Understanding the Response to Fesoterodine Through Genetic Evaluation in the Elderly (URGE)

Urge urinary incontinence (UUI), characterized by unpredictable and embarrassing large volume
urine leakage, is a major public health burden to elderly women, given its high prevalence,
impairment of quality of life, associated caregiver burden, and substantial economic costs.
UUI is significantly more prevalent in older adults and disproportionately affects women,
with a prevalence of 19% in community-dwelling women over 65 and 60-78% in long-term care
female residents.

Anticholinergic medications are the most common first-line therapy for UUI. Although numerous
trials have demonstrated that anticholinergics are efficacious for UUI, the response to these
medications is variable, as their effectiveness is often limited by poor response or adverse
events (AEs), such as cognitive impairment or constipation, which are particularly
problematic in older adults. Furthermore, a comprehensive systematic review concluded that no
one drug is definitively superior, leaving clinicians without any evidence to guide
decision-making regarding drug choice. As a result, UUI pharmacotherapy is empiric and not
personalized, even though it is clear that individual variations exist in both response and
toxicity. The treatment of UUI is especially challenging in the geriatric population, given
their higher risk for AEs, polypharmacy, and pharmacokinetic changes that occur with age. The
ability to predict which elderly women with UUI will experience low efficacy or develop
significant adverse events from anticholinergic medications would be a paradigm shift in the
therapeutic practice to this highly prevalent and bothersome condition.

Pharmacogenetics may provide insight into how to predict response to anticholinergic UUI
therapy. Research has already shown that genetic differences in drug metabolism impact a
patient's drug response. For example, "fast metabolizers" may metabolize the drug so rapidly
that therapeutic levels are never reached, limiting effectiveness. In contrast, "slow
metabolizers" may develop high drug concentrations, resulting in significantly more AEs.
While pharmacogenetic research exists for numerous classes of drugs, including
anticoagulants, selective serotonin-reuptake inhibitors,14 beta-blockers, immunosuppressants
and opioids, this type of translational research does not exist for anticholinergics for UUI.
Thus, this proposed project represents a novel concept and unique opportunity to dramatically
change UUI pharmacotherapy.

Fesoterodine is an ideal anticholinergic medication to launch a pharmacogenetic study in this
field. Fesoterodine's active metabolite, 5-hydroxymethyl tolterodine (5-HMT), is metabolized
by a well-characterized cytochrome P450 (CYP) enzyme, CYP2D6. The CYP2D6 gene has several
genetic variants, which result in different metabolizer statuses ranging from poor
metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM), to ultrarapid
metabolizers (UM). These different CYP2D6 profiles may be clinically important, as they may
contribute to the variability in efficacy and AEs. In fact, pharmaceutical company data for
fesoterodine demonstrated that PMs have a two-fold higher plasma concentration than EMs;
however, no published data exist on how CYP2D6 metabolizer status correlates with clinical
outcomes such as efficacy or AEs. The ability to use CYP2D6 metabolizer status to predict
which individuals will experience low efficacy or develop AEs to fesoterodine, and to utilize
alternative therapies in these women, would challenge existing therapeutic paradigms and
would significantly advance clinical practice via a pharmacogenetic approach.

Specific Aim 1: To explore whether CYP2D6 metabolizer status can predict efficacy during 4
weeks of fesoterodine fumarate therapy in elderly women with UUI. All subjects will be
started on fesoterodine 4mg for 2 weeks followed by 8mg for 2 weeks. The primary outcome will
be patient-reported treatment response based on a 4-point scale utilized in phase III
clinical trials.8,9 We hypothesize that women who rapidly metabolize fesoterodine based on
CYP2D6 metabolizer status are more likely to have low efficacy.

Specific Aim 2: To explore whether CYP2D6 metabolizer status can predict moderate to severe
adverse events during 4 weeks of fesoterodine fumarate therapy in elderly women with UUI. In
the same study design as Aim #1, we will identify subjects with moderate to severe
fesoterodine-related AEs. We hypothesize that women who are CYP2D6 poor metabolizers are more
likely to have moderate to severe AEs.

Specific Aim 3: To utilize preliminary data from this pilot, proof-of-concept study to plan a
future large-scale trial to predict outcomes of anticholinergic UUI therapy based on CYP2D6
metabolizer status. Data regarding efficacy rates, risk of moderate-severe AEs, and the
impact of CYP2D6 metabolizer status on efficacy and AEs, in addition to information regarding
recruitment, drop-out, and questionnaire burden, will critically inform the study design,
outcome measures and sample size of future, definitive trials.

This proposal represents an innovative approach to pharmacotherapy for UUI, a highly
prevalent condition with significant morbidity. Pharmacogenetics has tremendous potential to
identify ideal candidates for anticholinergic UUI therapy and to distinguish individuals who
may benefit from alternative treatment options. This pioneering pharmacogenetic research has
the potential to lay the necessary groundwork for future long-term research which would
optimize and personalize UUI therapy for millions of elderly women.

Design & Procedures:

Patient Population: All women aged 50 years or older who desire treatment for bothersome UUI
will be approached for enrollment. Women with ≥ 3 UUI episodes on a 3-day voiding diary will
be included. Although women who have previously failed fesoterodine will be excluded, those
who have failed other UUI anticholinergics remain eligible after a 2-week washout period.

Subjects with auditory or visual sensory impairment will be included. If visual impairment
exists, the research coordinator will provide assistance to complete the necessary documents.
However, those who are unable to complete the study-related items and visits, such as women
with cognitive impairment, based on the Mini-Cog validated questionnaire will be excluded.

Inclusion Criteria:

- Women ≥ 50 years

- ≥ 3 UUI episodes on a 3-day voiding diary

- Urge-predominant incontinence, >50% of total incontinence episodes

- No history of failure to fesoterodine

- 2-week washout period if currently on an anticholinergic for UUI

- Willingness to avoid off-protocol UUI therapy during the study period

- Post Void Residual (PVR) <150 mL

Exclusion Criteria:

- Contraindications to fesoterodine (e.g., bladder outlet obstruction, narrow angle
glaucoma, myasthenia gravis, severe hepatic or renal impairment)

- Inability to complete study-related items and visits - i.e., cognitive impairment
based on Mini-Cog test score (exclude if score of 0 or 1-2 (Abnormal))

- Urinary retention requiring catheterization

- Symptomatic, untreated urinary tract infection not resolved prior to starting
fesoterodine

- Botulinum toxin injection for UUI in the last year

- Current therapy with peripheral or sacral neuromodulation

- Neurologic conditions that may affect urinary function (stroke, multiple sclerosis,
spinal cord injury, Parkinson's disease)

- Women taking potent CYP3A4 inhibitors