 14 days of diagnosis (baseline) and had treatment data for ≥12 months. Of those prescribed pharmacological treatment at baseline, 1461 patients (16.1%) had 12 months of follow-up data. Antidepressants were the most frequently prescribed medication at baseline (80.4%) either alone or in combination with other medication classes, followed by second-generation antipsychotics (SGAs), anxiolytics and mood stabilisers. In the 12 months post-baseline, the most frequently recorded treatment pathway was a switch from 1 antidepressant to another. Sertraline (5.5%), fluoxetine (5%), and citalopram (5%) were the most-prescribed antidepressants; lamotrigine (24.9%), gabapentin (15.4%), and valproate (7.1%) were the most prescribed mood stabilisers; and quetiapine (22.1%) and aripiprazole (19.0%) were the most prescribed SGAs. Polypharmacy (defined as the prescription of ≥ 1 psychotropic medication) was observed in 83.1% of patients at baseline and increased with follow-up time and age. The high rates of polypharmacy observed suggest that current clinical practices may not fully align with treatment guidelines for BPD, and that patients with BPD experience a considerable treatment burden. Limitations of this study include the absence of psychotherapy data and the use of prescription records without information on treatment adherence. Nonetheless, the diversity of treatment patterns observed reflects the complex symptomatology of BPD and highlights the need to deepen our understanding of its neurobiology to improve pharmacological treatment strategies and translate to meaningful patient outcomes. Not applicable.

Radiolabeled human mass balance studies are crucial for identifying circulating metabolites and understanding drug absorption, excretion, and clearance pathways. Metabolite profiling involves quantifying all drug-related entities, including parent drug and metabolites in plasma and excreta, using extended liquid chromatography methods coupled with detection through scintillation counting, accelerator mass spectrometry, or non-radiolabeled approaches. Given the labor-intensive nature of sample extraction and analysis, we propose a new paradigm that maximizes gathering information through sample pooling strategies. Our proposal introduces sample pooling strategies by integrating both individual and pooled sample schemes, simplifying decisions, and consolidating existing knowledge into a cohesive document. This aligns with the low statistical power typically associated with mass balance studies that dose six to eight subjects. In metabolite profiling, it is common practice to pool samples either from the limited number of subjects participating in a human mass balance study or from different time points of sample collection. This approach improves efficiency while preserving data integrity. Pooling reduces resource constraints and enables the concentration of samples with relatively low radioactivity levels, resulting in higher quality metabolite profiles. Nevertheless, there are situations when analyzing samples from individual subjects or time points may be preferred. This proposal presents guidance and decision trees designed to facilitate informed decisions about sample pooling to maximize data quality of metabolite profiling in human mass balance studies while efficiently managing resources. These recommendations stem from discussions within the mass balance working group of the IQ Consortium.

The emergence of nucleic acid (NA) therapeutics, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), which are usually delivered directly, and messenger RNAs (mRNAs), which are typically encapsulated in lipid nanoparticles (LNPs), marks a transformative era in precision medicine. While these therapies offer precise approaches for gene regulation or expression, they can trigger unwanted innate and/or adaptive immune responses that can either have no significant impact or adversely affect treatment efficacy and/or patient safety. Consequently, therapies where an adaptive immune response is desired, such mRNA/LNP-based vaccines against infectious diseases or cancer are out of scope of this article. In the present work, the Innovation and Quality Consortium Nucleic Acids Immunogenicity Working Group examines how the various components of NA-based therapies might contribute to their immunogenic potential and describes risk mitigation strategies through product design adaptations during early development stages. In addition, a comprehensive immunogenicity risk assessment framework is described, allowing to effectively define a tailored clinical testing strategy for different NA modalities with varying immunogenicity (IG) consequences. A streamlined monitoring strategy is recommended when minimal impact is expected, whereas extensive testing is suggested when safety concerns arise. Overall, these recommendations ensure that safe and effective NA-based therapies reach patients with an appropriate assessment of the IG potential.

Material-sparing tablet development (MSTD) describes an approach to tablet formulation development that uses the active pharmaceutical ingredient's (API) material properties to guide formulation design. The work presented here expands on this methodology and demonstrates its application for any API. Four APIs were randomly selected from the Boehringer Ingelheim opnMe platform to demonstrate the universal applicability of the MSTD regardless of the API properties. Small batches of each API (<20 g of API) were used to mimic early-phase development. Each API was analyzed for particle morphology, flowability, density, and compression behavior. Formulations were then designed to complement these API properties using standard tableting excipients. The powder blends were tested for flowability (≤ 12 mm Flodex) and tensile strength (> 2 MPa) to ensure manufacturability. Tablet disintegration (< 15 min) and friability (NMT 0.8 % loss) were tested to verify tablets met current federal performance standards. Stability testing was done to determine excipient compatibility and overall drug product stability (NMT 0.3 % API loss). This work demonstrated that for a wide variety of different APIs, formulations could be designed and tested for critical manufacturing attributes, and possible failure points could be determined using less than 20 g of API in less than 14 days.