Despite a short-notice transition to a fully virtual format, the 2021 American Urological Association annual meeting did not disappoint. Like prior years’ meetings, this one was rich in exciting science, high-yield instructional courses and plenary programming with engaging panels and discussions amongst foremost experts in the field.
As Female Pelvic Medicine & Reconstructive Surgery (FPMRS) specialists, we were especially excited by reports on translational research in the pipeline that should be very impactful for some challenging issues that plague our patients and field.
1. A Sublingual Vaccine for Recurrent Urinary Tract Infections
During Sunday’s morning plenary, Dr. Curtis Nickel presented his late-breaking abstract with exciting trial data on a sublingual vaccine for recurrent UTIs in women. The study was a multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled clinical trial of the M140 sublingual vaccine in women with recurrent UTI. The M140 vaccine is a mucosal vaccine containing four whole cell inactivated bacteria (Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Enterococcus faecalis) applied sublingually. The study randomized 240 women to placebo, 3-month or 6-month daily vaccine and followed for a total of nine months. Participants had a median of six UTIs in the preceding year. The treatment groups had dramatically fewer UTIs compared to placebo, with a median of zero compared to three in placebo. There was no difference between the 3- and 6-month treatment arms, and there were no serious adverse events. Patients in the study who did experience UTI reported lower severity in the treatment arms. Interestingly, the causative species for breakthrough UTI in treatment and control patients did not differ.
Outstanding questions include the vaccine’s impact, if any, on gut microflora and the length of protection or need for “booster” courses. Nonetheless, this therapy, if ultimately approved after full safety and efficacy trials, promises to be a much-welcome game-changer in treatment of recurrent UTIs. Apart from vaginal estrogen therapy in post-menopausal women, there are few efficacious options in treating recurring UTIs in women. The usefulness of prophylactic antibiotics is furthermore limited, and the threat of antibiotic resistance looms large. These trial results suggest superior efficacy compared to antibiotics without the associated risks. We look forward to the publication of this data and eagerly await future investigation with regards to the therapy.
2. Stem Cell Therapy for Persistent Stress Urinary Incontinence
Saturday afternoon’s podium session on Female Incontinence (PD06-01&02) started with Drs. Melissa Kaufman and Michael Chancellor summarizing interim results from the CELLEBRATE trial, a randomized, double-blinded, placebo-controlled phase III trial of intraurethral injection of autologous muscle-derived stem cells (AMDC-USR) for stress urinary incontinence in women. For inclusion, patients needed to have demonstrated mild to moderate stress-predominant incontinence with low hypermobility and failed conservative measures. The authors presented on data from 297 women randomized in 2:1 ratio to treatment vs placebo. Using a minimally significant difference threshold of 75% improvement in stress incontinence frequency as definition for success, the overall intervention cohort did not significantly differ from placebo at 2-year follow-up. However, there were significantly greater improvements seen in patients with prior surgeries as well as those with greater baseline severity in SUI. Dr. Chancellor reported on the sub analysis in patients with persistent or recurrent stress incontinence following failed surgery for SUI. In this group, 40% of patients demonstrated treatment success with AMDC-USR compared to 0% with placebo. Notably, patients in the placebo arm demonstrated similar rate of success with AMDC-USR under open label.
In response to these promising results, the FDA has granted expedited Regenerative Medicine Advanced Therapy (RMAT) designation.
The data in patients with persistent or recurrent SUI is particularly exciting, as this population can be especially difficult to treat and many would like to avoid continued invasive surgeries. While the trial is not complete, AMDC-USR could become the first regenerative medicine therapy to make it to market in our field.
3. Early Chemodenervation to Prevent Detrusor Hypertrophy and Fibrosis Following Spinal Cord Injury
During Saturday’s podium session (PD27-03) Dr. Claire Yang reported data from a rat spinal cord injury (SCI) model showing injection with botulinum toxin A (BoNT-A) at time of suprasacral SCI significantly reduced detrusor hypertrophy and fibrosis compared to saline injection. The histologic slides she presented comparing treatment and control groups were striking and were a powerful visual summary of the results.
This project is at the early stages of a translational pipeline, but nonetheless its results are extremely exciting. Further study is needed in animal models to further confirm findings and elucidate the time window of possible efficacy following injury. If successfully translatable to humans, the results suggest that early bladder chemodenervation may significantly mitigate the pathologic reflexes and subsequent bladder decompensation that follow suprasacral SCI, reducing patient’s risk for upper tract damage and urgency incontinence.
Dr. Zillioux is a second year FPMRS Urology Fellow at the Cleveland Clinic. She has no conflicts of interest or disclosures.
Dr. Goldman is Professor and Vice Chairman of the Glickman Urologic Institute at the Cleveland Clinic. He is an investigator on the CELLEBRATE trial.