142
`Chapple C1
`1. Royal Hallamshire Hospital
`
`FESOTERODINE
`
`A
`
`NEW
`
`EFFECTIVE
`
`AND
`
`WELL-TOLERATED
`
`TREATMENT OF URGENCY-FREQUENCY
`ANTIMUSCARINIC FOR THE
`SYNDROME: RESULTS OF A PHASE 2 CONTROLLED STUDY.
`
`Hypothesis I aims of study
`Fesoterodine is a novel derivative of 3,3—diphenylpropyl—amine developed by Schwarz
`Pharma for the treatment of urgency—frequency syndrome (UFS also known as overactive
`bladder). The drug is a potent antimuscarinic, rapidly absorbed and immediately hydrolyzed to
`the active metabolite, SPM 7605, without requiring hepatic metabolism.
`The objective of this trial was to determine the optimal dose of fesoterodine measuring
`efficacy, tolerability and safety in subjects with UFS.
`
`Study design, materials and methods
`Israel, and South Africa. After a 1-week
`This trial was conducted at 81 sites in Europe,
`placebo run—in, eligible subjects were randomized to receive placebo or 4, 8, or 12 mg of
`fesoterodine once daily for 12 weeks.
`Efficacy variables were measured as change from baseline to 12 weeks after treatment.
`Primary variables were change in the mean number of micturitions per 24 hours and change
`in the mean number of urge incontinence episodes per week. Treatment efficacy was
`assessed by comparing the change from baseline in a 7-day micturition diary.
`Safety was assessed by monitoring adverse events and changes in clinical laboratory
`values, vital signs, ECGs, physical and urological examinations, and residual urinary
`volume. Treatment tolerance was evaluated subjectively.
`
`Results
`
`A total of 728 subjects were randomized and treated; 698 subjects were evaluable for the
`primary efficacy analysis. The mean age was 56 (age range 18-79 years) and 84% of
`subjects were female.
`
`Mean chan es from baseline to end of treatment
`
`-2.20
`
`-2.37
`
`-2.41
`
`-0.72; p=0.0030*
`
`— 0.82; p=0.0012*
`
`— 0.94; p=0.0002*
`
`Micturitionsf24 hours
`
`Mean change
`Difference from placebo
`(ANCOVA
`adjusted
`estimate)
`incontinence
`Urge
`episodesfweek
`Mean change
`Difference from placebo
`(ANCOVA
`adjusted
`estimate
`-V5 U95 are 0r1e—sre;
`
`{T195118 Sl'g‘l'll' ICEI1 H”!
`
`
`
`-12.79
`
`-11.79
`
`-13.43
`
`-3.96; p=0.0045
`
`-2.54; p=0.0521
`
`-4.61; p=0.0013*
`
`B C DS9 BS PWOCBUVB.
`
`There is a rapid improvement in both primary efficacy variables within the first two weeks of
`double-blind treatment as contrasted to placebo. Fesoterodine treatment
`results show
`significantly greater decreases in micturition frequency than placebo at all 3 doses. Early
`improvements were also seen in the reduction of the number of urge urinary incontinence
`episodes. The reduction was also seen in the 4 mg group.
`The most frequently reported AE in this trial was dry mouth (placebo 9%, 4 mg 25%, 8 mg
`26%) increasing to 34% in the 12 mg group. The use of a VAS (visual analogue scale) to
`assess dry mouth may have triggered the reporting. Dry mouth was rated as mild to moderate
`in most cases in the 4 and 8 mg groups. Drop out rates due to AE were 4% of subjects in
`placebo group, 6%, 2%, 12% in the 4 mg, 8 mg and 12 mg Fesoterodine groups, respectively.
`Adverse events with a fre uenc
`- reater than 1% in an treatment - rou -
` Adverse events > 1 %
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2076 - 0001
`
`

`
`-@
`m
`
`N=173
`
`N=186
`
`N=186
`
`I Abnormal vision
`
`II‘If|U8I1Z8 Ilka
`s mtoms
`
`Abdominal pain
`
`80/0
`
`90/0
`
`40/0
`
`40/0
`
`1%
`
`0%
`
`0%
`
`1%
`
`*after randomisation
`
`All other adverse events were in the range of placebo for all the treatment groups. Low rates
`were seen for constipation and vision disorders, which were in the placebo range.
`Fesoterodine had no clinically relevant effects on vital signs or ECG parameters.
`Based on patient assessments,
`the doses of 4mg and 8mg showed the best
`efficacy/tolerance ratios.
`
`Interpretation of results
`in the treatment of urgency-
`Fesoterodine once daily is an effective antimuscarinic agent
`frequency syndrome at all of the three doses tested.
`It significantly improved micturition
`frequency and urge incontinence episodes as compared to placebo.
`Fesoterodine was generally well tolerated, and no safety concerns were raised. Except for dry
`mouth all side effects were low or in the range of placebo,
`including constipation and vision
`disorders.
`
`Concluding message
`In conclusion, fesoterodine is a potent and well-tolerated antimuscarinic in all doses tested
`(4 mg, 8 mg and 12 mg). The most favourable efficacy—safety ratio was observed in the 4 and
`8 mg groups.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2076 - 0002