Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder and associated with lower urinary tract symptoms that persists for more than 6-weeks in the absence of infection or other identifiable causes.(1)  Patients experiencing IC/BPS commonly report severe pain attacks or “flares” of extended duration which significantly impact comorbid illness and quality of life.(2)  Stabilization of these symptoms may improve future flare frequency and patient outcomes.(3)  Intravesical lidocaine is used clinically to reduce pain associated with IC/BPS.  There are no FDA approved intravesical lidocaine formulations available. Currently employed "off-label" lidocaine preparations are limited by pharmacokinetic factors leading to a short duration of effect.  IMB-150 (formerly LYT-503) is a novel microparticle formulation designed to target inflamed tissues, provide continuous lidocaine bladder concentrations and a sustained duration of effect. 

Cyclophosphamide (CYP)-induced inflammatory visceral pain is commonly used as an experimental model for acute IC/BPS in rodents. In rats, systemic administration of CYP injection leads to accumulation of its toxic metabolite acrolein in the urinary bladder resulting in urinary bladder inflammation, visceral pain and increased micturition frequency.  While some chronic models of CYP-induced IC/BPS have been reported to often lead to severe toxicity causing 50% mortality, our chronic rat model of CYP-induced IC/BPS (consisting of 3 injections (40mg/kg, i.p.) every 3 days) resulted in prolonged IC/BPS symptoms, no weight loss, and 100% survival rate. 

The aim of these studies was to examine the efficacy of IMB-150 on visceral pain response using both acute and chronic CYP-induced IC/BPS models in female Sprague-Dawley rats and to examine single and multiple dose safety and pharmacokinetics following intravesical administration in beagle dogs.

In an acute model of IC/BPS, rats were administered a single dose of intraperitoneal CYP 150mg/kg. Four hours after CYP administration, intravesical IMB-150 (34mM), or intravesical free lidocaine (34mM) was administered.  Tactile sensitivity was measured at baseline, 6, 8 and 24 hr after CYP administration.  In a chronic model of IC/BPS, rats received intraperitoneal 40 mg/kg CYP on days 0, 3 and 6. On day 7, animals received intravesical IMB-150 (11mM), or intravesical free lidocaine (11mM). Tactile sensitivity was assessed at baseline, 4hr after the last CYP dose and at 2, 4, 24, 48 and 72hr post-treatment.  In both acute and chronic models of IC/BPS, tactile sensitivity was assessed using von Frey fibers of increasing force 1, 2, 4, 6, 8, 10, 15 and 26g at 5 second interstimulus intervals. The nociceptive threshold was defined as the force (g) for which the stimulus produced a nocifensive response. An integrated (area under the curve) analgesic effect was calculated using trapezoidal approximation for individual animals as the nociceptive threshold vs time graph from 6–24hr and 2–48hr for the acute IC/BPS and chronic IC/BPS models, respectively. A comparison of the integrated analgesic effect values of vehicle, free lidocaine, and IMB-150 was performed using an ordinary one-way analysis of variance (ANOVA) with a Tukey multiple comparisons test to assess differences between the groups.

To study safety and pharmacokinetics, adult beagle dogs were anesthetized, catheterized and given intravesical IMB-150 at low (2.4mg/kg), mid (7.2mg/kg) and high – maximally feasible dose (24mg/kg). All animals were administered IMB-150 once weekly for 8 weeks (a total of 8 administrations).  Intravesical doses were held in the bladder for 1hr post-administration and subsequently the bladder was evacuated.  Plasma lidocaine concentrations were measured on days 1, 22, and 50 corresponding to the first, fourth and last dose respectively. Urinary lidocaine concentrations were measured daily for 15 days after the last dose on week 8.  Throughout the study and for a 2-week recovery period, assessments included mortality checks, clinical observations, body weight, food consumption, ophthalmology and electrocardiograms.

In the acute IC/BPS model, free lidocaine increased nociceptive thresholds at 6hr and 8hr (p<0.05)).  IMB-150 increased nociceptive threshold at 6hr and 8hr (p<0.001) as well as at 24hr (p<0.05). In the chronic IC/BPS model, free lidocaine produced a transient increase in threshold at 4hr, 24hr and 48hr (p<0.05).  IMB-150 had a marked and significant effect at 2hr (p<0.001) and maintained a significant effect through 72hr. Across the study period for both the acute and chronic IC/BPS models, the integrated analgesic effect, was significantly greater in IMB-150 treated animals when compared to vehicle.  In the acute IC/BPS model, the integrated analgesic effect with IMB-150 was significantly greater with IMB-150 when compared to free lidocaine (p < 0.05). (Figure 1) 

In beagle dogs, following an intravesical dose of IMB-150, plasma lidocaine concentrations were generally observed up to 8 hours at low dose (2.4mg/kg) and up to 24 hours at the mid (7.2mg/kg) and high dose (24mg/kg).  When administered weekly to male dogs for 8 weeks, at the high dose (24mg/kg) Cmax plasma lidocaine was 789±437, 695±426, and 640±352ng/ml on days 1, 22 and 50 respectively.  At the same dose in female dogs, Cmax plasma lidocaine was 956±416, 491±155, and 411±97ng/ml on days 1, 22 and 50 respectively. IMB-150 instillation at both mid and high doses resulted in detectable lidocaine in urine samples of male and female animals up to 15 days post last dose administration at 8 weeks (Figure 2). Weekly IMB-150 was well tolerated at all doses tested.  There was no clear trend in the body weight/body weight change and food consumption. IMB-150 had no observed effect on ocular, electrocardiology, hematology, coagulation, clinical chemistry and urinalysis measures

Administration of CYP in both acute and chronic model paradigms in rats reduces nociceptive thresholds suggesting that CYP produces a model of disease appropriate for assessing the anti-nociceptive effect of test agents. Intravesical lidocaine produces an anti-nociceptive effect as evidenced by increased nociceptive sensory thresholds in both the acute and the chronic CYP model providing further model validation. IMB-150 also produces an anti-nociceptive effect as evidenced by increased nociceptive sensory thresholds in both the acute and the chronic CYP models. In comparing the integrated analgesic effect (which considers magnitude as well duration of efficacy response), we see a numerically greater effect of IMB-150 over free lidocaine in both models which reaches statistical significance in the acute model. These response attributes are a desirable characteristic for managing severe and prolonged pain associated IC/BPS. 

In dogs dosed with intravesical IMB-150 once per week for 8 consecutive weeks, rapid onset and relatively short-lived plasma concentrations (largely cleared by 24 hours post-dose) were observed. In contrast, while urinary concentrations fell to relatively low levels by 72 hours post-dosing a low, prolonged  urinary concentration of lidocaine was observed up to 15 days post-dosing (the last time point tested). IMB-150 was well tolerated and was without findings that would constitute a safety concern at the doses tested. As such these data suggest a satisfactory safety profile with the potential for sustained bladder concentrations of lidocaine following intravesical administration of IMB-150.

In both acute and chronic CYP models of IC/BPS, treatment with IMB-150 resulted in a statistically significant analgesic effect. Following intravesical administration of IMB-150 in beagle dogs, lidocaine was detectable in the urine for two weeks with plasma concentrations well below the clinical threshold for lidocaine toxicity.  These data suggest IMB-150 has the potential to deliver lasting analgesia. Phase 1 clinical studies are ongoing to support further understanding of the pharmacokinetics and pharmacodynamics in patients with IC/BPS.

Clemens JQ, Erickson DR, Varela NP, Lai HH, Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome. The Journal of Urology® (2022), doi:10.1097/JU.0000000000002756.
Sutcliffe S, Bradley CS, Clemens JQ, et al. Urological chronic pelvic pain syndrome flares and their impact: qualitative analysis in the MAPP network. Int Urogynecol J. 2015;26(7):1047-1060. doi:10.1007/s00192-015-2652-6
Sutcliffe S, Newcomb C, Bradley CS, et al. Associations Between Urological Chronic Pelvic Pain Syndrome Symptom Flares, Illness Impact, and Health Care Seeking Activity: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study [published online ahead of print, 2023 Jan 11]. J Urol.

Continence 7S1 (2023) 100766
DOI: 10.1016/j.cont.2023.100766