NEJM original articles

Background. Current U.S. and European guidelines recommend oral anticoagulation as a class IIa indication in patients with atrial fibrillation at intermediate risk for stroke; however, evidence from randomized trials is needed.

Methods. We conducted a multicenter, open-label, adjudicator-masked superiority trial in South Korea involving patients with atrial fibrillation and an intermediate risk of stroke (a score of 1 in men and 2 in women on the CHA₂DS₂-VASc scale; range, 0 to 9, with higher scores indicating a greater risk of stroke). Patients were randomly assigned in a 1:1 ratio to receive either direct oral anticoagulant (DOAC) therapy or no anticoagulation. The primary end point was a composite of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months.

Results. Of 1803 patients who underwent randomization, 902 were assigned to receive DOAC therapy and 901 were assigned to receive no anticoagulant therapy. The mean age of the patients was 60.4 years, and 23.7% were women. At 24 months, a primary end-point event had occurred in 4 patients (cumulative incidence, 0.5%) in the DOAC group and in 13 (cumulative incidence, 1.5%) in the no-anticoagulant group (difference, -1.0 percentage points; 95% confidence interval [CI], -2.0 to -0.1; P = 0.03; hazard ratio, 0.31; 95% CI, 0.10 to 0.94). Stroke occurred in 3 patients (cumulative incidence, 0.3%) in the DOAC group and in 10 (cumulative incidence, 1.1%) in the no-anticoagulant group. The incidence of systemic embolism and major bleeding appeared to be similar in the two trial groups, and no deaths from cardiovascular causes occurred in either group. Serious adverse events occurred in 80 patients (8.9%) in the DOAC group and in 84 (9.3%) in the no-anticoagulant group.

Conclusions. Among patients with atrial fibrillation at intermediate risk for stroke, DOAC therapy led to a lower risk of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months than no anticoagulation. (Funded by the Ministry of Health and Welfare, South Korea, and others; SINGLE-AF ClinicalTrials.gov number, NCT04437654.).

Background. Narcolepsy type 1 is characterized by excessive daytime sleepiness, cataplexy, disrupted sleep, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, reduced symptoms of narcolepsy type 1 in a previous phase 2 trial.

Methods. We conducted two phase 3, randomized, placebo-controlled trials evaluating the efficacy and safety of oveporexton over a period of 12 weeks. Participants 16 to 70 years of age with narcolepsy type 1 were randomly assigned in a 3:3:2 ratio to receive twice-daily oveporexton (1 mg or 2 mg) or placebo in the First Light trial and in a 2:1 ratio to receive twice-daily oveporexton (2 mg) or placebo in the Radiant Light trial. The primary end point was the change from baseline to week 12 in mean sleep latency (the ability to stay awake under soporific conditions) on the Maintenance of Wakefulness Test (MWT; range, 0 to 40 minutes; normal, ≥20). Key secondary end points included the change from baseline to week 12 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, ≤10) and the weekly cataplexy rate at week 12.

Results. A total of 168 participants were enrolled in the First Light trial and 105 in the Radiant Light trial. Mean changes from baseline to week 12 in mean sleep latency on the MWT ranged from 14.3 to 19.8 minutes with oveporexton, as compared with -0.4 to -0.8 minutes with placebo (adjusted P<0.001 for all comparisons vs. placebo). Mean changes in the ESS total score ranged from -9.7 to -11.8 with oveporexton, as compared with -1.5 to -1.7 with placebo (adjusted P<0.001 for all comparisons vs. placebo). Median percent reductions in the weekly cataplexy rate ranged from 79.0 to 88.8% with oveporexton, as compared with 27.7 to 39.1% with placebo (adjusted P<0.001 for all comparisons vs. placebo). Adverse events occurred in 86 to 89% of the participants with oveporexton, as compared with 43 to 54% with placebo; the most common adverse events were increased urinary frequency and transient insomnia, which occurred in a majority of participants receiving oveporexton.

Conclusions. Over a period of 12 weeks, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy in participants with narcolepsy type 1. Increased urinary frequency and transient insomnia were common side effects. (Funded by Takeda Development Center Americas; the First Light and Radiant Light ClinicalTrials.gov numbers, NCT06470828 and NCT06505031.).

Background. Anitocabtagene autoleucel (anito-cel), a B-cell maturation antigen (BCMA)-directed autologous chimeric antigen receptor (CAR) T-cell therapy with a synthetic d-domain binder (ddBCMA), may have efficacy in patients with relapsed or refractory multiple myeloma.

Methods. In a phase 1 study, we evaluated the safety and efficacy of anito-cel (dose level 1, 100×10⁶ CAR+ T cells; dose level 2, 300×10⁶ CAR+ T cells) in patients with relapsed or refractory multiple myeloma who had received three or more lines of therapy previously or had triple-class refractory disease. Primary end points were adverse events during the treatment period and establishment of the recommended phase 2 dose. In complementary in vitro studies, we compared the anito-cel ddBCMA binder with a dual variable heavy-chain domain of a heavy chain-only antibody (dual-VHH) binder corresponding to the published sequence for ciltacabtagene autoleucel.

Results. Of 40 patients enrolled, 38 received anito-cel. All 38 patients had an adverse event during the treatment period, and 37 patients (97%) had an adverse event of grade 3 or higher. Among patients who received the recommended phase 2 dose (100×10⁶ CAR+ T cells), 94% had cytokine release syndrome of grade 1 or 2, with no events of grade 3 or higher. A total of 16% of the patients had immune effector cell-associated neurotoxicity syndrome (ICANS) of grade 1 or 2, and 1 patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. At a median follow-up of 38.1 months, all 38 patients (100%) had had a response, with 79% having a complete response. The 24-month progression-free survival was 57%; the median progression-free survival was 30.2 months. The 36-month overall survival was 65%. The ddBCMA binder had a faster off-rate than the dual-VHH binder; although cytotoxicity was similar with the two therapies, ddBCMA CAR T cells led to less cytokine release and did not result in activation without antigen or in off-target cytotoxic effects.

Conclusions. Anito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma. Cytokine release syndrome and ICANS of grade 3 or higher were rare. (Funded by Arcellx and Kite, a Gilead company; ClinicalTrials.gov number, NCT04155749.).

Background. Wiskott-Aldrich syndrome is a rare, X-linked, life-threatening inborn error of immunity and platelet disorder caused by variants in the gene WAS. Etuvetidigene autotemcel (etu-cel) is an autologous gene therapy consisting of hematopoietic stem and progenitor cells that have been transduced ex vivo with a lentiviral vector encoding WAS complementary DNA.

Methods. We integrated data from two prospective open-label clinical studies (a phase 1-2 study with 8 participants and a phase 3 study with 10 participants) and an expanded-access program with 9 participants to evaluate the efficacy and safety of etu-cel in patients with Wiskott-Aldrich syndrome. The participants received a single intravenous infusion of etu-cel after rituximab administration and reduced-intensity conditioning. The primary efficacy end points were overall survival, severe infections from 6 to 18 months after gene therapy, and moderate and severe bleeding events in the first 12 months after gene therapy. Results for severe infections and moderate and severe bleeding are reported as the rate of events (number per person-year of observation), which was compared with the rate in the year before gene therapy.

Results. The median follow-up among the surviving participants was 5.7 years (range, 2.3 to 13.3), and the median age at the time of gene therapy was 2.6 years (range, 1.0 to 35.1). Overall survival at both 1 year and 5 years was 96%; one participant died. The most common adverse event of grade 3 or higher was central venous catheter-related infection. No evidence of insertional oncogenesis was observed. The rate of severe infections per person-year of observation decreased from 2.00 (95% confidence interval [CI], 1.50 to 2.61) in the year before gene therapy to 0.15 (95% CI, 0.04 to 0.39) in the period beyond 6 months up to 18 months after treatment. The rate of moderate or severe bleeding events per person-year of observation decreased from 2.00 (95% CI, 1.50 to 2.61) in the year before gene therapy to 0.80 (95% CI, 0.49 to 1.22) in the year after treatment.

Conclusions. Our results show that the effects of etu-cel are consistent with a sustained clinical benefit in persons with Wiskott-Aldrich syndrome. (Funded by Fondazione Telethon and others; TIGET-WAS and OTL-103-4 ClinicalTrials.gov numbers, NCT01515462 and NCT03837483, respectively.).