NEJM original articles

Background. Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory effects. In a phase 2 trial involving patients with idiopathic pulmonary fibrosis, treatment with nerandomilast stabilized lung function over a period of 12 weeks.

Methods. In this phase 3, double-blind trial, we randomly assigned patients with idiopathic pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background antifibrotic therapy (nintedanib or pirfenidone vs. none). The primary end point was the absolute change from baseline in forced vital capacity (FVC), measured in milliliters, at week 52.

Results. A total of 1177 patients underwent randomization, of whom 77.7% were taking nintedanib or pirfenidone at enrollment. Adjusted mean changes in FVC at week 52 were -114.7 ml (95% confidence interval [CI], -141.8 to -87.5) in the nerandomilast 18-mg group, -138.6 ml (95% CI, -165.6 to -111.6) in the nerandomilast 9-mg group, and -183.5 ml (95% CI, -210.9 to -156.1) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 68.8 ml (95% CI, 30.3 to 107.4; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 44.9 ml (95% CI, 6.4 to 83.3; P = 0.02). The most frequent adverse event in the nerandomilast groups was diarrhea, reported in 41.3% of the 18-mg group and 31.1% of the 9-mg group, as compared with 16.0% in the placebo group. Serious adverse events were balanced across trial groups.

Conclusions. In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-IPF ClinicalTrials.gov number, NCT05321069.).

Background. Nerandomilast (BI 1015550) is an orally administered preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. Nerandomilast has been shown to slow the progression of idiopathic pulmonary fibrosis, but an assessment of its effects in other types of progressive pulmonary fibrosis is needed.

Methods. In a phase 3, double-blind trial, we randomly assigned patients with progressive pulmonary fibrosis in a 1:1:1 ratio to receive nerandomilast at a dose of 18 mg twice daily, nerandomilast at a dose of 9 mg twice daily, or placebo, with stratification according to background therapy (nintedanib vs. none) and fibrotic pattern on high-resolution computed tomography (usual interstitial pneumonia-like pattern vs. other patterns). The primary end point was the absolute change from baseline in the forced vital capacity (FVC), measured in milliliters, at week 52.

Results. A total of 1176 patients received at least one dose of nerandomilast or placebo, of whom 43.5% were taking background nintedanib therapy at baseline. The adjusted mean change in the FVC at week 52 was -98.6 ml (95% confidence interval [CI], -123.7 to -73.4) in the nerandomilast 18-mg group, -84.6 ml (95% CI, -109.6 to -59.7) in the nerandomilast 9-mg group, and -165.8 ml (95% CI, -190.5 to -141.0) in the placebo group. The adjusted difference between the nerandomilast 18-mg group and the placebo group was 67.2 ml (95% CI, 31.9 to 102.5; P<0.001), and the adjusted difference between the nerandomilast 9-mg group and the placebo group was 81.1 ml (95% CI, 46.0 to 116.3; P<0.001). The most frequent adverse event was diarrhea, reported in 36.6% of the patients in the nerandomilast 18-mg group, 29.5% of those in the nerandomilast 9-mg group, and 24.7% of those in the placebo group. Serious adverse events occurred in similar percentages of patients in the trial groups.

Conclusions. In patients with progressive pulmonary fibrosis, treatment with nerandomilast led to a smaller decline in the FVC than placebo over a period of 52 weeks. (Funded by Boehringer Ingelheim; FIBRONEER-ILD ClinicalTrials.gov number, NCT05321082.).

Background. Evidence suggests that incretin-based dual agonist pharmacotherapy is helpful in persons with obesity. Mazdutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, may have efficacy in persons with overweight or obesity.

Methods. In a phase 3, double-blind, placebo-controlled trial in China, we randomly assigned, in a 1:1:1 ratio, adults 18 to 75 years of age who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 28 or had a BMI of 24 to less than 28 plus at least one weight-related coexisting condition to receive 4 mg of mazdutide, 6 mg of mazdutide, or placebo for 48 weeks. The two primary end points were the percentage change in body weight from baseline and a weight reduction of at least 5% at week 32, as assessed in a treatment-policy estimand analysis (which assessed effects regardless of early discontinuation of mazdutide or placebo and the initiation of new antiobesity therapies).

Results. Among 610 participants, the mean body weight was 87.2 kg and the mean BMI was 31.1 at baseline. At week 32, the mean percentage change in body weight from baseline was -10.09% (95% confidence interval [CI], -11.15 to -9.04) in the 4-mg mazdutide group, -12.55% (95% CI, -13.64 to -11.45) in the 6-mg mazdutide group, and 0.45% (95% CI, -0.61 to 1.52) in the placebo group, and 73.9%, 82.0%, and 10.5% of the participants, respectively, had a weight reduction of at least 5% (P<0.001 for all comparisons with placebo). At week 48, the mean percentage change in body weight from baseline was -11.00% (95% CI, -12.27 to -9.73) in the 4-mg mazdutide group, -14.01% (95% CI, -15.36 to -12.66) in the 6-mg mazdutide group, and 0.30% (95% CI, -0.98 to 1.58) in the placebo group, and 35.7%, 49.5%, and 2.0% of the participants, respectively, had a weight reduction of at least 15% (P<0.001 for all comparisons with placebo). Beneficial effects on all prespecified cardiometabolic measures were seen with mazdutide. The most frequently reported adverse events were gastrointestinal and mostly mild to moderate in severity. The incidence of adverse events leading to discontinuation of the trial regimen was 1.5% with the 4-mg mazdutide dose, 0.5% with the 6-mg mazdutide dose, and 1.0% with placebo.

Conclusions. In Chinese adults with overweight or obesity, once-weekly mazdutide at a dose of 4 mg or 6 mg for 32 weeks led to clinically relevant reductions in body weight. (Funded by Innovent Biologics; GLORY-1 ClinicalTrials.gov number, NCT05607680.).

Background. Adeno-associated virus (AAV)-mediated gene therapy has emerged as a promising treatment for hemophilia B. Data on safety and durability from 13 years of follow-up in a cohort of patients who had been successfully treated with scAAV2/8-LP1-hFIXco gene therapy are now available.

Methods. Ten men with severe hemophilia B received a single intravenous infusion of the scAAV2/8-LP1-hFIXco vector in one of three dose groups (low-dose: 2×10¹¹ vector genomes [vg] per kilogram of body weight [in two participants]; intermediate-dose: 6×10¹¹ vg per kilogram [in two]; or high-dose: 2×10¹² vg per kilogram [in six]). Efficacy outcomes included factor IX activity, the annualized bleeding rate, and factor IX concentrate use. Safety assessments included clinical events, liver function, and imaging.

Results. Participants were followed for a median of 13.0 years (range, 11.1 to 13.8). Factor IX activity remained stable across the dose cohorts, with mean factor IX levels of 1.7 IU per deciliter in the low-dose group, 2.3 IU per deciliter in the intermediate-dose group, and 4.8 IU per deciliter in the high-dose group. Seven of the 10 participants did not receive prophylaxis. The median annualized bleeding rate decreased from 14.0 episodes (interquartile range, 12.0 to 21.5) to 1.5 episodes (interquartile range, 0.7 to 2.2), which represented a reduction by a factor of 9.7. Use of factor IX concentrate decreased by a factor of 12.4 (interquartile range, 2.2 to 27.1). A total of 15 vector-related adverse events occurred, primarily transient elevations in aminotransferase levels. Factor IX inhibitor, thrombosis, or chronic liver injury did not develop in any participant. Two cancers were identified but were deemed by the investigators, together with an expert multidisciplinary team, as being unrelated to the vector. A liver biopsy that was conducted in 1 participant 10 years after the infusion revealed transcriptionally active transgene expression in hepatocytes without fibrosis or dysplasia. Levels of neutralizing antibodies to AAV8 remained high throughout follow-up, thus indicating potential barriers to readministration of the vector.

Conclusions. A single administration of scAAV2/8-LP1-hFIXco gene therapy resulted in durable factor IX expression, sustained clinical benefit, and no late-onset safety concerns over a period of 13 years. These data support the long-term efficacy and safety of AAV gene therapy for severe hemophilia B. (Funded by the U.K. Medical Research Council and others; ClinicalTrials.gov number, NCT00979238; EudraCT number, 2005-005711-17.).

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).