Use of Quantitative Pharmacology in the Development of HAE1, a High-Affinity Anti-IgE Monoclonal Antibody

HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (≤10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data

Community perceptions of malaria and vaccines in the South Coast and Busia regions of Kenya

<p>Abstract</p> <p>Background</p> <p>Malaria is a leading cause of morbidity and mortality in children younger than 5 years in Kenya. Within the context of planning for a vaccine to be used alongside existing malaria control methods, this study explores sociocultural and health communications issues among individuals who are responsible for or influence decisions on childhood vaccination at the community level.</p> <p>Methods</p> <p>This qualitative study was conducted in two malaria-endemic regions of Kenya--South Coast and Busia. Participant selection was purposive and criterion based. A total of 20 focus group discussions, 22 in-depth interviews, and 18 exit interviews were conducted.</p> <p>Results</p> <p>Participants understand that malaria is a serious problem that no single tool can defeat. Communities would welcome a malaria vaccine, although they would have questions and concerns about the intervention. While support for local child immunization programs exists, limited understanding about vaccines and what they do is evident among younger and older people, particularly men. Even as health care providers are frustrated when parents do not have their children vaccinated, some parents have concerns about access to and the quality of vaccination services. Some women, including older mothers and those less economically privileged, see themselves as the focus of health workers' negative comments associated with either their parenting choices or their children's appearance. In general, parents and caregivers weigh several factors--such as personal opportunity costs, resource constraints, and perceived benefits--when deciding whether or not to have their children vaccinated, and the decision often is influenced by a network of people, including community leaders and health workers.</p> <p>Conclusions</p> <p>The study raises issues that should inform a communications strategy and guide policy decisions within Kenya on eventual malaria vaccine introduction. Unlike the current practice, where health education on child welfare and immunization focuses on women, the communications strategy should equally target men and women in ways that are appropriate for each gender. It should involve influential community members and provide needed information and reassurances about immunization. Efforts also should be made to address concerns about the quality of immunization services--including health workers' interpersonal communication skills.</p

α-Amylase and α-glucosidase inhibitors from Zanthoxylum chalybeum Engl. root bark

A systematic analysis of the root bark of Zanthoxylum chalybeum was conducted to establish the antidiabetic potential of isolated compounds based on its ethnomedicinal use to manage diabetes. Chromatographic separation of alkaloid extracts led to isolation of three undescribed amides, chaylbemide A (1), chalybemide B (2) and chalybemide C (3) alongside the known fagaramide (4); four known benzophenanthridine alkaloids skimmianine (5), norchelerythrine (6), 6-acetonyldihydrochelerythrine (7) and 6-hydroxy-N-methyl decarine (8). The alkaloid free extracts yielded three known lignans, ailanthoidol (9), 2,3-epoxy-6,7-methylenedioxy coniferyl alcohol (10), sesamine (11), together with five known triterpenoids, lupeol (12), lupanone (13), 3α,20-dihydroxy-28-lupanoic acid (14), 20-hydroxy-3-oxo-28-lupanoic acid (15) and 3α,20,28-trihydroxylupane (16). The structures of the compounds were established based on 1D and 2D NMR spectroscopic and mass spectrometric experiments. Compounds 1–8 displayed inhibitory activities against both α-amylase and α-glycosidase in the range of IC50 = 43.22–49.36 μM which showed no significant (P > 0.05) difference to the positive control acarbose (IC50 = 42.67; 44.88 μM). The results confirmed anti-hyperglycemic potential of alkaloids from Z. chalybeum which lends credence to its use towards management of diabetes susceptibilities

Efficacy of dupilumab in patients with a history of prior sinus surgery for chronic rhinosinusitis with nasal polyps

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammatory disease treated with sinus surgery when refractory to medical intervention. However, recurrence postsurgery is common. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor for interleukin 4 (IL-4) and IL-13, key and central drivers of type 2 inflammation. We report the efficacy of dupilumab in patients with CRSwNP from the SINUS-24/SINUS-52 trials (NCT02912468/NCT02898454), by number of prior surgeries and time since last surgery. Methods Patients were randomized to placebo or dupilumab 300 mg every 2 weeks. Post hoc subgroup analyses were performed for patients with 0, >= 1, 1/2, or >= 3 prior surgeries, and for patients who had surgery within = 10 years. Efficacy outcomes at 24 weeks included co-primary endpoints nasal polyp score (NPS) and nasal congestion (NC), and Lund-Mackay (LMK), 22-item Sino-Nasal Outcome Test (SNOT-22), and smell scores. Results Of 724 patients randomized, 459 (63.4%) had >= 1 prior surgery. Baseline sinus disease (NPS, NC, LMK) and olfactory dysfunction (University of Pennsylvania Smell Identification Test [UPSIT] and loss of smell) scores were worse for patients with >= 3 prior surgeries vs no surgery. Baseline NPS and LMK were worse in patients with Dupilumab improved CRSwNP outcomes irrespective of surgery history, with greater improvements in endoscopic outcomes in patients with shorter duration since last surgery

Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study

Guilbert TW, Murphy KR, Hamelmann E, et al. Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study. Journal of Asthma and Allergy . 2024;17:81-87.Background: Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab. Methods: This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils >= 150 cells/mu L or fractional exhaled nitric oxide >= 20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (>= 5% or >= 10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV(1)) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV(1) to Week 12. Results: At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of >= 5% in ppFEV(1); 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV(1) >= 10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P= 5%. Conclusion: Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV(1), with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV(1) response at Week 12

AROMA: real-world global registry of dupilumab for chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease of the nasal and paranasal sinuses. Dupilumab is a monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, which are key and central drivers of type 2 inflammation. In clinical trials, dupilumab significantly improved objective and patient-reported measures of CRSwNPversusplacebo and was well tolerated. Dupilumab is approved in the European Union, USA and Japan as add-on maintenance treatment for adults with inadequately controlled CRSwNP. There exists an important evidence gap between efficacy and effectiveness data for dupilumab in severe CRSwNP. In order to bridge this gap, the AROMA prospective global registry (ClinicalTrials.gov:NCT04959448) was established. AROMA will collect long-term data on the utilisation, effectiveness and safety of dupilumab for CRSwNP treatment in real-world clinical practice. AROMA will enrol approximately 1000 adults starting dupilumab for severe CRSwNP across 120 global sites. Baseline data will include patient demographics, medical/surgical history and presence of type 2 comorbidities. Effectiveness outcome assessments will include objective measures of CRSwNP assessed as part of routine clinical care and various patient-reported questionnaires. Treatment patterns, concomitant medications and long-term safety will also be recorded. Results from AROMA, the first prospective, real-world, global registry to characterise patients with severe CRSwNP starting dupilumab, will provide evidence on the real impact of dupilumab in patients with CRSwNP and complement the data from randomised clinical trials. The registry will also provide evidence on disease progression in patients with CRSwNP, including those with coexisting diseases.</jats:p