AstraZeneca (United Kingdom)

Renin-angiotensin-aldosterone system inhibitor (RAASi) therapies are a cornerstone of guideline-directed medical therapy in the management of cardiorenal disease, including chronic kidney disease and heart failure. Management guidelines state that these therapies should be prescribed at the maximum licensed or tolerated dose in order to prevent disease progression and adverse events. However, both cardiorenal disease and RAASi therapies increase the risk of hyperkalaemia. When hyperkalaemia occurs, clinicians often down-titrate or discontinue these important RAASi therapies, leaving patients at risk of adverse cardiorenal outcomes. Eleven cardiorenal experts considered how hyperkalaemia can act as a barrier to optimised RAASi therapy in patients with cardiorenal disease and how these issues could be mitigated. Four key areas of suboptimal and variable clinical practice were identified: optimisation of RAASi therapy; definition and management of acute hyperkalaemia; secondary to primary care communications; and patient education. In this podcast article, two of the experts discuss the clinical challenges and principles of optimal care for each of the four areas identified. The experts agreed that hyperkalaemia should be considered a predictable and manageable condition, requiring a pre-emptive and long-term approach. When hyperkalaemia occurs, down-titrating or discontinuing RAASi therapy should be a last resort, after all other management approaches have been employed. Healthcare professionals in secondary and primary care must communicate and collaborate to ensure effective, consistent management of patients with cardiorenal disease. Finally, patients should be educated to understand their cardiorenal disease and its management and the importance of optimal RAASi therapy. Supplementary file1 (MP4 173853 KB).

Asthma among adolescents (aged 12-<18 years) is a common condition with high disease burden. Many are undertreated, at risk of adverse outcomes and exhibit poor adherence to maintenance medication. As-needed albuterol-budesonide 180/160 µg reduced the risk of severe exacerbations by 27% compared with as-needed albuterol 180 µg in patients aged ≥12 years, with moderate-to-severe asthma receiving inhaled corticosteroid (ICS) maintenance therapy in the MANDALA trial. A small number of adolescents were included in MANDALA, but data were inconclusive. The randomised, double-blind, multicentre, phase IIIb ACADIA trial is evaluating as-needed albuterol-budesonide versus as-needed albuterol in adolescents with asthma. A planned 440 adolescents (aged 12-<18 years) with asthma using as-needed albuterol with low- to high-dose ICS-containing maintenance medications (with or without other controllers) and who had ≥1 severe exacerbation in the previous 12 months are randomised to as-needed albuterol-budesonide 180/160 µg or as-needed albuterol 180 µg for 52 weeks while continuing their own maintenance therapy. The primary endpoint is the annualised rate of severe asthma exacerbations. Secondary endpoints are the time to first severe asthma exacerbation and annualised total systemic corticosteroid exposure for asthma per participant. To minimise the number of adolescents exposed to study medications, the treatment effect will be estimated by partially extrapolating results from the patient population in the MANDALA trial using a Bayesian dynamic borrowing approach. Ethical approval was obtained from the investigators' institutional review boards. Enrolment began in May 2024. Results will be presented at respiratory congresses and published in peer-reviewed journals. NCT06307665.

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-HER2 antibody and a cytotoxic topoisomerase I inhibitor, is approved for the treatment of HER2-positive and HER2-low breast cancer as well as HER2-high gastric and HER2-mutant lung cancer tumours. The AKT inhibitor capivasertib is approved for the treatment of HER2- ER+ breast cancer with alterations in PIK3CA, PTEN and AKT-1. The potential for the combination of T-DXd with AKT inhibition to enhance anti-tumour activity was explored in HER2+ or HER2-low preclinical models. In vitro, combination activity was observed in both HER2-high and HER2-low expressing breast cancer as well as in gastric, endometrial and ovarian models, irrespective of HER2 expression level or PI3K-AKT status pathway alterations. The T-DXd-capivasertib combination effect translated in vivo with increased anti-tumour benefit in HER2 expressing, PI3K-AKT pathway altered tumour xenografts when compared to the combination of trastuzumab and capivasertib. In cell lines sensitive to the combination, combining T-DXd with capivasertib targeted complimentary pathways which resulted in disruption of the cell cycle and increased cell death. These results suggest that T-DXd combined with capivasertib has the potential to be active in HER2-positive as well as HER2-low tumours independent of PI3K pathway alteration status.

Abstract Background: Saruparib (AZD5305) is a highly selective, potent inhibitor and trapper of PARP1. Camizestrant is an oral next generation SERD and complete ER antagonist. PETRA (NCT04644068) is a Phase 1/2a, modular, open label, multicenter study of saruparib as monotherapy or in combination with anticancer agents in pts with advanced solid malignancies. We present safety and preliminary efficacy of saruparib + camizestrant in pts with advanced/relapsed ER+/HER2- breast cancer. Methods: Pts were aged ≥18 years with histologically/cytologically confirmed breast adenocarcinoma, a locally-documented ER+ and HER2- tumor and an ECOG PS 0/1. Pts were required to have recurrence or progression on ≥1 line of endocrine therapy, and were allowed ≤2 prior lines of chemotherapy in the advanced setting and ≤1 prior PARP inhibitor. Pts could receive prior CDK4/6 inhibitors or fulvestrant, but not oral SERDs. Pts received 60 mg saruparib + 75 mg camizestrant daily orally. The primary objective was assessment of safety and tolerability; secondary objectives included pharmacokinetic (PK) assessments and preliminary antitumor activity. Results: At data cutoff (Mar 31, 2025), 38 pts had received ≥1 dose of the combination. Median age was 56 years; median prior lines of therapy was 3.5 (range, 1-13). BRCA1/BRCA2 mutation (m) and PALB2m were detected in 8 (21.1%) and 2 (5.3%) pts, respectively, based on local testing. Safety is summarized in the Table. Hematological toxicities included anemia and neutropenia; gastrointestinal toxicities included nausea and vomiting. PK data showed no evidence of drug interaction between saruparib and camizestrant. Saruparib exposure was comparable following single-dose saruparib versus saruparib at steady-state in combination with camizestrant, for AUC (42,219 vs 41,703 h*ng/mL) and Cmax (2,834 vs 3,250 ng/mL). Eight of 35 evaluable pts achieved confirmed partial responses (by RECIST v1.1) for an objective response rate (ORR) of 22.9%; median duration of response was 5.5 months. In addition, 12 pts (34.3%) achieved stable disease for a disease control rate of 57.1%. An ORR of 33.3% was reported in 9 pts with measurable disease and BRCA1/BRCA2m or PALB2m. The median progression-free survival was 4.4 months (80% CI, 2.0-5.6) overall and 6.1 months (80% CI, 4.4-7.3) in pts with mutations. Conclusion: Saruparib + camizestrant was well tolerated with no new safety signals versus prior monotherapy studies of each drug. PK of saruparib in combination with camizestrant was consistent with monotherapy data. Preliminary efficacy of the combination was promising and compared favorably with camizestrant monotherapy. This combination is being tested in a randomized Phase 3 trial in pts with ER+/HER2- and BRCA1m/BRCA2m or PALB2m (EvoPAR-Breast01; NCT06380751). Citation Format: T. A. Yap, K. Yonemori, W. Li, S. Kitano, F. Lynce, A. Sharp, A. Falcón, J. Garcia-Corbacho, R. D. Baird, J. Balmaña, S. Nanda, I. Song, K. Sugibayashi, L. Womersley, M. Squatrito, E. Gangl, T. Milenkova, S. J. Luen. Phase 1/2a trial of new generation PARP1-selective inhibitor saruparib + next generation selective ER degrader (SERD) camizestrant in patients (pts) with advanced/relapsed ER+/HER2-negative or low (HER2−) breast cancer (PETRA Module 6) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-28.

The SOURCE phase 3 oral corticosteroid (OCS)-sparing study of tezepelumab indicated an OCS-sparing effect with tezepelumab versus placebo in patients with OCS-dependent asthma and baseline blood eosinophil counts (BECs) of at least 150 cells per μL. The WAYFINDER study aimed to further evaluate the ability of tezepelumab to reduce or discontinue OCS use in a larger cohort of patients with OCS-dependent severe, uncontrolled asthma. WAYFINDER was a phase 3b, multicentre, single-arm, open-label, OCS-sparing study. Adults (aged 18-80 years) with severe, uncontrolled asthma receiving a maintenance OCS dose of 5-40 mg per day (or equivalent) of prednisone or prednisolone were recruited from 68 clinical centres across 11 countries (Argentina, Belgium, Bulgaria, France, Germany, Latvia, Mexico, Poland, Spain, UK, and USA). Participants received tezepelumab 210 mg subcutaneously once every 4 weeks for up to 52 weeks. The co-primary endpoints, assessed at weeks 28 and 52, were the proportion of participants who reduced their prescribed maintenance OCS dose to 5 mg per day or less without loss of asthma control and the proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to below 5 mg per day were contingent on participants demonstrating preserved adrenal function. This completed study was registered with ClinicalTrials.gov (NCT05274815). WAYFINDER was conducted between May 17, 2022, and Sept 9, 2024. Overall, 382 participants were enrolled and 298 participants (206 female [69·1%]) received tezepelumab and were included in the efficacy and safety analyses. The mean baseline maintenance OCS dose was 10·8 (SD 6·5) mg per day. The proportion of participants who had a maintenance OCS dose of 5 mg per day or less without loss of asthma control was 265 of 298 (88·9% [95% CI 84·8-92·3]) at week 28 and 268 of 298 (89·9% [85·9-93·1]) at week 52. The proportion of participants who discontinued OCS without loss of asthma control was 96 of 298 (32·2% [26·9-37·8]) at week 28 and 150 of 298 (50·3% [44·5-56·2]) at week 52. OCS reduction and discontinuation were achieved across pre-specified subgroups based on baseline BEC, fractional exhaled nitric oxide level, or allergy status. Serious adverse events were reported in 28 (9·4%) of 298 participants (asthma [13 participants] and pneumonia [three participants] were the most common), and four participants (1·3%) had adverse events leading to tezepelumab discontinuation. Two participants died during the study but neither death was considered to be causally related to tezepelumab treatment. After 52 weeks of open-label tezepelumab treatment, nearly 90% of patients with OCS-dependent severe, uncontrolled asthma had a maintenance OCS dose of 5 mg per day or less and more than 50% completely discontinued OCS, while maintaining asthma control. These findings indicate that tezepelumab treatment can help enable patients with severe asthma to reduce their OCS use and its associated burden, with broad applicability across patient phenotypes. AstraZeneca and Amgen.

Boron heterocycles can be formed at ambient temperature through the reaction of alpha-thio or alpha-amino boronates with nitriles or carbodiiimides. The chemistry can be applied to a wide range of unactivated nitriles. A range of amino acid and peptide analogues containing novel boron heterocycles were generated using these reactions.