Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Background ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.Methods In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy end-point was change in cough frequency assessed over 24 h. The primary safety end-point was frequency and severity of adverse events (AEs).Results 37 patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg: 25% (90% CI 11.5–36.5%); p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant; all were mild.Conclusions Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC

A Novel Fluorescent Imaging Agent for Diffuse Optical Tomography of the Breast: First Clinical Experience in Patients

Purpose: This is the first clinical evaluation of a novel fluorescent imaging agent (Omocianine) for breast cancer detection with diffuse optical tomography (DOT). Procedures: Eleven women suspected of breast cancer were imaged with DOT at multiple time points (up to 24 h) after receiving an intravenous injection of Omocianine (doses 0.01 to 0.1 mg/kg bodyweight). Breast MRI was obtained for comparison. Results: Histopathology showed invasive cancer in ten patients and fibroadenoma in one patient. With the lowest dose of Omocianine, two of three lesions were detected; with the second dose, three of three lesions were detected; with the two highest doses, none of five lesions were detected. Lesion location on DOT showed excellent agreement with MRI. Optimal lesion-tobackground signals were obtained after 8 h. No adverse events occurred. Conclusions: Lowest doses of Omocianine performed best in lesion detection; DOT using a lowdose fluorescent agent is feasible and safe for breast cancer visualization in patients

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study

BACKGROUND AND OBJECTIVE: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. METHODS: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. RESULTS: Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. CONCLUSIONS: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-022-01126-1

The effect of a combined indomethacin and levonorgestrel-releasing intrauterine system on short-term postplacement bleeding profile: a randomized proof-of-concept trial

Background Long-acting reversible contraceptives, including hormonal levonorgestrel-releasing intrauterine systems, are the most effective methods of reversible contraception. However, unfavorable bleeding, particularly during the first months of use, is one of the most important reasons for discontinuation or avoidance. Minimizing this as early as possible would be highly beneficial. Nonsteroidal anti-inflammatory drugs inhibiting prostaglandin synthesis are known to reduce bleeding and pain at time of menses. A levonorgestrel-releasing intrauterine system has been developed with an additional reservoir containing indomethacin, designed to be released during the initial postplacement period. Objective This proof-of-concept study aimed to establish whether the addition of indomethacin to the currently available levonorgestrel-releasing intrauterine system (average in vivo levonorgestrel release rate of 8 μg/24 h during the first year of use) reduces the number of bleeding and spotting days during the first 90 days of use compared with the unmodified system. The dose-finding analysis included 3 doses of indomethacin—low (6.5 mg), middle (12.5 mg), and high (15.4 mg)—to determine the ideal dose of indomethacin to reduce bleeding and spotting days with minimal side-effects. Study Design This was a multicenter, single-blinded, randomized, controlled phase II trial conducted between June 2018 and June 2019 at 6 centers in Europe. Three indomethacin dose-ranging treatment groups (low-, middle-, and high-dose indomethacin/levonorgestrel-releasing intrauterine system) were compared with the unmodified levonorgestrel-releasing intrauterine system group, with participants randomized in a 1:1:1:1 ratio. The primary outcome was the number of uterine bleeding and spotting days over a 90-day reference (treatment) period. Secondary outcomes were the number of women showing endometrial histology expected for intrauterine levonorgestrel application and the frequency of treatment-emergent adverse events. Point estimates and 2-sided 90% credible intervals were calculated for mean and median differences between treatment groups and the levonorgestrel-releasing intrauterine system without indomethacin. Point and interval estimates were determined using a Bayesian analysis. Results A total of 174 healthy, premenopausal women, aged 18 to 45 years, were randomized, with 160 women eligible for the per-protocol analysis set. Fewer bleeding and spotting days were observed in the 90-day reference period for the 3 indomethacin/levonorgestrel-releasing intrauterine system dose groups than for the levonorgestrel-releasing intrauterine system without indomethacin group. The largest reduction in bleeding and spotting days was achieved with low-dose indomethacin/levonorgestrel-releasing intrauterine system, which demonstrated a point estimate difference of −32% (90% credible interval, −45% to −19%) compared with levonorgestrel-releasing intrauterine system without indomethacin. Differences for high- and middle-dose indomethacin/levonorgestrel-releasing intrauterine system groups relative to levonorgestrel-releasing intrauterine system without indomethacin were −19% and −16%, respectively. Overall, 97 women (58.1%) experienced a treatment-emergent adverse event considered related to the study drug, with similar incidence across all treatment groups including the unmodified levonorgestrel-releasing intrauterine system. These were all mild or moderate in intensity, with 6 leading to discontinuation. Endometrial biopsy findings were consistent with effects expected for the levonorgestrel-releasing intrauterine system. Conclusion All 3 doses of indomethacin substantially reduced the number of bleeding and spotting days in the first 90 days after placement of the levonorgestrel-releasing intrauterine system, thus providing proof of concept. Adding indomethacin to the levonorgestrel-releasing intrauterine system can reduce the number of bleeding and spotting days in the initial 90 days postplacement, without affecting the safety profile, and potentially improving patient acceptability and satisfaction

The safety and pharmacokinetics of rapid iloprost aerosol delivery via the BREELIB nebulizer in pulmonary arterial hypertension

The BREELIB nebulizer was developed for iloprost to reduce inhalation times for patients with pulmonary arterial hypertension (PAH). This multicenter, randomized, unblinded, four-part study compared inhalation time, pharmacokinetics, and acute tolerability of iloprost 5 mu g at mouthpiece delivered via BREELIB versus the standard I-Neb nebulizer in 27 patients with PAH. The primary safety outcome was the proportion of patients with a maximum increase in heart rate (HR) >= 25% and/or a maximum decrease in systolic blood pressure >= 20% within 30 min after inhalation. Other safety outcomes included systolic, diastolic, and mean blood pressure, HR, oxygen saturation, and adverse events (AEs). Median inhalation times were considerably shorter with BREELIB versus I-Neb (2.6 versus 10.9 min; n = 24). Maximum iloprost plasma concentration and systemic exposure (area under the plasma concentration-time curve) were 77% and 42% higher, respectively, with BREELIB versus I-Neb. Five patients experienced a maximum systolic blood pressure decrease >= 20%, four with BREELIB (one mildly and transiently symptomatic), and one with I-Neb; none required medical intervention. AEs reported during the study were consistent with the known safety profile of iloprost. The BREELIB nebulizer offers reduced inhalation time, good tolerability, and may improve iloprost aerosol therapy convenience and thus compliance for patients with PAH