Investigational OAB agent efficacious, well tolerated

Milan, Italy-THVD-201 (Tolenix), a novel formulation combining tolterodine and pilocarpine, was found safe, well tolerated, and effective against overactive bladder (OAB) in a recent study.

The investigational agent was associated with similar efficacy but significantly less incidence of dry mouth than tolterodine (Detrol).

The phase II randomized, double-blind, multiple-crossover study with placebo and an active control group (immediate-release tolterodine, 2 mg) was conducted to evaluate the safety and efficacy of THVD-201 in 138 women with OAB. The study was preceded by a 6-week tolterodine, 2 mg twice-daily, lead-in period, which was administered to all 138 subjects. The subjects were then randomized to treatment group A: THVD-201, 2 mg/9 mg twice daily; treatment group B: tolterodine, 2 mg twice daily; or treatment group C: placebo twice daily, for a duration of 4 weeks.

Each subject was crossed over to receive treatments A, B, and C over a 12-week period, for 4 weeks each. The study was followed by a 12-week open-label extension period in which all subjects were given THVD-201, 3 mg/13.5 mg twice daily and tolterodine, 4 mg daily.

THVD-201, an oral capsule, fixed-dose combination drug product containing immediate-release tolterodine (2 mg) and a proprietary, delayed-onset formulation of pilocarpine (9 mg), was administered twice daily. The number of micturitions/day and incontinence episodes/day were collected using standard 3-day urinary diaries at the end of each treatment. Dry mouth severity was assessed using a 100-mm visual analog scale (VAS; 0 mm=not dry, 100 mm=very dry). Subjects with <13 micturitions/day, ≤5 incontinence episodes/3 days, and a dry mouth score ≥35 mm at the end of the lead-in period were eligible.

Study participants also took part in a sub-study of stimulated salivary flow (SSF). Saliva was collected prior to and following a single administration of each treatment.

“What we found was quite pleasing with respect to OAB symptoms and improvements in both urinary frequency and incontinence episodes,” said senior author Roger Flugel, PhD, CEO of TheraVida Inc., which is developing THVD-201. “There was no difference in efficacy between Tolenix and tolterodine alone. However, when we looked at the dry mouth side effect, we saw a very statistically significant and clinically meaningful improvement with Tolenix.”

Dr. Flugel spoke at the European Association of Urology annual congress in Milan, Italy on behalf of TheraVida and first author Roger Dmochowski, MD, of Vanderbilt University, Nashville, TN.

Efficacy similar between therapies

The trial revealed that SSF following THVD-201 was similar to placebo, while there was a marked decrease in SSF following administration of tolterodine. The mean number of micturitions per day for tolterodine and THVD-201 were similar (8.74 for both), and both were statistically superior to placebo (p<.0001). The mean number of incontinence episodes per day for tolterodine and THVD-201 were 0.50 and 0.46, respectively, and were statistically superior to placebo (p<.0001).

Subjects receiving THVD-201 reported a mean dry mouth score of 28.7 mm, which was significantly lower than the score in patients taking tolterodine (40.4 mm, p<.0001). There were no serious study drug-related adverse events or unanticipated adverse events with THVD-201.

Dr. Flugel noted that although theoretically, one should lose efficacy in terms of bladder control when giving both a muscarinic and antimuscarinic drug together, tolterodine targets primarily M2 and M3 muscarinic receptors while pilocarpine targets mostly M1 muscarinic receptors, which play a much larger role in saliva production than in the bladder.

“The tolterodine treats the OAB and the pilocarpine offsets or reduces the dry mouth side effect typically associated with tolterodine use. We believe this product has the potential to effectively treat OAB and reduce or eliminate the very problematic dry mouth side effect,” Dr. Flugel said.UT