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NEW ORLEANS -- A form of gene therapy led to clinically significant short-term improvement in women with longstanding overactive bladder (OAB), a preliminary placebo-controlled study showed.

After 12 weeks of follow-up, patients who received a single injection of either of two doses of URO-902 averaged 2.5 to 3 fewer micturitions daily versus patients who received a placebo injection. The average number of daily urgency episodes and episodes of urge urinary incontinence (UUI) declined by a similar degree.

The symptom bother score declined significantly in both URO-902 groups compared with placebo. Significantly more patients allocated to the higher dose of the gene therapy met criteria for clinical response by the Patient Global Impression of Change (PGI-C) questionnaire, reported Kenneth M. Peters, MD, of the Oakland University William Beaumont School of Medicine in Rochester, Michigan, during the American Urological Association meeting.

"In this prespecified 12-week analysis of a phase IIa trial of women with overactive bladder and urge urinary incontinence, a single dose of URO-902, at 24 and 48 mg, was associated with clinically relevant improvements in efficacy and, importantly, quality-of-life endpoints compared to placebo," said Peters. "Very importantly, this was very well tolerated. There were no significant adverse events. Long-term follow-up will be ongoing, and we'll be presenting 48-week data in the future."

Background

URO-902 consists of a plasmid vector that expresses the alpha-subunit of the human BK (big potassium), a large-conductance calcium ion-activated potassium channel. After direct injection into the detrusor, the plasmid increases the number of large potassium channels to reduce bladder contractility, said Peters.

In a , a single dose of URO-902 led to significant reductions in urgency episodes and daily voids, with no serious treatment-related adverse events. The results supported continued clinical evaluation of the gene therapy in a phase II trial.

Investigators in the multicenter trial enrolled women ages 40 to 79 with at least a 6-month history of OAB with UUI not adequately controlled by oral medications. Patients were randomized 2:1 to two separate placebo-controlled cohorts, one of each of the two doses of URO-902. Outcomes of interest included change from baseline in daily micturitions, urgency episodes, and UUI episodes, as well as quality of life and safety.

Data analysis included 22 patients randomized to the lower dose of URO-902, 26 to the higher dose, and 26 to placebo. The study population had a mean age of 65. Three-fourths of the patients reported at least three UUI episodes daily, 15% had prior treatment with onabotulinumtoxinA, and 58% had documented urodynamic detrusor overactivity.

Key Findings

The two URO-902 groups separated early from the placebo group, as average daily micturitions declined by 1.7 within 2 weeks as compared with a decline of 0.24 in the placebo arm. By 12 weeks, daily micturitions had decreased by 2.48 with the lower dose of URO-902 and 2.95 with the higher dose versus 0.96 in the placebo group, both achieving statistical significance versus placebo (P=0.0297 and P=0.0044).

Daily urgency decreased by 2.09 episodes by week 2 with the higher dose of URO-902, 3.09 at week 6, and 3.39 at week 12, which was significantly different from the 1.17-episode decline in the placebo arm (P=0.0176). Mean urgency episodes decreased by 2.34 episodes a day by week 2 in the lower-dose group before losing much of the improvement at week 6 (-1.80 vs baseline) and then declining to 2.37 at week 12, which did not differ from the placebo group.

Daily UUI episodes declined to a similar degree from baseline in all three treatment arms (2.25 to 2.62) and did not differ significantly at week 12.

Quality of life, as assessed by the Overactive Bladder Questionnaire-symptom bother, improved significantly from baseline in patients allocated to the lower dose (P=0.0431) and higher dose (P=0.0246) of URO-902 versus placebo patients. Almost twice as many patients treated with the higher dose of URO-902 met response criteria by the PGI-C questionnaire (15 patients) as compared with the placebo group (eight patients; P=0.0256), whereas the PGI-C response did not differ significantly with the lower dose of the gene therapy (nine patients).

Treatment-emergent adverse events occurred in a similar proportion of patients in all three groups. Treatment-related adverse events occurred in two patients in each of the URO-902 arms versus one in the placebo group. Four patients treated with the higher dose of URO-902 developed urinary tract infection, as compared with one in the placebo group and none of the patients who received the lower dose.

A single case of urinary retention occurred in the higher-dose group. The episode was asymptomatic and resolved without incident after 4 weeks, said Peters.

The early data are favorable but longer follow-up is needed to determine the durability of the therapy, commented Jeffrey Proctor, MD, of Georgia Urology in Cartersville, who was not involved in the study.

"The length of time it holds the effects is key," Proctor told MedPage Today. "If it provides a cure or lasts a year or two, that's much better than having to take a pill all the time. It also seems to be well tolerated and has minimal side effects. That's also going to make it more marketable."

If the results hold up over long-term follow-up, the question of when to use the therapy will come into play, Proctor added. Urologists and patients would like to see more second-line options for OAB, but most patients would probably prefer to take a pill as opposed to getting an intravesical injection. Those tradeoffs will have to be considered if the therapy shows long-term efficacy and tolerability.

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