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6571 Background: Anemia and transfusion dependence affect nearly all pts with MF and are associated with poor prognosis.The phase 3 MOMENTUM trial (NCT04173494) evaluatedMMB—a JAK1, JAK2, and ACVR1 inhibitor—vs DAN (2:1 randomization) in JAK inhibitor (JAKi)–experienced pts with MF and anemia who had symptoms and splenomegaly. While MMB showed spleen, symptom, and anemia benefits vs DAN at wk 24, comparative estimates of long-term overall and leukemia-free survival (OS and LFS) are confounded and may underestimate the MMB effect, as all pts in the DAN arm who entered the open-label phase of the trial crossed over to receive MMB at wk 24. We used a rank-preserving structural failure time (RPSFT) model to estimate the OS and LFS that might have been observed without crossover. Methods: This exploratory analysis evaluated survival over the entire MOMENTUM trial period; most pts entered an extended access study (NCT03441113) after wk 48. The RPSFT model assumes that treatment slows the speed of disease progression and death proportionally regardless of time of crossover. Analyses were conducted with and without recensoring, and CIs were constructed to appropriately account for additional model fitting uncertainty. Results: As of December 29, 2022, 38 (29%) and 20 (31%) deaths had occurred in the MMB and DAN arms, respectively. Risk of death was reduced with MMB vs DAN by 11% (HR, 0.89) with no crossover adjustment, and by 22% (HR, 0.78) and 13% (HR, 0.87) using the RPSFT model with and without recensoring, respectively. Similarly, 40 (31%) and 22 (34%) LFS events had occurred at data cutoff in the MMB and DAN arms, respectively. Risk of an LFS event was reduced with MMB vs DAN by 20% (HR, 0.80) with no crossover adjustment, and by 36% (HR, 0.64) and 23% (HR, 0.77) using the RPSFT model with and without recensoring, respectively (Table). Conclusions: Consistent with the original unadjusted survival analysis, RPSFT models adjusting for the effects of treatment crossover showed prolonged OS and LFS in pts initially randomized to MMB vs those initially randomized to DAN; HRs in favor of MMB were lower after crossover adjustment. While these RPSFT analyses maintain the significance level of the original unadjusted analysis ( P>.05), these results support the trend of long-term survival benefits with MMB vs DAN in JAKi–experienced pts with MF and anemia. Clinical trial information: NCT04173494 . Clinical trial information: NCT03441113 .[Table: see text]

Accurate and rapid predictions of the binding affinity of a compound to a target are one of the ultimate goals of computer aided drug design. Alchemical approaches to free energy estimations follow the path from an initial state of the system to the final state through alchemical changes of the energy function during a molecular dynamics simulation. Herein, we explore the accuracy and efficiency of two such techniques: relative free energy perturbation (FEP) and multisite lambda dynamics (MSλD). These are applied to a series of inhibitors for the bromodomain-containing protein 4 (BRD4). We demonstrate a procedure for obtaining accurate relative binding free energies using MSλD when dealing with a change in the net charge of the ligand. This resulted in an impressive comparison with experiment, with an average difference of 0.4 ± 0.4 kcal mol–1. In a benchmarking study for the relative FEP calculations, we found that using 20 lambda windows with 0.5 ns of equilibration and 1 ns of data collection for each window gave the optimal compromise between accuracy and speed. Overall, relative FEP and MSλD predicted binding free energies with comparable accuracy, an average of 0.6 kcal mol–1 for each method. However, MSλD makes predictions for a larger molecular space over a much shorter time scale than relative FEP, with MSλD requiring a factor of 18 times less simulation time for the entire molecule space.

Community acquired pneumonia (CAP) is a major health problem in India with high morbidity and mortality. The threat posed by this infection is further intensified by the continued emergence of resistance to the currently available antibiotics. With a heritage of more than 24 years in India, amoxicillin+clavulanic acid is one of the most common antibiotics used for CAP. It was developed with an intent to sustain the efficacy of amoxicillin which was challenged due to the emergence of the beta-lactamase producing microorganism. Over a period, it has been included in national and international guidelines for the treatment of CAP. To assure the highest probability of clinical cure and to combat development of resistance: It is imperative for amoxicillin+clavulanic acid to reaffirm itself. Optimization of the PK/PD and higher dose of amoxicllin+clavulanic acid will tackle the burden of the future difficult to manage respiratory infections.

Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting.

ABSTRACTBackgroundThe Coronavirus diseases (COVID-19) pandemic is not abating and there is no approved treatment yet. The development of vaccines is hoped to help in addressing this disease outbreak. However, in the face of anti-vaccines uprise, it is important to understand the factors that may influence the uptake of COVID-19 vaccines as this will influence how successful the fight against COVID-19 will be in the long term.MethodsA cross-sectional study among 776 adult Nigerians (age ≥18 years) was conducted in the 36 States of Nigeria and the Capital City with online questionnaire. The questionnaire consisted of 5 sections: socio-demographic characteristics of respondents, respondent’s knowledge of COVID-19, respondents risk perception of COVID-19, vaccination history of respondents, and willingness to receive COVID-19 vaccine. Descriptive analysis of variables was done and multivariate analysis using logistic regression was carried out to determine the predictors of uptake of a potential COVID-19 vaccine. The level of significance was predetermined at a p-value < 0.05. Data analysis was done with SPSS version 21.ResultsMost of the respondents were male (58.1%). Most participants were willing to take a potential COVID-19 vaccine (58.2%), while 19.2% would not take it with 22.6% indecisive. 53.5% would prefer a single dose COVID-19 vaccine. For vaccine uptake, being male (p= 0.002) and the perception that “vaccines are good” (p< 0.001) were the positive predictor of uptake of a potential COVID-19 vaccine.ConclusionMost Nigerians were willing to take a potential COVID-19 vaccine with the male gender and perception that “vaccines are good” being positive predictors. There is a need for public enlightenment aim at encouraging those that are indecisive or averse to receiving COVID-19 vaccines.