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Crizanlizumab and inclacumab are equally potent inhibitors of cell adhesion in the blood of patients with sickle cell disease.
No full textAcute painful vaso-occlusive episodes (VOEs) are the primary reason for emergency
department visit by sickle cell disease (SCD) patients and contribute to significant morbidity
in SCD. Crizanlizumab, a first-in-class humanized anti-P-selectin IgG2 monoclonal antibody,
is approved in more than 40 countries for prevention of VOEs in 16 years or older SCD
patients. Inclacumab, a fully human anti-P-selectin IgG4 mAb in clinical development is
believed to have stronger affinity to P-selectin and greater maximal inhibition of cell–cell
interactions than crizanlizumab. Using in vitro blinded experiments, we investigated whether
crizanlizumab and inclacumab can be differentiated in terms of P-selectin binding affinity
and inhibition of P-selectin-mediated cell adhesion in blood samples from healthy volunteers
or SCD patients. Surface Plasmon Resonance revealed that inclacumab had higher P-selectin
binding affinity than crizanlizumab, however, the inhibition of P-selectin-mediated cell
adhesion was higher or comparable with crizanlizumab than inclacumab. Crizanlizumab and
inclacumab were comparable in inhibiting leukocyte and erythrocyte adhesion to P-selection
under vascular mimetic flow in microfluidic channels, leukocyte-platelet aggregation, and
platelet aggregation in SCD patient or control human blood. In summary, these results
suggest that comparable or higher inhibition of cell adhesion with crizanlizumab vs
inclacumab does not correlate with P-selectin binding affinity. Ultimately, clinical trials are
required to evaluate how crizanlizumab vs inclacumab translate into treatment outcomes in
SCD patients
Immune and biological changes during treatment in patients with non-segmental vitiligo and their relation to repigmentation.
No full textBackground: The treatment of non-segmental vitiligo (NSV) remains a challenge and is poorly understood. The aim of this study was to evaluate protein differences in lesional and non-lesional skin and changes of cellular and proteomic markers early in treatment in lesional skin and blood in relation to clinical response.
Methods and Results: This prospective exploratory study was conducted in 30 NSV patients, 11 starting with standard-of-care topical therapy and 19 in combination with narrowband (NB)-UVB phototherapy. We identified 53 proteins that differed significantly between blister fluid from lesional and non-lesional skin, prior to treatment. After 3-months of treatment, CD3+, CD8+ T and TRM (CD69+CD103-) cell populations decreased in skin biopsies, together with changes in 47 blister fluid proteins. Percentages of cTfh17, CD336+Nkbright, type 1 regulatory T (Tr1) and Interleukin-10-secreting Tr1 cells decreased in blood. Decrease in TRM (blister fluid), Tr1 and Interleukin-10-secreting Tr1 (blood), and Fatty Acid-Binding Protein 4 (FABP4; blister fluid), were associated with repigmentation, measured with the Vitiligo Extent Score at baseline and 6-months.
Conclusion: Differences in lesional and non-lesional skin prior to treatment, do not reflect changes in lesional skin early in therapy nor associations with clinical repigmentation response. We found that a decrease of FABP4 protein and TRM cells in skin and IL10 secreting Tr1 cells in blood were significantly associated with the repigmentation response to treatment of vitiligo
Physiologically based pharmacokinetic modelling to predict artemether and lumefantrine exposure in neonates weighing less than 5 kg treated with artemether-lumefantrine to supplement the clinical data from the CALINA study.
No full textEvidence-based recommendations for malaria treatment in patients weighing < 5 kg are lacking as a consequence of differences in pharmacokinetics due to age and/or body weight (BW), and recruitment challenges in conducting trials in this population. A physiologically based pharmacokinetic (PBPK) model was developed and validated to predict artemether and lumefantrine concentrations in patients < 5 kg BW aged 1-28 days. The model predictions supplemented data from a trial (CALINA; NCT04300309) with an optimized dose of artemether-lumefantrine (5 mg artemether: 60 mg lumefantrine) in patients < 5 kg with Plasmodium falciparum malaria.PBPK models of artemether and lumefantrine were developed using Simcyp (Version 22) and validation was performed using historical data from adults and paediatric patients. To compare model-predicted and observed values, populations were matched to clinical trial populations (ranging from adults to infants) for patient numbers and demographics. The models were applied to predict artemether maximal concentration (Cmax) and lumefantrine Cmax and Day 7 concentration (C168h) in neonates of < 5 kg BW aged 1-28 days, and for subgroups aged 1-7, 8-14, and 15-28 days.Validated models for artemether and lumefantrine were used to predict plasma concentrations in neonates and young infants with BW < 5 kg after 3-day administration of 5 mg artemether and 60 mg lumefantrine twice daily with high confidence. The PBPK model using Upreti hepatic cytochrome P450 (CYP)3A4 ontogeny predicted observed artemether and lumefantrine exposure in infants and neonates better than Salem ontogeny. The predicted variability in neonates was comparable to or larger than the variability of observed concentrations in infants and older neonates in the CALINA study.Based on the success of the PBPK models for artemether and lumefantrine in predicting drug concentrations in adults and children, including neonates, modelling and simulation results can be used with confidence to supplement the limited available data for neonates (1-28 days old) < 5 kg BW obtained from the CALINA study for this rarer and more difficult to recruit patient population
Identification of cellular and molecular risk signatures for progression to late stage of age-related macular degeneration through utilization of the 9-step Minnesota Grading System
No full textAge-related macular degeneration (AMD) is a complex multifactorial disease, and the molecular mechanisms underpinning the progression of intermediate AMD to geographic atrophy are not fully understood. To better understand mechanisms driving progression, we performed bulk RNA sequencing on dissected macular and peripheral RPE/choroid and neural retina tissue from postmortem human eyes graded using the 9-step Minnesota Grading System (MGS). Binning of intermediate AMD cases into three distinct groups (AMD3L, AMD3M, AMD3H) based on the 5-year risk of progression enabled identification of distinct gene and pathway changes associated with progression to late-stage disease. Identified changes in gene expression were validated using ELISA or histological methods. RPE-specific genes and lipid metabolic pathways showed a transient increase in AMD3L followed by a pronounced decrease in AMD3H. In AMD3H, immune response genes such as C3, TREM2, and OLR1 were upregulated when compared to AMD3L samples, as well as genes specific to Müller glia/astrocytes (NGFR, SPP1, GPX3). Our findings support complement inhibition as a promising therapeutic option for slowing conversion to advanced AMD and identify macrophage and Müller/astrocyte genes as potential cell types to target in AMD. Further, we demonstrate the value of combining emerging, outcomes-based, clinically relatable grading systems with profiling technologies to generate new insights in ocular diseases
Data sharing for small aromatic amines
No full textThis is the yearly donation for the aromatic amine data sharing project in Vitic led by Lhasa. Only small chemicals will be shared and no project disclosed
A note on phase I interleaved versus parallel group ascending dose designs for concentration-QTc analyses.
No full textPK-QTc analyses are an integral part of drug development programs. These analyses are often based on phase I study data, and the question may be asked whether the design of these phase I studies has an impact on the precision of the corresponding PK-QT analysis. More precisely, we are interested whether one can increase the power of such analyses when using interleaved ascending dose designs rather than parallel group ascending dose designs. Based on a simulation study, previous authors have concluded that this is the case. Their conclusions, however, are based on assumptions regarding the magnitude of the random effect variances, and on a very specific set-up of their simulation study. In this paper we provide a study re-analysis of historical QTc data. The resulting estimates of these random effect variances are much smaller than those used by the previous authors. We also propose a simulation set-up that adequately mimics the data generation process and the correlation between the primary endpoint change from baseline and the covariate baseline. We present a simulation study using the revised simulation set-up and random effect variances as observed in our study re-analysis. We did not find major differences in power between the different designs when the number of observations is the same. We also provide a justification based on causal analysis why we think our simulation set-up is more adequate for situations when change from baseline is the primary endpoint, specifically when baseline is used as a covariate
Viral Kinetics Model of SARS-CoV-2 Infection Informs Drug Discovery, Clinical Dose, and Regimen Selection.
No full textQuantitative systems pharmacology (QSP) has been an important tool to project safety and efficacy of novel or repurposed therapies for the SARS-CoV-2 virus. Here, we present a QSP modeling framework to predict response to antiviral therapeutics with three mechanisms of action (MoA): cell entry inhibitors, anti-replicatives, and neutralizing biologics. We parameterized three distinct model structures describing virus-host interaction by fitting to published viral kinetics data of untreated COVID-19 patients. The models were used to test theoretical behaviors and map therapeutic design criteria of the different MoAs, identifying the most rapid and robust antiviral activity from neutralizing biologic and anti-replicative MoAs. We found good agreement between model predictions and clinical viral load reduction observed with anti-replicative nirmatrelvir/ritonavir (Paxlovid®) and neutralizing biologics bamlanivimab and casirivimab/imdevimab (REGEN-COV®), building confidence in the modeling framework to inform a dose selection. Finally, the model was applied to predict antiviral response with ensovibep, a novel DARPin therapeutic designed as a neutralizing biologic. We developed a new in silico measure of antiviral activity, area under the curve (AUC) of free spike protein concentration, as a metric with larger dynamic range than viral load reduction. By benchmarking to bamlanivimab predictions, we justified dose levels of 75, 225, and 600 mg ensovibep to be administered intravenously in a Phase 2 clinical investigation. Upon trial completion, we found model predictions to be in good agreement with the observed patient data. These results demonstrate the utility of this modeling framework to guide the development of novel antiviral therapeutics
H12: Adverse Events and Animal Welfare in Biotech and Academia Alike: Creating Efficiency, an Open Program, and Automated Functions of Reporting
No full textThis was previously submitted and approved through OAK as a conference presentation. PRIMR will be publishing some of the presentations in journal format on their website.
Reporting adverse events in animal research is important and essential for several key reasons: Animal Welfare, Scientific Integrity, Regulatory Compliance, Transparency and Accountability, Preventive Recurrence, and Protocol and Procedural Improvements as it pertains to the principle of the 3Rs.
Efficient reporting mechanisms can assist in efforts to encourage researchers to be more transparent when unanticipated events occur. It also promotes animal welfare by identifying procedures that may cause undue suffering, enabling researchers and to revise protocols or introduce refinements to minimize harm. It also gives IACUCs an opportunity to discuss scientific integrity and courses of action the lab should or must take to prevent recurrence, and make recommendations as necessary for researchers to consider for better scientific outcomes.
Reporting unanticipated events enhances data integrity in animal research studies. Unreported adverse effects can lead to biased results or misinterpretation of outcomes, potentially skewing the broader scientific understanding. Sharing this information helps other researchers anticipate potential issues, adapt their methodologies, and build upon existing knowledge with greater accuracy. It also helps to build public trust within the animal research and scientific community.
From a regulatory perspective, reporting adverse events ensures compliance with institutional and national policies and guidelines that govern the humane use of animals in research. It fosters accountability and supports post-approval monitoring of ongoing research, assessing risks, and enforcing the principles of the 3Rs (Replacement, Reduction, and Refinement). This oversight helps maintain public trust in scientific institutions and upholds the moral obligation to treat research animals with care and respect.
Moreover, adverse event data can lead to innovation in experimental design, animal care and the development of safer experimental techniques. It also aids in refining humane endpoints, reducing unnecessary suffering. In conclusion, researchers should understand that accountability and transparency in reporting adverse events is a cornerstone of responsible, transparent, and ethical animal research
Comparative assessment of the efficacy and safety associated with the delivery of AAV9-GFP vector via lumbar puncture route to juvenile Cynomolgus Macaques with and without anti-AAV9 preexisting IgG antibodies
No full textAdministration of AAV-based gene therapies into the intra-cerebrospinal fluid (CSF) compartments via routes such as lumbar puncture (LP) has been implemented as an alternative to intravenous dosing to target the CNS regions. This allows to lower doses, decrease toxicity, and circumvent intravascular pre-existing anti-AAV antibodies. In this study, AAV9-GFP vector was administered via LP to juvenile cynomolgus macaques with and without pre-existing anti-AAV9 IgG antibodies at a 5.0 x 1013 vector genome (vg) dose and examined for 28 days. CNS and peripheral tissues were surveyed for vector genome, mRNA, and protein expression. Histopathology, clinical pathology, and the humoral immune response to the viral capsid and transgene were also assessed. In addition, serum and CSF samples were analyzed to examine 276 proteomic markers curated to evaluate neural injury, organ damage, and inflammatory response. This study reveals no noticeable difference in AAV9-mediated gene transfer in the CNS tissues examined between the two groups, however qualitative and quantitative differences were observed for endpoints such as liver enzyme activities, histopathology, and levels of protein markers in the serum and CSF. These findings provide a view into nonclinical efficacy and safety following LP-delivered AAV9-GFP to juvenile cynomolgus macaques with and without pre-existing anti-AAV9 IgG antibodies
Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness.
No full textThe COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (Mpro), we constructed a structurally diverse Mpro panel by clustering all known coronavirus sequences by Mpro active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple Mpro homologues. Additionally, we solved the first X-ray cocrystal structure of Mpro from the human-infecting OC43 coronavirus, providing insights into potency differences among compound-target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses