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Medscape
26-06-2025
- Health
- Medscape
Nerandomilast May Slow Down Progressive Pulmonary Fibrosis
TOPLINE: In a phase 3 study, nerandomilast administered at 18 mg or 9 mg twice daily slowed the progression of pulmonary fibrosis in adults with progressive pulmonary fibrosis. METHODOLOGY: In a previous study, nerandomilast, a preferential inhibitor of phosphodiesterase 4B, was found to slow the progression of idiopathic pulmonary fibrosis. The present phase 3, randomized trial conducted at multiple sites across 44 countries investigated the efficacy and safety of nerandomilast in patients with a confirmed diagnosis of interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis. The study enrolled 1176 patients (mean age, 66.4 years; mean forced vital capacity [FVC], 70.1% of the predicted value) who were randomly assigned to receive either 18 mg or 9 mg nerandomilast or placebo twice daily. Patients were stratified on the basis of background nintedanib therapy and fibrotic patterns observed on high-resolution CT. The mean exposure duration was approximately 14.5 months in each group. The primary endpoint was the absolute change from baseline in FVC at week 52, and key secondary endpoints were time to first acute exacerbation of ILD, respiratory-related hospitalization, or death. TAKEAWAY: Nerandomilast significantly reduced the decline in FVC compared with placebo, with adjusted differences of 67.2 mL for the 18 mg dose and 81.1 mL for the 9 mg dose (P < .001 for both). This reduction in lung function decline was sustained regardless of background therapy. The study could not confirm the less frequent occurrence of a first acute exacerbation of ILD, respiratory-related hospitalization, or death in the nerandomilast groups compared with the placebo group. Deaths occurred in a lower proportion of patients receiving nerandomilast at 18 mg (hazard ratio [HR], 0.48; 95% CI, 0.30-0.79), and 9 mg (HR, 0.60; 95% CI, 0.38-0.95) doses than in those receiving placebo. Diarrhea was the most frequently occurring adverse event, reported in 36.6%, 29.5%, and 24.7% patients in the 18 mg nerandomilast, 9 mg nerandomilast, and placebo groups, respectively. Adverse events leading to regimen interruption or permanent discontinuation occurred at similar rates across the groups. IN PRACTICE: 'The FIBRONEER-ILD trial showed that nerandomilast at a dose of 18 mg twice daily or 9 mg twice daily slowed the progression of pulmonary fibrosis in patients with progressive pulmonary fibrosis,' the authors wrote. 'The current clinical trials represent a meaningful advancement in the treatment landscape for persons living with IPF [idiopathic pulmonary fibrosis] and progressive ILD other than IPF,' the author of an associated editorial wrote. SOURCE: This study was led by Toby M. Maher, MD, Department of Pulmonary, Critical Care, and Sleep Medicine, Keck School of Medicine, University of Southern California, Los Angeles. It was published online on May 19, 2025, in The New England Journal of Medicine. LIMITATIONS: The trial was not powered to evaluate nerandomilast in specific subgroups, including patients grouped by ILD diagnosis. Additionally, patients taking certain medications, particularly mycophenolate, that are commonly used in treating autoimmune diseases were excluded from the trial. DISCLOSURES: This study was funded by Boehringer Ingelheim. Nine authors declared being employees of Boehringer Ingelheim, while few declared serving as consultants. Some other authors reported having other financial ties with various pharmaceutical companies. This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
Medscape
19-05-2025
- Health
- Medscape
Zimlovisertib and Tofacitinib Combo Shows Promise in RA
Zimlovisertib plus tofacitinib showed greater efficacy than tofacitinib alone in reducing Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) in patients with rheumatoid arthritis (RA), with a significant reduction observed at week 12. METHODOLOGY: This randomized, phase 2 study, conducted across 77 centers in 10 countries, aimed to evaluate the efficacy, safety, and pharmacokinetic profiles of zimlovisertib in combination with tofacitinib or ritlecitinib compared with tofacitinib alone in 460 patients (age, 18-70 years) with moderate to severe RA. Participants were randomly assigned to five groups: 400 mg zimlovisertib modified release (MR) + 11 mg tofacitinib MR (n = 103), 400 mg zimlovisertib MR + 100 mg ritlecitinib (n = 101), 400 mg zimlovisertib MR (n = 77), 100 mg ritlecitinib (n = 77), or 11 mg tofacitinib MR (n = 102). A screening period of ≤ 28 days was followed by a 24-week treatment period and a 4-week follow-up period without treatment. The primary endpoint was the change from baseline in DAS28-CRP at week 12; the secondary endpoint included DAS28-CRP remission rates at week 24. Patients were required to discontinue methotrexate prior to randomization and were monitored for treatment-emergent adverse events (TEAEs) throughout the study. TAKEAWAY: Overall, 88.7% of patients continued treatment at week 12, and 69.8% continued treatment at week 24; the main reason for discontinuation was failure to achieve the protocol-specific requirement of at least 20% improvement in American College of Rheumatology response criteria by week 12. Zimlovisertib plus tofacitinib resulted in a greater reduction in DAS28-CRP scores at week 12 than tofacitinib alone (mean change in scores from baseline, −2.65 vs −2.30; P = .032), but the reduction achieved with zimlovisertib plus ritlecitinib vs tofacitinib was not statistically significant. = .032), but the reduction achieved with zimlovisertib plus ritlecitinib vs tofacitinib was not statistically significant. The combination of zimlovisertib and tofacitinib resulted in a higher proportion of patients achieving DAS28-CRP remission at week 24 than tofacitinib alone (40.8% vs 24.0%). TEAEs were reported in 53.5% of patients, with the highest incidence in the tofacitinib monotherapy group (58.8%) and similar rates across all treatment groups. Infections and infestations were the most common TEAEs, affecting 12.6% of patients in the zimlovisertib plus tofacitinib group. IN PRACTICE: 'While improvements in clinical efficacy were seen with the combination groups vs monotherapies, there did not appear to be any increase in incidence, type, and severity of TEAEs,' the authors wrote. SOURCE: This study was led by Spencer I. Danto, MD, PhD, Pfizer Inc., Cambridge, Massachusetts. It was published online on April 14, 2025, in Arthritis & Rheumatology . LIMITATIONS: The relatively small sample size limited the generalizability of the findings. The lack of a placebo control group could have introduced bias and affected the interpretation of the results. Additionally, the study's design included programmatic discontinuation of nonresponders, which may have influenced the observed outcomes. DISCLOSURES: This study was funded by Pfizer. About 10 of the 12 authors reported being employees and shareholders of Pfizer. One author reported receiving principal investigator's grants and grants to support educational activities for physicians and employees from Pfizer.
