Discussion
bleeding, urothelial bleeding, itching, stinging, HC, edema, gastrointestinal damage, urinary incontinence, hematuria, cystitis, tissue damage
ADVERSE REACTIONS, BLEEDING, PROLIFERATION, EDEMA, ATOPIC DERMATITIS, URINARY INCONTINENCE, BLADDER HYPERACTIVITY, HEMATURIA, STERILE, REGRESSION, CYSTITIS
In this dose-ranging phase 2a study in 13 patients with sterile refractory HC, intravesical treatment with LP-10 was found to be safe and well tolerated, with no treatment-related severe or serious AEs and only 3 drug-related AEs that were transient in nature. The frequency of AEs was lowest in the 4 mg group. The analysis of tacrolimus blood levels demonstrated a short duration of systemic uptake, with tacrolimus levels below the safety threshold of 15 ng/mL in all patients and undetectable by 4 h in 85% of patients. These results are in line with those obtained in PK studies with topical tacrolimus in patients with atopic dermatitis, in which peak blood concentrations ranged from undetectable to 20 ng/mL after single or multiple doses of 0.03% and 0.1% tacrolimus ointment [Tacrolimus is a potent macrolide immunosuppressant that acts by inhibiting calcineurin, thereby inhibiting T cell proliferation and the production of a range of inflammatory cytokines [A key benefit of topical tacrolimus is that its side effects are limited to local immune response mechanisms and that severe adverse reactions seen with systemic administration are rare. Even with long-term use in atopic dermatitis, topical tacrolimus causes mainly local and transient symptoms, such as burning, stinging, soreness, or itching [The good tolerability of local tacrolimus prompted us to investigate its potential in modulating the immune response underlying sterile HC by intravesical delivery to the bladder urothelium, i.e., the primary site of tissue damage in cystitis [We also demonstrated, in the cyclophosphamide-induced HC rat model, that instillation of liposomal tacrolimus into the bladder reversed cyclophosphamide-induced bladder hyperactivity by suppressing the local inflammatory reaction as indicated by a decrease in the number of inflammatory cells and suppression of edema. Liposomal tacrolimus also reversed the cyclophosphamide-induced EP4 receptor upregulation in the bladder as well as increases in urine PGE2 and bladder tissue PGE2 and IL-2 levels [In a radiation-induced HC model in the rat, we found that intravesical liposomal tacrolimus resulted in a dose-dependent decrease in micturition intervals, an indicator of bladder function, without inducing short-term skin or gastrointestinal damage [The results of the nonclinical studies with liposomal tacrolimus are mirrored by the efficacy signals obtained in this clinical study. Treatment with LP-10 resulted in significant improvements in the number of bleeding sites on cystoscopy, RBC counts on urine microscopy measured by a central laboratory, hematuria on dipstick, and urinary incontinence. Moreover, two efficacy outcome measures, i.e., the number of bleeding sites on cystoscopy and urinary incontinence, showed a dose-dependent response, with improvements in the higher-dose groups (4 mg and 8 mg) more pronounced than in the low-dose group (2 mg). These improvements in objectively measured bleeding severity and patient-reported urinary incontinence were complemented by significant improvements in the investigator-reported cystoscopic GRA in all dose groups.The primary focus of this phase 2a dose-escalation study was to establish the most promising dose for the future development of LP-10 in the treatment of moderate to severe HC and to evaluate its initial clinical safety profile. The most favorable benefit-risk profile in this study was seen in the 4 mg group, supporting the further clinical development of LP-10 at a tacrolimus dose of 4 mg.Limitations of our study include the small sample size and the absence of a control group. Despite their preliminary nature, all efficacy results point in the same positive direction and derive from a combination of objectively measured, patient-reported, and investigator-reported measures.Of the objective outcome measures in this study, urine microscopy and urine dipstick blood measurements are prone to false-positive and false-negative results and are also subject to variability associated with the transitory nature of urothelial bleeding and urine production. Therefore, direct observation of bleeding sites by cystoscopy may be the most efficient efficacy indicator for measuring regression of HC. In the current study, 58% of patients demonstrated complete or near-complete resolution of bleeding on cystoscopy.