28043 Roflumilast cream significantly improves chronic plaque psoriasis in patients with steroid-sensitive area involvement

Roflumilast cream is a nonsteroidal, selective phosphodiesterase-4 inhibitor in development for plaque psoriasis (PsO). A double-blind, phase 2b trial randomized adults with PsO to once daily roflumilast 0.3%, 0.15%, or vehicle for 12 weeks (NCT03638258).(1) Efficacy was assessed using Investigator Global Assessment (IGA), Worst Itch Numeric Rating Scale (WI–NRS), and Psoriasis Symptom Diary (PSD). This posthoc analysis reports efficacy and safety in patients with steroid-sensitive area involvement (plaques on the face, neck, or in intertriginous areas). Of 331 patients, 160 had steroid-sensitive area involvement. The primary endpoint in the study, IGA status clear/almost clear at Week 6 was met by 27.2% patients with steroid sensitive areas (P =.007 vs vehicle), 22.3% (P =.026), and 6.3% on roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively; relative to 30.1% (P =.026), 24.1% (P =.098), and 12.0% patients without steroid-sensitive areas. Among patients with baseline WI–NRS score ≥4, 73.5%, 55.6%, and 32.6% of those with steroid-sensitive areas and 45.9%, 72.7%, and 23.7% of those without steroid-sensitive areas achieved a 4-point reduction with roflumilast 0.3%, 0.15%, or vehicle at Week 12. PSD improvement from baseline at Week 12 for patients with steroid-sensitive areas was -48.3 (P ˂.001), -43.1 (P =.012), and -24.9, and for patients without steroid-sensitive areas -35.7 (P =.003), -44.6 (P ˂.001), and -17.1. Most treatment emergent adverse events were mild to moderate and there was no evidence of local irritation. Once-daily roflumilast cream was well tolerated with significant improvements in investigator and patient assessed PsO outcomes in patients with steroid-sensitive area involvement on the face, neck, or intertriginous areas

27874 Correlation of itch response to roflumilast cream with disease severity and patient-reported outcomes in patients with chronic plaque psoriasis

Roflumilast cream is a nonsteroidal, selective phosphodiesterase-4 inhibitor in development for plaque psoriasis (PsO). A Phase 2b, double-blinded trial randomized adults with PsO (2-20% body surface area) to once daily roflumilast 0.3%, roflumilast 0.15%, or vehicle for 12 weeks (NCT03638258). Throughout the trial, itch and its impact were evaluated via patient reported outcomes (PROs): Worst Itch Numeric Rating Scale (WI–NRS), Itch related Sleep Loss (IRSL), and Dermatology Life Quality Index (DLQI). This posthoc analysis reports correlation of WI–NRS with other PROs and with disease severity. Overall, 331 patients were randomized (109 to roflumilast 0.3%, 113 to 0.15%, and 109 to vehicle). At baseline, the mean WI–NRS score was 5.87. Throughout the trial, both roflumilast doses showed similar improvements in WI–NRS starting at Week 2 and were significantly superior to vehicle (P ≤.002). At baseline, Pearson correlation coefficients (PCCs) for WI–NRS and Psoriasis Area and Severity Index (PASI) were 0.189, 0.282, 0.205 for roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively (P ≤.033 for all correlations); for WI–NRS and IRSL: 0.548, 0.646, 0.652 (P ˂.001); for WI–NRS and DLQI: 0.445, 0.617, 0.422 (P ˂.001). At Week 8, PCCs for WI–NRS and PASI were 0.420, 0.409, 0.365 (P ˂.001); for WI–NRS and IRSL: 0.673, 0.725, 0.696 (P ˂.001); for WI–NRS and DLQI: 0.607, 0.823, 0.529. Treatment with roflumilast resulted in rapid and robust improvement in the severity of itch associated with PsO. Itch response to roflumilast was independent of disease severity and positively correlated with patient-reported sleep loss and quality of life improvement

Exposure–response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection

To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies

28588 Efficacy and safety of roflumilast foam 0.3% in patients with seborrheic dermatitis in a randomized, double-blind, vehicle-controlled phase 2 study

Seborrheic dermatitis is a chronic inflammatory skin condition that may cause physical discomfort and emotional burden for patients including itching, stress, and embarrassment. Topical treatments, such as antifungals, steroids, immunomodulators, and dandruff shampoos are used, but there is a need for efficacious and safe options, especially for long-term use. A phase 2, 8-week study investigated roflumilast foam 0.3%, a potent, phosphodiesterase-4 inhibitor designed for once-daily treatment of lesions on the scalp, face, and body. Patients with at least moderate severity (mean IGA 3.1) and mean BSA 3.2% were randomized to roflumilast foam 0.3% (n = 154) or vehicle foam (n = 72). For the primary endpoint, IGA success at Week 8, 73.8% and 40.9% patients achieved IGA of clear/almost clear in the roflumilast foam and vehicle groups, respectively (P \u3c.0001). Improvement in IGA success was statistically significant starting at first postbaseline visit (Week 2, P =.0033) and continuing through Week 8 (P \u3c.0001). Scaling and erythema were both significantly reduced at Week 8 in patients on roflumilast foam compared with vehicle (P ≤.002). Among patients with baseline Worst Itch Numeric Rating Scale (WI–NRS) score ≥4 (n = 184/226), statistically significant 4-point reduction in WI-NRS was achieved as early as Week 2 with roflumilast foam compared with vehicle (P ≤.0007). Rates of application-site pain, treatment-related adverse events, and discontinuations due to adverse events were low and comparable to vehicle. Once-daily roflumilast foam 0.3% was safe, well tolerated, and effective in treating erythema, scaling, and itch of seborrheic dermatitis, and represents a promising and mechanistically novel treatment with early onset of action

Exposure-response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection.

PurposeTo characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.MethodsA population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.ResultsThere was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).ConclusionsIncreased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies