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Cultural diversity drives innovation: empowering teams for success
No full textThough there is broad agreement on the beneficial impact of diversity in management and
leadership roles, much of the innovative capacity of an organization is realized at the unit level in working teams. Recent research points to cultural diversity having an especially significant impact on innovation team performance. The reports also highlight the need for the optimal team operating principles to derive maximum benefit. To prepare such innovation teams for success, it is valuable to understand the dynamics of team diversity at the project level and the underlying barriers and opportunities presented
Management of pharmaceutical ICH M7 (Q)SAR predictions – The impact of model updates
No full textPharmaceutical applicants conduct (Q)SAR assessments on identified and theoretical impurities to predict their mutagenic potential. Two complementary models—one rule-based and one statistical-based—are used, followed by expert review. (Q)SAR models are continuously updated to improve predictions, with new versions typically released on a yearly basis. Numerous releases of (Q)SAR models will occur during the typical 6–7 years of drug development until new drug registration. Therefore, it is important to understand the impact of model updates on impurity mutagenicity predictions over time. Compounds representative of pharmaceutical impurities were analyzed with three rule- and three statistical-based models covering a 4–8 year period, with the individual time frame being dependent on when the individual models were initially made available. The largest changes in the combined outcome of two complementary models were from positive or equivocal to negative and from negative to equivocal. Importantly, the cumulative change of negative to positive predictions was small in all models (<5%) and was further reduced when complementary models were combined in a consensus fashion. We conclude that model updates of the type evaluated in this manuscript would not necessarily require re-running a (Q)SAR prediction unless there is a specific need. However, original (Q)SAR predictions should be evaluated when finalizing the commercial route of synthesis for marketing authorization
Generating three-dimensional human granulomas in vitro to study Mycobacterium tuberculosis-host interaction
No full textGranulomas are organized multicellular structures that constitute the hallmark of an infection by the human pathogen Mycobacterium tuberculosis (Mtb). A better understanding of the complex host-Mtb interactions within the granuloma’s environment may lead to new therapeutic or preventive tools to improve the control of the tuberculosis pandemic. To date, several in vitro models that are able to mimic human nascent granulomas have been reported. Here we describe a protocol in which Mtb-infected human peripheral blood mononuclear cells (PBMCs) are embedded within a collagen matrix leading to the formation of three-dimensional micro-granulomas. Subsequently, PBMCs and Mtb can be retrieved allowing multiparametric readouts from both the host and the pathogen. In addition to the incorporation of a physiological extracellular matrix, this model has the advantage of recapitulating dormant-like Mtb features, as well as reproducing Mtb resuscitation observed under immunomodulatory treatments
Mammalian Retinal Cell Quantification
No full textNormal retina and its cell layers are essential for processing visual stimuli, and loss of its integrity has been documented in many disease processes. The numbers and the axonal processes of retinal ganglion cells are reduced substantially in glaucoma, leading to vision loss and blindness. Similarly, selective loss of photoreceptors in age-related macular degeneration and hereditary retinal dystrophies also results in the compromise of visual acuity. Development of genetically modified mice has led to increased understanding of the pathogenesis of many retinal diseases. Similarly, in this digital era, usage of modalities to quantify the retinal cell loss has grown exponentially leading to a better understanding of the suitability of animal models to study human retinal diseases. These quantification modalities provide valuable quantifiable data in studying pathogenesis and disease progression. This review will discuss the immunohistochemical markers for various retinal cells, available automated tools to quantify retinal cells, and present an example of retinal ganglion cell quantification using HALO image analysis platform. Additionally, we briefly review retinal cell types and subtypes, salient features of retina in various laboratory animal species, and a few of the main disease processes that affect retinal cell numbers in humans
Assessment of Fatigue Using Wearable Sensors: A Pilot Study
No full textBackground: Fatigue is a broad, multifactorial concept encompassing feelings of reduced physical and mental energy levels. Fatigue strongly impacts patient health-related quality of life across a huge range of conditions, yet, to date, tools available to understand fatigue are severely limited.
Methods: After using a recurrent neural network-based algorithm to impute missing time series data form a multisensor wearable device, we compared supervised and unsupervised machine learning approaches to gain insights on the relationship between self-reported non-pathological fatigue and multimodal sensor data.
Results: A total of 27 healthy subjects and 405 recording days were analyzed. Recorded data included continuous multimodal wearable sensor time series on physical activity, vital signs, and other physiological parameters, and daily questionnaires on fatigue. The best results were obtained when using the causal convolutional neural network model for unsupervised representation learning of multivariate sensor data, and random forest as a classifier trained on subject-reported physical fatigue labels (weighted precision of 0.70 ± 0.03 and recall of 0.73 ± 0.03). When using manually engineered features on sensor data to train our random forest (weighted precision of 0.70 ± 0.05 and recall of 0.72 ± 0.01), both physical activity (energy expenditure, activity counts, and steps) and vital signs (heart rate, heart rate variability, and respiratory rate) were important parameters to measure. Furthermore, vital signs contributed the most as top features for predicting mental fatigue compared to physical ones. These results support the idea that fatigue is a highly multimodal concept. Analysis of clusters from sensor data highlighted a digital phenotype indicating the presence of fatigue (95% of observations) characterized by a high intensity of physical activity. Mental fatigue followed similar trends but was less predictable. Potential future directions could focus on anomaly detection assuming longer individual monitoring periods.
Conclusion: Taken together, these results are the first demonstration that multimodal digital data can be used to inform, quantify, and augment subjectively captured non-pathological fatigue measures
Modulating Target Engagement of Small Molecules Via Drug Delivery – Approaches and Applications in Drug Discovery and Development
No full textDrug delivery technologies for modified drug release have been in existence for a long time, but their utilization has been largely limited to extending market exclusivity and improving patient adherence to therapy. Recently, they are gaining renewed importance as pharmaceutical industry is steadily shifting to a more integrated discovery-development approach. In discovery, modulating target engagement via drug delivery technologies can enable crucial pharmacology studies for building a strong foundation and well-defined criteria for molecular design. In development, earlier implementation of delivery technologies can enhance the value of drug products through reduced dosing frequency, improved tolerability and/or safety profile, thereby leading to better adherence and therapeutic effectiveness
Moving the Dial on Heart Failure Patient Adherence Rates
No full textHeart failure patients with poor adherence have increased mortality, hospitalization needs, and health care costs. This review highlights current single-factor and multi-factor adherence methods. Against a backdrop of diversity of approaches, multi-factor solutions cast the widest net for positively influencing adherent behaviors. A key enabler lies in the development and leveraging of patient personas in the synthesis of successful intervention methods. Deployable solutions can also be envisioned in clinical trials where adherence tracking represents an essential component
Effect of capmatinib on the pharmacokinetics of digoxin and rosuvastatin administered as a two-drug cocktail in patients with MET-dysregulated advanced solid tumors: A phase I, multicenter, open-label, single-sequence drug-drug interaction study
No full textAims: Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic non-small cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin, administered orally as a two-drug cocktail in patients with MET-dysregulated advanced solid tumors.
Methods: This was a multicenter, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumors on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction (DDI) assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated.
Results: Thirty-two patients (median age: 61.5 years) were enrolled. Co-administration of capmatinib increased digoxin Cmax, and AUCinf by 74%, and 47%, respectively. Co-administration of capmatinib increased rosuvastatin Cmax, and AUCinf by 204%, and 108%, respectively. Most frequent adverse events (AEs; ≥25% for all grades) were nausea (56.3%), asthenia (43.8%), constipation and vomiting (40.6%, each), peripheral edema (28.1%) and pyrexia (25%). Most frequent Grade 3/4 AEs (≥ 5%) were anemia and pulmonary embolism (9.4%, each), asthenia, dyspnea, nausea and vomiting (6.3%, each).
Conclusion: This study demonstrated that capmatinib is an inhibitor of P-gp as well as BCRP transporters, with clinically relevant DDI potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed
Rituximab-specific DNA aptamers are able to selectively recognize heat-treated antibodies
No full textThe monoclonal anti-CD20 IgG1 antibody rituximab is used as a first-line treatment for B cell lymphoma. Like all therapeutic antibodies, it is a complex protein for which both safety and efficacy heavily depend on the integrity of its three-dimensional structure. Aptamers, short oligonucleotides with a distinct fold, can be used to detect minor modifications or structural variations of a molecule or protein. To detect antibody molecules in a fold state occurring prior to protein precipitation, we generated DNA aptamers that were selected for extensively heat-treated rituximab. Using the magnetic bead-based systematic evolution of ligands by exponential enrichment (SELEX), we obtained six DNA aptamer sequences (40-mers) specific for 80°C heat-treated rituximab. In silico fold prediction and circular dichroism analysis revealed a G-quadruplex structure for one aptamer, while all others exhibited a B-DNA helix. Binding affinities ranging from 8.8-86.7 nM were determined by an enzyme-linked apta-sorbent assay (ELASA). Aptamers additionally detected structural changes in rituximab treated for 5 min at 70°C, although with lower binding activity. Notably, none of the aptamers recognized rituximab in its native state nor did they detect the antibody after it was exposed to lower temperatures or different physical stressors. Aptamers also reacted with the therapeutic antibody adalimumab incubated at 80°C suggesting similar aptamer binding motifs located on extensively heat-treated IgG1 antibodies. Within this work, we obtained the first aptamer panel, which is specific for an antibody fold state specifically present prior to protein aggregation. This study demonstrates the potential of aptamer selection for specific stress-based protein variants, which has potential impact for quality control of biopharmaceuticals
First-in-human study demonstrating the safety and clinical efficacy of novel anti-IL-17A monoclonal antibody CJM112 in moderate to severe plaque psoriasis
No full textBackground and objective: Anti-IL-17A IgG/κ monoclonal antibody CJM112 binds both IL-17A and IL-17AF. The purpose of this First-in-Human study was to assess CJM112 effects on safety and efficacy in patients with moderate to severe plaque psoriasis. Methods: This study had two parts: single ascending doses of 5–450 mg subcutaneous (s.c.) CJM112 (SAD) and multi-dose parallel groups of CJM112 15 mg, 50 mg and 150 mg s.c. low frequency or high frequency (MD). SAD/MD were double-blind, randomized and placebo-controlled; MD also included a secukinumab 150 mg s.c. arm as an active comparator. Patients 18–65 years with moderate to severe psoriasis were included in this study. The efficacy outcome was the change in Psoriasis Area Severity Index (PASI) from baseline to Week 4 in the SAD part of the study, and from baseline to Week 12 in the MD part. Results: 96 patients were enrolled in this study (SAD, n = 42; MD, n = 54). In SAD, CJM112 doses from 15 mg and above demonstrated higher PASI responses compared with placebo at Week 12. CJM112 450 mg did not add further efficacy, but efficacy duration was prolonged compared with CJM112 150 mg. CJM112 MD resulted in a dose-dependent decrease in PASI over time to Week 12. CJM112 150 mg high frequency did not exceed the effect of CJM112 150 mg low frequency and had similar efficacy to secukinumab 150 mg. The safety profile of CJM112 was as expected for an antibody targeting IL-17A/IL-17AF. Conclusions: CJM112 had clinical efficacy in moderate to severe psoriasis and was generally safe and well tolerated in the doses tested. Additional neutralization of IL-17AF did not translate to increased clinical efficacy compared with secukinumab