Teva Pharmaceuticals (Israel)

<b>Conclusions:</b> LAIs, especially SG formulations, are associated with reduced rehospitalization in BD-I compared to OAs, supporting their broader use to improve adherence and reduce readmissions.

Native mesopredators face challenges adapting to landscapes modified by human activities, particularly in arid regions, where resources are naturally limited and ecological dynamics are sensitive to disturbance. The caracal (Caracal caracal), a behaviorally flexible predator found across Africa and Asia, offers insights into how such carnivores navigate the balance between natural habitat requirements and anthropogenic pressures. We investigated habitat selection and dietary patterns of caracals in southern Israel's hyperarid Arava Valley using radiotelemetry data from 10 collared individuals (n = 75 tracking days) and scat samples collected during 1986-1987, complemented by ranger observations spanning the four subsequent decades. Resource Selection Function analyzes revealed pronounced sex-specific and seasonal patterns of habitat selection within observed areas of use. Males exhibited larger areas of use than females, whereas habitat selection differed primarily through sex-dependent responses to topography, elevation, hydrological features, and anthropogenic drivers rather than consistent differences in overall terrain preferences. These sex-specific differences were evident in both seasons but were most pronounced during the dry season, suggesting increased habitat segregation under conditions of heightened resource limitation. Both sexes strongly selected for proximity to creek beds across seasons, likely reflecting high natural prey availability-particularly Cape hares, as well as more buffered microclimatic conditions. Caracals demonstrated context dependence in their response to human infrastructure-avoiding paved roads during the dry season, showing seasonal shifts in their use of dirt roads, and selecting areas closer to agricultural fields primarily during the dry season, especially females. Dietary analysis indicated a strong reliance on wild prey, dominated by Cape hares, small rodents, and desert partridge. Only 11.3% of fecal samples contained anthropogenic food items. Long-term observational data confirmed that both caracals and their primary prey exhibited significant spatial association with creek beds. Together, these complementary lines of evidence suggest that natural prey availability remains the dominant driver of caracal habitat selection in this resource-limited system. Conservation efforts should prioritize the protection and connectivity of creek bed habitats to support the persistence of caracals and other native species in increasingly human-dominated arid landscapes.

a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1535:"<h3>Introduction</h3> Fremanezumab, a calcitonin gene-related peptide monoclonal antibody, is approved for preventive migraine treatment in adults. The multicentre, parallel-group, Phase 3 SPACE study (NCT04458857) evaluated the efficacy and safety of fremanezumab in children and adolescents with episodic migraine (EM). <h3>Methods</h3> Eligible participants (aged 6–17 years, migraine diagnosis for ≥6 months and history of ≤14 headache days/month) were randomised 1:1 to monthly fremanezumab (120 mg for &lt;45kg, 225 mg for ≥45kg) or placebo. Primary endpoint: least-squares mean change from baseline in monthly average number of migraine days (MMD) during the 3-month double-blind period (DBP). Secondary endpoints included the proportion of participants achieving ≥50% reduction in MMD and change from baseline in monthly headache days of at least moderate severity (MHD). <h3>Results</h3> In total, 234 randomised participants (fremanezumab, n=123 [120 mg, n=36; 225 mg, n=87]; placebo, n=111) were included in the efficacy analysis. Fremanezumab significantly reduced MMD versus placebo (–2.5 vs –1.4; p=0.0210) during the DBP, with a ≥50% response rate of 47.2% versus 27.0% (p=0.0016). Reductions in MHD were significantly greater with fremanezumab versus placebo (–2.6 vs –1.5; p=0.0172). <h3>Conclusion</h3> These findings suggest that fremanezumab provides an effective preventive migraine treatment option in children and adolescents with EM. mark.fredericks{at}tevauk.com ";}

We appreciate the thoughtful comments of Jin et al. [1] on our prospective longitudinal study of potentially inappropriate prescribing (PIP) and all-cause mortality in community-dwelling older adults [2]. Regarding their concern of under-representation of low socioeconomic status (SES) individuals in our cohort, the Israel Study of Glucose Intolerance, Obesity and Hypertension (GOH Study) is a nationwide cohort drawn from the Central Population Registry, comprising Jewish individuals born between 1912 and 1941. The sample was designed to equally represent sex, ethnic origin, and length of residence [3], as most participants immigrated to Israel in its early days of formation during the 1940s–50s. The diversity of this cohort, comprised of individuals from all SES levels, was maintained over follow-up. In our study sample (third follow-up), 40.1% had fewer than 9 years of education and 43.8% were blue-collar workers (manual and skilled trade occupations, such as agriculture, fishing, craft, manufacturing, repair, construction, transport, cleaning, and packaging). Our findings result from multivariable models that accounted for all sociodemographic variables (e.g., education, occupation, ethnic origin). As noted in our paper [2], the cohort included relatively few cognitively impaired individuals, and we state that our findings apply primarily to relatively healthy older adults living in the community. Frailty was not directly measured, though one of Fried's frailty criteria is low physical activity [4], and 51.6% of our participants reported no leisure-time physical activity. In addition, 24.4% of participants rated their health as “poor” or “very poor”. Importantly, associations between PIP and mortality remained statistically significant even after adjusting for both subjective and objective health measures at baseline, including polypharmacy and chronic conditions. Nonetheless, given our finding of stronger associations between potentially inappropriate medication (PIM) use and mortality among those with better self-rated health at baseline, our argument that PIP should also be monitored in relatively healthy older adults remains valid. From a public health perspective, we believe that PIP criteria should be implemented in primary care as well, not just in hospitals or long-term care facilities. Early identification and correction of inappropriate prescribing could prevent adverse drug events and subsequent complications, supporting older adults in maintaining their independent lifestyle in the community. We agree with Jin et al. [1] that implicit clinician judgment should complement explicit PIP criteria. For example, the OPERAM (Optimizing thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial [5] showed that more than half of the clinical decision support system (CDSS) alerts for overuse, underuse, or misuse (STOPP/START criteria) were judged not clinically appropriate, and concluded that the involvement of a trained pharmacotherapy team (a physician and a pharmacist) is essential for translating these signals. Notably, the most frequently recommended action was “to stop a drug without a clear indication” (STOPP A1), which requires physician assessment. Finally, we also acknowledged [2] that further investigation into the effects of PIP fluctuations over time on clinical outcomes is warranted. Correction of potential prescribing omissions (PPOs) during follow-up may have attenuated the observed associations with mortality in our study. As for PIMs, non-differential misclassification likely biased results toward the null. It should be noted that deprescribing after an adverse event would not eliminate risk if the event already triggered downstream complications leading to premature mortality. The significant associations with mortality were still observed, despite these limitations, which reinforces the clinical importance of addressing PIP and promoting safe prescribing practices in community-dwelling relatively healthy older adults. We thank Jin et al. [1] for the opportunity to deepen the discussion on the important topic of the adequacy of drug treatment in older adults, and to emphasize our key message: independent older adults living in the community, especially women [6], should not be overlooked, as ensuring safe prescribing in this group has major public health implications. All authors have read and approved of the submission of this manuscript. R.D. contributed to the acquisition of data. L.O., A.C., and R.D. contributed to the study concept and design. L.O., A.C., R.D., and K.L. contributed to the analysis and interpretation of data. L.O. and A.C. drafted the manuscript. L.O., A.C., R.D., and K.L. contributed to critical revisions of the manuscript for important intellectual content and gave final approval of the final draft. This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Liat Orenstein, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Israel. The sponsor had no influence on the design, data collection, analysis, or writing of this article. The authors declare no conflicts of interest. This publication is linked to a related Letter to the Editor by Jin et al. To view this article, visit https://doi.org/10.1111/jgs.70153.

BackgroundDespite recent therapeutic advances in chronic lymphocytic leukemia (CLL), access to innovative treatments may still be uneven outside Western Europe. This study aimed to explore reimbursement policy and access to novel targeted CLL therapies across selected countries and to analyze factors associated with differences in treatment availability and reimbursement timelines.MethodsReimbursement frameworks, timelines, and accessibility of six novel CLL therapies were assessed across 15 countries in Central and Eastern Europe, the Balkans, Armenia, and Israel. Data were collected via expert surveys in late 2024, based on publicly available national and regional sources. The survey covered reimbursement extent, timelines, policy restrictions, coverage pathways, and health technology assessment (HTA) evaluations. Comparative analyses examined regional differences in reimbursement and their potential drivers. Spearman’s rank correlation was used to explore associations between the number of reimbursed therapies, reimbursement delays, and demographic, macroeconomic, and epidemiological variables.ResultsThe number of reimbursed therapies ranged from zero (Ukraine, Armenia) to five (Czech Republic), with a regional mean of 2.7 (SD = 1.38) and overall mean time to reimbursement of 29.3 months (SD = 21.4). Ibrutinib, reimbursed in 13 countries, had the longest mean reimbursement delay (35.6 months), while venetoclax (11 countries, 26.5 months), acalabrutinib (9 countries, 16.4 months), and zanubrutinib (6 countries, 15.2 months) had shorter delays. Gross domestic product (GPD) per capita showed a moderate positive correlation with the number of reimbursed therapies (ρ = 0.673, p = 0.006). Borderline significant associations were noted for CLL incidence and mortality (p = 0.050). Reimbursement indications were often restricted, particularly for patients without deletion 17p or TP53 mutations who experienced late relapses. Data on HTA outcomes and the number of treated patients were limited in several countries, and common challenges included funding constraints, administrative barriers, and the lack of centralized rare disease policies.ConclusionSignificant disparities in access to targeted CLL therapies persist across the analyzed countries, with the number of reimbursed therapies positively correlated with GDP per capita.

Abstract Background: Direct immune stimulation using cytokines, including interleukin-2 (IL-2), drives immune-mediated cytotoxic cancer responses. Toxicity of high-dose IL-2 limits its activity and clinical utility. Preclinical studies show that targeting IL-2 to specific cell subsets substantially increases its therapeutic index. In multiple cancers, tumor-infiltrating T-cells display higher levels of programmed cell death protein (PD-1) relative to circulating and tissue-resident T-cells, making PD-1 a target for selective delivery of IL-2. TEV-56278 is a human antibody-cytokine fusion protein comprised of an antibody targeting PD-1 and attenuated IL-2. TEV-56278 is designed to deliver IL-2 selectively to PD-1+ T cells, thus amplifying anti-tumor T-cell activity while minimizing off-target systemic toxicities. Furthermore, its binding to PD-1 receptors does not block ligand binding and does not compete for binding with known PD1-blocking antibodies, allowing for combination use. Here, we describe a phase 1a/1b trial design evaluating TEV-56278 as monotherapy and in combination with pembrolizumab. Methods: This multicenter, open-label, Phase 1, first-in-human, dose-escalation, dose-expansion study is being conducted in 3 parts. Patients &amp;gt;18 years of age with various locally advanced or metastatic solid tumors who have progressed on or were intolerant to standard of care therapies and resistant to anti-PD-(L)1 treatment will be included. The primary objective of dose escalation is to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of TEV-56278 alone and in combination with pembrolizumab. Secondary objectives include assessment of pharmacokinetics (PK) and anti-tumor activity. Determination of the maximum tolerated dose will be based on a Bayesian optimal interval (BOIN) design. Additional pharmacodynamic and biomarker data, including biomarkers of IL-2 signaling and activation of PD-1+ T cells, will be collected during backfill of monotherapy dose cohort(s). After determination of the monotherapy RP2D, 2 cohorts of patients with locally advanced or metastatic primary and secondary resistant melanoma (A&amp;B) and 2 cohorts of primary and secondary resistant non-small cell lung cancer (NSCLC; [C&amp;D]) will be accrued to evaluate the primary objective of anti-tumor activity. The Simon two-stage admissible design will be used for Cohort B (RP2D and a dose &amp;lt;rp2d); a="" bayesian="" approach="" will="" be="" used="" for="" a,="" c,="" and="" d="" with="" rp2d.="" the="" objective="" response="" rate="" (orr)="" duration="" of="" (dor)="" assessed="" based="" on="" evaluation="" criteria="" in="" solid="" tumors="" (recistv1.1).="" secondary="" objectives="" include="" safety,="" tolerability,="" pk="" other="" efficacy="" measures.="" this="" study="" is="" open="" participant="" enrollment,="" targeting="" up="" to="" 240="" patients="" (nct06480552). Citation Format: Jason John Luke, Lillian L. Siu, Mario Sznol, Yael Shalit, Jerry Weaver, Samhita Chakraborty. A first-in-human study evaluating safety, tolerability and efficacy of TEV-56278, as monotherapy and in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT198.

The human bone marrow is a complex organ that is critical for self-renewal and differentiation of hematopoietic progenitor cells into various lineages of blood cells. Perturbations of the hematopoietic system have been reported to cause numerous diseases. Yet, understanding the fundamental biology of the human bone marrow in health and disease and during the preclinical stages of drug development is challenging due to the complexity of studying or manipulating the human bone marrow. Human cell-based microfluidic bone marrow models are promising research tools to explore multi-lineage differentiation of human stem and progenitor cells over long periods of time. Human hematopoietic stem and progenitor cells were cultured with mesenchymal stromal cells on a zirconium oxide ceramic scaffold in a microfluidic device recapitulating the human bone marrow. NK cell differentiation was induced by the application of a lymphoid cultivation medium containing IL-15. The kinetics of differentiation into mature NK cells was traced by flow cytometry over a period of up to seven weeks, and functionality was measured by stimulation with phorbol myristate acetate (PMA) and ionomycin. The effect of an anti-IL-15 monoclonal antibody (TEV-53408) on different NK cell subtypes was tested at different time points. Our data shows that within 28 days of culture, differentiation into all developmental stages of NK cells was accomplished in this system. Alongside with the NK cells, myeloid cells developed in the system including granulocytes, monocytes and dendritic cells. The differentiated NK cells could be activated after stimulation with PMA and ionomycin indicating the functionality of the cells. Treatment with an anti-IL-15 antibody induced a reduction in proliferation of late-stage NK cells as shown by EdU staining. This led to significantly dose dependent reduction in the number of circulating stage 4 - 6 NK cells in the system after one week of treatment. This effect was partially reversible after a two-week treatment-free period. In summary, the presented model enables investigation of human NK cell development in the bone marrow and provides a basis to study related diseases and drug response effects in a microenvironment that is designed mimic human physiology.