Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain.

BACKGROUND: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain. OBJECTIVES: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain. STUDY DESIGN: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303). SETTING: Primary, secondary, and tertiary care settings in 16 countries. METHODS: Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulfate CR (40-100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: (1) completed the maintenance period, (2) a mean pain intensity < 5 during maintenance, and (3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration. RESULTS: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively. LIMITATIONS: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration. CONCLUSIONS: Results obtained during maintenance indicate that tapentadol PR (100-250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40-100 mg bid), but is associated with better gastrointestinal tolerability.