Hypothesis / aims of study
Nociceptin/orphanin-FQ peptide (NOP) receptors modulate bladder function and pain signaling [1]. Sunobinop is an oral, investigational NOP agonist that achieves high bladder exposure to affect sensory signaling. Bladder pain and urinary incontinence are hallmark symptoms of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Overactive Bladder (OAB) respectively, while both disorders share urinary urgency, frequency and nocturia with disturbed sleep [2]. An unmet need exists for improved treatments in both diseases. To efficiently explore the safety and efficacy of sunobinop in these bladder disorders, two translational signal detection studies of similar design were undertaken.
Study design, materials and methods
These translational studies employed a two-period, single-sequence, placebo-controlled design with investigative site personnel and patients blinded to both the study eligibility criteria and assigned treatment sequence. Patients that met inclusion/exclusion criteria and completed a 2-week single-blind placebo run-in, were enrolled into a double-blind treatment phase consisting of 2-weeks placebo treatment immediately followed by 6-weeks of sunobinop 1 mg. Entry into the double-blind treatment phase was based on meeting blinded threshold criteria for pain (IC/BPS) and voids (IC/BPS & OAB) using e Diary data gathered during the single-blind placebo run-in.
Results
Comparing the double-blind 2-week placebo treatment period with the double-blind 6-week sunobinop treatment period, sunobinop positively affected symptoms across both populations. In the IC/BPS (study 1) population (N=46), the mean change from baseline in worst bladder pain/discomfort overnight score (averaged over a 7-day period during the last week) with placebo was -0.7 (80%CI: -0.95, -0.39) and following sunobinop was -1.6 (80%CI: -2.02, -1.16). Within-subject improvement was also observed in bladder pain/discomfort over the day, daily micturitions, daily urgency episodes, and urine volume output. Improvement in composite assessment scores for BPIC-SS, ICPI, ICSI and Symptom Impact on Sleep (SISQ) were also observed. Notably, more patients reported moderate and marked improvement in IC/BPS condition at end of sunobinop treatment period (16 patients; 41%) compared to during placebo treatment period (4 patients; 9.3%). A summary of treatment difference in mean change from baseline (sunobinop minus placebo) for key IC/BPS endpoints is displayed in Figure 1.
In the OAB (study 2) population (N=50), mean change from baseline in daily number of incontinence episodes (averaged over a 7-day period during the last week) with placebo was -0.2 (80%CI: -0.32, -0.08) and following sunobinop was -0.4 (80%CI: -0.57, -0.24). Within-subject improvement was also observed for SISQ and sleep quality, PPBC, SGRA and OABq-LF composite sub-domain assessment scores for frequency, urgency, nocturia and sleep. Notably, more subjects reported moderate and marked improvement in OAB condition at end of sunobinop treatment period (11 patients; 23%) compared to during placebo treatment period (5 patients; 10%). A summary of treatment difference in mean change from baseline (sunobinop minus placebo) for key OAB endpoints is displayed in Figure 2.
Sunobinop was well tolerated in both studies. During the sunobinop treatment period, the most frequently reported treatment-related adverse events were urinary tract infection, somnolence, fatigue and nasopharyngitis with no deaths or SAEs reported.
Interpretation of results
Comparing placebo treatment period with sunobinop treatment period, sunobinop positively affected symptoms across both populations. It is notable that pain was reduced in IC/BPS patients and incontinence reduced in OAB patients considering these are disease hallmarks with major patient impact.