Pub Date : 2026-01-15DOI: 10.1038/s41591-025-04071-1
Atul Malhotra, Ronald Grunstein, Ali Azarbarzin, Scott Sands, Virend K. Somers, Louis J. Aronne, Ania M. Jastreboff, Jitong Lou, Sujatro Chakladar, Julia P. Dunn, Mathijs C. Bunck, Josef Bednarik
Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include changes in a homeostatic model assessment for insulin resistance and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea–hypopnea index and sleep apnea-specific hypoxic burden. In both study 1 and study 2 of SURMOUNT-OSA, tirzepatide treatment was associated with greater alleviation of cardiometabolic risk factors than placebo. Independent mediation effect of changes in OSA metrics was observed on high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance and triglycerides. The combination of changes in weight and OSA metrics, as well as weight alone, had a significant mediation effect on systolic blood pressure, but there was no significant mediation effect of weight or OSA metrics observed on diastolic blood pressure. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize the treatment effect on cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. The ClinicalTrials.gov registration number for this study is NCT05412004.
{"title":"Tirzepatide on obstructive sleep apnea-related cardiometabolic risk: secondary outcomes of the SURMOUNT-OSA randomized trial","authors":"Atul Malhotra, Ronald Grunstein, Ali Azarbarzin, Scott Sands, Virend K. Somers, Louis J. Aronne, Ania M. Jastreboff, Jitong Lou, Sujatro Chakladar, Julia P. Dunn, Mathijs C. Bunck, Josef Bednarik","doi":"10.1038/s41591-025-04071-1","DOIUrl":"https://doi.org/10.1038/s41591-025-04071-1","url":null,"abstract":"Obstructive sleep apnea (OSA) is associated with obesity and cardiovascular risk. The SURMOUNT-OSA master protocol comprised two, 52-week, randomized, double-blind, placebo-controlled phase 3 studies (study 1 and study 2) and demonstrated a significant reduction of a number of cardiometabolic risk measures in participants with OSA and obesity following treatment with tirzepatide. Here we report prespecified analysis of cardiometabolic risk measures in SURMOUNT-OSA. Post hoc analyses include changes in a homeostatic model assessment for insulin resistance and mediation analysis to determine the proportion of observed changes attributable to reductions in body weight, apnea–hypopnea index and sleep apnea-specific hypoxic burden. In both study 1 and study 2 of SURMOUNT-OSA, tirzepatide treatment was associated with greater alleviation of cardiometabolic risk factors than placebo. Independent mediation effect of changes in OSA metrics was observed on high-sensitivity C-reactive protein, homeostatic model assessment for insulin resistance and triglycerides. The combination of changes in weight and OSA metrics, as well as weight alone, had a significant mediation effect on systolic blood pressure, but there was no significant mediation effect of weight or OSA metrics observed on diastolic blood pressure. Based on the mediation analysis, treating both sleep-disordered breathing and obesity is likely required to optimize the treatment effect on cardiometabolic benefits for patients with moderate-to-severe OSA and obesity. The ClinicalTrials.gov registration number for this study is NCT05412004.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"29 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968774","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 : 2026-01-15DOI: 10.1038/s41591-025-04121-8
Matthew Ho, Luca Paruzzo, Julia Han Noll, Federico Stella, Pooja Devi, Sonia Ndeupen, Yael A. Day, Gregory M. Chen, Ivan J. Cohen, Angel Ramirez-Fernandez, Adam Waxman, Shivani Kapur, Fang Chen, Rong Xu, Andrew Huff, Danuta Jarocha, Vrutti Patel, Audrey C. Bochi-Layec, Ranjani Ramasubramanian, Shan Liu, Riemke Bouvier, Vitor B. de Souza, Heta Patel, Ziyu Li, Alberto Carturan, Peter Michener, Caitlin R. Hopkins, Owen Koucky, Janna Minehart, Alex Dimitri, Neel R. Nabar, Zainul S. Hasanali, Bryan T. Ciccarelli, Putzer Hung, Erik Williams, Robert Bartoszek, Maya Lavorando, Suyash Mohan, Vanessa E. Gonzalez, Patrizia Porazzi, Vijay G. Bhoj, Sokratis A. Apostolidis, Dan T. Vogl, David L. Porter, John Scholler, Caroline Diorio, Aoife M. Roche, John K. Everett, Frederic D. Bushman, Katherine L. Nathanson, Edward A. Stadtmauer, Sandra P. Susanibar-Adaniya, Alfred L. Garfall
B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021–December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4+ CAR T cell expansion (peak lymphocytes: 197 × 103 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P < 0.001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.
{"title":"CD4+ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy","authors":"Matthew Ho, Luca Paruzzo, Julia Han Noll, Federico Stella, Pooja Devi, Sonia Ndeupen, Yael A. Day, Gregory M. Chen, Ivan J. Cohen, Angel Ramirez-Fernandez, Adam Waxman, Shivani Kapur, Fang Chen, Rong Xu, Andrew Huff, Danuta Jarocha, Vrutti Patel, Audrey C. Bochi-Layec, Ranjani Ramasubramanian, Shan Liu, Riemke Bouvier, Vitor B. de Souza, Heta Patel, Ziyu Li, Alberto Carturan, Peter Michener, Caitlin R. Hopkins, Owen Koucky, Janna Minehart, Alex Dimitri, Neel R. Nabar, Zainul S. Hasanali, Bryan T. Ciccarelli, Putzer Hung, Erik Williams, Robert Bartoszek, Maya Lavorando, Suyash Mohan, Vanessa E. Gonzalez, Patrizia Porazzi, Vijay G. Bhoj, Sokratis A. Apostolidis, Dan T. Vogl, David L. Porter, John Scholler, Caroline Diorio, Aoife M. Roche, John K. Everett, Frederic D. Bushman, Katherine L. Nathanson, Edward A. Stadtmauer, Sandra P. Susanibar-Adaniya, Alfred L. Garfall","doi":"10.1038/s41591-025-04121-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04121-8","url":null,"abstract":"B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021–December 2024), 27 (13.6%) developed CirAEs. This included one remarkable case with three distinct CirAEs in association with an extreme CD4+ CAR T cell expansion (peak lymphocytes: 197 × 103 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.2, P = 0.006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4.5, P = 0.058), peak absolute lymphocyte count ≥ 2.4 × 103 per microliter in the first 14 days post-infusion (odds ratio = 4.3, P < 0.001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2.6, P = 0.048). We identified marked CD4+ CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4+ CAR T cell therapy as a key mediator of these toxicities.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968732","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 : 2026-01-15DOI: 10.1038/s41591-025-04175-8
Holly Lee, Sungwoo Ahn, Gerone A. Gonzales, Noemie Leblay, Elie Barakat, Dylan Greening, Pina Colarusso, Johnathan Canton, Sacha Benaoudia, Elham Hasheminasabgorji, Mansour Poorebrahim, David Jung, Marietta Truger, Jihong Jeong, Christine Riedhammer, Hermann Einsele, K. Martin Kortüm, Jan Eckmann, Jitka Somandin, Sara-Sheena Engel, Lawrence H. Boise, Jan Hendrik Frenking, Niels Weinhold, Konstantina Taouxi, Efstathios Kastritis, Sheri Skerget, Deeksha Vishwamitra, Yunje Cho, Francesco Maura, Marc S. Raab, Jill Corre, Leo Rasche, Hervé Avet-Loiseau, Paola Neri, Nizar J. Bahlis
Tumor-intrinsic adaptations with emerging resistant clones following T cell-targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma. Through integrated genomic, transcriptomic and epigenomic interrogation of clonal plasma cells, we observed antigenic drift in 68.4% of relapsed cases following anti-GPRC5D T cell-engager (TCE) therapy (n = 21). These escape events were driven by three distinct mutational mechanisms involving (1) focal to large biallelic deletions at the GPRC5D gene locus; (2) monoallelic deletion coupled with GPRC5D single-nucleotide variants or insertions/deletions (indels) on the remaining allele; as well as (3) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D single-nucleotide variants and indels mutate anti-GPRC5D TCE-binding epitopes or more commonly affect G-protein-coupled receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Of note, anti-GPRC5D TCEs with varying epitope specificity, affinity and valency differentially targeted mutant subclones, underscoring their nonredundant functional roles in overcoming resistance.
{"title":"Multimodal antigenic escape to GPRC5D-targeted T cell engagers in multiple myeloma","authors":"Holly Lee, Sungwoo Ahn, Gerone A. Gonzales, Noemie Leblay, Elie Barakat, Dylan Greening, Pina Colarusso, Johnathan Canton, Sacha Benaoudia, Elham Hasheminasabgorji, Mansour Poorebrahim, David Jung, Marietta Truger, Jihong Jeong, Christine Riedhammer, Hermann Einsele, K. Martin Kortüm, Jan Eckmann, Jitka Somandin, Sara-Sheena Engel, Lawrence H. Boise, Jan Hendrik Frenking, Niels Weinhold, Konstantina Taouxi, Efstathios Kastritis, Sheri Skerget, Deeksha Vishwamitra, Yunje Cho, Francesco Maura, Marc S. Raab, Jill Corre, Leo Rasche, Hervé Avet-Loiseau, Paola Neri, Nizar J. Bahlis","doi":"10.1038/s41591-025-04175-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04175-8","url":null,"abstract":"Tumor-intrinsic adaptations with emerging resistant clones following T cell-targeted immunotherapies pose a major barrier to durable remissions in multiple myeloma. Through integrated genomic, transcriptomic and epigenomic interrogation of clonal plasma cells, we observed antigenic drift in 68.4% of relapsed cases following anti-GPRC5D T cell-engager (TCE) therapy (n = 21). These escape events were driven by three distinct mutational mechanisms involving (1) focal to large biallelic deletions at the GPRC5D gene locus; (2) monoallelic deletion coupled with GPRC5D single-nucleotide variants or insertions/deletions (indels) on the remaining allele; as well as (3) epigenetic GPRC5D promoter/enhancer silencing. Beyond biallelic deletions resulting in complete antigenic loss, we demonstrate that GPRC5D single-nucleotide variants and indels mutate anti-GPRC5D TCE-binding epitopes or more commonly affect G-protein-coupled receptor family conserved motifs critical for protein membrane trafficking resulting in endoplasmic reticulum GPRC5D trapping. Multiple subclones bearing distinct genomic alterations at GPRC5D locus co-emerged within individual cases, depicting their convergent evolutionary trajectories. Of note, anti-GPRC5D TCEs with varying epitope specificity, affinity and valency differentially targeted mutant subclones, underscoring their nonredundant functional roles in overcoming resistance.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"33 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968738","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 : 2026-01-15DOI: 10.1038/s41591-025-04132-5
Carlos Collet, Thabo Mahendiran, William F. Fearon, Takuya Mizukami, Daniel Munhoz, Nico H. J. Pijls, Pim A. L. Tonino, Emanuele Barbato, Zsolt Piroth, Miodrag Sreckovic, Holger Thiele, Mohamed El Farissi, Nils Witt, Gilles Rioufol, Petr Kala, Thomas Engstrøm, Kreton Mavromatis, Ole Fröbert, Peter Verlee, Stefan Brunner, Martin Mates, Nikola Jagic, Gianluca Campo, Sofie Pardaens, Kazumasa Ikeda, Tiago Veiga Pereira, Bruno R. da Costa, Stephane Fournier, Bernard De Bruyne, Peter Jüni
In patients with stable coronary artery disease (CAD), the long-term benefits of revascularization over medical therapy remain unclear. In the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 trial, patients with hemodynamically significant stenoses (fractional flow reserve (FFR) ≤ 0.80) were randomized to receive FFR-guided percutaneous coronary intervention (PCI) plus medical therapy (n = 447) or medical therapy alone (n = 441). At 5 years, FFR-guided PCI reduced the risk of the primary composite outcome of time to death, myocardial infarction or urgent revascularization, largely because of fewer urgent revascularizations. We now report the long-term clinical outcomes from this trial. Sixteen hospitals, contributing 748 randomized patients (161 women, 21.5%), participated in the long-term follow-up. The primary composite outcome was analyzed hierarchically using the unstratified win ratio, which addressed differential missingness of data on nonfatal outcomes in deceased patients by prioritizing comparisons on time to death. At a median follow-up of 11.2 years, the primary endpoint occurred in 150 of 447 patients (33.6%) in the PCI group versus 182 of 441 (41.3%) in the medical therapy group. PCI was superior in 29.2% of comparisons, medical therapy in 23.3%, and the two groups were tied in 47.5%, resulting in a win ratio of 1.25 in favor of PCI (95% confidence interval (CI) 1.01–1.56, P = 0.043). The corresponding win difference was 5.9% (95% CI 0.2–11.6), and the number needed to treat was 17 (95% CI 9–500). Win ratios were 0.88 for all-cause death (95% CI 0.66–1.17), 1.50 for myocardial infarction (95% CI 0.98–2.31) and 4.57 for urgent revascularization (95% CI 2.53–8.24). During long-term follow-up, FFR-guided PCI in patients with stable CAD and hemodynamically significant stenoses reduced the composite of death, myocardial infarction or urgent revascularization, primarily because of fewer urgent revascularizations. These long-term findings reaffirm the efficacy of FFR-guided PCI over medical therapy in patients with stable CAD. ClinicalTrials.gov registration: NCT06159231 . In a long-term follow-up of the FAME 2 trial, fractional flow reserve-guided percutaneous coronary intervention plus medical therapy in patients with stable coronary artery disease reduced cardiovascular events compared to medical therapy alone, primarily due to a decrease in urgent revascularization events.
对于稳定性冠状动脉疾病（CAD）患者，血运重建术相对于药物治疗的长期益处尚不清楚。在分数血流储备与多血管造影评估2试验中，血流动力学显著狭窄（分数血流储备(FFR)≤0.80）的患者被随机分为两组，分别接受FFR引导下的经皮冠状动脉介入治疗（PCI）加药物治疗（n = 447）或单独药物治疗（n = 441）。在5年时，ffr引导下的PCI降低了主要复合结局的风险，包括死亡时间、心肌梗死或紧急血运重建术，主要是因为紧急血运重建术较少。我们现在报告这项试验的长期临床结果。16家医院参与了长期随访，共有748名随机患者（161名女性，21.5%）。主要综合结局采用非分层胜比进行分层分析，通过优先比较死亡时间来解决死亡患者非致命结局数据的差异缺失。在11.2年的中位随访中，PCI组447例患者中有150例（33.6%）出现主要终点，而药物治疗组441例患者中有182例（41.3%）出现主要终点。PCI的优势占29.2%，药物治疗的优势占23.3%，两组的优势为47.5%，PCI的优势比为1.25（95%可信区间（CI） 1.01-1.56, P = 0.043）。相应的win差异为5.9% (95% CI 0.2-11.6)，需要治疗的人数为17人（95% CI 9-500）。全因死亡的Win比为0.88 (95% CI 0.66-1.17)，心肌梗死的Win比为1.50 (95% CI 0.98-2.31)，紧急血运重建术的Win比为4.57 （95% CI 2.53-8.24）。在长期随访中，在稳定的CAD和血流动力学显著狭窄的患者中，ffr引导下的PCI降低了死亡、心肌梗死或紧急血运重建的综合发生率，主要是因为紧急血运重建的减少。这些长期研究结果再次肯定了ffr引导下的PCI在稳定型CAD患者中优于药物治疗的疗效。ClinicalTrials.gov注册：NCT06159231。
{"title":"Fractional flow reserve-guided percutaneous coronary intervention versus medical therapy for stable coronary artery disease: long-term results of the FAME 2 trial","authors":"Carlos Collet, Thabo Mahendiran, William F. Fearon, Takuya Mizukami, Daniel Munhoz, Nico H. J. Pijls, Pim A. L. Tonino, Emanuele Barbato, Zsolt Piroth, Miodrag Sreckovic, Holger Thiele, Mohamed El Farissi, Nils Witt, Gilles Rioufol, Petr Kala, Thomas Engstrøm, Kreton Mavromatis, Ole Fröbert, Peter Verlee, Stefan Brunner, Martin Mates, Nikola Jagic, Gianluca Campo, Sofie Pardaens, Kazumasa Ikeda, Tiago Veiga Pereira, Bruno R. da Costa, Stephane Fournier, Bernard De Bruyne, Peter Jüni","doi":"10.1038/s41591-025-04132-5","DOIUrl":"10.1038/s41591-025-04132-5","url":null,"abstract":"In patients with stable coronary artery disease (CAD), the long-term benefits of revascularization over medical therapy remain unclear. In the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 trial, patients with hemodynamically significant stenoses (fractional flow reserve (FFR) ≤ 0.80) were randomized to receive FFR-guided percutaneous coronary intervention (PCI) plus medical therapy (n = 447) or medical therapy alone (n = 441). At 5 years, FFR-guided PCI reduced the risk of the primary composite outcome of time to death, myocardial infarction or urgent revascularization, largely because of fewer urgent revascularizations. We now report the long-term clinical outcomes from this trial. Sixteen hospitals, contributing 748 randomized patients (161 women, 21.5%), participated in the long-term follow-up. The primary composite outcome was analyzed hierarchically using the unstratified win ratio, which addressed differential missingness of data on nonfatal outcomes in deceased patients by prioritizing comparisons on time to death. At a median follow-up of 11.2 years, the primary endpoint occurred in 150 of 447 patients (33.6%) in the PCI group versus 182 of 441 (41.3%) in the medical therapy group. PCI was superior in 29.2% of comparisons, medical therapy in 23.3%, and the two groups were tied in 47.5%, resulting in a win ratio of 1.25 in favor of PCI (95% confidence interval (CI) 1.01–1.56, P = 0.043). The corresponding win difference was 5.9% (95% CI 0.2–11.6), and the number needed to treat was 17 (95% CI 9–500). Win ratios were 0.88 for all-cause death (95% CI 0.66–1.17), 1.50 for myocardial infarction (95% CI 0.98–2.31) and 4.57 for urgent revascularization (95% CI 2.53–8.24). During long-term follow-up, FFR-guided PCI in patients with stable CAD and hemodynamically significant stenoses reduced the composite of death, myocardial infarction or urgent revascularization, primarily because of fewer urgent revascularizations. These long-term findings reaffirm the efficacy of FFR-guided PCI over medical therapy in patients with stable CAD. ClinicalTrials.gov registration: NCT06159231 . In a long-term follow-up of the FAME 2 trial, fractional flow reserve-guided percutaneous coronary intervention plus medical therapy in patients with stable coronary artery disease reduced cardiovascular events compared to medical therapy alone, primarily due to a decrease in urgent revascularization events.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":"318-324"},"PeriodicalIF":50.0,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968735","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 : 2026-01-15DOI: 10.1038/s41591-025-04138-z
Joseph Donovan, Nguyen Duc Bang, Huu Khanh Trinh Dong, Dang Trung Nghia Ho, Thi Anh Thu Nguyen, Thi Thu Hiep Nguyen, Hong Bao Ngoc Lam, Vo Khac Nguyen Phung, Truc Thanh Nguyen, Ho Hong Hanh Nguyen, Kieu Nguyet Oanh Pham, Dang Anh Thu Do, Thi Mai Trang Nguyen, Thi Minh Ha Dang, Huu Lan Nguyen, Van Vinh Chau Nguyen, Thanh Hai Hoang, Dinh Dinh Tran, Khanh Lam Phung, Lalita Ramakrishnan, Thanh Hoang Nhat Le, Thuy Thuong Thuong Nguyen, Marcel Wolbers, Evelyne Kestelyn, Ronald B. Geskus, Hoan Phu Nguyen, Guy E. Thwaites
Adjunctive corticosteroids such as dexamethasone are recommended in tuberculous meningitis treatment, despite modest and heterogeneous survival benefit. Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes. Here, in a phase 3, placebo-controlled trial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6–8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratio margin of 0.75) or its superiority. Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized. A total of 89 TT-genotype participants received open-label dexamethasone. In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratio of 0.99, 96% confidence interval (adjusted for multiple testing) 0.748–1.31). The number of observed primary endpoints (n = 218) exceeded the prespecified number (n = 184) used to calculate the trial’s sample size and power. Placebo noninferiority was not established in the CC and CT population or in individual genotype subpopulations. Benefit or heterogeneity of effect was not observed by any prespecified subgroup. In TT-genotype participants, the primary endpoint occurred in 28/89 (31.5%) participants, similar to CC and CT participants. Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants. In CC- and CT-genotype participants, serious adverse events occurred in 161/305 (52.8%) dexamethasone-treated participants and 160/308 (51.9%) placebo-treated participants. In conclusion, neither noninferiority nor superiority of placebo was established in human immunodeficiency virus-negative LTA4H CC- and CT-genotype adults with tuberculous meningitis, and dexamethasone was safe. The modest and heterogeneous benefit of dexamethasone indicates that greater understanding of tuberculous meningitis pathophysiology is needed, alongside better targeted, more effective anti-inflammatory agents than corticosteroids (ClinicalTrials.gov NCT03100786).
{"title":"Genotype-stratified adjunctive dexamethasone for tuberculous meningitis in HIV-negative adults: a randomized controlled phase 3 trial","authors":"Joseph Donovan, Nguyen Duc Bang, Huu Khanh Trinh Dong, Dang Trung Nghia Ho, Thi Anh Thu Nguyen, Thi Thu Hiep Nguyen, Hong Bao Ngoc Lam, Vo Khac Nguyen Phung, Truc Thanh Nguyen, Ho Hong Hanh Nguyen, Kieu Nguyet Oanh Pham, Dang Anh Thu Do, Thi Mai Trang Nguyen, Thi Minh Ha Dang, Huu Lan Nguyen, Van Vinh Chau Nguyen, Thanh Hai Hoang, Dinh Dinh Tran, Khanh Lam Phung, Lalita Ramakrishnan, Thanh Hoang Nhat Le, Thuy Thuong Thuong Nguyen, Marcel Wolbers, Evelyne Kestelyn, Ronald B. Geskus, Hoan Phu Nguyen, Guy E. Thwaites","doi":"10.1038/s41591-025-04138-z","DOIUrl":"https://doi.org/10.1038/s41591-025-04138-z","url":null,"abstract":"Adjunctive corticosteroids such as dexamethasone are recommended in tuberculous meningitis treatment, despite modest and heterogeneous survival benefit. Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes. Here, in a phase 3, placebo-controlled trial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6–8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratio margin of 0.75) or its superiority. Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized. A total of 89 TT-genotype participants received open-label dexamethasone. In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4%) given dexamethasone and 110/308 (35.7%) given placebo (hazard ratio of 0.99, 96% confidence interval (adjusted for multiple testing) 0.748–1.31). The number of observed primary endpoints (n = 218) exceeded the prespecified number (n = 184) used to calculate the trial’s sample size and power. Placebo noninferiority was not established in the CC and CT population or in individual genotype subpopulations. Benefit or heterogeneity of effect was not observed by any prespecified subgroup. In TT-genotype participants, the primary endpoint occurred in 28/89 (31.5%) participants, similar to CC and CT participants. Outcomes were not significantly better in TT-genotype participants versus CC- or CT-genotype participants. In CC- and CT-genotype participants, serious adverse events occurred in 161/305 (52.8%) dexamethasone-treated participants and 160/308 (51.9%) placebo-treated participants. In conclusion, neither noninferiority nor superiority of placebo was established in human immunodeficiency virus-negative LTA4H CC- and CT-genotype adults with tuberculous meningitis, and dexamethasone was safe. The modest and heterogeneous benefit of dexamethasone indicates that greater understanding of tuberculous meningitis pathophysiology is needed, alongside better targeted, more effective anti-inflammatory agents than corticosteroids (ClinicalTrials.gov NCT03100786).","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"5 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968733","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 : 2026-01-14DOI: 10.1038/s41591-025-04105-8
Jun Li,Jie Hu,Huan Yun,Zhendong Mei,Xingyan Wang,Kai Luo,Marta Guasch-Ferré,Xikun Han,Buu Truong,Jordi Merino,Chengyong Jia,Miguel Ruiz-Canela,Casey M Rebholz,Eun Hye Moon,Taryn Alkis,Guning Liu,Jie Yao,Xiyuan Zhang,Bianca C Porneala,Jordi Salas-Salvadó,Thomas J Wang,Josée Dupuis,Elizabeth Selvin,Xiuqing Guo,Shilpa N Bhupathiraju,Jennifer A Brody,Yongmei Liu,Alexis C Wood,Kari E North,Su Yon Jung,Ching-Ti Liu,Nona Sotoodehnia,Simin Liu,Lesley F Tinker,A Heather Eliassen,JoAnn E Manson,Jose C Florez,Robert E Gerszten,Clary B Clish,Liming Liang,Rozenn N Lemaitre,Katherine L Tucker,Stephen S Rich,Jerome I Rotter,Miguel Angel Martínez-González,Kathryn M Rexrode,James B Meigs,Eric Boerwinkle,Robert C Kaplan,Frank B Hu,Bing Yu,Qibin Qi
The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.
{"title":"Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.","authors":"Jun Li,Jie Hu,Huan Yun,Zhendong Mei,Xingyan Wang,Kai Luo,Marta Guasch-Ferré,Xikun Han,Buu Truong,Jordi Merino,Chengyong Jia,Miguel Ruiz-Canela,Casey M Rebholz,Eun Hye Moon,Taryn Alkis,Guning Liu,Jie Yao,Xiyuan Zhang,Bianca C Porneala,Jordi Salas-Salvadó,Thomas J Wang,Josée Dupuis,Elizabeth Selvin,Xiuqing Guo,Shilpa N Bhupathiraju,Jennifer A Brody,Yongmei Liu,Alexis C Wood,Kari E North,Su Yon Jung,Ching-Ti Liu,Nona Sotoodehnia,Simin Liu,Lesley F Tinker,A Heather Eliassen,JoAnn E Manson,Jose C Florez,Robert E Gerszten,Clary B Clish,Liming Liang,Rozenn N Lemaitre,Katherine L Tucker,Stephen S Rich,Jerome I Rotter,Miguel Angel Martínez-González,Kathryn M Rexrode,James B Meigs,Eric Boerwinkle,Robert C Kaplan,Frank B Hu,Bing Yu,Qibin Qi","doi":"10.1038/s41591-025-04105-8","DOIUrl":"https://doi.org/10.1038/s41591-025-04105-8","url":null,"abstract":"The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"81 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968616","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 : 2026-01-14DOI: 10.1038/d41591-026-00003-9
Karen O'Leary
{"title":"Mpox infection in pregnancy linked to high risk of adverse outcomes.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00003-9","DOIUrl":"https://doi.org/10.1038/d41591-026-00003-9","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"20 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971813","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 : 2026-01-13DOI: 10.1038/s41591-025-04157-w
Timothy A. Yap, Randy F. Sweis, Ulka Vaishampayan, Deepak Kilari, Justin F. Gainor, Meredith McKean, Minal Barve, Ahmad A. Tarhini, Bruno Bockorny, Guru Sonpavde, David Park, Sunil Babu, Yawen Ju, Lan Liu, Susan Henry, Giridhar S. Tirucherai, Stephen DeWall, Mohammed Qatanani, Jing L. Marantz, Lu Gan
Although immune checkpoint inhibitor therapies have revolutionized oncology, many cancers are unresponsive or develop resistance that involves transforming growth factor-β1 (TGFβ1). This multicenter, open-label, phase 1 study (DRAGON trial, SRK-181-001) evaluated safety, pharmacokinetics, pharmacodynamics, predictive biomarkers and efficacy of linavonkibart, a first-in-class fully human selective anti-latent TGFβ1 antibody with anti-programmed cell death protein 1 (PD-1) therapy. The DRAGON trial was divided into three treatment parts: part A1 (dose-escalation cohorts with single-agent linavonkibart), part A2 (dose-escalation cohorts with the combination treatment of linavonkibart and pembrolizumab) and part B (dose-expansion cohorts with the combination treatment). The primary objective of the study was to determine the safety and tolerability of linavonkibart alone and in combination with pembrolizumab. Secondary objectives included evaluation of linavonkibart pharmacokinetics for each treatment paradigm, assessment of anti-linavonkibart antibody development (parts A and B) and measurement of antitumor activity (part B) after treatment. All primary and secondary objectives were met in the study. Overall, linavonkibart had a manageable safety profile, and combined therapy with pembrolizumab was generally consistent with that of pembrolizumab monotherapy. Dermatological reactions were the only additional risk identified. Neither cytokine release syndrome nor infusion interruption was observed in any patient enrolled in DRAGON. In part A (n = 34), no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred (linavonkibart; ≤3,000 mg once every 3 weeks (Q3W) and 2,000 mg once every 2 weeks (Q2W)). In part B (n = 78), patients progressing on prior anti-PD-1 therapy received linavonkibart (1,500 mg Q3W/1,000 mg Q2W) with pembrolizumab (200 mg Q3W). This combination demonstrated confirmed objective response rates of 20.0%, 18.2%, 9.1% and 9.1% in anti-PD-1-resistant patients with clear cell renal cell cancer (ccRCC), melanoma, head and neck squamous cell cancer and urothelial cancer, respectively. Biomarker data provide proof of mechanism and a potential ccRCC patient selection strategy. ClinicalTrials.gov identifier: NCT04291079.
{"title":"Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial","authors":"Timothy A. Yap, Randy F. Sweis, Ulka Vaishampayan, Deepak Kilari, Justin F. Gainor, Meredith McKean, Minal Barve, Ahmad A. Tarhini, Bruno Bockorny, Guru Sonpavde, David Park, Sunil Babu, Yawen Ju, Lan Liu, Susan Henry, Giridhar S. Tirucherai, Stephen DeWall, Mohammed Qatanani, Jing L. Marantz, Lu Gan","doi":"10.1038/s41591-025-04157-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04157-w","url":null,"abstract":"Although immune checkpoint inhibitor therapies have revolutionized oncology, many cancers are unresponsive or develop resistance that involves transforming growth factor-β1 (TGFβ1). This multicenter, open-label, phase 1 study (DRAGON trial, SRK-181-001) evaluated safety, pharmacokinetics, pharmacodynamics, predictive biomarkers and efficacy of linavonkibart, a first-in-class fully human selective anti-latent TGFβ1 antibody with anti-programmed cell death protein 1 (PD-1) therapy. The DRAGON trial was divided into three treatment parts: part A1 (dose-escalation cohorts with single-agent linavonkibart), part A2 (dose-escalation cohorts with the combination treatment of linavonkibart and pembrolizumab) and part B (dose-expansion cohorts with the combination treatment). The primary objective of the study was to determine the safety and tolerability of linavonkibart alone and in combination with pembrolizumab. Secondary objectives included evaluation of linavonkibart pharmacokinetics for each treatment paradigm, assessment of anti-linavonkibart antibody development (parts A and B) and measurement of antitumor activity (part B) after treatment. All primary and secondary objectives were met in the study. Overall, linavonkibart had a manageable safety profile, and combined therapy with pembrolizumab was generally consistent with that of pembrolizumab monotherapy. Dermatological reactions were the only additional risk identified. Neither cytokine release syndrome nor infusion interruption was observed in any patient enrolled in DRAGON. In part A (n = 34), no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred (linavonkibart; ≤3,000 mg once every 3 weeks (Q3W) and 2,000 mg once every 2 weeks (Q2W)). In part B (n = 78), patients progressing on prior anti-PD-1 therapy received linavonkibart (1,500 mg Q3W/1,000 mg Q2W) with pembrolizumab (200 mg Q3W). This combination demonstrated confirmed objective response rates of 20.0%, 18.2%, 9.1% and 9.1% in anti-PD-1-resistant patients with clear cell renal cell cancer (ccRCC), melanoma, head and neck squamous cell cancer and urothelial cancer, respectively. Biomarker data provide proof of mechanism and a potential ccRCC patient selection strategy. ClinicalTrials.gov identifier: NCT04291079.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"57 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956265","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 : 2026-01-13DOI: 10.1038/s41591-025-04173-w
C. Kulkarni, T. Fardeen, J. Gubatan, J. Ye, K. Jarr, E. Dickson, H. Jang, M. Temby, A. Patel, Y. Jiang, G. Singh, K. Keyashian, S. Streett, E. Ho, G. Barber, S. Singh, D. Limsui, N. Anaizi, L. Becker, S. P. Spencer, D. Mehrish, D. Perelman, V. D. Longo, V. Charu, J. F. Ashouri, M. M. Davis, A. Habtezion, J. L. Sonnenburg, C. Gardner, S. R. Sinha
In healthy individuals, short cycles of a fasting-mimicking diet (FMD) decrease systemic inflammatory markers and improve metabolic health. Potential benefits of FMD have not been investigated in Crohn’s disease (CD). We conducted an open-label, randomized, controlled trial to assess the effects of FMD in adults with mild-to-moderate CD. Patients in the FMD group followed an FMD for five consecutive days per month for three consecutive months, returning to their regular baseline diet on non-FMD days. Control participants continued their baseline diet. The primary outcome of clinical response was a reduction in CD Activity Index (CDAI) of at least 70 points or CDAI of ≤150 after the third 5-day diet cycle. Forty-five patients in the FMD group (69.2%) and 14 patients in the control group (43.8%) met the primary outcome of clinical response (P = 0.03). Forty-two patients in the FMD group (64.6%) and 12 patients in the control group (37.5%) achieved the secondary outcome of clinical remission (P = 0.02). There was also a decline from baseline in fecal calprotectin (an inflammatory marker) in the FMD group compared with the control group (−22.0% versus 8.0%, P = 0.03). Exploratory analyses of plasma metabolites and peripheral blood mononuclear cell gene expression revealed post-FMD decreases in key inflammatory lipid mediators and immune-effector transcripts, concordant with reduced CD activity. Together, these findings demonstrate that FMD is superior to a baseline diet for inducing clinical response, clinical remission and biochemical improvement in mild-to-moderate CD, and support further investigation of FMD as an adjunctive therapy for chronic inflammatory diseases. ClinicalTrials.gov registration: NCT04147585.
{"title":"A fasting-mimicking diet in patients with mild-to-moderate Crohn’s disease: a randomized controlled trial","authors":"C. Kulkarni, T. Fardeen, J. Gubatan, J. Ye, K. Jarr, E. Dickson, H. Jang, M. Temby, A. Patel, Y. Jiang, G. Singh, K. Keyashian, S. Streett, E. Ho, G. Barber, S. Singh, D. Limsui, N. Anaizi, L. Becker, S. P. Spencer, D. Mehrish, D. Perelman, V. D. Longo, V. Charu, J. F. Ashouri, M. M. Davis, A. Habtezion, J. L. Sonnenburg, C. Gardner, S. R. Sinha","doi":"10.1038/s41591-025-04173-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04173-w","url":null,"abstract":"In healthy individuals, short cycles of a fasting-mimicking diet (FMD) decrease systemic inflammatory markers and improve metabolic health. Potential benefits of FMD have not been investigated in Crohn’s disease (CD). We conducted an open-label, randomized, controlled trial to assess the effects of FMD in adults with mild-to-moderate CD. Patients in the FMD group followed an FMD for five consecutive days per month for three consecutive months, returning to their regular baseline diet on non-FMD days. Control participants continued their baseline diet. The primary outcome of clinical response was a reduction in CD Activity Index (CDAI) of at least 70 points or CDAI of ≤150 after the third 5-day diet cycle. Forty-five patients in the FMD group (69.2%) and 14 patients in the control group (43.8%) met the primary outcome of clinical response (P = 0.03). Forty-two patients in the FMD group (64.6%) and 12 patients in the control group (37.5%) achieved the secondary outcome of clinical remission (P = 0.02). There was also a decline from baseline in fecal calprotectin (an inflammatory marker) in the FMD group compared with the control group (−22.0% versus 8.0%, P = 0.03). Exploratory analyses of plasma metabolites and peripheral blood mononuclear cell gene expression revealed post-FMD decreases in key inflammatory lipid mediators and immune-effector transcripts, concordant with reduced CD activity. Together, these findings demonstrate that FMD is superior to a baseline diet for inducing clinical response, clinical remission and biochemical improvement in mild-to-moderate CD, and support further investigation of FMD as an adjunctive therapy for chronic inflammatory diseases. ClinicalTrials.gov registration: NCT04147585.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"34 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956264","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 : 2026-01-13DOI: 10.1038/s41591-025-04164-x
Brendan M. Crowley, Helena I. Boshoff, Aidan Boving, Vee Y. Tan, Jianghai Zhu, Forrest Hoyt, Randy R. Miller, Julie Ehrhart, Christopher W. Boyce, Katherine Young, Philippe G. Nantermet, Jing Su, Lihu Yang, Ronald E. Painter, Emily B. Corcoran, Jason L. Hoar, Sangmi Oh, David L. Holtzman, Micha Levi, Aparna Anderson, Monicah A. Otieno, Matthew Zimmerman, Firat Kaya, Lisa M. Massoudi, Michelle E. Ramey, Allison A. Bauman, Anne J. Lenaerts, Gregory T. Roberston, Véronique Dartois, Charles D. Wells, Clifton E. Barry III, David B. Olsen
Linezolid, an oxazolidinone, is a cornerstone of treatment regimens for highly drug-resistant tuberculosis but cannot be used in drug-susceptible disease because of toxicity. This toxicity results from inhibition of mammalian mitochondrial protein synthesis. Here we show the development of a new oxazolidinone, MK-7762, with antitubercular activity that is better than linezolid and limited mitochondrial protein synthesis inhibition. The cryogenic electron microscopy structure of the stalled mycobacterial ribosome with MK-7762 revealed the basis for this selectivity. BALB/c mouse models of disease showed MK-7762 reduced lung bacterial burden by a 3-log-fold decrease in an acute model (N = 18) and a 2-log-fold decrease in chronically infected animals (N = 18). MK-7762 showed lesion penetration similar to linezolid in C3HeB/FeJ mice. MK-7762 had pharmacokinetic properties predicting low once-daily doses in humans and a favorable 14-day preclinical safety profile in Wistar Han rats (N = 30) and Beagle dogs (N = 6). Four-month safety studies in both rats (N = 20) and dogs (N = 24) showed no changes in hematology parameters at exposures well above the 100-mg predicted human dose. These data will enable MK-7762 to be explored as a component of new tuberculosis treatment combinations for all forms of the disease.
{"title":"Discovery and development of a new oxazolidinone with reduced toxicity for the treatment of tuberculosis","authors":"Brendan M. Crowley, Helena I. Boshoff, Aidan Boving, Vee Y. Tan, Jianghai Zhu, Forrest Hoyt, Randy R. Miller, Julie Ehrhart, Christopher W. Boyce, Katherine Young, Philippe G. Nantermet, Jing Su, Lihu Yang, Ronald E. Painter, Emily B. Corcoran, Jason L. Hoar, Sangmi Oh, David L. Holtzman, Micha Levi, Aparna Anderson, Monicah A. Otieno, Matthew Zimmerman, Firat Kaya, Lisa M. Massoudi, Michelle E. Ramey, Allison A. Bauman, Anne J. Lenaerts, Gregory T. Roberston, Véronique Dartois, Charles D. Wells, Clifton E. Barry III, David B. Olsen","doi":"10.1038/s41591-025-04164-x","DOIUrl":"https://doi.org/10.1038/s41591-025-04164-x","url":null,"abstract":"Linezolid, an oxazolidinone, is a cornerstone of treatment regimens for highly drug-resistant tuberculosis but cannot be used in drug-susceptible disease because of toxicity. This toxicity results from inhibition of mammalian mitochondrial protein synthesis. Here we show the development of a new oxazolidinone, MK-7762, with antitubercular activity that is better than linezolid and limited mitochondrial protein synthesis inhibition. The cryogenic electron microscopy structure of the stalled mycobacterial ribosome with MK-7762 revealed the basis for this selectivity. BALB/c mouse models of disease showed MK-7762 reduced lung bacterial burden by a 3-log-fold decrease in an acute model (N = 18) and a 2-log-fold decrease in chronically infected animals (N = 18). MK-7762 showed lesion penetration similar to linezolid in C3HeB/FeJ mice. MK-7762 had pharmacokinetic properties predicting low once-daily doses in humans and a favorable 14-day preclinical safety profile in Wistar Han rats (N = 30) and Beagle dogs (N = 6). Four-month safety studies in both rats (N = 20) and dogs (N = 24) showed no changes in hematology parameters at exposures well above the 100-mg predicted human dose. These data will enable MK-7762 to be explored as a component of new tuberculosis treatment combinations for all forms of the disease.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"10 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956356","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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