Efficacy and Safety of Eliapixant in Overactive Bladder: The 12-Week, Randomised, Placebo-controlled Phase 2a OVADER Study.

BACKGROUND: Effective, well-tolerated novel treatments for overactive bladder (OAB) are lacking. The P2X3 receptor antagonist eliapixant demonstrated potential to reduce OAB symptoms in preclinical studies. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of eliapixant in patients with OAB with urgency urinary incontinence (UUI). DESIGN, SETTING AND PARTICIPANTS: OVADER was a 12-wk, randomised, placebo-controlled, double-blind, parallel-group, multicentre, phase 2a study (NCT04545580) conducted between 2020 and 2022 in private and institutional clinical practices. Eligible patients were aged ≥18 yr with wet OAB symptoms (urgency, urinary frequency, and urinary incontinence) for ≥3 mo before screening. INTERVENTION: Randomisation (1:1 ratio) to oral eliapixant 125 mg or placebo twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the mean change from baseline in the mean number of UUI episodes/24 h over weeks 4, 8, and 12 according to an electronic bladder diary, evaluated using a repeated-measurement model in a Bayesian framework. RESULTS AND LIMITATIONS: Of 202 patients enrolled, 85 were valid for per-protocol analysis. The primary efficacy endpoint was not met. The posterior probability for eliapixant superiority over placebo was 40% (point estimate 0.05, 95% credible interval -∞ to 0.38), which did not meet the predefined criterion of ≥90% probability. Secondary and exploratory endpoints were not met. The incidence of adverse events was similar in the eliapixant (n = 32, 63%) and placebo (n = 27, 56%) groups; most were mild and five led to discontinuation of eliapixant. CONCLUSIONS: OVADER did not meet its clinical efficacy endpoints. Potential reasons include the nonspecific OAB symptom complex, the poorly understood pathophysiology, and the coinciding COVID-19 pandemic. PATIENT SUMMARY: We tested whether a new drug called eliapixant would reduce symptoms of overactive bladder in comparison to placebo. We found that the drug did not work. More knowledge on how overactive bladder occurs is needed to find new drugs to treat this condition.

First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity.

BACKGROUND: Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies. MATERIAL AND METHODS: In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose-response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated. RESULTS: Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment. CONCLUSION: The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.

Bilateral anterior thalamic nucleus lesions are not protective against seizures in chronic pilocarpine epileptic rats.

AIMS: To investigate whether anterior thalamic nucleus (AN) lesions are protective against spontaneous recurrent seizures in the chronic phase of the pilocarpine model of epilepsy. METHODS: Two groups of rats were treated with bilateral AN radiofrequency thalamotomies or sham surgery 2 weeks after pilocarpine-induced status epilepticus. After the lesions, animals were videotaped from the 2nd to the 8th week after status epilepticus (total 180 h). RESULTS: During the 6 weeks of observation, no differences in the frequency of spontaneous seizures were found between animals that had bilateral AN lesions (n = 26; 3.1 +/- 0.6 seizures per animal) and controls (n = 25; 3.0 +/- 0.6 seizures per animal; p = 0.8). CONCLUSIONS: We conclude that AN thalamotomies were not effective in reducing the frequency of seizures during the chronic phase of the pilocarpine model of epilepsy.

Bilateral anterior thalamic nucleus lesions and high-frequency stimulation are protective against pilocarpine-induced seizures and status epilepticus.

OBJECTIVE: The thalamus is thought to play an important role in secondary generalization of seizures. The aim of the present study was to investigate the influence of anterior thalamic nucleus lesions and high-frequency stimulation in the pilocarpine model of secondarily generalized seizures in rats. METHODS: Adult Wistar rats underwent unilateral (n = 7) or bilateral anterior nucleus thalamotomies (n = 10), or unilateral (n = 4) or bilateral (n = 9) anterior thalamic nucleus stimulation through implanted electrodes. Control animals (n = 9) received bilateral implants but no stimulation. Seven days after these procedures, animals were provided pilocarpine (320 mg/kg intraperitoneally) to induce seizures and status epilepticus (SE). Electrographic recordings from hippocampal and cortical electrodes were evaluated, and ictal behavior was assessed. RESULTS: In the control group, 67% of the animals developed SE 15.3 +/- 8.8 minutes after pilocarpine administration. Neither unilateral anterior nucleus lesions nor stimulation significantly reduced the propensity or latency for developing seizures and SE. Bilateral thalamic stimulation did not prevent SE (observed in 56% of the animals), but it significantly prolonged the latency to its development (48.4 +/- 17.7 min, P = 0.02). Strikingly, no animal with bilateral anterior nucleus thalamotomies developed seizures or SE with pilocarpine. CONCLUSION: Bilateral anterior thalamic nuclear complex stimulation and thalamotomies were protective against SE induced by pilocarpine.