BackgroundDravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known.MethodsWe enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1–2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (≤45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated.ResultsA total of 81 patients were enrolled in the phase 1–2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post–lumbar puncture syndrome (in 25% of patients) in the phase 1–2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1–2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from −58.82% to −90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies.ConclusionsThe safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome. (Supported by Stoke Therapeutics; MONARCH and SWALLOWTAIL ClinicalTrials.gov numbers, NCT04442295 and NCT04740476, respectively; ADMIRAL and LONGWING ISRCTN Registry numbers, ISRCTN99651026 and ISRCTN12811235, respectively.)

BackgroundNo neoadjuvant treatment has been considered to be standard therapy for patients with resectable intrahepatic cholangiocarcinoma with high-risk factors for recurrence. The GOLP regimen (gemcitabine–oxaliplatin, lenvatinib, and an anti–programmed death 1 antibody) has shown promising efficacy with a manageable safety profile in advanced intrahepatic cholangiocarcinoma and biliary tract cancer.MethodsIn a phase 2–3 trial, we randomly assigned, in a 1:1 ratio, patients with resectable high-risk intrahepatic cholangiocarcinoma to the neoadjuvant group (intravenous gemcitabine–oxaliplatin plus toripalimab every 3 weeks for three cycles and oral lenvatinib once daily for 9 weeks, followed by curative resection) or the control group (curative resection and no neoadjuvant treatment). All patients received adjuvant capecitabine for eight cycles after surgery. The primary end point was event-free survival. Secondary end points included overall survival and safety.ResultsA total of 178 patients underwent randomization (88 patients to the neoadjuvant group and 90 to the control group). At the interim analysis at a median follow-up of 16.9 months, the median event-free survival was significantly longer in the neoadjuvant group (18.0 months; 95% confidence interval [CI], 13.8 to 27.6) than in the control group (8.7 months; 95% CI, 7.2 to 12.4) (P<0.001). Overall survival at 24 months was 79% (95% CI, 70 to 90) in the neoadjuvant group and 61% (95% CI, 50 to 75) in the control group (hazard ratio for death, 0.43; 95% CI, 0.23 to 0.79; P=0.005, which did not meet the significance criterion [two-sided alpha, 0.0019]). Across all treatment phases, adverse events occurred in 97% of the patients in the neoadjuvant group and in 70% of those in the control group. During the neoadjuvant phase, adverse events of grade 3 or higher occurred in 28% of the patients, and treatment-related adverse events of grade 3 or higher in 26%. No treatment-related adverse event led to death.ConclusionsNeoadjuvant GOLP led to significantly longer event-free survival than control therapy, with mainly low-grade adverse events, among patients with resectable high-risk intrahepatic cholangiocarcinoma. (Funded by the Clinical Research Plan of Shanghai Hospital Development Center and others; ZSAB-neoGOLP ClinicalTrials.gov number, NCT04669496.)

BackgroundThe nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve kidney and cardiovascular outcomes in persons with type 2 diabetes and chronic kidney disease (CKD). The efficacy and safety of finerenone in persons with type 1 diabetes and CKD are unknown.MethodsWe conducted a phase 3 trial involving adults who had type 1 diabetes, CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m2 of body-surface area), and albuminuria (urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams], 200 to <5000) and were receiving an angiotensin-converting–enzyme (ACE) inhibitor or an angiotensin-receptor blocker. Participants were randomly assigned to receive finerenone (10 or 20 mg per day, depending on the eGFR) or matching placebo. The primary outcome was the relative change in the urinary albumin-to-creatinine ratio over a period of 6 months.ResultsA total of 242 participants underwent randomization. The median urinary albumin-to-creatinine ratio decreased from 574.6 at baseline to 373.5 at 6 months among all the participants assigned to receive finerenone and from 506.4 to 475.6 among those assigned to receive placebo. Over a period of 6 months, the urinary albumin-to-creatinine ratio decreased by 34% with finerenone (geometric mean ratio to baseline, 0.66; 95% confidence interval [CI], 0.60 to 0.73) and 12% with placebo (geometric mean ratio to baseline, 0.88; 95% CI, 0.79 to 0.98), which corresponded to a 25% greater reduction with finerenone than with placebo (geometric mean ratio for finerenone vs. placebo, 0.75; 95% CI, 0.65 to 0.87; P<0.001). The most common adverse event was hyperkalemia (in 12 participants [10.1%] with finerenone and in 4 [3.3%] with placebo); 2 participants (1.7%) discontinued finerenone because of hyperkalemia. At 6 months, the change in the eGFR was –5.6 ml per minute per 1.73 m2 with finerenone and –2.7 ml per minute per 1.73 m2 with placebo (difference, –2.9 ml per minute per 1.73 m2; 95% CI, –5.1 to –0.7); eGFR values approached baseline levels during the washout period.ConclusionsIn adults with type 1 diabetes and CKD, finerenone resulted in a significantly greater decrease in the urinary albumin-to-creatinine ratio than placebo. (Funded by Bayer; FINE-ONE ClinicalTrials.gov number, NCT05901831.)

Private equity firms have gained increasing control of U.S. health care infrastructure. Along with other potential consequences, this growth threatens to undermine progress in health equity.

Multivessel coronary artery disease is seen on invasive coronary angiography in approximately 50% of patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Previous trials have shown that in patients with hemodynamically stable disease, revascularization with percutaneous coronary intervention (PCI) of a nonculprit coronary lesion results in better outcomes than PCI of the infarct-related artery only when the severity of the nonculprit coronary lesion is evaluated either with angiography alone1 or by measurement of the pressure gradient across the stenosed artery with a pressure wire during maximal flow and calculation of the fractional flow reserve (FFR).2 What remains less clear, .

Medical credit cards have emerged as a popular financing tool for patients seeking care they might otherwise be unable to afford. But these cards may ultimately increase financial burdens on patients.

Type 1 diabetes is characterized by an absolute insulin deficiency and immune dysregulation. Nearly one in three persons with type 1 diabetes will go on to have diabetic kidney disease,1 an independent risk factor for cardiovascular events and premature death.2 Glomerular hyperfiltration and other changes precede structural abnormalities and a decline in kidney function. Early diabetic kidney disease frequently remains undetected owing to its asymptomatic nature, and kidney damage may precede the onset of albuminuria or elevated creatinine levels.3 However, kidney biopsies have not been routine in patients with type 1 diabetes, which prevents deep phenotyping and additional mechanistic assessment. .

The AHEAD model was intended to slow health care cost growth, improve population health, and advance health equity. But under the new administration, its focus has shifted from equity to efficiency.

The authors describe the scientific foundations of a study of zorevunersen, an antisense oligonucleotide, for the treatment of a severe epilepsy syndrome.

To the Editor: In the Placebo-Controlled Efficacy in iNPH Shunting (PENS) trial, Luciano et al. (Dec. 4 issue)1 investigated the effectiveness of shunting in participants with idiopathic normal-pressure hydrocephalus (iNPH). Of 99 participants who had undergone ventriculoperitoneal shunt surgery, 49 were assigned to a placebo valve setting and did not have their newly placed ventriculoperitoneal shunt perform drainage for 3 months after this invasive procedure, despite having a gait-velocity response to temporary cerebrospinal fluid (CSF) drainage before surgery. I had a ventriculoperitoneal shunt placed for normal-pressure hydrocephalus 13 months ago and had marked improvement in gait, balance, urinary control, and .