Liposomal botulinum shows promise for refractory OAB

Stockholm, Sweden-Intravesical administration of a liquid liposomal formulation of onabotulinumtoxinA (“Liposomal BoNT-A") shows promise as a safe and effective treatment for refractory overactive bladder (OAB), according to a pilot study presented at the European Association of Urology annual congress in Stockholm, Sweden.

This first clinical evaluation of the investigational topical BoNT-A formulation for treatment of OAB was undertaken as a physician-sponsored, single-institution, double-blind study at Tzu Chi University, Hualien, Taiwan. It enrolled 24 patients who had urgency frequency and/or urgency urinary incontinence, an urgency severity scale score ≥2, failed oral antimuscarinic therapy, and no previous BoNT-A treatment. They were randomized to receive Liposomal BoNT-A or normal saline. The total volume (50 mL) was kept in the bladder for 60 minutes.

Change from baseline to 1 month in total urinary frequency per 3 days was assessed as the primary endpoint. Mean baseline frequency per 3 days was 34 in the Liposomal BoNT-A group and 29 in the controls, and there was a statistically significant reduction in the Liposomal BoNT-A group but not in the controls (median, −6.5 vs. 0.0). Urgency episodes per 3 days were also decreased significantly in the Liposomal BoNT-A group, but not in the controls (median, −12.0 vs. −1.0). There were no significant changes in maximum flow rate, voided volume, or post-void residual urine in either study group, and there were no cases of urinary tract infection or urinary retention.

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Formulation may overcome current challenges

Dr. Chancellor“There is a lot of excitement in urology about neurotoxin treatment for various conditions of the bladder. However, the administration by intradetrusor injections requires a cystoscopic procedure performed under anesthesia or sedation and has been associated with risks of infection and urinary retention,” said study co-author Michael B. Chancellor, MD, founder and chief medical officer of Lipella Pharmaceuticals and professor and director of neurourology at William Beaumont School of Medicine, Oakland University, Royal Oak, MI.

“The liposomal formulation of BoNT-A aims to overcome the urothelial barrier to penetration and deliver the toxin preferentially to the urothelium and submucosa in order to achieve efficacy with fewer side effects. The results from this first clinical investigation are encouraging. Data from a second, larger multicenter double-blind placebo trial with longer follow-up will be presented at the 2014 annual meeting of the American Urological Association in May.”

Change in urge urinary incontinence was also evaluated in the study. While it did not change significantly in the Liposomal BoNT-A group, the mean number of episodes per 3 days at baseline was only 0.5 as not all participants had wet OAB.

Biopsies were also obtained at baseline and after 3 months to study the mechanism of action of Liposomal BoNT-A. Analyses with immunohistochemistry and Western blot studies showed synaptic vesicle glycoprotein 2A (SV2A), the binding receptor for BoNT-A, and synaptosome-associated protein, 25 kDA (SNAP25), the protein mediating the effect of BoNT-A for inhibiting acetylcholine release, were both expressed in urothelial cells and suburothelial tissues. However, there was no significant change in SNAP25 expression from baseline to 3 months.

“The finding of SV2A and SNAP25 in the biopsied tissue provides a physiologic basis to explain the efficacy observed in the pilot trial. The relevance of the lack of change in SNAP25 from baseline is unknown as it is possible the proteins may have recovered at 3 months,” Dr. Chancellor said.

Dr. Chancellor developed the liposomal formulation of BoNT-A while at the University of Pittsburgh through research supported by a National Institutes of Health grant.

Findings from the study were published online ahead of print in European Urology (Feb. 11, 2014).UT

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