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CSL-Tox: An open-source analytical framework for the comparison of short-term and long-term toxicity end points and exploring the opportunities for decreasing in-vivo studies conducted for drug development programs.”
No full textIn-vivo toxicity assessment is an important step prior to clinical development and is still the main source of data for overall risk assessment of a new molecular entity (NCE). All in-vivo studies are performed according to regulatory requirements and many efforts have been exerted to minimize these studies in accordance with the (Replacement, Reduction and Refinement) 3Rs principle. Many aspects of in-vivo toxicology packages can be optimized to reduce animal use, including the number of studies performed as well as study durations, which is the main focus of this analysis. We performed a statistical comparison of the adverse findings observed in 116 short-term versus 78 long-term studies in order to explore the possibility of using only short-term studies as a prediction tool for the longer-term effects. Annotation of the treatment related findings was one of the challenges faced during this work. A specific focus was therefore put on the summary and conclusion sections of the reports since they contain expert assessments on whether the findings were considered adverse or were attributed to other reasons. Our analysis showed a general good concordance between short-term and long-term toxicity findings for large molecules and the majority of small molecules. Less concordance was seen for certain target organ systems findings’. While this work supports the minimization of in-vivo study durations, a larger-scale effort would be needed to provide more evidence. We therefore present the steps performed in this study as an open-source R workflow (CSL-Tox) and we provide the dataset used in the work to allow researchers to reproduce such analysis and to promote large-scale application of this study
Editorial for "MRI Fat-Saturated T2-Weighted Radiomics Model for Predicting the Ki-67 Index of Soft Tissue Sarcomas”
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Explaining compound activity predictions with a substructure-aware loss for graph neural networks
No full textExplainable machine learning is increasingly used in drug discovery to help rationalize compound property predictions. Feature attribution techniques are popular choices within this toolbox that aim to identify which substructures of a molecule are responsible for a predicted property change. However, established molecular feature attribution methods have so far displayed low performance for popular deep learning algorithms such as graph neural networks (GNNs), particularly when compared with simpler modeling alternatives such as random forests coupled with atom masking. To mitigate this problem, in this work we present a modification to the regression objective of GNNs to specifically account for common core structures between pairs of molecules. The proposed approach shows higher accuracy on a recently-proposed explainability benchmark. We expect this methodology to be useful in drug discovery pipelines, and specifically in lead optimization efforts where specific chemical series of related compounds are investigated
Discovery of a brain sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation
No full textAtrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). Here we describe 14b, a potent GIRK1/4 inhibitor developed to cardiovert AF to sinus rhythm while minimizing central nervous system exposure – an issue with preceding GIRK1/4 clinical candidates
Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals.
No full textTherapeutically relevant proteins naturally adsorb to interfaces, causing aggregation which in turn potentially leads to numerous adverse consequences such as loss of activity or unwanted immunogenic reactions. Surfactants are ubiquitously used in biotherapeutics drug development to oppose interfacial stress, yet, the choice of the surfactant is extremely limited: to date, only polysorbates (PS20/80) and poloxamer 188 are used in commercial products. However, both surfactant families suffer from severe degradation and impurities of the raw material, which frequently increases the risk of particle generation, chemical protein degradation, and potential adverse immune reactions. Herein, we assessed a total of 40 suitable alternative surfactant candidates and subsequently performed a selection through a three-gate screening process employing four protein modalities encompassing six different formulations. The screening is based on short-term agitation-induced aggregation studies coupled to particle analysis and surface tension characterization, followed by long-term quiescence stability studies connected to protein purity measurements and particle analysis. The study concludes by assessing the surfactant's chemical and enzymatic degradation propensity. The candidates emerging from the screening are de novo α-tocopherol-derivatives named VEDG-2.2 and VEDS, produced ad hoc for this study. They display protein stabilization potential comparable or better than polysorbates together with an increased resistance to chemical and enzymatic degradation, thus representing valuable alternative surfactants for biotherapeutics
Differential proteins expression distinguished between patients with infectious and noninfectious uveitis
No full textUveitis is associated with a number of inflammatory diseases and can be infectious or noninfectious. The diagnosis of uveitis is usually based on typical clinical presentation, but sometimes the signs and symptoms are not clear, and the discovery of new biomarkers may help to distinguish between infectious and noninfectious uveitis. In the current study, we investigate the proteome of aqueous humor and associated blood plasma from patients with confirmed infectious or noninfectious uveitis. Aqueous humor (AH) and plasma were obtained from 28 patients with infectious uveitis (IU), 29 patients with noninfectious uveitis (NIU) and 35 healthy controls undergoing cataract surgery. The protein profiles were analyzed by SomaScan proteomic profiling technology. Our results showed proteins differentially expressed in the AH and plasma from IU and NIU patients in comparison with cataract patients. Importantly, 18 proteins were up-regulated and 1 protein was down-regulated in both AH and plasma from IU patients. Furthermore, in NIU patients, 142 proteins were up-regulated and 7 proteins down-regulated in both AH and blood plasma. The results of pathway enrichment analysis for both IU and NIU groups identified mostly to inflammatory and regulatory processes. In conclusion, SomaScan assay was able to detect novel AH and plasma protein biomarkers in IU and NIU patients. The unique proteins found in both AH and plasma suggests a protein signature that could distinguish between infectious and noninfectious uveitis patient populations
Restoring the biological activity of crizanlizumab at physiological conditions through a pH-dependent aspartic acid isomerization reaction
No full textIn this study, we report the isomerization of an aspartic acid residue in the CDR of crizanlizumab as a major degradation pathway. The succinimide intermediate and iso-aspartic acid degradation products were successfully isolated by ion exchange chromatography for characterization. The isomerization site was identified at a DG motif in the CDR by peptide mapping and the biological characterization of the isolated variants showed that the succinimide variant exhibited a loss in target binding and biological activity compared to the aspartic acid and iso-aspartic acid variants of the molecule. The pH influence of this isomerization reaction was investigated using capillary zone electrophoresis (CZE). Below pH 6.3, the succinimide formation was predominant, whereas at pH values above 6.3, iso-aspartic acid was formed and the initial amounts of succinimide dropped to levels even lower than those observed in the starting material. Importantly, while the succinimide accumulated at long term storage conditions of 2 to 8ºC at pH values below 6.3, complete hydrolysis of succinimide was observed at physiological conditions (pH 7.4, 37°C) resulting in full recovery of the biological activity. In this study, we demonstrate that the critical quality attribute succinimide with reduced potency has little or no impact on the efficacy of crizanlizumab due to the full recovery of the biological activity within a few hours under physiological conditions
Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings.
No full textHuman gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly
Pharmacokinetics of Tamoxifen and Its Major Metabolites and the Effect of the African Ancestry Specific CYP2D6*17 Variant on the Formation of the Active Metabolite, Endoxifen.
No full textTamoxifen (TAM) is widely used in the treatment of hormone receptor-positive breast cancer. TAM is metabolized into the active secondary metabolite endoxifen (ENDO), primarily by CYP2D6. We aimed to investigate the effects of an African-specific CYP2D6 variant allele, CYP2D6*17, on the pharmacokinetics (PK) of TAM and its active metabolites in 42 healthy black Zimbabweans. Subjects were grouped based on CYP2D6 genotypes as CYP2D6*1/*1 or *1/*2 or *2/*2 (CYP2D6*1 or *2), CYP2D6*1/*17 or 2*/*17, and CYP2D6*17/*17. PK parameters for TAM and three metabolites were determined. The pharmacokinetics of ENDO showed statistically significant differences among the three groups. The mean ENDO AUC0-∞ in CYP2D6*17/*17 subjects was 452.01 (196.94) h·*ng/mL, and the AUC0-∞ in CYP2D6*1/*17 subjects was 889.74 h·ng/mL, which was 5-fold and 2.8-fold lower than in CYP2D6*1 or *2 subjects, respectively. Individuals who were heterozygous or homozygous for CYP2D6*17 alleles showed a 2- and 5-fold decrease in Cmax, respectively, compared to the CYP2D6*1 or *2 genotype. CYP2D6*17 gene carriers have significantly lower ENDO exposure levels than CYP2D6*1 or *2 gene carriers. Pharmacokinetic parameters of TAM and the two primary metabolites, N-desmethyl tamoxifen (NDT) and 4-hydroxy tamoxifen (4OHT), did not show any significant difference in the three genotype groups. The African-specific CYP2D6*17 variant had effects on ENDO exposure levels that could potentially have clinical implications for patients homozygous for this variant
The most common linkers in bioactive molecules and their bioisosteric replacement network.
No full textStructures of the large majority of bioactive molecules are composed of several rings that are decorated by substituents and connected by linkers. While numerous cheminformatics studies focusing on rings and substituents are available, practically nothing has been published about the third important structural constituent of bioactive molecules - the linkers. The current study attempts to fill this gap. The most common linkers present in bioactive molecules are identified, their properties analyzed and a method for linker similarity search introduced. The bioisosteric replacement network of linkers is generated based on a large corpus of structure-activity data from medicinal chemistry literature. The results are presented in a graphical form and the underlying data are also made available for download. This analysis is intended to help medicinal chemists to better understand the role of linkers, particularly heterocyclic rings in bioactive molecules and to select an optimal set of linkers in their future project