NEJM original articles

Background. Patients with severe hypertriglyceridemia have an increased risk of acute pancreatitis. The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population.

Methods. We conducted two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b). Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months. The primary outcome was the percent change in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change in the triglyceride level at 12 months and in apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials.

Results. A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo). Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons). The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001). The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted.

Conclusions. Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo. (Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).

Background. Central retinal artery occlusion can result in permanent vision loss. Effective treatment is lacking.

Methods. We conducted a phase 3, double-blind, double-dummy, randomized, controlled trial involving adults with acute, nonarteritic central retinal artery occlusion who had symptom onset within 4.5 hours before treatment. Patients were assigned, in a 1:1 ratio, to receive intravenous tenecteplase (at a dose of 0.25 mg per kilogram of body weight) and oral placebo or intravenous placebo and oral aspirin (at a dose of 300 mg). The primary end point was vision recovery, defined as a best corrected visual acuity (BCVA) in the affected eye at 30 days of up to 0.7 logMAR (logarithm of the minimum angle of resolution; equivalent to ≥20/100). Key secondary visual end points were a BCVA of up to 0.5 logMAR (equivalent to ≥20/63), mean improvement in BCVA, and perimetry score at 30 days. Key safety end points included symptomatic intracranial hemorrhage, major bleeding, and death.

Results. A total of 78 patients at 16 sites in six countries underwent randomization, with 40 assigned to receive tenecteplase and 38 to receive aspirin. At 30 days, 8 patients (20%) in the tenecteplase group and 9 patients (24%) in the aspirin group had vision recovery (risk difference, -3.7 percentage points; 95% confidence interval, -22.0 to 14.7; P = 0.69). The outcomes with regard to the secondary visual end points did not differ substantially between the groups. There was a greater incidence of adverse events in the tenecteplase group, including one fatal intracranial hemorrhage.

Conclusions. Intravenous tenecteplase administered within 4.5 hours after onset of central retinal artery occlusion did not result in significantly greater vision recovery at 30 days than oral aspirin but was associated with serious safety concerns. (Funded by Oslo University Hospital and others; TenCRAOS ClinicalTrials.gov number, NCT04526951; EU Clinical Trials number, 2024-517606-29-00.).

Background. Dual anti-human epidermal growth factor receptor 2 (HER2) therapy plus chemotherapy followed by maintenance treatment with HER2-targeted and endocrine therapies is standard first-line treatment for hormone-receptor-positive, HER2-positive metastatic breast cancer. On the basis of preclinical and clinical data, the addition of palbociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) may overcome resistance to both endocrine and HER2-directed therapies.

Methods. In this phase 3, open-label, randomized trial, we enrolled patients with hormone-receptor-positive, HER2-positive metastatic breast cancer who did not have disease progression after four to eight cycles of chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio to receive maintenance HER2-targeted and endocrine therapies with or without palbociclib. The primary end point was investigator-assessed progression-free survival. Secondary end points included the objective response, clinical benefit, safety, and overall survival.

Results. A total of 518 patients underwent randomization: 261 were assigned to receive palbociclib and 257 to receive standard therapy. At a median follow-up of 53.5 months, patients in the palbociclib group had significantly longer progression-free survival than those in the standard-therapy group (median duration, 44.3 months vs. 29.1 months; hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; two-sided P = 0.02). Grade 3 and 4 adverse events, predominantly from neutropenia, occurred in 79.7% and 10.0% of the patients, respectively, in the palbociclib group, as compared with 30.6% and 3.6% of the patients, respectively, in the standard-therapy group.

Conclusions. The addition of palbociclib to maintenance anti-HER2 and endocrine therapies led to a significant improvement in progression-free survival over standard therapy, with increased toxic effects, mainly neutropenia. (Funded by Pfizer and others; PATINA ClinicalTrials.gov number, NCT02947685.).

Background. Prophylactic treatment for hemophilia B necessitates lifelong, regular intravenous factor IX infusions. Gene therapy offers the possibility of a single-dose treatment that produces durable endogenous factor IX expression and disease control. Etranacogene dezaparvovec comprises an adeno-associated virus serotype 5 (AAV5) vector and the highly active Padua factor IX variant. The primary analysis of this study showed that etranacogene dezaparvovec reduced annualized bleeding rates and adverse events were mainly of low-grade severity. Final data from 5 years of follow-up are now available.

Methods. In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered a single infusion of etranacogene dezaparvovec in men with hemophilia B (factor IX activity level, ≤2 IU per deciliter), regardless of preexisting AAV5 neutralizing antibodies. The prespecified 5-year analyses included adjusted annualized bleeding rates (difference between the post-treatment period of months 7 through 60 after gene therapy and the lead-in period), factor IX expression, and safety outcomes.

Results. In the full analysis population (54 participants), the adjusted annualized bleeding rate for all bleeding events was 4.16 during the lead-in period and 1.52 during months 7 through 60 after gene therapy, a reduction of 63% (95% confidence interval, 24 to 82). During the 5-year follow-up period, endogenous factor IX expression remained stable; at 5 years, the mean (±SD) factor IX activity level was 36.1±15.7 IU per deciliter and the mean exogenous factor IX consumption for routine prophylaxis and treatment of bleeding events had decreased by 96%, from 257,339 IU per year during the lead-in period to 10,924 IU per year during months 7 through 60 after gene therapy. Efficacy did not differ substantially between participants with and those without AAV5 neutralizing antibodies at baseline. Adverse events that were possibly related to treatment were rare after month 6.

Conclusions. Sustained endogenous factor IX expression and low annualized bleeding rates over a 5-year period were observed after an infusion of etranacogene dezaparvovec. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).