Pub Date : 2026-03-25DOI: 10.1038/s41591-025-04115-6
Mohamed Abou-el-Enein, Mark C. Walters, Darshak Sanghavi, Donald B. Kohn
{"title":"A blueprint to accelerate rare pediatric gene therapy approvals","authors":"Mohamed Abou-el-Enein, Mark C. Walters, Darshak Sanghavi, Donald B. Kohn","doi":"10.1038/s41591-025-04115-6","DOIUrl":"https://doi.org/10.1038/s41591-025-04115-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"22 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507191","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}
Pub Date : 2026-03-25DOI: 10.1038/s41591-026-04299-5
Wungki Park (박웅기), Catherine A. O’Connor, Joanne F. Chou, Marc Hilmi, Zeynep Tarcan, Carly Schwartz, Mary Larsen, Ramzi Homsi, Karthigayini Sivaprakasam, Shigeaki Umeda (梅田茂明), Maria A. Perry, Anna M. Varghese, Kenneth H. Yu, Fiyinfolu Balogun, Alice Zervoudakis, Seth S. Katz, Tae-Hyung Kim (김태형), Ken Zhao, Allison L. Richards, Nicolas Lecomte, Daniel Martin Muldoon (Domhnall Ó Maoldúin), Elias Karnoub, Walid Chatila, Jessica Yang, Imane El-Dika, Devika Rao, Smita Joshi, Michael B. Foote, Ryan Sugarman, James J. Harding, Andrew S. Epstein, David Kelsen, Sree Chalassani, Fergus Keane, Joshua D. Schoenfeld, Anupriya Singhal, Erin Diguglielmo, Chaitanya Bandlamudi, Junmin Song (송준민), Hulya Sahin Ozkan, Junguei Hong, Haochen Zhang (张皓辰), Agustin III Cardenas, Maria Lao, Jerry Melchor, Ronak Shah, Wenfei Kang, Francesca Mazzoni, Kevin Soares, Mark TA Donoghue
Homologous recombination deficiency (HRD) arising from BRCA1or BRCA2 or PALB2 mutations confers sensitivity to platinum chemotherapy and PARP inhibition in pancreatic cancer (PC) and may enable prolonged disease control with immune checkpoint blockade (ICB). The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib following platinum-based chemotherapy in biomarker-stratified metastatic PC. Sixty-three participants were enrolled into three cohorts: cohort A (BRCA1/BRCA2-mutated or PALB2-mutated HRD, n = 33), cohort B (non-core HRD, n = 15) and cohort C (platinum sensitive, HRD-wild type, n = 15). Cohort A used a two-stage design with co-primary endpoints of at least 43% Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate (ORR) and at least 77% 6-month progression-free survival (PFS) rate. Among RECIST-evaluable participants in cohort A (n = 20), ORR was 35% (95% confidence interval (CI): 15−59%), whereas 6-month PFS rate in the full cohort (n = 33) was 64% (95% CI: 49−82%), not meeting the primary endpoint. At a median follow-up of 37 months (95% CI: 27−47), median PFS and overall survival (OS) for cohort A were 8.3 (95% CI: 5.3−not reached (NR)) and 28 (95% CI: 12−NR) months, with 2-year and 3-year OS rates of 56% (95% CI: 41−76%) and 44% (95% CI: 28−69%), respectively. In cohorts B and C, ORR was 8% (95% CI: 0−38%) and 14% (95% CI: 2%-43%); median PFS was 4.8 (95% CI: 4.0−12) and 3.3 (95% CI: 1.9−4.8) months; and median OS was 18 (95% CI: 13−NR) and 10 (95% CI: 8.9−24) months, respectively. Preplanned translational analyses showed that circulating tumor DNA response, increased tumor-infiltrating lymphocytes and enrichment of frameshift indel neoantigens were associated with durable clinical benefit. These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740.
{"title":"Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial","authors":"Wungki Park \u0000 (박웅기), Catherine A. O’Connor, Joanne F. Chou, Marc Hilmi, Zeynep Tarcan, Carly Schwartz, Mary Larsen, Ramzi Homsi, Karthigayini Sivaprakasam, Shigeaki Umeda \u0000 (梅田茂明), Maria A. Perry, Anna M. Varghese, Kenneth H. Yu, Fiyinfolu Balogun, Alice Zervoudakis, Seth S. Katz, Tae-Hyung Kim \u0000 (김태형), Ken Zhao, Allison L. Richards, Nicolas Lecomte, Daniel Martin Muldoon \u0000 (Domhnall Ó Maoldúin), Elias Karnoub, Walid Chatila, Jessica Yang, Imane El-Dika, Devika Rao, Smita Joshi, Michael B. Foote, Ryan Sugarman, James J. Harding, Andrew S. Epstein, David Kelsen, Sree Chalassani, Fergus Keane, Joshua D. Schoenfeld, Anupriya Singhal, Erin Diguglielmo, Chaitanya Bandlamudi, Junmin Song \u0000 (송준민), Hulya Sahin Ozkan, Junguei Hong, Haochen Zhang \u0000 (张皓辰), Agustin III Cardenas, Maria Lao, Jerry Melchor, Ronak Shah, Wenfei Kang, Francesca Mazzoni, Kevin Soares, Mark TA Donoghue","doi":"10.1038/s41591-026-04299-5","DOIUrl":"https://doi.org/10.1038/s41591-026-04299-5","url":null,"abstract":"Homologous recombination deficiency (HRD) arising from BRCA1or BRCA2 or PALB2 mutations confers sensitivity to platinum chemotherapy and PARP inhibition in pancreatic cancer (PC) and may enable prolonged disease control with immune checkpoint blockade (ICB). The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib following platinum-based chemotherapy in biomarker-stratified metastatic PC. Sixty-three participants were enrolled into three cohorts: cohort A (BRCA1/BRCA2-mutated or PALB2-mutated HRD, n = 33), cohort B (non-core HRD, n = 15) and cohort C (platinum sensitive, HRD-wild type, n = 15). Cohort A used a two-stage design with co-primary endpoints of at least 43% Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate (ORR) and at least 77% 6-month progression-free survival (PFS) rate. Among RECIST-evaluable participants in cohort A (n = 20), ORR was 35% (95% confidence interval (CI): 15−59%), whereas 6-month PFS rate in the full cohort (n = 33) was 64% (95% CI: 49−82%), not meeting the primary endpoint. At a median follow-up of 37 months (95% CI: 27−47), median PFS and overall survival (OS) for cohort A were 8.3 (95% CI: 5.3−not reached (NR)) and 28 (95% CI: 12−NR) months, with 2-year and 3-year OS rates of 56% (95% CI: 41−76%) and 44% (95% CI: 28−69%), respectively. In cohorts B and C, ORR was 8% (95% CI: 0−38%) and 14% (95% CI: 2%-43%); median PFS was 4.8 (95% CI: 4.0−12) and 3.3 (95% CI: 1.9−4.8) months; and median OS was 18 (95% CI: 13−NR) and 10 (95% CI: 8.9−24) months, respectively. Preplanned translational analyses showed that circulating tumor DNA response, increased tumor-infiltrating lymphocytes and enrichment of frameshift indel neoantigens were associated with durable clinical benefit. These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506160","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}
Pub Date : 2026-03-25DOI: 10.1038/s41591-026-04244-6
Ning An, Di Wang, Peiling Zhang, Jishuai Zhang, Philippe Parone, Jianlin Hu, Yuhan Bao, Li Xu, Haitao Ruan, Ying Wan, Xinyu Wen, Yang Gao, Chunrui Li
In vivo chimeric antigen receptor (CAR)-T cell generation can bypass ex vivo manufacturing and lymphodepletion, potentially simplifying and accelerating access to cellular therapy; preliminary clinical experience supports feasibility and suggests preliminary efficacy. This phase 1, single-arm, open-label trial evaluated the safety and tolerability of ESO-T01, a nanobody-directed, immune-shielded lentiviral vector encoding a humanized anti-B cell maturation antigen (BCMA) CAR, in adults with relapsed or refractory multiple myeloma. ESO-T01 was administered as a single intravenous infusion of 0.2 × 109 transduction units without leukapheresis, ex vivo manufacturing or lymphodepleting chemotherapy. Five heavily pretreated male patients (median three prior lines) were consecutively enrolled and followed for a median of 6.0 months. The trial was stopped early in 2025, and no further enrollment was performed. The primary endpoint was safety and tolerability, and secondary endpoints included efficacy, pharmacokinetics and pharmacodynamics of ESO-T01. No dose-limiting toxicities occurred. All patients developed grade 3 or higher adverse events. Cytokine release syndrome occurred in four patients (three grade 3 and one grade 2) and was managed with corticosteroids, tocilizumab, or supportive care. The most frequent toxicities were transient cytopenias and reversible hepatic enzyme elevations, and three patients experienced grade 2 infections. One patient developed grade 1 immune effector cell-associated neurotoxicity and died from extramedullary lesion-related spinal cord compression. Preliminary antimyeloma activity was observed: four of five patients achieved objective responses, including three stringent complete remissions, with minimal residual disease negativity (10−5) in all evaluable responders (4/4) by day 60. These findings provide preliminary evidence on the feasibility and safety of in vivo CAR-T generation using an immune-shielded vector. ClinicalTrials.gov registration: NCT06791681.
{"title":"In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study","authors":"Ning An, Di Wang, Peiling Zhang, Jishuai Zhang, Philippe Parone, Jianlin Hu, Yuhan Bao, Li Xu, Haitao Ruan, Ying Wan, Xinyu Wen, Yang Gao, Chunrui Li","doi":"10.1038/s41591-026-04244-6","DOIUrl":"https://doi.org/10.1038/s41591-026-04244-6","url":null,"abstract":"In vivo chimeric antigen receptor (CAR)-T cell generation can bypass ex vivo manufacturing and lymphodepletion, potentially simplifying and accelerating access to cellular therapy; preliminary clinical experience supports feasibility and suggests preliminary efficacy. This phase 1, single-arm, open-label trial evaluated the safety and tolerability of ESO-T01, a nanobody-directed, immune-shielded lentiviral vector encoding a humanized anti-B cell maturation antigen (BCMA) CAR, in adults with relapsed or refractory multiple myeloma. ESO-T01 was administered as a single intravenous infusion of 0.2 × 109 transduction units without leukapheresis, ex vivo manufacturing or lymphodepleting chemotherapy. Five heavily pretreated male patients (median three prior lines) were consecutively enrolled and followed for a median of 6.0 months. The trial was stopped early in 2025, and no further enrollment was performed. The primary endpoint was safety and tolerability, and secondary endpoints included efficacy, pharmacokinetics and pharmacodynamics of ESO-T01. No dose-limiting toxicities occurred. All patients developed grade 3 or higher adverse events. Cytokine release syndrome occurred in four patients (three grade 3 and one grade 2) and was managed with corticosteroids, tocilizumab, or supportive care. The most frequent toxicities were transient cytopenias and reversible hepatic enzyme elevations, and three patients experienced grade 2 infections. One patient developed grade 1 immune effector cell-associated neurotoxicity and died from extramedullary lesion-related spinal cord compression. Preliminary antimyeloma activity was observed: four of five patients achieved objective responses, including three stringent complete remissions, with minimal residual disease negativity (10−5) in all evaluable responders (4/4) by day 60. These findings provide preliminary evidence on the feasibility and safety of in vivo CAR-T generation using an immune-shielded vector. ClinicalTrials.gov registration: NCT06791681.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"58 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506159","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}
Pub Date : 2026-03-24DOI: 10.1038/s41591-026-04304-x
Floris Chabrun, Daniel E. Schwartz, Susanna Gentile, Elias K. Mai, Tulika R. Gupta, Jacqueline Perry, David M. Cordas dos Santos, Thomas Hielscher, Annika Werly, Sophia K. Schmidt, Foteini Theodorakakou, Despina Fotiou, Christine Ivy Liacos, Nikolaos Kanellias, Noelia Collado Gisbert, Esperanza Martin-Sanchez, Rosalinda Termini, Johannes Waldschmidt, Selina J. Chavda, Louise Ainley, Matteo Claudio Da Vià, Claudio De Magistris, Loredana Pettine, Michael A. Timonian, Jean-Baptiste Alberge, Vidhi Patel, Patrick Costello, Catherine Tobia, Sally Phan, Jennifer Lamb, Maria-Theresa Silverio, Maya Davis, Elizabeth K. O’Donnell, Catherine R. Marinac, Omar Nadeem, Niccolo Bolli, Kwee Yong, K. Martin Kortüm, Hermann Einsele, María-Victoria Mateos, Shaji Kumar, Jesús F. San-Miguel, Bruno Paiva, Efstathios Kastritis, Meletios A. Dimopoulos, Marc S. Raab, Lorenzo Trippa, Irene M. Ghobrial
Accurate prediction of risk of progression from smoldering multiple myeloma (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled a cohort of 2,344 patients with SMM from seven international centers with longitudinal clinical and biological data to train and validate the Precursor Asymptomatic Neoplasms by Group Effort Analysis (PANGEA)-SMM risk models. Four evolving biomarkers were significantly associated with shorter time to progression: M-protein increase ≥0.2 g dl−1, involved/uninvolved serum free light chain ratio increase ≥20, creatinine increase >25% and hemoglobin decrease ≥1.5 g dl−1. PANGEA-SMM outperforms established models, including the 20/2/20 and IMWG models, by more accurately predicting progression (C-statistic = 0.79), even without biomarker history (C-statistic = 0.78) or recent bone marrow biopsy (C-statistic = 0.78). We present PANGEA-SMM to the community as an easy-to-use, open-access tool for risk stratification in SMM. Validation tools are available to compare PANGEA-SMM to established models.
准确预测从阴燃型多发性骨髓瘤（SMM）发展为活动性多发性骨髓瘤（MM）的风险对于个性化的早期治疗策略至关重要，并将过度治疗的风险降到最低。目前的风险分层模型没有考虑到生物标志物的发展轨迹。我们收集了来自7个国际中心的2344名SMM患者的纵向临床和生物学数据，通过群体努力分析(PANGEA)-SMM风险模型来训练和验证前驱无症状肿瘤。四个进化中的生物标志物与更短的进展时间显著相关：m蛋白升高≥0.2 g dl−1，累及/未累及血清游离轻链比升高≥20，肌酐升高bbb25 %，血红蛋白降低≥1.5 g dl−1。PANGEA-SMM优于已建立的模型，包括20/2/20和IMWG模型，即使没有生物标志物病史（C-statistic = 0.78）或近期骨髓活检（C-statistic = 0.78），也能更准确地预测进展（C-statistic = 0.79）。我们将PANGEA-SMM作为易于使用、开放获取的SMM风险分层工具呈现给社区。验证工具可用于比较PANGEA-SMM与已建立的模型。
{"title":"Enhanced dynamic risk stratification of smoldering multiple myeloma","authors":"Floris Chabrun, Daniel E. Schwartz, Susanna Gentile, Elias K. Mai, Tulika R. Gupta, Jacqueline Perry, David M. Cordas dos Santos, Thomas Hielscher, Annika Werly, Sophia K. Schmidt, Foteini Theodorakakou, Despina Fotiou, Christine Ivy Liacos, Nikolaos Kanellias, Noelia Collado Gisbert, Esperanza Martin-Sanchez, Rosalinda Termini, Johannes Waldschmidt, Selina J. Chavda, Louise Ainley, Matteo Claudio Da Vià, Claudio De Magistris, Loredana Pettine, Michael A. Timonian, Jean-Baptiste Alberge, Vidhi Patel, Patrick Costello, Catherine Tobia, Sally Phan, Jennifer Lamb, Maria-Theresa Silverio, Maya Davis, Elizabeth K. O’Donnell, Catherine R. Marinac, Omar Nadeem, Niccolo Bolli, Kwee Yong, K. Martin Kortüm, Hermann Einsele, María-Victoria Mateos, Shaji Kumar, Jesús F. San-Miguel, Bruno Paiva, Efstathios Kastritis, Meletios A. Dimopoulos, Marc S. Raab, Lorenzo Trippa, Irene M. Ghobrial","doi":"10.1038/s41591-026-04304-x","DOIUrl":"https://doi.org/10.1038/s41591-026-04304-x","url":null,"abstract":"Accurate prediction of risk of progression from smoldering multiple myeloma (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled a cohort of 2,344 patients with SMM from seven international centers with longitudinal clinical and biological data to train and validate the Precursor Asymptomatic Neoplasms by Group Effort Analysis (PANGEA)-SMM risk models. Four evolving biomarkers were significantly associated with shorter time to progression: M-protein increase ≥0.2 g dl−1, involved/uninvolved serum free light chain ratio increase ≥20, creatinine increase >25% and hemoglobin decrease ≥1.5 g dl−1. PANGEA-SMM outperforms established models, including the 20/2/20 and IMWG models, by more accurately predicting progression (C-statistic = 0.79), even without biomarker history (C-statistic = 0.78) or recent bone marrow biopsy (C-statistic = 0.78). We present PANGEA-SMM to the community as an easy-to-use, open-access tool for risk stratification in SMM. Validation tools are available to compare PANGEA-SMM to established models.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"16 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506164","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}
Pub Date : 2026-03-24DOI: 10.1038/s41591-026-04262-4
Omar S. Mabrouk, Ben Tichler, H. Moore Arnold, Eva C. Thoma, Sara M. Alexanian, Jingxian Chen, Tzu-Ying Liu, Beth Hirschhorn, Roy Llorens Arenas, John W. Annand, Unnati Kapadnis, Alan A. Shomo, Kelly E. Glajch, Kyle Ferber, Yuka Moroishi, Julie Czerkowicz, Jennifer Inra, Ronald B. Postuma, Tanya Gurevich, Pablo Mir, Huw R. Morris, Jason Aldred, Matthew A. Brodsky, Aaron Ellenbogen, Danielle Larson, Christopher M. Tolleson, Andrew Siderowf, Charalampos Tzoulis, Ernest Balaguer, Maria J. Marti, Hien T. Zhao, Holly B. Kordasiewicz, Roger Lane, Warren D. Hirst, Stephanie Fradette, Danielle L. Graham
LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson’s disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants, stratified by LRRK2 variant status, received four doses of BIIB094 40–120 mg or placebo every 4 weeks. Adverse events were reported by 64.5% (20/31) of participants in part A and by 84.8% (28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in CSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, NCT03976349; EudraCT number, 2018-002995-42.
{"title":"LRRK2-targeting antisense oligonucleotide in Parkinson’s disease: a phase 1 randomized controlled trial","authors":"Omar S. Mabrouk, Ben Tichler, H. Moore Arnold, Eva C. Thoma, Sara M. Alexanian, Jingxian Chen, Tzu-Ying Liu, Beth Hirschhorn, Roy Llorens Arenas, John W. Annand, Unnati Kapadnis, Alan A. Shomo, Kelly E. Glajch, Kyle Ferber, Yuka Moroishi, Julie Czerkowicz, Jennifer Inra, Ronald B. Postuma, Tanya Gurevich, Pablo Mir, Huw R. Morris, Jason Aldred, Matthew A. Brodsky, Aaron Ellenbogen, Danielle Larson, Christopher M. Tolleson, Andrew Siderowf, Charalampos Tzoulis, Ernest Balaguer, Maria J. Marti, Hien T. Zhao, Holly B. Kordasiewicz, Roger Lane, Warren D. Hirst, Stephanie Fradette, Danielle L. Graham","doi":"10.1038/s41591-026-04262-4","DOIUrl":"https://doi.org/10.1038/s41591-026-04262-4","url":null,"abstract":"LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson’s disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants, stratified by LRRK2 variant status, received four doses of BIIB094 40–120 mg or placebo every 4 weeks. Adverse events were reported by 64.5% (20/31) of participants in part A and by 84.8% (28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in CSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, NCT03976349; EudraCT number, 2018-002995-42.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"19 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506165","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}
Pub Date : 2026-03-24DOI: 10.1038/d41591-026-00016-4
Karen O’Leary
{"title":"A pocket-sized drug for p53-mutant cancers","authors":"Karen O’Leary","doi":"10.1038/d41591-026-00016-4","DOIUrl":"https://doi.org/10.1038/d41591-026-00016-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"23 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507193","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}
Pub Date : 2026-03-24DOI: 10.1038/s41591-026-04221-z
Erika R. Manuli, Xinyi Hua (华心怡), Gabriel C. Scachetti, Julia Forato, Ingra M. Claro, Geovana M. Pereira, Livia Sacchetto, Oscar Cortes-Azuero, Ana Carolina Bernardo, Cláudia F. Resende, Natália B. S. Bacarov, Ligia Capuani, Shirlene T. S. de Lima, Ronaldo de Jesus, Rodrigo B. Kato, Bárbara B. Salgado, Carolina M. L. Singh, Nadielle C. Pereira, Renato S. Reis, Sérgio R. L. Albuquerque, Richard Stanton, Vanderson S. Sampaio, Ana I. Bento, Marielton P. Cunha, Oliver Ratmann, Nuno R. Faria, Scott C. Weaver, Pritesh J. Lalwani, Henrik Salje, Allyson G. Costa, José Luiz Proenca-Modena, Ester C. Sabino, William M. de Souza
Oropouche virus (OROV) is an arbovirus endemic to the Amazon region since the 1950s that re-emerged in late 2023, causing a major epidemic across Central and South America. Here we investigated the transmission dynamics of the 2023–2024 epidemic in Manaus City (Amazonas state, Brazil), a major metropolitan hub in the Amazon, and estimated OROV infections across Latin America and the Caribbean. OROV re-emergence in Manaus resulted in an increase of IgG seroprevalence from 11.4% in November 2023 to 25.7% in November 2024. The neutralizing capacity of OROV-specific IgG antibodies from individuals collected before and after the re-emergence demonstrated a median plaque reduction neutralization test 50% titer of 640 against both the historical and contemporary OROV isolates. A historical reconstruction of OROV circulation in Manaus indicated a continuous low-level transmission with two major outbreaks of comparable seasonality and magnitude in 1980–1981 and 2023–2024. We estimate approximately 336,000 OROV infections in the Amazon region under a scenario of continuous endemic transmission without major outbreaks and over 9.4 million OROV infections during major outbreaks from 1960 to 2025. Collectively, our findings provide a comprehensive assessment of OROV transmission in Manaus and contribute to a better understanding of the OROV burden.
{"title":"Transmission dynamics of Oropouche virus in Latin America and the Caribbean","authors":"Erika R. Manuli, Xinyi Hua \u0000 (华心怡), Gabriel C. Scachetti, Julia Forato, Ingra M. Claro, Geovana M. Pereira, Livia Sacchetto, Oscar Cortes-Azuero, Ana Carolina Bernardo, Cláudia F. Resende, Natália B. S. Bacarov, Ligia Capuani, Shirlene T. S. de Lima, Ronaldo de Jesus, Rodrigo B. Kato, Bárbara B. Salgado, Carolina M. L. Singh, Nadielle C. Pereira, Renato S. Reis, Sérgio R. L. Albuquerque, Richard Stanton, Vanderson S. Sampaio, Ana I. Bento, Marielton P. Cunha, Oliver Ratmann, Nuno R. Faria, Scott C. Weaver, Pritesh J. Lalwani, Henrik Salje, Allyson G. Costa, José Luiz Proenca-Modena, Ester C. Sabino, William M. de Souza","doi":"10.1038/s41591-026-04221-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04221-z","url":null,"abstract":"Oropouche virus (OROV) is an arbovirus endemic to the Amazon region since the 1950s that re-emerged in late 2023, causing a major epidemic across Central and South America. Here we investigated the transmission dynamics of the 2023–2024 epidemic in Manaus City (Amazonas state, Brazil), a major metropolitan hub in the Amazon, and estimated OROV infections across Latin America and the Caribbean. OROV re-emergence in Manaus resulted in an increase of IgG seroprevalence from 11.4% in November 2023 to 25.7% in November 2024. The neutralizing capacity of OROV-specific IgG antibodies from individuals collected before and after the re-emergence demonstrated a median plaque reduction neutralization test 50% titer of 640 against both the historical and contemporary OROV isolates. A historical reconstruction of OROV circulation in Manaus indicated a continuous low-level transmission with two major outbreaks of comparable seasonality and magnitude in 1980–1981 and 2023–2024. We estimate approximately 336,000 OROV infections in the Amazon region under a scenario of continuous endemic transmission without major outbreaks and over 9.4 million OROV infections during major outbreaks from 1960 to 2025. Collectively, our findings provide a comprehensive assessment of OROV transmission in Manaus and contribute to a better understanding of the OROV burden.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506161","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}
Pub Date : 2026-03-24DOI: 10.1038/s41591-026-04253-5
Nick Woznitza, Lesley Smith, Janette Rawlinson, Iain Au-Yong, Bindu George, Madava G. Djearaman, Arjun Nair, Richard W. Lee, Neal Navani, Siyabonga Ndwandwe, Caroline S. Clarke, Andrew Creeden, Josh Newsome, Indrajeet Das, Sylvia Abaokporo, Richard Tucker, James Hathorn, David R. Baldwin
Prioritizing artificial intelligence (AI)-detected imaging findings may reduce the time to diagnosis of lung cancer. This prospective, multicentre, randomized controlled trial tested whether immediate AI prioritization of primary care-requested chest X-rays (CXR) influenced time to computed tomography (CT) and lung cancer diagnosis, the primary outcomes. Secondary outcomes included the number of urgent suspected lung cancer referrals, incidence and stage of lung cancer, times to urgent referral and treatment, concordance between AI and radiology reports, and algorithm accuracy. AI was available in both study arms, with AI prioritization randomized by day. Of 97,731 participant CXRs, 4,405 were excluded due to data compliance issues or failure of randomization, resulting in 93,326 CXRs analyzed (45,987 and 47,339 in the prioritization ‘on’ or ‘off’ arms, respectively). A total of 13,347 CTs were identified, with 2,766 performed within 14 days of CXR. Median (interquartile range) times to CT were 53 days (17–145) and 53 days (19–141), with and without AI prioritization, corresponding to a ratio of geometric means of 0.97 (95% confidence interval (CI) = 0.93–1.02; P = 0.31). When restricted to CTs performed within 14 days of CXR, the median time to CT was 8 days (5–11) in both groups. Lung cancer was diagnosed in 558 people (0.6% of CXRs). Median times to diagnosis were 44 days (26–90) and 46 days (24–105) respectively, with a ratio of geometric means of 0.98 (95% CI = 0.83–1.16; P = 0.84). No significant differences were observed in time to lung cancer referral (14 versus 15 days; P = 0.13), time to treatment (76 versus 72.5 days; P = 0.99) or stage at diagnosis (P = 0.34). Discordance between AI and radiology reports occurred in 28,261 CXRs (30.3%) and expert radiology review identified actionable findings in 6,750 cases (23.9%). AI prioritization of CXR requested by UK primary care has no significant impact on the lung cancer pathway. Therefore, CXR AI deployments should not include worklist prioritization in this context. Future research should differentiate between primary pathway changes and the direct impact of AI. ISRCTN registration: 78987039.
{"title":"AI-based chest X-ray prioritization in the lung cancer diagnostic pathway: the LungIMPACT randomized controlled trial","authors":"Nick Woznitza, Lesley Smith, Janette Rawlinson, Iain Au-Yong, Bindu George, Madava G. Djearaman, Arjun Nair, Richard W. Lee, Neal Navani, Siyabonga Ndwandwe, Caroline S. Clarke, Andrew Creeden, Josh Newsome, Indrajeet Das, Sylvia Abaokporo, Richard Tucker, James Hathorn, David R. Baldwin","doi":"10.1038/s41591-026-04253-5","DOIUrl":"https://doi.org/10.1038/s41591-026-04253-5","url":null,"abstract":"Prioritizing artificial intelligence (AI)-detected imaging findings may reduce the time to diagnosis of lung cancer. This prospective, multicentre, randomized controlled trial tested whether immediate AI prioritization of primary care-requested chest X-rays (CXR) influenced time to computed tomography (CT) and lung cancer diagnosis, the primary outcomes. Secondary outcomes included the number of urgent suspected lung cancer referrals, incidence and stage of lung cancer, times to urgent referral and treatment, concordance between AI and radiology reports, and algorithm accuracy. AI was available in both study arms, with AI prioritization randomized by day. Of 97,731 participant CXRs, 4,405 were excluded due to data compliance issues or failure of randomization, resulting in 93,326 CXRs analyzed (45,987 and 47,339 in the prioritization ‘on’ or ‘off’ arms, respectively). A total of 13,347 CTs were identified, with 2,766 performed within 14 days of CXR. Median (interquartile range) times to CT were 53 days (17–145) and 53 days (19–141), with and without AI prioritization, corresponding to a ratio of geometric means of 0.97 (95% confidence interval (CI) = 0.93–1.02; P = 0.31). When restricted to CTs performed within 14 days of CXR, the median time to CT was 8 days (5–11) in both groups. Lung cancer was diagnosed in 558 people (0.6% of CXRs). Median times to diagnosis were 44 days (26–90) and 46 days (24–105) respectively, with a ratio of geometric means of 0.98 (95% CI = 0.83–1.16; P = 0.84). No significant differences were observed in time to lung cancer referral (14 versus 15 days; P = 0.13), time to treatment (76 versus 72.5 days; P = 0.99) or stage at diagnosis (P = 0.34). Discordance between AI and radiology reports occurred in 28,261 CXRs (30.3%) and expert radiology review identified actionable findings in 6,750 cases (23.9%). AI prioritization of CXR requested by UK primary care has no significant impact on the lung cancer pathway. Therefore, CXR AI deployments should not include worklist prioritization in this context. Future research should differentiate between primary pathway changes and the direct impact of AI. ISRCTN registration: 78987039.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"16 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506162","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}
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