NEJM original articles

Background. Hereditary angioedema is a rare and potentially life-threatening genetic condition characterized by recurrent and debilitating swelling attacks. Lonvoguran ziclumeran (lonvo-z) - an investigational, in vivo gene-editing treatment based on clustered regularly interspaced short palindromic repeats (CRISPR) - is being developed as a single-dose treatment for hereditary angioedema.

Methods. In a phase 3, double-blind trial, we randomly assigned, in a 2:1 ratio, patients who were 16 years of age or older and had hereditary angioedema with C1 inhibitor deficiency to receive a single intravenous infusion of lonvo-z (at a dose of 50 mg) or placebo. The primary end point was the number of investigator-confirmed hereditary angioedema attacks per month (the monthly attack rate) from week 5 through week 28 after infusion.

Results. A total of 80 patients underwent randomization; 52 were assigned to receive lonvo-z and 28 to receive placebo. As of February 10, 2026, the median duration of follow-up was 7.5 months (range, 4.9 to 12.8). The least-squares mean monthly attack rate from weeks 5 through 28 was 0.26 (95% confidence interval [CI], 0.15 to 0.45) in the lonvo-z group and 2.10 (95% CI, 1.55 to 2.86) in the placebo group (relative difference, -87%; 95% CI, -93 to -78; P<0.001). Adverse events that occurred during or after infusion of lonvo-z or placebo were reported in 92% and 86% of the patients in the lonvo-z and placebo groups, respectively, from day 1 through week 28. Among the adverse events that occurred during or after infusion and more often in the lonvo-z group than in the placebo group, the most common (occurring in >10% of the patients in the lonvo-z group) included infusion-related reaction, headache, fatigue, back pain, and upper respiratory tract infection. No serious or grade 3 or higher adverse events were reported in the lonvo-z group.

Conclusions. Among patients with hereditary angioedema, a single intravenous infusion of lonvo-z resulted in a significantly lower rate of hereditary angioedema attacks than placebo. (Funded by Intellia Therapeutics; HAELO ClinicalTrials.gov number, NCT06634420.).

Background. The outcome of Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) has greatly improved with the use of tyrosine kinase inhibitors and immunotherapy.

Methods. In this trial, we randomly assigned adult patients with Ph-positive ALL in a 2:1 ratio to receive ponatinib plus blinatumomab (intervention group) or imatinib plus chemotherapy (control group) as frontline treatment. A crossover to the intervention group was allowed for patients with persistence or reappearance of measurable residual disease in the control group. The primary end point was event-free survival.

Results. A total of 236 patients underwent randomization: 158 to the intervention group and 78 to the control group. The median age of the patients was 55 years (range, 24 to 82). At a median follow-up of 23.7 months, the estimated 24-month event-free survival was 86% in the intervention group and 67% in the control group (P<0.001). Survival with no measurable residual disease was 68% and 42%, respectively. At the end of induction, a complete hematologic response was observed in 94% of the patients in the intervention group and in 79% of those in the control group. After blinatumomab consolidation, a molecular response was observed in 71% and 49% of the patients, respectively. After crossover to the intervention group, 20 of 31 patients (64%) had a molecular response. Overall survival was 90% in the intervention group and 85% in the control group. The cumulative incidence of relapse was 5% and 13%, respectively. As of this report, only 19% of the patients in the intervention group had undergone hematopoietic stem-cell transplantation after having had a first complete hematologic response.

Conclusions. In this phase 3 trial, a frontline chemotherapy-free targeted and immunotherapeutic approach was superior to the use of imatinib and chemotherapy. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA ALL2820 ClinicalTrials.gov number, NCT04722848.).

Background. Monoclonal antibodies targeting the interleukin-23 pathway are effective in treating inflammatory bowel disease. However, these therapies must be administered intravenously or by subcutaneous injection.

Methods. We conducted a phase 2b, double-blind, randomized trial of oral icotrokinra, a peptide that blocks the interleukin-23 receptor, in adults with moderately to severely active ulcerative colitis. Participants were assigned to receive icotrokinra at a once-daily dose of 400 mg, 200 mg, or 100 mg or placebo. The primary end point was clinical response at week 12. Secondary end points included clinical remission, remission of symptoms, and endoscopic improvement at week 12.

Results. A total of 252 participants underwent randomization: 63 were assigned to the 400-mg group, 62 to the 200-mg group, 64 to the 100-mg group, and 63 to the placebo group. All the doses of icotrokinra were superior to placebo with respect to a clinical response at week 12, which occurred in 63% of the participants in the 400-mg group, 58% in the 200-mg group, and 55% in the 100-mg group, as compared with 27% in the placebo group (P<0.001 for all comparisons with placebo). The percentage of participants with clinical remission at week 12 was also significantly higher in the 400-mg group than in the placebo group (30% vs. 11%, P = 0.006), as were the percentage of participants with symptomatic remission (46% vs. 19%, P<0.001) and the percentage of participants with endoscopic improvement (37% vs. 14%, P = 0.002). Clinical remission at week 12 occurred in 24% of the participants in the 200-mg group (P = 0.054 for the comparison with placebo); in accordance with the fixed-sequence testing procedure to account for multiple comparisons, no further formal testing of secondary end points was conducted. Through week 28, the percentage of participants with adverse events was 60% in the 400-mg group, 66% in the 200-mg group, 66% in the 100-mg group, and 62% in the placebo group. For serious adverse events, the percentages were 2%, 5%, 0%, and 10%, respectively.

Conclusions. Among participants with moderately to severely active ulcerative colitis, a clinical response at week 12 was significantly more common with once-daily oral icotrokinra at each of three tested doses than with placebo. (Funded by Johnson & Johnson; ANTHEM-UC ClinicalTrials.gov number, NCT06049017.).

Background. In eastern and southern Africa, approximately 1 million people living with human immunodeficiency virus (HIV) and receiving oral therapy do not have viral suppression because of adherence challenges.

Methods. We conducted a phase 3b, open-label, randomized trial to compare long-acting injectable cabotegravir plus rilpivirine with oral dolutegravir-based therapy among adults with virally suppressed HIV type 1 (viral load, <200 copies per milliliter) and suboptimal adherence or care engagement. The participants were assigned in a 1:1 ratio to receive intramuscular injections of cabotegravir (600 mg) plus rilpivirine (900 mg) every 8 weeks, with the first two injection visits occurring 4 weeks apart, or to continue daily oral dolutegravir-based therapy; baseline drug-resistance testing was not performed. The primary end point was a viral load of less than 50 copies per milliliter at week 48; noninferiority was assessed with a margin of -10 percentage points. Confirmed virologic failure (two consecutive viral loads of ≥200 copies per milliliter) was a key secondary end point.

Results. A total of 540 participants were enrolled across seven sites in Kenya, South Africa, and Uganda; 537 were included in the primary analysis. At 48 weeks, 244 of 268 participants (91.0%) in the long-acting-therapy group had a viral load of less than 50 copies per milliliter, as compared with 240 of 269 participants (89.2%) in the oral-therapy group (risk difference, 1.9 percentage points; 95% confidence interval [CI], -3.1 to 6.9), which met the criterion for noninferiority. The results of a per-protocol analysis were consistent with those of the primary analysis. Confirmed virologic failure occurred in 5 participants (1.9%) in the long-acting-therapy group and in no participants in the oral-therapy group (risk difference, 1.9 percentage points; 95% CI, 0.3 to 3.5). Serious adverse events were reported in 11 of 271 participants (4.1%) who received long-acting therapy and in 8 of 269 participants (3.0%) who received oral therapy (risk difference, 1.1 percentage points; 95% CI, -1.1 to 4.2).

Conclusions. Among persons with HIV in Africa who have adherence challenges, long-acting cabotegravir plus rilpivirine was noninferior to oral dolutegravir-based therapy for maintaining a viral load of less than 50 copies per milliliter. (Funded by Johnson & Johnson; IMPALA ClinicalTrials.gov number, NCT05546242; Pan African Clinical Trials Registry number, PACT202301600757432TMC278LAHTX3005.).