Novel gene therapy appears safe, reduces episodes in women with OAB, UUI

Single-dose URO-902 appeared to be safe and effective in treating women with overactive bladder (OAB) and urge urinary incontinence (UUI), according to the final analysis of a phase 2a trial (NCT04211831) presented at the 2023 AUA Annual Meeting.¹

“I think the important thing is, because it's a stage 2a trial, was it safe or not?” said Kenneth M. Peters, MD. “And we found no significant adverse events associated with the treatment. … It was an incredibly safe drug.”

The investigational gene therapy, at both 24 mg and 48 mg, demonstrated clinically relevant reductions from baseline in daily micturitions, urgency episodes, and UUI episodes, compared with placebo.

“It's a novel mechanism of action, because it's actually a plasmid vector. It's a gene therapy that you inject, similar to Botox, [via] intradetrusor [injection] that opens up the potassium channels and allows a relaxation of the detrusor muscle, is the mechanism of action behind it,” Kenneth M. Peters, MD, professor and chair of urology at Oakland University William Beaumont School of Medicine, said in an interview with Urology Times. “So I find it an exciting, novel, new way to manage overactive bladder, and I think the long-term data is certainly supportive of what we saw [at the 12-week interim analysis²].”

In the 48-week, multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial, 45.5% of the 24-mg dose group, 53.8% of the 48-mg dose group, and 53.8% of the placebo group experienced 1 or more treatment-emergent adverse events (AEs), with the most common including urinary tract infection (0% vs 15.4% vs 3.8%, respectively) and hematuria (4.5% vs 7.7% vs 7.7%).

Peters et al reported no deaths or serious AEs related to URO-902; however, they did note 1 patient who received the 48-mg dose experienced asymptomatic, elevated post void residual (PVR) urine volume, which was resolved spontaneously without catheterization.

“I think the important thing is, because it's a stage 2a trial, was it safe or not?” Peters said. “And we found no significant adverse events associated with the treatment. … It was an incredibly safe drug.”

Previous interim analysis

At the 2022 AUA Annual Meeting, Peters presented on data from the prespecified, 12-week interim analysis of the 48-week trial.

At week 12 of the trial, both 24- and 48-mg doses of URO-902, compared with placebo, demonstrated clinically relevant improvements in mean daily micturitions (LS mean change from baseline [CFB], ‒2.5 [95% CI, ‒3.5 to ‒1.4; P = .0297] and ‒3.0 [95% CI, ‒4.0 to ‒1.9; P = .0044] vs ‒1.0 [95% CI, ‒2.0 to 0.1], respectively); urgency episodes (LS mean CFB, ‒2.4 [95% CI, ‒3.9 to ‒0.8; P = .2060] and ‒3.4 [95% CI, ‒4.9 to ‒1.9; P = 0176] vs ‒1.2); UUI episodes (LS mean CFB, ‒2.4 [95% CI, ‒3.4 to ‒1.4; P = .8564] and ‒2.6 [95% CI, ‒3.6 to ‒1.6; P = .5690] vs ‒2.3); OAB questionnaire symptom bother score (LS mean CFB, ‒24.1 [95% CI, ‒34.5 to 13.7; P = .0431] and ‒25.3 [95% CI, ‒35.3 to ‒15.2; P = .0246] vs ‒11.2); and proportion of patient global impression of change responders (LS mean CFB, 40.9% [95% CI, ‒15.4% to 37.9%; P = .4093] and 57.7% [95% CI, 3.4%-52.8%; P = .0256] vs 30.8%).

Study background

Investigators randomized 80 patients 2:1 to receive either single-dose URO-902 24 mg (n = 26), URO-902 48 mg (n = 27), or placebo (n = 27) administered by intradetrusor injection via cystoscopy.

The trial included women aged 40 to 79 years with OAB and UUI who were not adequately managed with 1 or more oral or transdermal pharmacologic therapy. Key inclusion criteria included OAB related to any known neurologic reason, stress-predominant urinary incontinence, and treatment with onabotulinumtoxinA for a urologic indication within 12 months of screening.

To collect data, patients completed a 3-day bladder diary within 7 days before study visits to collect information on daily number of micturitions, urgency episodes, and UUI episodes

Safety served as the primary end point and was assessed by AEs and PVR urine volume. Exploratory end points included change from baseline in mean daily micturitions, urgency episodes, and UUI episodes.

Peters et al noted that patients could receive additional OAB treatments after week 24; however, those patients were excluded from efficacy analyses starting at that timepoint.

In the intent-to-treat exposed patient population (n = 74), mean age was 64.7 years (SD, 7.1) and 13.5% had prior treatment with onabotulinumtoxinA.

In total, 67 patients reached week 24 of the trial. Of the 13 patients who did not, 6 withdrew consent, 2 were lost to follow-up, and 1 each withdrew due to protocol violation, AE, inability to complete procedure, lack of efficacy, and other.

At baseline, the majority of patients experienced more than 3 UUI episodes per day in the 24-mg (77.3%), 48-mg (65.4%), and placebo (69.2%) groups at baseline.

Addressing unmet needs

With OAB, a chronic condition that can decrease quality of life for patients, current guidelines for pharmacologic therapy consist of oral anticholinergics or β3-adrenergic receptor agonists; however, there is an unmet need for a novel mechanism of action, Peters et al wrote.

“If retention holds true, this could be efficacious, with is one of the hopes over onabotulinumtoxinA,” Peters explained; however, he added that durability will be the next challenge to address with this agent.

“We need bigger studies. But if you can [achieve] durability with this gene therapy and the integration into the cells, and that can last even beyond the 6 months, [compared with what] we see with onabotulinumtoxinA, I think it can be a game changer for us in the office [with it] being safer and [having] longer efficacy, but we need more data.”

References

1. Peters KM, Enemchukwu EA, Kalota S, et al. Long-term Efficacy and Safety of URO-902 (pVAX/hSlo) in Women With Overactive Bladder and Urge Urinary Incontinence: Final Results of a Phase 2a Trial. J Urol. 2023;209(4):e1184. doi:10.1097/JU.0000000000003360.19

2. Peters K, Enemchukwu E, Kalota S, Greene H. Efficacy and safety of a novel gene therapy (URO-902; pVAX/hSlo) in female patients with overactive bladder and urge urinary incontinence: results from a phase 2a trial. J Urol. 2022;207(5S):e1048. doi:10.1097/JU.0000000000002671.03