Sanofi (Germany)

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.

A major challenge in organic synthesis is the selective functionalization of C-H bonds. As most organic compounds contain multiple C-H bonds with similar properties, distinguishing between them requires precise control. In this study, we show how transition metal catalysts can adopt many of the characteristics associated with enzymes, leading to unprecedented site-selectivity in the C-H functionalization step. The catalysts are dirhodium complexes that adopt a bowl-shaped shape on formation. The flexible microenvironment within the bowl causes an induced fitting to occur as the reagent and substrate approach the catalyst. The key factors controlling the selectivity are noncovalent interactions between the approaching substrate and the catalyst wall, which cause a specific C-H bond in the substrate to be placed close to the metal-bound reagent.

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8+ T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8+ T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC.

BackgroundChronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines.ObjectiveWe sought to compare individual versus simultaneous blockade of TNF-α and OX40L in controlling inflammation.MethodsAnalysis was conducted of the murine xenograft graft-versus-host disease model, a novel cynomolgus monkey model of simultaneous T cell–dependent antibody response (TDAR) and delayed-type hypersensitivity (DTH) skin reaction, and samples of patients with hidradenitis suppurativa (HS).ResultsCompared with individual inhibition, combined targeting of TNF-α and OX40L using mAbs more potently suppressed TDAR and DTH in cynomolgus monkey. We therefore created SAR442970, a bispecific pentavalent Nanobody containing 2 domains each binding to OX40L and TNF-α and 1 domain binding serum albumin to extend half-life. In xenograft graft-versus-host disease, disease control by SAR442970 was superior compared with treatment with monospecific anti-TNF-α or anti-OX40L Nanobodies. In cynomolgus monkey, SAR442970 potently suppressed TDAR and DTH. The transcriptional signature of inflamed monkey skin showed similarities to that of lesional skin of patients with atopic dermatitis and, even more so, HS and was inhibited by SAR442970 treatment. Increased numbers of cells expressing OX40 were observed in HS lesions, and bioinformatics analyses of single-cell and bulk RNA sequencing data identified cells expressing OX40 as T cells with a highly mobile phenotype.ConclusionOX40-OX40L interaction is a key pathogenetic feature in HS, and patients with HS might benefit from combined TNF-α/OX40L blockade by SAR442970, which is currently investigated in a clinical phase 2 trial.

Dysmenorrhea symptoms are frequent and often self-treated using non-prescription medicines. To further characterize women with dysmenorrhea using a combination of hyoscine butylbromide plus paracetamol (PLUS) for self-management of their complaints, we performed a secondary analysis of a published pharmacy-based patient survey. A total of 314 women (mean age: 32.3 years) with dysmenorrhea reported a pain and cramps intensity of 7.45 ± 2.13 (means ± SD) on a 0-10 Likert scale, which was reduced to 2.86 ± 1.81 upon treatment. Associated impairments of work/daily chores, leisure activities, and sleep were improved by 64.6, 62.2, and 70.4%, respectively. The onset of symptom relief was within 60 min in 84.7%. Tolerability was rated as very good or good by 97.2%; 82.8% were repeat users, 97.5% reported their intention to purchase the product again, and 97.1% reported their intention to recommend it to relatives, friends, and colleagues. These findings confirm the efficacy and tolerability data on PLUS from randomized controlled trials in a larger group of women conducting self-management of their dysmenorrhea in a real-world setting. Future studies should compare PLUS to other non-prescription treatments.

Abstract Background and ObjectivesParkinson’s disease (PD) progression can be characterized in terms of healthcare utilization by analyzing clinical events across different stages of disease.MethodsPD progression was measured by the Hoehn & Yahr (H&Y) clinical rating scale and clinical events at each stage were evaluated. Natural language processing and a large language model were used to extract H&Y values from real-world data enabling a larger cohort than manually collected studies, and multi-state hidden Markov models were used for H&Y progression likelihood.ResultsWithin the one year, most patients in H&Y stages 2-5 remained in the same stage. Stage transitions, when they occurred, were most frequently to the next higher stage. Higher H&Y stages were associated with discharges into long term care and higher rates of additional clinical events.ConclusionsStratifying key clinical events by H&Y score demonstrates the increases of health care utilization and economic burden with PD severity. Modelling the progression likelihood establishes a progression timeline and emphasizes the unmet need to identify treatment options that stop or slow these transitions.

ObjectiveExplore the effects of baseline characteristics on long-term safety/efficacy of avalglucosidase alfa (AVA) in subgroups of patients with late-onset Pompe disease enrolled in COMET (Phase 3; NCT02782741).MethodsCOMET randomised treatment-naïve patients to AVA (n=51) or alglucosidase alfa (ALG; n=49). After a 49-week primary analysis period, all patients from the AVA-arm continued and 44 patients in the ALG-arm switched to AVA (extended treatment period); total duration 145 Weeks. Subgroups and analyses included: 1) the impact of baseline age (≥18–<45y, ≥45y) on the change in 6-minute walk test (6MWT) distance and upright forced vital capacity (FVC) % predicted, 2) the impact of baseline 6MWT (<403.5, ≥403.5m) on the change in FVC % predicted, and 3) the impact of baseline FVC % predicted (<55, ≥55%) on the change in 6MWT distance. Mean estimates (95% CI) were calculated from linear mixed effects models stratified by treatment group.ResultsOverall, the change from baseline to Week 145 was stable or improved for all subgroups analysed for the different outcomes. From baseline to Week 145: younger patients in the AVA-arm had a significant improvement in 6MWT distance (9.8m [4.4,15.1]; p=0.0004) and AVA-arm patients with baseline FVC ≥55% had a significant improvement in 6MWT distance (6.8m [2.4,11.2]; p=0.0026). Changes over time remained stable in all other subgroups with nonsignificant p values.ConclusionsThese data indicate that the positive changes seen during treatment with AVA are not driven by any subgroup and demonstrate that AVA is effective in patients with varying baseline characteristics.Funded: Sanofi.