Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma.

BACKGROUND: Prostaglandin D2 receptor 2 (DP2) antagonists inhibit prostaglandin D2-induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist. RESEARCH QUESTION: What is the effect of the DP2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma? STUDY DESIGN AND METHODS: In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/µL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment. RESULTS: A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg. INTERPRETATION: Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03683576; URL: www. CLINICALTRIALS: gov.

A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild-to-moderate asthma.

BACKGROUND: GB001 is an oral antagonist of the prostaglandin D2 receptor that may inhibit recruitment and activation of airway eosinophils, reducing airway inflammation. OBJECTIVE: To assess GB001 safety, efficacy and pharmacokinetics from a Phase 2 study and explore the association between type 2 biomarkers (fractional exhaled nitric oxide and blood eosinophils) and asthma control markers following GB001 administration. METHODS: A randomized, placebo-controlled, double-blind study evaluating 36 patients with mild-to-moderate atopic asthma. Patients receiving fluticasone propionate ≤500 mcg/day or equivalent were randomized (2:1) to GB001 (30 mg) or placebo once daily for 28 days. Safety, pharmacokinetics, forced expiratory volume in 1 second, asthma control questionnaire and rescue medication use were assessed. Clinical outcomes were analysed post hoc by baseline fractional exhaled nitric oxide (<35 and ≥35 ppb) and blood eosinophil (<250 and ≥250 cells/µL) subgroups. RESULTS: GB001 was well tolerated and rapidly absorbed with a 14.5-hour terminal half-life. Overall, GB001 demonstrated greater improvement relative to placebo in forced expiratory volume in 1 second at Day 28 (102 mL [95% CI: -110, 314]). Greater effects on forced expiratory volume in 1 second were observed in the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups (207 mL [95% CI: -283, 698];133 mL [95% CI: -422, 687], respectively). These effects were observed as early as Day 2 (229 mL [95% CI: -170, 628]; 163 mL [95% CI: -223, 550] for the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups, respectively) and were sustained through treatment completion. CONCLUSION AND CLINICAL RELEVANCE: GB001 was well tolerated, with the estimated half-life supporting once-daily (QD) dosing. GB001 may have a rapid and sustained effect on lung function, particularly in patients with type 2 phenotype. Further studies are needed to confirm these findings.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator.

Ozanimod (RPC1063) is an oral selective modulator of the sphingosine-1-phosphate 1 and 5 receptors under development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. The effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod were evaluated in 24 healthy volunteers in a randomized, open-label crossover trial. Each subject received a 1-mg dose of ozanimod hydrochloride under 3 meal conditions (fasted, high-fat, and low-fat), each separated by 7 days. Mean plasma concentration-time profiles for ozanimod and its active metabolites (RP101988 [major], RP101075 [minor]) were similar under all 3 conditions. Moreover, all PK parameters for ozanimod, RP101988, and RP101075 were similar under the 3 meal conditions. The 90% confidence intervals (CIs) for the ratios of geometric least-squares mean (fed/fasted) were within the equivalence limits of 0.80 to 1.25 for area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) and maximum plasma concentration (Cmax ) for ozanimod, RP101988, and RP101075, except for the high-fat effect on RP101075 Cmax (90%CI, 0.76-0.88). Given this lack of a food effect on the exposure of ozanimod and its active metabolites, ozanimod can be taken without regard to meals.