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Evaluating Drug‐Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady‐state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4‐component transporter cocktail. This open‐label, non‐randomized, 2‐period fixed‐sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18‐55 years with body mass index 18.5‐29.9 kg/m2. During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0‐∞) and the maximum measured concentration of the analyte in plasma (Cmax), and the secondary endpoint was the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0‐tz). Steady‐state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (−2% to −9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE‐1/MATE‐2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0‐∞/Cmax/AUC0‐tz) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug‐transporter interactions in vivo. [ABSTRACT FROM AUTHOR]

BI 730357 is investigated as an oral treatment of plaque psoriasis. We analyzed the impact of three dosage regimens on the Psoriasis Area and Severity Index (PASI) response with modeling based on phase I and II data from 109 healthy subjects and 274 patients with moderate‐to‐severe plaque psoriasis. The pharmacokinetics (PK) was characterized by a two‐compartment model with dual absorption paths and a first‐order elimination. Higher baseline C‐reactive protein was associated with lower clearance and patients generally had lower clearance compared with healthy subjects. A bounded integer PK/pharmacodynamic model characterized the effect on the observed PASI. The maximum drug effect was largest for patients with no prior biologic use, smaller for patients with prior use of non‐interleukin‐17 inhibitors, and smallest for patients with prior interleukin‐17 inhibitor use. The models allowed robust simulation of large patient populations, predicting a plateau in PASI outcomes for BI 730357 exposure above 2000 nmol/L. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of single‐ and multiple‐rising doses (MRDs) of BI 705564 and establish proof of mechanism. Methods: BI 705564 was studied in 2 placebo‐controlled, Phase I clinical trials testing single‐rising doses (1–160 mg) and MRDs (1–80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. Results: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half‐life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single‐dose administration. Functional effects of BTK signalling were demonstrated by dose‐dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding‐related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. Conclusion: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B‐cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding‐related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition. [ABSTRACT FROM AUTHOR]

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin‐23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/NCT03000075), a phase 2/3, double‐blinded, placebo‐controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross‐over to 75 mg risankizumab and placebo with cross‐over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross‐over to risankizumab at week 16. The primary end‐point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI‐90) at week 16 for risankizumab versus placebo. Missing data were imputed as non‐response. All primary and psoriasis‐related secondary end‐points were met for both risankizumab doses (P < 0.001). At week 16, PASI‐90 responses were significantly higher in patients receiving 75 mg (76%) or 150 mg (75%) risankizumab versus placebo (2%). Corresponding response rates were 86%, 93% and 10% for static Physician Global Assessment (sPGA) score of clear/almost clear; 90%, 95% and 9% for PASI‐75; and 22%, 33% and 0% for PASI‐100, with significantly higher responses for both risankizumab doses versus placebo. Through week 52, PASI and sPGA responses increased or were maintained and treatment‐emergent adverse events were comparable across treatment groups. Both doses of risankizumab were superior to placebo in treating patients with moderate to severe plaque psoriasis. The safety profile was consistent with previous risankizumab trials, with no new or unexpected safety findings. [ABSTRACT FROM AUTHOR]

Background: Current topical therapies for cold sores are only marginally beneficial due to poor skin penetration. We assessed the safety and efficacy of a novel topical antiviral nanoemulsion (NB-001) with high tissue bioavailability., Objectives: The primary endpoint was the time to lesion healing., Methods: 482 subjects with recurrent cold sores were randomized to self-initiate treatment with either vehicle or NB-001 (0.1%, 0.3% or 0.5%) at the first signs or symptoms of a cold sore episode. Lotion was applied 5 times per day, approximately 3 to 4 hours apart, for 4 days. Time to lesion healing was correlated with NB-001 bioavailability determined in human cadaver skin., Results: Subjects treated with 0.3% NB-001 showed a 1.3-day improvement in the mean time to healing compared to vehicle (P=0.006). This was consistent with human cadaver skin data indicating that the 0.3% nanoemulsion had the highest bioavailability, compared to 0.1% and 0.5% emulsions. No significant safety or dermal irritation concerns or systemic absorption were noted with any of the doses., Conclusions: Topical NB-001 (0.3%) was well tolerated and highly efficacious in shortening the time to healing of cold sores. The improvement in time to healing was similar to that reported for oral nucleoside analogues, but without systemic exposure. Topical agents for recurrent herpes labialis (cold sores) reduce healing time by one half day, compared to oral therapies that speed healing by a day or more. A topical antiviral nanoemulsion was well tolerated and improved cold sore healing time by over a day compared to vehicle control. Nanoemulsion (NB-001) could represent a more efficacious topical treatment for recurrent cold sores.