Nature Medicine最新文献

{"title":"Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial","authors":"Lixin Guo \u0000 (郭立新), Dongni Yu \u0000 (于冬妮), Yimei Xu \u0000 (徐奕玫), Guo Tang \u0000 (唐果), Liang Peng \u0000 (彭亮), Chao Meng \u0000 (孟超), Meng Zhao \u0000 (赵猛), Wen Hu \u0000 (胡文), Debin Huang \u0000 (黄德斌), Chaoyang Zeng \u0000 (曾朝阳), Lei Yu \u0000 (于磊), Guangxiu Wu \u0000 (吴光秀), Lihui Zhang \u0000 (张力辉), Yuan Gao \u0000 (高远), Tingyan Zhong \u0000 (钟庭艳), Zi Ye \u0000 (叶子), on behalf of the OUTSTAND-2 Investigator Group","doi":"10.1038/s41591-026-04713-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04713-y","url":null,"abstract":"Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety versus dapagliflozin in OUTSTAND-2, a phase 3, multicenter, randomized, double-blind, double-dummy, active-comparator-controlled trial conducted at 98 sites in China. We randomized 810 adults (mean hemoglobin A1C (HbA1c) 8.60%, median diabetes duration 5.0 years, 35.7% women) to safiglipron 30 mg (n = 202), safiglipron 60 mg (n = 203), safiglipron 90 mg (n = 203) or dapagliflozin 10 mg (n = 202) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, treatment differences versus dapagliflozin in change from baseline in HbA1c at week 32 under the primary non-inferiority estimand were −0.30% (95% confidence interval (CI): −0.51 to −0.09), −0.22% (−0.44 to −0.01) and −0.40% (−0.62 to −0.19) for safiglipron 30 mg, 60 mg and 90 mg, respectively, establishing non-inferiority for all three doses (all P < 0.0001; non-inferiority margin 0.4%). Under the treatment policy estimand, 90 mg met the prespecified statistical criterion for superiority (difference −0.25%; 95% CI: −0.45 to −0.05; one-sided P = 0.0067), whereas 60 mg did not (P = 0.0789), after which fixed-sequence testing stopped. HbA1c target attainment rates with safiglipron versus dapagliflozin were 54.9−63.5% versus 36.5% for HbA1c <7.0% and 38.9−48.6% versus 16.1% for HbA1c ≤6.5%. Mean body weight changes were −2.35%, −3.55%, −4.17% and −3.60% for safiglipron 30 mg, safiglipron 60 mg, safiglipron 90 mg and dapagliflozin, respectively. Fasting plasma glucose, seven-point self-monitored blood glucose profiles, waist circumference, HOMA-β, HOMA-IR and changes in treatment satisfaction showed varying degrees of improvement from baseline with both safiglipron and dapagliflozin. Rescue therapy was used by 0.5−1.5% versus 0% of participants, respectively. Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to treatment discontinuation in 4.0%, 4.0%, 3.9% and 1.5% of participants, respectively. Safiglipron provides an effective oral treatment option for adults with type 2 diabetes inadequately controlled with metformin. ClinicalTrials.gov identifier: NCT06589765.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"75 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The missing links in agentic AI autonomy","authors":"Mahmud Omar,&nbsp;Raja-Elie E. Abdulnour,&nbsp;Girish N. Nadkarni","doi":"10.1038/s41591-026-04658-2","DOIUrl":"10.1038/s41591-026-04658-2","url":null,"abstract":"A new study tackles issues around operational and decisional trust of agentic artificial intelligence (AI), using locally deployed, on-premise agents and consistency-based gating to refer uncertain cases — but what happens after referral remains untested.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3539-3540"},"PeriodicalIF":52.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149091923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small quantity lipid-based nutritional supplementation and measles vaccination coverage in children aged 6−23 months: a pragmatic cluster-randomized trial","authors":"Cécile Cazes,&nbsp;Baba Waru Goni,&nbsp;Delphine Gabillard,&nbsp;Olumuyiwa Owolabi,&nbsp;Brice Yapi,&nbsp;Juliet Nabunje,&nbsp;Irine Atanga,&nbsp;Ariong’o M. Akinyi,&nbsp;Serge Danho,&nbsp;Eric Balestre,&nbsp;Anani Badje,&nbsp;Fatima Idriss,&nbsp;Mohammed Kasim,&nbsp;Muhammad M. Audu Bukarti,&nbsp;Chikezie Ugonna Emeka,&nbsp;Michelle Chouinard,&nbsp;Jean-Paul Mushenvula,&nbsp;Soma Bahonan,&nbsp;Mélanie Plazy,&nbsp;Ousmane Abdoulaye,&nbsp;Umar Chiroma,&nbsp;Hadiza Maina Adam,&nbsp;Camille Montfort,&nbsp;Nuru Suleiman Muhammad,&nbsp;Renaud Becquet,&nbsp;Kevin P. Q. Phelan","doi":"10.1038/s41591-026-04675-1","DOIUrl":"10.1038/s41591-026-04675-1","url":null,"abstract":"Undernutrition and infectious diseases pose a double threat to child survival, especially in areas with a high malnutrition burden and low vaccination coverage. In this study, we evaluated whether distributing preventive small-quantity lipid-based nutrient supplements (SQ-LNS) alongside routine immunization services may increase vaccine uptake in a pediatric, pragmatic, cluster-randomized controlled trial in northern Nigeria. Twenty geographically defined clusters across two Local Government Areas were randomized 1:1 to the NutriVax strategy (intervention) or standard National Program of Immunization (NPI) services (control). NutriVax provided a monthly ration of SQ-LNS to children aged 6−23 months after routine NPI delivery at primary healthcare centers. The primary outcome was coverage of the first dose of measles-containing vaccine (MCV1) verified by vaccination card among children aged 12−23 months, assessed in an endline population-based household cross-sectional survey 12 months after conducting a similar baseline survey. The endline survey included 1,604 children (801 control, 803 NutriVax); 48% of children surveyed in intervention clusters had ever received SQ-LNS. The odds of receiving card-verified MCV1 were two times higher in the NutriVax arm than in the control arm (odds ratio = 2.08, 95% confidence interval (CI): 1.30−3.35, P = 0.004). The difference-in-differences, cluster conditional analysis indicated a 20.1 percentage-point (pp) increase in MCV1 coverage from baseline (95% CI: 13.7−26.5 pp, P &lt; 0.0001) relative to the control arm. Co-delivering SQ-LNS with routine immunization substantially improved card-verified MCV1 uptake, supporting a scalable strategy to make progress toward targets set by the World Health Organizationʼs Immunization Agenda 2030 in similar settings. ClinicalTrials.gov identifier: NCT06387511 . A pragmatic, superiority, cluster-randomized trial done in Yobe State, northern Nigeria, found that distributing small-quantity lipid-based nutrient supplements alongside routine immunization services substantially increased measles vaccination uptake in children aged 12−23 months.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3622-3632"},"PeriodicalIF":52.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41591-026-04675-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urine cell-free RNA for bladder cancer detection and treatment response prediction","authors":"Kevin J. Liu, William Y. Shi, Monica C. Nesselbush, Nick A. Phillips, Kathleen E. Mach, Bogdan Luca, Ravi K. Bajpai, Isabel Jabara, Jordan C. Cheng, Takeshi Sugio, Navika Shukla, Emily C. Shen, Ivy Lee Koh, Douglas J. Wu, Chih-Long Liu, Diego Almanza, Soyeong Jun, Feng Tian, Emily G. Hamilton, Christian R. Hoerner, Rui Wang, Mohammad S. Esfahani, Angela Hui, Vinh La, Grace Holton, Gabriela Rodriguez, Timothy J. Lee, Xi Ling, Nikitha Kalahasti, Spoorthi Vallamkonda, Patrick Mullane, Simon B. Chen, Eugene Shkolyar, Kris Prado, Ali Raza Khaki, Emily Chan, Mark K. Buyyounouski, Alice C. Fan, Eila C. Skinner, Ash A. Alizadeh, Joseph C. Liao, Maximilian Diehn","doi":"10.1038/s41591-026-04673-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04673-3","url":null,"abstract":"Urine biomarkers promise to improve noninvasive detection and molecular characterization of genitourinary malignancies. Here we describe urine random priming and affinity capture of cell-free RNA (cfRNA) fragments for enrichment analysis by sequencing (uRARE-seq), a liquid biopsy method for urine cfRNA profiling, and apply it to 683 urine samples from patients with cancer and controls. Urine cfRNA contained transcripts from genitourinary tissues and, in patients with prostate, kidney or bladder cancer, tumor-derived transcripts. uRARE-seq demonstrated 95% sensitivity at 90% specificity for detecting localized bladder cancer. The method outperformed urine tumor DNA analysis and was unaffected by the presence of field-effect mutations. Urine cfRNA analysis also sensitively detected minimal residual disease and distinguished complete molecular responses after surgery from those after intravesical Bacillus Calmette–Guérin (BCG). Pretreatment urine from complete responders to BCG was enriched for T cell and other immune signatures, suggesting a preexisting antitumor immune response, whereas nonresponders showed higher expression of proliferation-related genes. In pretreatment urine from 114 patients, this biological difference enabled development of a biomarker predicting likelihood of response to BCG versus chemotherapy (area under the curve 0.93) that was strongly associated with risk of recurrence. Urine cfRNA analysis is therefore a promising biomarker approach for bladder cancer and potentially other urologic malignancies, although prospective studies are needed to assess its clinical utility.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"166 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial","authors":"Katherine R. Tuttle, Petter Bjornstad, Cathy Smith, Menno Pruijm, Phillip J. McCown, Jeffrey B. Hodgin, David Z. I. Cherney, Nicolas Belmar, Milenta Mariam Chacko, Vivek Das, Thomas P. Gunnarsson, Thomas Idorn, Philip A. Schytz, Amaya Zaratiegui, Matthias Kretzler","doi":"10.1038/s41591-026-04674-2","DOIUrl":"https://doi.org/10.1038/s41591-026-04674-2","url":null,"abstract":"The GLP-1 receptor agonist semaglutide preserves kidney function in people with type 2 diabetes and chronic kidney disease, but the underlying mechanisms are unclear. Here we report a 52-week randomized trial of subcutaneous semaglutide 1 mg once weekly versus placebo (n = 106 (n = 25 women, n = 81 men)) in participants with type 2 diabetes and chronic kidney disease. To identify kidney-specific mechanisms of action for semaglutide, we performed integrated multiparametric magnetic resonance imaging of the kidney and biopsy for histology (n = 33), alongside single-nucleus (n = 22) and spatial transcriptomics (n = 13) on paired samples with before- and after-treatment measurements. Coprimary magnetic resonance imaging outcomes (oxygenation by R2*, global perfusion and tissue inflammation by T1 mapping) were not significantly altered by semaglutide versus placebo treatment. Secondary outcomes revealed that semaglutide treatment, as compared to placebo, was associated with a significantly reduced renal artery resistive index and stabilization of the apparent diffusion coefficient, indicating prevention of fibrosis progression. Moreover, secondary transcriptomic outcomes revealed pronounced effects of semaglutide on glomerular endothelial cells, consistent with the results of spatial analyses indicating reduced numbers of immune cells in the proximity of these endothelial cells. The results from this trial indicate that mechanisms of kidney protection by semaglutide may include reduced vascular resistance, prevention of fibrosis and improved underlying molecular programs promoting endothelial cell health. ClinicalTrials.gov identifier: NCT04865770.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"11 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)","authors":"Georgina V. Long, Inês Pires da Silva, Kristen A. Perry, Jurriaan Romano, Serigne N. Lo, Piyush Grover, Paolo A. Ascierto, Rodabe N. Amaria, Tina J. Hieken, Caroline Robert, Lucie Heinzerling, Shahneen Sandhu, Milton Barros, Tara C. Mitchell, Zeynep Eroglu, Igor V. Samoylenko, Lukas Flatz, Céleste Lebbé, Douglas B. Johnson, Piotr Rutkowski, Eva Muñoz-Couselo, Omid Hamid, Claudia Trojaniello, Domenico Mallardo, Matthew S. Block, Naima Hammoudi, Naima Benannoune, Dirk Tomsitz, Yang Wang, Cigdem Dinckal, Angelina Kuzmenko, Andrea Forschner, Matteo S. Carlino, Mathilde Jalving, Michael A. Postow, P. Francesco Ferrucci, Ellen Kapiteijn, Astrid A. M. van der Veldt, Karijn P. M. Suijkerbuijk, Laetitia da Meda, Hannah Burnette, Anna Czarnekca, Inderjit Mehmi, Geke Hospers, Sarah Lochrin, Alexander C. J. van Akkooi, Hussein A. Tawbi","doi":"10.1038/s41591-026-04677-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04677-z","url":null,"abstract":"Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB–D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs (n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF-mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"3 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous hyaluronidase-expressing oncolytic adenovirus with chemotherapy in metastatic pancreatic cancer: a randomized phase 2b trial","authors":"Rocio Garcia-Carbonero, Roberto Pazo Cid, Teresa Macarulla, Berta Laquente, Alana Nguyen, Carmen Guillén-Ponce, Andrés Muñoz, Edward J. Kim, Mireya Cazorla, Tara Seery, Miriam Lobo de Mena, Chris Nevala-Plagemann, Vivek Sharma, Eva Martínez de Castro, Mohammad Hojouj, Charles Le, Ana Mato-Berciano, Sheila Connelly, Mike Kaleko, Luis A. Rojas, Vincent J. Wacher, Mary Ann Shallcross, Carmen Blasco, Manel Cascallo, Manuel Hidalgo","doi":"10.1038/s41591-026-04705-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04705-y","url":null,"abstract":"Zabilugene almadenorepvec (VCN-01) is a hyaluronidase-expressing oncolytic adenovirus with a favorable safety profile and encouraging antitumor activity in patients with pancreatic ductal adenocarcinoma. This randomized phase 2b trial evaluated the efficacy and safety of two doses of intravenous VCN-01 with gemcitabine and nab-paclitaxel (GnP) versus GnP alone as first-line therapy in metastatic pancreatic ductal adenocarcinoma. The primary endpoints were overall survival (OS) in the intent-to-treat and full analysis set (FAS) populations, and safety and tolerability in the safety population. In the intent-to-treat population (VCN-01 + GnP, n = 53; GnP, n = 48), median OS in the VCN-01 + GnP versus GnP group was 10.6 versus 8.6 months (hazard ratio (HR) = 0.69 (95% confidence interval (CI) 0.42–1.12), P = 0.196) and progression-free survival was 5.6 versus 4.6 months (HR = 0.63 (95% CI 0.4–1.00), P = 0.046). In the FAS population (n = 48 per group), median OS was 10.8 months in the VCN-01 + GnP group versus 8.6 months in the GnP group (HR = 0.57 (95% CI 0.34-0.96), P = 0.055) and progression-free survival was 7.0 versus 4.6 months (HR = 0.55 (95% CI, 0.34-0.88), P = 0.011). The primary efficacy endpoint of OS was met in the FAS population. Duration of response was 11.2 versus 5.4 months (HR = 0.22 (95% CI 0.08–0.63), P = 0.004). No statistically significant differences were observed in overall response rate, disease control rate or carbohydrate antigen 19-9 levels between treatment groups. In addition, survival rates in the VCN-01 + GnP group versus the GnP group were 35.5% versus 12.8% at 15 months, and 31.1% versus 8.5% at 18 months. Patients receiving two VCN-01 doses 14 weeks apart showed greater survival benefit, with sustained circulating viral genomes indicating ongoing viral replication and preserved second-dose bioactivity despite persistent neutralizing antibodies. More frequent VCN-01-related events included pyrexia, flu-like symptoms, elevation in liver enzymes and decreases in platelet counts, with serious events occurring in 22.6% of patients. Milder toxicity was observed after the second administration. Two fatal events occurred, one in each treatment group; neither was considered related to study treatment. These results further support VCN-01 combined with GnP as a first-line therapy for metastatic pancreatic ductal adenocarcinoma and warrant evaluation in a blinded phase 3 trial. ClinicalTrials.gov identifier: NCT05673811.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A synthetic lethal drug for microsatellite instability cancers.","authors":"Jia Liu","doi":"10.1038/s41591-026-04693-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04693-z","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial.","authors":"Timothy A Yap, Elisa Fontana, Natalie Cook, Marwan Fakih, Oliver Bechter, Erica S Tsang, Emiliano Calvo, Kristoffer S Rohrberg, Javier Ros, Ignacio Matos, John H Strickler, Malaka Ameratunga, Meredith Pelster, Adam Sharp, Jaspreet Grewal, Susanna Ulahannan, Rajesh Belani, Matthew P Patricelli, Sophia M Blake, David Dejardin, Stephen Fowler, Christina Godfried Sie, Astrid Heller, Nina Henkel, Michael Hettich, Angelika Lahr, David Lamparter, Charlotte Lane, Ting Liu, Hélène Meistermann, Christophe Meille, Neil Parrott, Sotirios K Sotiriou, Denise Reeves, Barbara Romagnoli, Piergiorgio Pettazzoni, Daniel Waterkamp, Matthias Wittwer, Yali Fu, Sophie Postel-Vinay","doi":"10.1038/s41591-026-04657-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04657-3","url":null,"abstract":"<p><p>Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 patients with MSI and/or deficient DNA mismatch repair advanced solid tumors. RO7589831 was administered once daily (150 mg), twice daily (BID; 150-1,000 mg) or three-times daily (TID; 200-600 mg). Primary objectives were to evaluate safety and tolerability, and identify the recommended phase 2 dose and schedule (RP2D). Secondary objectives included evaluation of antitumor activity (end points: disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)). One dose-limiting toxicity of grade 2 nausea occurred in the 600-mg TID cohort; however, the maximum tolerated dose was not identified per protocol. Treatment-emergent adverse events (TEAEs) occurring in ≥10% were mostly grade 1-2; events in ≥30% were nausea (54.5%, 48/88; grade 3+: 2.3%, 2/88), diarrhea (43.2%, 38/88; grade 3+: 1.1%, 1/88), fatigue (39.8%, 35/88; grade 3+: 2.3%, 2/88), anemia (37.5%, 33/88; grade 3+: 11.4%, 10/88), and vomiting (30.7%, 27/88, grade 3+: 1.1%, 1/88). TEAEs leading to RO7589831 discontinuation were uncommon (3.4%, 3/88). No grade 5 TEAEs occurred. The DCR among MSI efficacy-evaluable patients was 74.2% (49/66). Seven patients achieved confirmed RECIST v.1.1 partial responses (ORR 10.6%, 7/66); median DOR was 10.2+ months. Among MSI efficacy-evaluable patients, median PFS was 6.7 months (95% CI 4.1-8.5); median OS was 17.6 months (95% CI 17.6-not estimable). Although direct target engagement in tumor tissue could not be demonstrated, exploratory analyses of ctDNA molecular response and FDG-PET metabolic response supported biological activity. The 150-mg and 600-mg BID doses were selected as RP2Ds for dose optimization. These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing. ClinicalTrials.gov identifier: NCT06004245 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial.","authors":"Miao Yu, Liang Peng, Chengyan Jiang, Xianghua Zhang, Qifu Li, Lihui Zhang, Xiuhai Su, Zhaoyang Zeng, Shuang Yan, Jinyang Wang, Debin Huang, Sihong Wang, Na Liu, Yimei Xu, Guo Tang, Fangli Dong, Yanlin Ma, Zi Ye, Xinhua Xiao","doi":"10.1038/s41591-026-04651-9","DOIUrl":"https://doi.org/10.1038/s41591-026-04651-9","url":null,"abstract":"<p><p>Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety in OUTSTAND-1, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 46 sites in China. We randomized 284 adults with type 2 diabetes managed with diet and exercise alone (mean baseline HbA1c 7.95%, median diabetes duration 1.6 years, 33.1% women) to once-daily safiglipron 30 mg (n = 70), 60 mg (n = 70), 90 mg (n = 72) or placebo (n = 72) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, placebo-adjusted treatment differences in HbA1c change from baseline to week 32 were -1.22% (95% CI, -1.53 to -0.91), -1.20% (95% CI, -1.52 to -0.89) and -1.45% (95% CI, -1.75 to -1.14) for 30 mg, 60 mg and 90 mg, respectively (all P < 0.0001; treatment policy estimand). Secondary outcomes showed HbA1c < 7.0% in 71.4-77.8% versus 25.0%, HbA1c ≤ 6.5% in 58.6-68.1% versus 16.7% and placebo-adjusted fasting plasma glucose differences of -1.58, -1.68 and -2.08 mmol l^-¹, respectively (all P < 0.0001). Body weight differences were modest (-0.65%, -2.23% and -3.56% versus placebo). Other secondary outcomes generally favored safiglipron for HbA1c < 5.7% attainment, postprandial glycemia, homeostatic model assessment of β cell function (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), disposition index and waist circumference, with less rescue therapy use. Insulin and C-peptide responses varied by dose, and changes in treatment satisfaction were limited. Gastrointestinal adverse events were most common and mostly mild or moderate. Adverse events led to treatment discontinuation in 1.4%, 2.9%, 6.9% and 0% of participants receiving safiglipron 30 mg, 60 mg, 90 mg and placebo, respectively. These findings support once-daily oral safiglipron as an effective treatment option for type 2 diabetes. ClinicalTrials.gov identifier: NCT06672172 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}