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Nature Medicine · Dec 01, 2025

Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer’s disease syndrome. ‘Evaluating liraglutide in Alzheimer’s disease’ (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer’s disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = −0.17; 95% confidence interval: −0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome—score on the Alzheimer’s Disease Assessment Scale-Executive domain (ADAS-Exec)—performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03−0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (−0.58; 95% confidence interval: −3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (−0.06; 95% confidence interval: −0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer’s disease. ClinicalTrials.gov identifier: NCT01843075 . Results from the phase ELAD 2 trial reveal that liraglutide is safe and well tolerated in people with mild to moderate Alzheimer’s disease but does not significantly slow brain metabolism decline.

Alzheimer's disease Cell death in the nervous system biology
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Nature Medicine · Nov 28, 2025

Targeting of HIF2-driven cachexia in kidney cancer

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show thatPTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increasedPTHLHexpression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.

Cancer metabolism Renal cancer Targeted therapies biology mouse experiments
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Nature Medicine · Nov 24, 2025

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting children and young adults that is driven by a chimeric protein, DNAJ-PKAc. The development of molecular inhibitors of DNAJ-PKAc has been hampered by unacceptable on-target toxicity, but the chimera results in a tumor-specific antigen (neoantigen) that may be targeted immunologically. Here we conducted a phase 1 clinical trial of a therapeutic peptide vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC, who had not previously received immune checkpoint therapy. The primary objectives were safety and T cell responses after week 10 (priming phase). Of the 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. The median age was 24 years (range 12–47 years). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from which we identified multiple class-II-restricted T cell receptors with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in T cell receptor repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or human leukocyte antigen loss. Our findings demonstrate the potential for therapeutic vaccines targeting ‘undruggable’ oncogenic drivers and suggest a rubric for evaluating effective anti-neoantigen immunity. ClinicalTrials.gov identifier:NCT04248569.

Cancer immunotherapy Immunology biology
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Nature Medicine · Nov 20, 2025

Factor IX-Padua AAV gene therapy in hemophilia B: phases 1/2 and 3 trials

Gene therapy for hemophilia B with adeno-associated virus (AAV) vector has achieved great advances over the last decade. We previously conducted a pilot study demonstrating the safety and efficacy of AAV-factor IX (FIX) Padua gene therapy (BBM-H901) in ten male participants with hemophilia B. Here we report a single-arm dose-escalation phase 1/2 trial in 6 male participants and a multicentre phase 3 trial in 26 participants with hemophilia B in China. The phase 1/2 study tested a dose of 5 × 1012vg kg−1(n= 6), with primary endpoints assessing dose-limiting toxicities (DLT) and adverse events (AEs). The primary endpoint was met with no DLT observed in the 10 weeks postinfusion. The most common drug-related AEs were transaminitis (33.3%), and no grade 3 drug-related AE occurred within 52 weeks postintervention. The phase 3 study tested the 5 × 1012vg kg−1dose, as determined in the phase 1/2 study, in 26 patients. The primary endpoint evaluated the annualized bleeding rate (ABR) after gene therapy and secondary endpoints included vector-derived FIX:C, target joint and percentage of participants with zero bleeds postgene therapy. The study met its primary endpoint as the mean (95% confidence interval (CI)) ABR within 52 weeks after BBM-H901 infusion decreased to 0.60 (0.18–1.99), and the upper limit of the 95% CI (1.99) was lower than the predefined superiority margin of 5.0 (historical ABR assumed for patients receiving prophylactic FIX treatment in China). In the phase 3 trial, the most common drug-related AEs were transaminitis as well, and the vector-derived FIX:C had a mean of 41.9 (28.7) IU dl−1at week 52. None of the participants had a target joint, and 80.8% of participants experienced zero bleeds during the 52-week follow-up. Our study supports the safety and efficacy of AAV-FIX Padua gene therapy in a large Chinese cohort. ClinicalTrials.gov registration:NCT05203679.

Drug development Haematological diseases biology
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Nature Medicine · Nov 17, 2025

Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide

Obesity and related conditions are associated with distressing food preoccupation that often culminates in dysregulated eating behaviors. Incretin-based therapies can reduce excessive weight in obesity, but their impact on dysregulated eating behaviors remains largely unexamined. Understanding how these pharmacologics engage the brain’s mesolimbic circuitry may inform the expansion of their therapeutic potential. We report a rare, first-in-human exploration of the physiological action of these therapies by examining the electrophysiology directly within the human nucleus accumbens. After a short-term course of tirzepatide, the patient-participant exhibited increased severe food preoccupation episodes, which were preceded by an increased delta–theta frequency (≤7 Hz) power in the nucleus accumbens region. We propose that the effects of an incretin-based therapy (tirzepatide) on food preoccupation may be associated with modulation of aberrant activity within this key hub of human mesolimbic circuitry.

Biomarkers Obesity Psychiatric disorders Reward biology
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Nature Medicine · Nov 14, 2025

Microbial signals in primary and metastatic brain tumors

Gliomas and brain metastases are associated with poor prognosis, necessitating a deeper understanding of brain tumor biology and the development of effective therapeutic strategies. Although our group and others have demonstrated microbial presence in various tumors, recent controversies regarding cancer-type-specific intratumoral microbiota emphasize the importance of rigorous, orthogonal validation. This prospective, multi-institutional study included a total of 243 samples from 221 patients, comprising 168 glioma and brain metastases samples and 75 non-cancerous or tumor-adjacent tissues. Using stringent fluorescence in situ hybridization, immunohistochemistry and high-resolution spatial imaging, we detected intracellular bacterial 16S rRNA and lipopolysaccharides in both glioma and brain metastases samples, localized to tumor, immune and stromal cells. Custom 16S and metagenomic sequencing workflows identified taxa associated with intratumoral bacterial signals in the tumor microenvironment; however, standard culture methods did not yield readily cultivable microbiota. Spatial analyses revealed significant correlations between bacterial 16S signals and antimicrobial and immunometabolic signatures at regional, neighborhood and cellular levels. Furthermore, intratumoral 16S bacterial signals showed sequence overlap with matched oral and gut microbiota, suggesting a possible connection with distant communities. Together, these findings introduce microbial elements as a component of the brain tumor microenvironment and lay the foundation for future mechanistic and translational studies.

Bacterial host response CNS cancer biology
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Nature Medicine · Nov 10, 2025

Endotyping-informed therapy for patients with chest pain and no obstructive coronary artery disease: a randomized trial

Patients undergoing invasive coronary angiography for the investigation of chest pain commonly do not have obstructive coronary artery disease. In contemporary practice, most of these individuals do not undergo functional diagnostic tests, leaving the cause of the chest pain uncertain. Stress cardiovascular magnetic resonance imaging (MRI) can be used to measure myocardial blood flow, detect coronary microvascular dysfunction and endotype individual patients, but evidence of clinical utility from randomized trials is lacking. This study was a prospective, multicenter, parallel group, 1:1 randomized, controlled superiority trial of adenosine stress cardiovascular MRI-guided management in 250 patients (mean age, 63.3 years; 50.4% female) with chest pain and unobstructed coronary arteries. The primary outcome of the diagnostic study, defined as the reclassification of the initial diagnosis based on the angiogram, occurred in 131 patients (53.0% (95% confidence interval: 46.6−59.3%);P< 0.001), indicating that the primary outcome for the diagnostic study was met. The primary outcome of the randomized trial was the Seattle Angina Questionnaire (SAQ) summary score at 12 months after randomization. The mean ± s.d. SAQ summary scores at 12 months in the intervention and control groups were 70.9 ± 23.6 (21.7 ± 22.6 change from baseline) and 52.1 ± 24.1 (−0.8 ± 20.4 change from baseline) (adjusted mean difference: 20.9 (95% confidence interval: 15.8–26.0)), respectively, indicating that the primary outcome of the randomized trial was met. Improvements were also observed in the prespecified secondary outcome of the EQ-5D-5L questionnaire at 12 months (adjusted mean difference 0.09 (95% confidence interval: 0.04−0.13)). In this study of patients with chest pain and unobstructed coronary arteries, endotyping-informed therapy revised the diagnosis in more than half of the participants and improved angina and health-related quality of life. ClinicalTrials.gov identifier:NCT04805814.

Chronic pain Ischaemia Randomized controlled trials Clinical Cardiology MRI Human
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Nature Medicine · Nov 09, 2025

Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice

Cardiovascular outcome trials of the incretin-based medicines tirzepatide and semaglutide have shown benefits in populations with varying levels of cardiovascular risk. However, without direct head-to-head comparisons, treatment decisions rely on indirect evidence from heterogeneous trial populations, leaving optimal treatment choices uncertain. We therefore conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in United States between 2018 and 2025. First, we emulated two cardiovascular outcome trials, SUSTAIN-6 (semaglutide versus sitagliptin as placebo proxy) and SURPASS-CVOT (tirzepatide versus dulaglutide), to benchmark and critically evaluate our design, data, and analytic framework. Second, we assessed each drug in expanded populations reflective of patients routinely seen in clinical practice. Third, we directly compared tirzepatide versus semaglutide. Baseline confounders were balanced using propensity score matching. For the primary composite end point of myocardial infarction, stroke, or all-cause mortality, benchmarking identified high agreement between the reference trials and their emulations for all individual end points except for all-cause mortality in SUSTAIN-6, informing subsequent analyses. In expanded populations, comparing semaglutide versus sitagliptin for the composite outcome of myocardial infarction or stroke yielded a hazard ratio of 0.82 (95% CI, 0.74 to 0.91), and comparing tirzepatide versus dulaglutide for the composite outcome including mortality yielded a hazard ratio of 0.87 (0.75 to 1.01). In the head-to-head comparison of tirzepatide versus semaglutide, the hazard ratio was 1.06 (0.95 to 1.18). These findings support a comparable cardiovascular benefit of tirzepatide and semaglutide in clinical practice and demonstrate how rigorously designed real-world evidence can complement randomized clinical trials.

Cardiovascular diseases Epidemiology Outcomes research Randomized controlled trials other
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Nature Medicine · Nov 07, 2025

Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

Functional cure is a goal for the treatment of chronic hepatitis B virus (HBV) infection; however, it is infrequently achieved with currently approved treatments. Here we provide a randomized evaluation of the small interfering RNA elebsiran, in combination with pegylated interferon alfa (PEG-IFNα), compared with PEG-IFNα monotherapy. In addition, this study evaluates the potential role of the HBV therapeutic vaccine BRII-179 in identifying immunologically responsive patients and improving hepatitis B surface antigen (HBsAg) loss rates. In part I (cohorts 1–3), virally suppressed participants with chronic HBV infection naive to BRII-179 were randomized 1:1:1 to receive 48 weekly doses of PEG-IFNα alone or in combination with 13 doses of elebsiran (200 mg or 100 mg) administered every 4 weeks. In part II (cohort 4), participants who had previously received 9 doses of elebsiran and BRII-179 in a prospective study (BRII-179-835-001) were categorized as BRII-179 anti-HBs responders or nonresponders based on their peak hepatitis B surface antibody (anti-HBs) levels (≥10 IU l−1or <10 IU l−1, respectively) and subsequently received 13 doses of elebsiran 100 mg every 4 weeks plus 48 weekly doses of PEG-IFNα. Primary endpoints were HBsAg loss at the end of treatment (EOT) and 24 weeks post-EOT. In part I, at 24 weeks post-EOT, HBsAg loss was observed in 4 out of 19 (21.1%) participants receiving elebsiran 200 mg plus PEG-IFNα, 6 out of 18 (33.3%) participants receiving elebsiran 100 mg plus PEG-IFNα and 1 out of 18 (5.6%) participants receiving PEG-IFNα monotherapy. In part II, HBsAg loss was observed in 9 out of 31 (29.0%) participants at 24 weeks post-EOT, with a higher response among BRII-179 anti-HBs responders (8 out of 19 participants, 42.1%) compared with nonresponders (1 out of 12 participants, 8.3%). Elebsiran and PEG-IFNα combination therapy was generally safe and well tolerated. These results demonstrate an additive benefit of elebsiran when combined with PEG-IFNα in achieving sustained HBsAg loss. Furthermore, the increased HBsAg loss rate in BRII-179 anti-HBs responders suggests that BRII-179 may be a valuable tool for immunological profiling to optimize curative outcomes in patients with HBV infection. ClinicalTrials.gov registration:NCT05970289.

Hepatitis B Phase II trials biology
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Nature Medicine · Nov 06, 2025

A meta-analysis of albuminuria as a surrogate endpoint for kidney failure

Albuminuria is a central biomarker in chronic kidney disease (CKD), used for the detection and prognosis of the disease. In clinical trials assessing CKD progression, change in the level of albuminuria is a candidate surrogate endpoint for kidney failure. Evaluation of the validity of this surrogate endpoint across a diverse range of interventions and populations is required to support its further acceptance. Here, in an individual participant data analysis of 48 randomized controlled trials (studies) involving 85,681 participants, we assessed the association between treatment effects on 6-month urinary albumin:creatinine ratio (UACR) change and the established clinical endpoint of kidney failure or doubling of serum creatinine concentrations. Across all trials, each 30% reduction in the geometric mean of the UACR in the treatment group relative to the control group was associated with an average of 19% lower hazard for the clinical endpoint (95% Bayesian credible interval (BCI): 5−30%); median coefficient of determination (R2) = 0.66 (95% BCI: 0.06−0.98). There was no clear evidence that this association varied by CKD etiology. These results provide further support for use of albuminuria change as a surrogate endpoint in CKD clinical trials.

Chronic kidney disease Predictive markers biology