NEJM original articles

Background. Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration, small interfering RNA targeting hepatic synthesis of lipoprotein(a), are unknown.

Methods. We randomly assigned participants in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180, all administered by subcutaneous injection. Data from the two groups that received lepodisiran at a dose of 400 mg at baseline were pooled for the primary analysis. The primary end point was the time-averaged percent change from baseline in the serum lipoprotein(a) concentration (lepodisiran difference from placebo [i.e., placebo-adjusted]) during the period from day 60 to day 180.

Results. A total of 320 participants underwent randomization; the median baseline lipoprotein(a) concentration was 253.9 nmol per liter. The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups. The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively. Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group.

Conclusions. Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.).

Background. Secondary erythrocytosis often results from conditions that cause tissue hypoxia or an improper increase in erythropoietin (EPO) production. EPO, the major regulator of erythropoiesis, has a complex and tightly regulated expression during development, with a liver-to-kidney switch shortly after birth.

Methods. We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range and characterized as a novel molecular and functional entity. We investigated the effect of the identified pathogenic variants using EPO promoter-driven luciferase reporter genes. Induced pluripotent stem cells (iPSCs) were generated from patient cells and differentiated into hepatocyte-like EPO-producing cells. Samples of circulating EPO from patients with hereditary erythrocytosis and from healthy newborns were analyzed by means of isoelectric focusing, and EPO activity was assessed.

Results. Three novel variants were identified in the noncoding regions of EPO. Experiments with reporter assays and iPSC-derived hepatocyte-like cells showed that the variants targeted previously uncharacterized regulatory elements of the gene, which, when the variants were present, showed high responsiveness to hypoxia. EPO samples from all the patients showed a modified isoelectric-focusing profile, identical to hepatic EPO that is expressed in premature neonates and in patients with acquired erythrocytosis associated with liver diseases. EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro, which suggests a potential gain of function linked to the liver-type glycosylation of EPO.

Conclusions. We found that secondary erythrocytosis can be related to variants in EPO that lead to the production of hepatic-like EPO with an atypical glycosylation pattern and increased activity. (Funded by Région des Pays de la Loire and others; ClinicalTrials.gov number, NCT03957863.).

Background. The β₂ common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in ITGB2, which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure.

Methods. In a phase 1-2, multinational, open-label study, we enrolled nine children who had severe LAD-I and treated them with marnetegragene-autotemcel (marne-cel), a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2, and followed them for 24 months. The primary efficacy end point of the phase 2 study was survival without allogeneic HSCT (HSCT-free survival) at least 1 year after marne-cel infusion and at 2 years of age among the patients who were younger than 1 year of age at enrollment, tested against a null hypothesis of survival of 39% of the patients. We also report interim data from six patients enrolled in the long-term follow-up study.

Results. Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure. HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001). All the patients who were enrolled at younger than 1 year of age were alive beyond 2 years of age. Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved. The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower.

Conclusions. In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I. (Funded by Rocket Pharmaceuticals and the California Institute for Regenerative Medicine; ClinicalTrials.gov numbers, NCT03812263 and NCT06282432.).

Background. Mepolizumab is a humanized monoclonal antibody that targets interleukin-5, a cytokine that plays a central role in eosinophilic inflammation, which is present in 20 to 40% of patients with chronic obstructive pulmonary disease (COPD).

Methods. In a phase 3, double-blind, randomized, placebo-controlled trial, patients with COPD, a history of exacerbations, and a blood eosinophil count of at least 300 cells per microliter who were receiving triple inhaled therapy were assigned, in a 1:1 ratio, to receive mepolizumab (at a dose of 100 mg) or placebo subcutaneously every 4 weeks for 52 to 104 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Secondary end points, tested hierarchically to control for multiplicity, were moderate or severe exacerbation as assessed in a time-to-first-event analysis, measures of health-related quality of life and symptoms, and the annualized rate of exacerbations leading to an emergency department visit, hospitalization, or both.

Results. Of the 804 patients who underwent randomization, 403 were assigned to receive mepolizumab and 401 to receive placebo. The annualized rate of moderate or severe exacerbations was significantly lower with mepolizumab than with placebo (0.80 vs. 1.01 events per year; rate ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.01). The time to the first moderate or severe exacerbation was longer with mepolizumab than with placebo (Kaplan-Meier median time to the first moderate or severe exacerbation, 419 vs. 321 days; hazard ratio, 0.77; 95% CI, 0.64 to 0.93; P = 0.009). Between-group differences in measures of health-related quality of life and symptoms were not significant; thus, no statistical inferences regarding subsequent secondary end points in the statistical testing hierarchy were made. The incidence of adverse events was similar in the mepolizumab and placebo groups.

Conclusions. Treatment with mepolizumab led to a lower annualized rate of moderate or severe exacerbations when added to background triple inhaled therapy among patients with COPD and an eosinophilic phenotype. (Funded by GSK; MATINEE ClinicalTrials.gov number, NCT04133909.).