Vertex Pharmaceuticals

Dacomitinib is an approved second-generation EGFR tyrosine kinase inhibitor. In the phase 3 ARCHER 1050 trial, both progression-free survival (PFS) and overall survival (OS) were improved with first-line dacomitinib compared with gefitinib. Post hoc analysis revealed that efficacy (PFS, OS) was similar in both dose-reduced patients and the overall study population. ATORG-003 evaluated a dose-titration strategy to improve tolerability while maintaining efficacy. This is also the first prospective study of dacomitinib's intracranial efficacy and resistance (tissue and plasma next-generation sequencing). ATORG-003 (Asian Thoracic Oncology Research Group; five Asian countries) was a single-arm, investigator-initiated phase 2 trial that enrolled patients with treatment-naive stages IIIB to IV EGFR-mutated NSCLC. Patients received dacomitinib 30 mg daily for 4 weeks, with a shared investigator and patient decision for titration to 45 mg in patients with grade less than or equal to 1 toxicity (Common Terminology Criteria for Adverse Events version 5.0). The primary end point was the 12-month PFS rate (in patients without central nervous system metastases only) compared with the historical control. Secondary end points were time to treatment failure (TTF), objective response rate (ORR), OS, intracranial ORR (iORR) and intracranial PFS (iPFS), and safety and tolerability. From September 2019 to October 2022, 118 patients were enrolled. The median age was 65 (range 33-84) years, and 54% were female. EGFR mutation type was exon 19 deletion in 57%, L858R mutation in 42%, and both in 1%. There were 18% of patients who were dose titrated to 45 mg at cycle 2, and 70% tolerated 30 mg (67%) or 45 mg (3%) without dose reduction. The primary end point was met, with a 12-month PFS proportion rate of 59.6% (90% confidence interval [CI]: 50.6%-68.1%) and a 12-month PFS rate of 61.2% (95% CI: 50.5%-70.3%) in the primary analysis cohort. The median PFS was 16.1 months (95% CI: 12.1-19.2), and the median TTF was 19.3 months (95% CI: 16.1-22.1). In the overall study population, the ORR was 77% and the median OS was not reached. In patients with central nervous system metastases (n = 24), the iORR was 54% and the median iPFS was 17.6 months (95% CI: 7.2-23.1). All patients had treatment-related adverse events (TRAEs), with grade 3/4 TRAEs occurring in 25%. The most common grade 3/4 TRAEs were rash (7%), paronychia (4%), and hypokalemia (3%). EGFR T790M resistance was detected in 29 of 96 patients (30%) through plasma next-generation sequencing and in 15 of 29 patients (52%) through tissue next-generation sequencing. ATORG-003 prospectively revealed that dacomitinib with dose titration is a viable strategy in advanced EGFR-mutated NSCLC, maintaining efficacy while improving tolerability. Dacomitinib has substantial intracranial activity and high rates of T790M resistance, making it suitable for sequential treatment approaches.

Pluripotent stem cell-derived alpha cells (SC-α cells) represent a promising component of next-generation cell therapies designed to more fully recapitulate human islet function; however, heterogeneity and the presence of undesired side populations limit their functional maturity and therapeutic potential. Here, we identify the cell surface protein CD98hc (SLC3A2), that when highly expressed in precursor cells, is associated with differentiation toward a more transcriptionally and functionally mature population of human SC-α cells. Directed differentiation was used to generate SC-α cells from pluripotent stem cells, which were assessed via single cell RNA sequencing, flow cytometry, and immunofluorescence imaging. Following magnetic activated cell sorting (MACS) of CD98hc enriched precursors, SC-α cell function was assessed using glucose stimulated glucagon secretion (GSGS). We show that CD98hc is upregulated in SC-α cells expressing high levels of genes known to play important roles in α cell identity and function, and that CD98hc expression is elevated at the pre-α precursor stage relative to non-α cell populations. We demonstrate that magnetic enrichment of CD98hc⁺ pre-α cells derived from multiple pluripotent stem cell lines selectively increases the proportion of the highest CD98hc expressing glucagon-copositive precursors while depleting multiple undesired side populations, including somatostatin-positive and SOX9-positive cells. Although total α cell yield equalizes following complete differentiation, SC-α cells derived from high-CD98hc enriched precursors exhibit significantly enhanced glucose-responsive glucagon secretion compared to sham-sorted controls, indicating improved functional maturation of this precursor population. Together, these findings establish that high expression levels of CD98hc marks a functionally superior α cell precursor, that enrichment at the precursor stage can bias differentiation toward higher functional α cell output, that stem cell-derived α cell populations harbor intrinsic functional heterogeneity, and that selective targeting of precursor populations represents a generalizable strategy to improve the quality and performance of stem cell-derived endocrine cell products.

Matrix metalloproteinase-8 (MMP-8) regulates inflammatory responses, but its contributions to the pathogenesis of influenza A viral (IAV) disease are not known. Plasma MMP-8 levels were increased 30-fold in subjects infected with H1N1 or seasonal IAV and were inversely associated with the PaO2/FiO2 ratio, suggesting potential value as a candidate marker of lung injury severity that requires validation in larger cohorts. MMP-8 levels were elevated in the lungs of H1N1-infected wild-type (WT) mice and localized to airway epithelial cells, macrophages, and polymorphonuclear neutrophils (PMNs). H1N1-infected Mmp-8-/- mice exhibited lower mortality and reduced lung viral burdens, but developed more severe lung injury than WT mice. Gene expression profiling revealed enhanced necroptosis and an exaggerated immune response in the lungs of infected Mmp-8-/- mice. Infected Mmp-8-/- mice had increased airway epithelial necroptosis with higher pulmonary levels of Type I interferons (IFNs), and increased frequencies of Class II MHC molecule-expressing macrophages and CD4+ and CD8+ T cells, and higher levels of some Th1 cytokines. In vitro, MMP-8 cleaved IL-1β and IL-6, but not Type I IFNs. These findings suggest that Mmp-8 deficiency is associated with restricted influenza virus spread and increased lung injury, accompanied by enhanced Type I IFN-associated necroptotic signaling and augmented antiviral immune responses. The latter may partly involve loss of MMP-8-mediated processing of pro-inflammatory mediators. MMP-8 may represent a host-response target in severe influenza infection, although therapeutic strategies targeting MMP-8 will need to balance enhanced viral clearance against the risk of increased lung immunopathology.

β-Thalassemia, a major genetic disease affecting the global population, has seen new strategies being pursued in terms of curative attempts directed at the specific gene defect present. Iron chelation therapy and lifelong blood transfusions have historically been used to treat β-thalassemia, a severe hereditary hemoglobin condition marked by decreased or missing β-globin chain synthesis. These methods have significantly increased patient survival, but they do not offer a permanent solution and are linked to serious side effects and a high cost of care. With a focus on hematopoietic stem cell transplantation (HSCT), lentiviral gene-addition treatment, and future genome-editing techniques, this study outlines new and creative methods to long-term disease correction in β-thalassemia. Although allogeneic HSCT is still a proven treatment option, its use is constrained by the availability of donors, graft-related issues, and transplant-related hazards. Autologous hematopoietic stem cell-based gene therapy has become a significant substitute, provided the possibility of long-term transfusion independence while prevented graft-versus-host disease. With the creation of exagamglogene autotemcel (exa-cel; Casgevy), which reactivates fetal hemoglobin expression through modification of the BCL11A erythroid enhancer and has shown significant rates of sustained transfusion independence in eligible patients with transfusion-dependent β-thalassemia, CRISPR/Cas9-based genome editing has recently marked a significant clinical milestone. Notwithstanding these encouraging developments, myeloablative conditioning, long-term safety and durability, high treatment costs, complicated manufacturing requirements, and restricted accessibility continue to be major obstacles, especially in low- and middle-income nations. All things considered, the therapeutic landscape for β-thalassemia is changing from lifelong supportive management to potentially curative and transformative interventions; however, the wider application of these cutting-edge therapies depends on ongoing long-term evaluation and efforts to increase affordability and global accessibility.

People with cystic fibrosis (PwCF) face considerable financial burdens. PwCF who are most likely to make financial and healthcare tradeoffs, had the lowest comfort discussing financial issues with their CF team. The association of comfort with financial discussions and accessing resources is unknown. Our study assessed the relationship between comfort discussing financial issues with the CF care team and PwCF accessing resources. We evaluated responses of adults with CF, parents/guardians of children with CF, and spouses/partners/guardians of PwCF from the 2024 COST-CF survey. We examined financial discussion frequency, resource usage, barriers, and perceptions of accessing resources as a function of comfort discussing financial issues with the care team. 875 respondents reported their comfort with financial discussions, with 51% feeling comfortable/very comfortable, 38% slightly/somewhat comfortable, and 11% not at all comfortable. Overall, 50% had cost discussions with their CF care team that cost of care presented a financial burden in the last 12 months. Most respondents (69%) experienced at least 1 barrier to accessing financial resources. Those reporting lower comfort with discussions generally endorsed higher need (e.g., understanding and planning for healthcare costs), lower confidence in getting support to prevent/reduce cost burden, and more barriers to accessing care (e.g., did not know where to find financial resources). Our results show patient/family comfort level with financial discussions is related to levels of need, confidence in getting support, and barriers to accessing care. The CF care team should be proactive in assessing financial needs and connecting PwCF to resources.

To characterize infectious complications in adults during frontline treatment of acute lymphoblastic leukemia (ALL), evaluating the incidence of invasive fungal infections (IFI) in the absence of routine antifungal prophylaxis. Single-center retrospective cohort study of adults with ALL (2010-2023). Patients were followed from induction through consolidation. IFI were defined using EORTC/MSG criteria. Among 295 patients, 119 (40.3%) developed ≥1 infection. Bacterial infections predominated, affecting 117 (39.7%) patients, whereas IFI were infrequent, occurring in 9 (3.1%) patients during induction and 4 (1.8%) during consolidation despite minimal antifungal prophylaxis. IFI-related intensive care unit admission and mortality were rare (2/295, 0.7%). No IFI occurred among patients receiving chemotherapy-free regimens. Chemotherapy-containing regimens were associated with higher bacterial infection rates during induction (38.2% vs. 10.4%, p <0.0001) and consolidation (24.2% vs. 8.3%, p =0.008). In multivariable analysis, chemotherapy-containing regimens (OR 3.39, 95% CI 1.42-8.08) and neutropenia duration ≥7 days (OR 1.85, 95% CI 1.05-3.25) independently predicted bacterial infection during induction. Bacterial infections represented the primary infectious burden and were associated with chemotherapy-containing regimens and prolonged neutropenia. IFI were uncommon and severe fungal outcomes were rare in this antifungal-naïve cohort. These findings support a risk-adapted approach to antifungal prophylaxis in adults with ALL, particularly for patients with established risk factors for IFI.

Standardized metrics such as the numeric rating scale (NRS) provide essential quantitative pain benchmarks but can be augmented by capturing the functional and emotional context of a patient's lived experience. Adding surveys creates a "contextual disconnect" (increasing data yield with diminishing insights) and adds patient burden. The CONNECT (Collecting Communication Data to Enhance Patient-Physician Interaction) study proposes a structured, multimodal framework integrating patient narratives, drawings, and mobility assessments to capture each patient's holistic "pain story" and create a comprehensive ground truth dataset for developing digital health tools. This study aims to (1) evaluate the feasibility of capturing multimodal communication data (narratives, drawings, and mobility) from patients with chronic pain, (2) quantify gaps between standard clinical metrics (eg, the NRS) and patient-defined key functional limitations, and (3) evaluate the usability and perceived communication value of software prototypes (myStory). CONNECT is a multiphase, multicenter, exploratory feasibility study using human-centered design. Up to 3 tertiary care interventional pain practices in the United States will enroll 2 mutually exclusive cohorts (up to 40 patients each). Phase 1 conceptualizes the patient narrative as a "clinical sensor," collecting a foundational ground truth dataset via video-recorded pain narratives, guided drawings, standardized mobility assessments, and validated surveys. Phase 2 uses phase 1 learnings to develop and evaluate up to 5 myStory prototypes, assessing utility, usability, and perceived communication value via task-based evaluation and think-aloud protocols. Exploratory analyses include dual-coder thematic analysis, pose estimation mobility assessments, and AI-assisted narrative summarization. Recruitment began in May 2026. As of September 2026, one site is active, with 37 participants enrolled. Anticipated outcomes include (1) a rich, multimodal dataset establishing a ground truth of patient-derived functional limitations, goals, and expectations; (2) characterization of pain story gaps missed by the NRS via the contextual disconnect rate (defined as NRS ≤6 with ≥1 key functional limitation); (3) evaluation of at least one feasible prototype concept (mean score of 3.0 on a 5-point Likert scale); and (4) initial user testing of new communication assessment scales. Results are anticipated in late 2026 and will be disseminated through peer-reviewed publications and conferences. This protocol establishes a reproducible framework for understanding the holistic "pain story" by capturing narrative, visual, and functional dimensions of chronic pain. Findings will inform new communication tools intended to enhance patient-provider communication and align care with outcomes that matter most to patients with chronic pain.