吉利德科学

BACKGROUND AND AIMS:Ulcerative colitis (UC) is a chronic inflammatory condition of the colon with heterogeneous patient responses to treatment. Janus kinase (JAK) inhibitors such as filgotinib reduce inflammation through the blockade of cytokine signaling. We sought to characterize the mechanism of action of filgotinib on peripheral immune cells to improve our understanding of dysregulated cell populations in UC and their response to treatment. METHODS:Peripheral blood mononuclear cells (PBMCs) were isolated from UC patients at baseline or after 10 weeks of filgotinib treatment in the SELECTION trial. PBMCs were analyzed alongside healthy controls by flow cytometry and sorted into 12 cell populations for transcriptome sequencing to correlate with treatment response. RESULTS:Following 10 weeks of filgotinib treatment, changes in the frequency of peripheral B cell populations were observed, with more significant changes seen in treatment-responsive patients in memory B cells and plasmablasts. Transcriptomic changes associated with filgotinib treatment were modest but overall reverted UC-induced gene expression changes toward control samples in B cells and phagocytic mononuclear cells. These changes were greater in treatment-responsive than in non-responsive patients. CONCLUSIONS:Filgotinib response was associated with normalization of the cellular frequency and gene expression levels of B cells and phagocytic mononuclear cells in UC patients, resulting in immune profiles resembling those of healthy controls.

Causal inference from a randomized trial becomes challenging when interest focuses on a specific subpopulation and when the causal effect involves both the randomized binary treatment and a non-randomized continuous exposure. This study is motivated by a clinical trial conducted among women of childbearing potential to evaluate the effectiveness of a malaria vaccine during pregnancy within the subpopulation of women who would have become pregnant under placebo conditions. Although the primary policy-relevant contrast concerns the binary randomized treatment-vaccine versus placebo-there also exists a continuous post-randomization exposure-exposure to pregnancy-characterized by the timing of conception. Given the seasonality of malaria transmission and waning of vaccine-induced immunity, vaccine effectiveness during pregnancy may vary with conception timing, motivating causal evaluations that consider both exposures. We propose methodological approaches for causal inference in this setting, study their large-sample and finite-sample properties, and apply them to the malaria vaccine trial to provide a comprehensive assessment of vaccine effectiveness against pregnancy malaria in the target subpopulation while accounting for temporal variation in disease transmission.

Obeldesivir is an orally administered prodrug of the nucleoside GS-441524. In vitro and preclinical studies have shown that obeldesivir can inhibit severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus, and filoviruses with a high barrier to resistance. Prior population pharmacokinetic modeling has shown that certain factors, such as coronavirus disease 2019 (COVID-19), body weight, and renal function, can impact GS-441524 exposure. This study aimed to evaluate the pharmacokinetics and safety of obeldesivir in Japanese and white participants. In this phase 1 study, healthy Japanese and white participants in the USA who were aged 18–65 years, were nonsmokers, had a body mass index of 18.0–30.0 kg/m2, and had normal renal/hepatic function were administered a single 350 mg oral dose of obeldesivir. Serial blood samples were collected up to 72 h postdose. Safety was assessed via physical examinations, clinical laboratory parameters, and treatment-emergent adverse events. Plasma pharmacokinetic exposures of GS-441524 were higher in Japanese participants compared with white participants but were within the ranges observed in previous phase 1 studies. Differences in body weight between the populations in the study likely contributed to the increases in exposure. Obeldesivir was generally safe and well tolerated in both Japanese and white participants. These findings indicate that obeldesivir is likely to have favorable pharmacokinetic exposures and safety across different racial populations, supporting its potential use in treating multiple viral infections.

LBA109 Background: Although PD-1/PD-L1 inhibitors plus chemo have expanded treatment options for previously untreated PD-L1–positive advanced TNBC, there still remains a critical unmet need to improve outcomes. SG previously demonstrated significant clinical benefit in pretreated metastatic TNBC (mTNBC). We report results from the ASCENT-04/KEYNOTE-D19 study in patients with previously untreated, PD-L1–positive (CPS ≥ 10; 22C3 assay) locally advanced unresectable or mTNBC. Methods: Patients were randomized 1:1 to SG (10 mg/kg IV, day 1 & 8) + pembro (200 mg, day 1, max 35 cycles) in 21-day cycles or chemo (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel) + pembro until disease progression or unacceptable toxicity. Randomization was stratified by curative treatment-free interval, geography, and prior exposure to anti–PD-(L)1 therapy in the curative setting. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Key secondary endpoints include overall survival (OS); objective response rate (ORR) and duration of response (DOR) by BICR; and safety. Results: 443 patients were randomized at a 1:1 ratio: 221 to SG + pembro and 222 to chemo + pembro. The median follow-up was 14 mo. SG + pembro showed a significant improvement in PFS by BICR compared with chemo + pembro (hazard ratio [HR], 0.65; 95% CI, 0.51-0.84; P = .0009; Table). Median DOR was 16.5 mo for SG + pembro vs 9.2 mo for chemo + pembro (Table). Although OS data were immature, a positive early trend in OS improvement was also noted. The most frequent (≥ 10% of patients) grade ≥ 3 treatment-emergent adverse events (TEAEs) with SG + pembro were neutropenia (43%) and diarrhea (10%); and with chemo + pembro were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). Conclusions: SG + pembro led to a statistically significant and clinically meaningful improvement in PFS vs chemo + pembro with durable responses, no new safety concerns for SG or pembro, and a lower rate of treatment discontinuation due to TEAEs in patients with previously untreated, PD-L1–positive advanced TNBC. These data support the use of SG + pembro as a potential new standard of care treatment in this patient population. Clinical trial information: NCT05382286 . Efficacy, BICR, intent-to-treat SG + pembro(n = 221) Chemo + pembro(n = 222) Median PFS (95% CI), mo 11.2 (9.3-16.7) 7.8 (7.3-9.3) HR (95% CI); P -value (adjusted for randomization stratification factors) 0.65 (0.51-0.84); P = .0009 ORR (95% CI), % 59.7 (52.9-66.3) 53.2 (46.4-59.9) Median DOR (95% CI), mo 16.5 (12.7-19.5) 9.2 (7.6-11.3) Safety (TEAEs), all treated, n (%) n = 221 n = 220 Any grade; grade ≥ 3 220 (> 99); 158 (71) 219 (> 99); 154 (70) Led to dose reduction 78 (35) 96 (44) Led to any treatment discontinuation 26 (12) 68 (31)

Detection of N-nitrosamines (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed drugs, otherwise known as NA Drug Substance-Related Impurities (NDSRIs). The Ames test is used to assess the mutagenic potential of drug impurities, including NAs. Concerns over the sensitivity of the Ames test, as recommended in Organization for Economic Co-operation and Development Test Guideline 471, in predicting the rodent carcinogenic potential of NAs has prompted optimization of several test parameters used for detecting the mutagenicity of NAs (e.g. methods used for metabolic activation and the selection of tester strains). In order to discuss optimal Ames test conditions for the evaluation of NAs, including NDSRIs, the Office of New Drugs in the US Food and Drug Administration's Center for Drug Evaluation and Research and the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee co-organized and co-sponsored a workshop entitled "Nitrosamines: Ames Data Review and Method Development Workshop". The workshop featured five sessions addressing charge questions pertinent to the Ames test conditions and performance through the presentation of data and panel discussions. This report outlines the key takeaway points from the workshop.