葛兰素史克

There is an unmet need for developing drugs for the treatment of gonorrhea due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug-resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On 23 April 2021, the US Food and Drug Administration, Centers for Disease Control and Prevention, and National Institute of Allergy and Infectious Diseases of the National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of that workshop.

BACKGROUND:Recombinant zoster vaccine (RZV) was approved for adults aged ≥50 years in the United States to prevent herpes zoster (HZ) and postherpetic neuralgia (PHN). This study evaluated real-world vaccine effectiveness (VE) of RZV in adults aged ≥50 years. METHODS:A cohort study was conducted at Kaiser Permanente Southern California (KPSC). The exposed cohort included members aged ≥50 years who received 1 or 2 RZV doses April 2018 to December 2020. They were matched 1:4 with unvaccinated individuals by age, sex, and race/ethnicity, then followed until December 2022. Adjusted VE (aVE) and 95% confidence interval (CI) were estimated via stratified Cox models for 1 dose and 2 doses against HZ (diagnostic codes B02.xx plus antiviral within 7 days) and PHN (chart review for HZ-related pain persisting >3 months). Stratified aVE by demographic characteristics, immunocompromised status, comorbidities, concomitant vaccination, and overall durability were assessed. RESULTS:Among N = 102 766 (median age 68 years) who received 2 RZV doses (4 weeks-6 months apart), 48 028 (46.7%) had previously received zoster vaccine live; aVE was 73.9% (95% CI: 71.8%-75.8%) for HZ and 83.7% (95% CI: 75.1%-89.3%) for PHN. VE against HZ was comparable across individuals with concomitant vaccinations and different comorbidities. VE against HZ and PHN remained stable over 4 years post-vaccination. One-dose VE was 60.3% (56.4%-63.9%) against HZ and 45.6% (11.4%-66.6%) against PHN. CONCLUSIONS:Two doses of RZV were effective in preventing HZ and PHN in adults aged ≥50 years, with durable protection. These findings underscore the importance of adhering to the recommended vaccination schedule.

Structural knowledge of antigens in their native state can drive the design of optimized vaccine antigens that mimic the native epitope exposure and conformation. Here, by hydrogen-deuterium exchange mass spectrometry, we assessed the structural features of Neisseria Adhesin A (NadA), a meningococcal trimeric outer membrane protein, included as soluble recombinant antigen in the 4CMenB vaccine. We propose a structural annotation of the recombinant NadA and compare its structural dynamics with NadA in situ, as embedded in meningococcal outer membrane vesicles (OMVs). The observed conformational differences suggest that OMV-embedded NadA could be more susceptible to trimer opening and display a larger antigenic surface than the soluble antigen. Accordingly, mice immunized with OMV-embedded NadA elicited antibodies with superior bactericidal activity compared to the soluble antigen. Collectively, these data support the hypothesis that protein vaccine antigens presented in native-like environments can elicit a more potent immune response than recombinant forms.

IL-5, a key mediator of type 2 inflammation, underlies various diseases, including severe asthma, CRSwNP, EGPA, and HES. Reduction in blood eosinophil count (BEC), a biomarker of IL-5 activity, is commonly used to evaluate the efficacy of anti-IL-5 biologic therapies. Model-informed drug development (MIDD) and quantitative decision making (QDM) were used to shorten the clinical development of depemokimab (an ultra-long-acting anti-IL-5 biologic). A Bayesian nonlinear mixed effects dose-time response model predicted the depemokimab dose in severe asthma achieving comparable BEC reductions to those observed in mepolizumab (an approved anti-IL-5 biologic) Phase III MUSCA and MENSA trials. Prespecified QDM go/no-go criteria were applied to assess success probability. Phase IIb efficacy-based trial simulations were conducted using negative binomial distribution to simulate individual annualized exacerbation rate. A depemokimab PK/PD (BEC) model predicted Phase III trial doses in CRSwNP/EGPA/HES. Single depemokimab doses were well-described by the Bayesian model; a single depemokimab dose ≥ 60 mg had probability ≥ 80% of exceeding Minimum (78%; MUSCA) and ≥ 10% probability of exceeding Target (84%; MENSA) values for trough BEC reduction from baseline vs. placebo. Clinical trial simulations demonstrated < 3% probability of more precise estimation of the Phase III dosing regimen with a conventional efficacy-based dose-ranging study. Depemokimab 100 mg for severe asthma/CRSwNP and 200 mg for EGPA/HES, administered subcutaneously every 26 weeks, were selected for Phase III trials. MIDD and QDM shortened the depemokimab development program by 2-3 years, emphasizing the potential of this approach for progressing new therapies from Phase I directly to Phase III.

The role of perioperative immunotherapy as a chemotherapy-free option for patients with resectable mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colon cancer is evolving, with early-phase neoadjuvant studies reporting favorable long-term outcomes. AZUR-2 is an ongoing global, Phase III, open-label, randomized study evaluating the efficacy of perioperative dostarlimab monotherapy compared with standard of care (SoC) (adjuvant chemotherapy or surveillance) in adult patients with previously untreated, pathologically confirmed, radiologically evaluable T4N0 or Stage III resectable dMMR/MSIH colon adenocarcinoma. Patients will be randomized 2:1 to receive neoadjuvant dostarlimab 500 mg every 3 weeks (4 cycles), followed by surgery, then adjuvant dostarlimab 1000 mg every 6 weeks (6 cycles), or to receive immediate surgery followed by SoC. The primary endpoint is event-free survival assessed by blinded independent central review. The key secondary endpoint is overall survival; additional secondary endpoints include pathological response assessed by residual viable tumor determined by local assessment, safety, and tolerability.Clinical trial registration: NCT05855200 (www.clinicaltrials.gov).