NEJM original articles

Background. Two phase 3, randomized trials of inhaled treprostinil for idiopathic pulmonary fibrosis (IPF) were conducted on the basis of preclinical and clinical evidence of an antifibrotic mechanism. TETON-2 was completed first, and results were published; the results of TETON-1 and of both trials combined are reported here.

Methods. In the double-blind TETON-1 trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily). The primary end point was the change in forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening (the first occurrence of death from any cause, hospitalization for a respiratory cause, or a relative decline of ≥10% in the percentage of predicted FVC) and acute exacerbation of IPF (each assessed in a time-to-event analysis), survival, change in percentage of predicted FVC, quality of life, and change in diffusion capacity of the lungs for carbon monoxide at week 52.

Results. A total of 598 patients underwent randomization and received at least one dose of treprostinil (299 patients) or placebo (299 patients). Of these, 434 completed the assessments through week 52 (218 in the treprostinil group and 216 in the placebo group). The mean age of the patients was 73.0 years, 77.3% were men, and 77.6% were receiving background antifibrotic therapy; the percentage of predicted FVC at baseline was 74.6%. The median change in FVC at week 52 was -43.3 ml (95% confidence interval [CI], -92.1 to -9.1) with treprostinil and -196.2 ml (95% CI, -227.1 to -155.6) with placebo (difference, 130.1 ml; 95% CI, 82.2 to 178.1; P<0.001). Clinical worsening occurred in 95 patients (31.8%) with treprostinil and in 133 patients (44.5%) with placebo (hazard ratio, 0.67; 95% CI, 0.52 to 0.88; P = 0.003). No significant difference was observed in the time to an IPF exacerbation, and no further inferences regarding secondary end points were made. The most frequent adverse event was cough (reported in 54.8% of the patients in the treprostinil group and 33.1% patients in the placebo group). Discontinuation of treprostinil or placebo occurred in 40.5% and 32.8% of the patients, respectively, with adverse event being the primary reason (20.7% and 14.7%). Efficacy and safety outcomes were similar in analyses of the combined trial data.

Conclusions. In patients with IPF, treatment with inhaled treprostinil led to a smaller decline in FVC and fewer clinical-worsening events than placebo over the course of 52 weeks. (Funded by United Therapeutics; TETON-1 ClinicalTrials.gov number, NCT04708782.).

Background. Preclinical data indicate that inhaled treprostinil may be useful for the treatment of idiopathic pulmonary fibrosis (IPF) through an antifibrotic mechanism, a premise that is supported by clinical observation.

Methods. In this phase 3, double-blind trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily) over a period of 52 weeks. The primary end point was the change from baseline in the absolute forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening and acute exacerbation of IPF (each assessed in a time-to-event analysis), death by week 52, and the change from baseline in the percentage of predicted FVC, quality of life, and the diffusing capacity of the lungs for carbon monoxide by week 52. Safety was also assessed.

Results. A total of 593 patients underwent randomization and received at least one dose of treprostinil (298 patients) or placebo (295 patients). Of these, 463 patients (224 in the treprostinil group and 239 in the placebo group) completed the trial assessments through week 52. The mean age of the patients was 71.7 years, 80.1% were men, the mean FVC at baseline was 76.8%, and 75.4% of the patients were receiving background antifibrotic therapy. The median change in FVC at week 52 was -49.9 ml (95% confidence interval [CI], -79.2 to -19.5) in the treprostinil group and -136.4 ml (95% CI, -172.5 to -104.0) in the placebo group; the between-group difference in the change in FVC was 95.6 ml (95% CI, 52.2 to 139.0; P<0.001). Clinical worsening occurred in 81 patients (27.2%) in the treprostinil group and 115 patients (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; P = 0.02). No substantial between-group difference in the time to IPF exacerbation was observed, and so no further inferences with regard to subsequent secondary end points were made. The most common adverse event was cough, reported in 48.3% of the patients in the treprostinil group and 24.1% of those in the placebo group. Discontinuation of treprostinil or placebo occurred in 33.6% and 24.7%, respectively, with approximately half these patients citing adverse events as the primary reason for discontinuation.

Conclusions. In patients with IPF, inhaled treprostinil was associated with a smaller decline in FVC and fewer clinical-worsening events than placebo over a period of 52 weeks. (Funded by United Therapeutics; TETON-2 ClinicalTrials.gov number, NCT05255991.).

Background. A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed.

Methods. We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age.

Results. From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache.

Conclusions. Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).

Background. Anaplastic lymphoma kinase (ALK) inhibitors have emerged as promising agents for patients with resectable ALK-positive non-small-cell lung cancer (NSCLC). Whether ensartinib, a second-generation ALK inhibitor, is safe and effective in such patients is unknown.

Methods. In this phase 3, double-blind, randomized trial involving patients with completely resected, ALK-positive stage IB to IIIB NSCLC after adjuvant chemotherapy, we randomly assigned patients in a 1:1 ratio to receive ensartinib at a dose of 225 mg once daily or placebo for 24 months. The primary end point was disease-free survival in patients with stage II to IIIB NSCLC. The key secondary end point was disease-free survival in the overall patient population.

Results. A total of 274 patients were randomly assigned to receive ensartinib or placebo (137 patients in each group). At 24 months, the percentage of patients with stage II to IIIB disease who were alive and disease-free was 86.4% in the ensartinib group and 53.5% in the placebo group (hazard ratio for disease recurrence or death, 0.20; 95% confidence interval [CI], 0.11 to 0.38; P<0.001). In the overall patient population, the percentage of patients who were alive and disease-free was 87.3% in the ensartinib group and 57.2% in the placebo group (hazard ratio, 0.20; 95% CI, 0.10 to 0.37; P<0.001). Overall survival data were immature. Adverse events of grade 3 or higher occurred in 35.8% of the patients who received ensartinib (most commonly rash) and in 18.2% of those who received placebo.

Conclusions. Among patients with completely resected stage IB to IIIB ALK-positive NSCLC, the percentage of patients who were alive and disease-free at 24 months was significantly higher with ensartinib than with placebo. (Funded by Betta Pharmaceuticals; ELEVATE ClinicalTrials.gov number, NCT05341583.).