Summary of Efficacy

1
Summary of Efficacy
2
Efficacy
Efficacy Assessment
Clinical Considerations in ED

• Erection
• Intercourse
• Timing/onset of action
• Couple/physician choice

3
Efficacy
Efficacy Assessment
Measurements of ED in Clinical Trials

• No standard physical measurement
• No accepted means of determining etiologies in
  most cases
• Duplex ultra sound, pharmacotesting and Nocturnal
  Penile Tumescense (NPT) are not used routinely
• The International Index of Erectile Function
  (IIEF) and Brief Sexual Function Inventory
  (BSFI) are validated clinical trial instruments

Rosen et al. Urology 49822-830,
1997. OLeary et al. Urology 46697-706, 1995.
4
Efficacy
Efficacy Assessment
Uprima Endpoints

• Determined after each dose administration (every
  attempt) from the home-use questionnaire
• Erection firm enough for intercourse based on
  patient response
• Erection firm enough for intercourse based on
  partner response
• Intercourse rates based on patient/partner
  responses

5
Advantages of Home-Use Questionnairevs.
Retrospective Questionnaire (e.g., IIEF)
Efficacy Assessment
Efficacy

• Direct assessment of efficacy at each dosing
  attempt
• Does not require patient to
• Recall attempts after a 4-week period
• Create an estimate of average erectile function
  during that 4-week period

6

Representative ED Patient Population

7
Patient Population
Patient Population
Phase III Studies (M96-470, M97-658, M98-941,
M97-763)

• Heterosexual males, ages 18 70
• Partner consent
• Confirmed presence of ED (inability to attain and
  maintain erection firm enough for intercourse
  ³50 of attempts ³3 months prior to study)
• Physically able to obtain an erection documented
  by
• Ability to attain and maintain an erection
  sufficient for intercourse on some occasion
  during 3 months prior to study i.e.,
  nocturnal/morning erections or masturbation
• Nocturnal Penile Tumescence (NPT) testing with
  55 or greater base rigidity for at least 10
  minutes on at least 1 of 2 nights of NPT testing

8
Patient Population (cont.)
Patient Population
Phase III Studies (M96-470, M97-658, M98-941,
M97-763)

• No uncontrolled disease
• Clinically acceptable pre-study laboratory
  values, including normal testosterone and
  prolactin
• Diabetic patients fasting glucose values mg/dL, no episode of ketoacidosis within 3
  months prior to study
• Hypertensive patients Systolic Blood Pressure
  (SBP) (DBP)
• Smokers ?1/2 pack per day
• Patients were excluded with a history of allergic
  reaction to morphine (or other opiates) or a
  history of pharmacotherapy for ED (within 3
  months prior to study)

9
Definition of No Major Organic Component
Patient Population

• This term was used to exclude
• Prostatectomy
• Spinal cord injury
• Parkinsons disease
• Multiple sclerosis
• Penile prosthesis, penile deformity
• End-stage and unstable disease

10
Patient Demographics
Patient Population
Phase II/III Studies
Range
N
Mean

• Age (yrs) 55.1 21 - 76 2379
• Weight (lbs) 199.9 112 - 355 2376
• Duration of Erectile Dysfunction 4.8 yrs 3 mo. -
  47 yrs 1771
• Race
• Caucasian 88.6 2107
• Black 6.3 150
• Hispanic 3.6 85
• Asian/Pacific Islander 0.8 20
• Other 0.7 17

11
Representative ED Patient Population
Patient Population

• Subgroups with organic disease
• Baseline ED severity based on IIEF criteria
• RigiScan values compared with established norms
• Duration of ED

12
Major Subgroups
Patient Population
Phase II/III Studies

• Hypertension 31
• Diabetes 16
• Coronary Artery Disease 16
• Benign Prostatic Hyperplasia 16
• Alcohol Use 63
• Smoking 16

13
Baseline ED Severity Based on IIEF
Patient Population
Phase III Studies (M97-658, M97-763, M97-804,
M98-941 and M98-876)

• Severe 39.3
• Moderate 35.4
• Mild 24.9
• No ED 0.5

Mild 25 No ED
14
ED Population
Patient Population
Uprima Studies
Viagra Studies1
MMAS2
Duration of ED (mean) 4.8 years 5 years Medical
Condition () Hypertension 31 25 33
Coronary Artery Disease (CAD) 16 14 16
Hyperlipidemia 16 14 Diabetes 16 18 9
1 Approval Package for Viagra (Sildenafil
Citrate). FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/
HTM. Joint Clinical Review p. 14. April
1999. 2 Johannes et al. J. Urology 163 460-463,
2000.
15
Comparison of Uprima NPT Valueswith Values for
Normals
Patient Population
Maximum Tip Rigidity Activity Unit (RAU)



Maximum Tip RAU Values
Note Data from Normals Extrapolated from Graph
in Levine and Carroll,Journal of Urology, Vol.
152, 1103-1107, Oct. 1994.
16
Comparison of Uprima NPT Valueswith Values for
Normals
Patient Population
Maximum Base RAU



Maximum Base RAU Values
Note Data from Normals Extrapolated from Graph
in Levine and Carroll,Journal of Urology, Vol.
152, 1103-1107, Oct. 1994.
17
Representative ED Patient Population Conclusion
Patient Population

• Reflective of the ED patient population as a
  whole including both organic and non-organic
  disease
• Clearly defined and relevant to clinical practice
• Consistent with the Viagra patient population
• Consistent with MMAS
• Included patients with mild, moderate and severe
  ED
• RigiScans abnormal
• The patient population studied does support the
  proposed indication

18
Efficacy Endpoints

19
Efficacy Endpoints for Phase III Studies
Efficacy Endpoints
Home-Use Questionnaire Completed After Every
Attempt

• Primary Endpoint
• Percent of patient Yes responses to the
  questionDid you attain and maintain an
  erection firm enough for intercourse?
• Secondary Endpoints
• Percent of partner Yes responses to the
  questionWas the erection firm enough for
  intercourse?
• Percent of patient/partner Yes responses to the
  questionDid you have intercourse with your
  partner?
• Time to erection

20
Efficacy Endpoints for Phase III Studies
Efficacy Endpoints
Secondary (cont.)

• Patient Brief Sexual Function Inventory (BSFI)
  data
• Partner Brief Sexual Function Inventory data
• Patient International Index of Erectile Function
  (IIEF) data

21
Uprima-Efficacy Endpoints
Efficacy Endpoints

• Consistent
• Clear
• Relevant
• Rigorous

22
Efficacy
Efficacy

• Crossover studies
• Primary endpoint (patient and partner)
• Subgroup analyses
• Validated questionnaires
• Diabetes
• Parallel study (M97-763)
• Long-term studies

Results are shown from the 3 crossover studies
combined, but the results from the
individual studies are consistent with the
combined data
23
Crossover Study Schematic
Phase IIIM96-470, M97-658 M98-941
Efficacy-Crossover Studies
2 mg
Placebo
Washout Period
Uprima
Washout Period
Placebo
2 mg
Randomization
Uprima
Placebo
4 mg
Washout Period
Uprima
Placebo
4 mg
Washout Period
Open-Label Flexible Dose Long-Term Study
Baseline
Uprima
Placebo
5 mg
Washout Period
Uprima
Placebo
5 mg
Washout Period
Uprima
Placebo
6 mg
Washout Period
Uprima
Placebo
6 mg
Washout Period
Uprima
2-4 Week Baseline
4 Week Treatment Period 1
4 Week Treatment Period 2
24-96 Hours Washout
24
Crossover Studies
Efficacy-Crossover Studies
Rationale for Crossover Study Design

• Suggested by the FDA and provided a powerful
  design
• Allows patients to be their own control
• All patients are exposed to study drug
• Appropriate for stable chronic diseases

25
Patient Response (per attempt)Erection Firm
Enough for Intercourse
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Crossover
Combined Data Phase III Crossover Studies

Yes
pppp 26
Patient Response (per attempt) Did Attempt
Result in Intercourse
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Crossover
Combined Data Phase III Crossover Studies

Yes
pppp 27
Intercourse RatesComparison of Uprima to Viagra
Uprima vs. Viagra
Efficacy-Viagra
Uprima
Viagra1


Phase III Crossover Studies
Phase III Studies
1 Calculated from data provided in the Approval
Package for Viagra (Sildenafil Citrate).
FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/HTM.
Joint Clinical Review. April 1999.
28
Partner Responses
29
Partner Involvement in Uprima Studies
Efficacy-Crossover

• Partner responses were a unique factor for the
  Uprima clinical trials
• Partner BSFI was developed, utilized and
  validated
• Partner consent and participation were required
  for all studies
• ED is a couples issue

30
Partner Response (per attempt)Erection Firm
Enough for Intercourse
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Crossover
Combined Data Phase III Crossover Studies

Yes
pppp 31
Partner Response (per attempt) Did Attempt
Result in Intercourse
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Crossover
Combined Data Phase III Crossover Studies

Yes
pppp 32
Primary Endpoint Subgroup Analyses
Efficacy-Crossover/Subgroups

• Organic
• Non-organic
• Hypertensive Patients
• Diabetic Patients
• Coronary Artery Disease

• Benign Prostatic Hyperplasia
• Alcohol Users
• Smokers
• Age 65
• ED Severity

33
Patient Response (per attempt)Erection Firm
Enough for Intercourse
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy - Subgroups
Subgroup Documented Organic Disease(Hypertension
, CAD or Diabetes)

Yes
pppp 34
Patient Response (per attempt) Erection Firm
Enough for Intercourse
Phase III Crossover M96-470, M97-658 M98-941
Efficacy - Subgroups
Subgroup Age 65

Yes
p.027
p.002
pp 35
ED Severity
36
Assessment of Effect of ED Severity on Efficacy
Efficacy - ED Severity

• Analyses were performed in patients with
• mild, moderate and severe ED severity scores at
  baseline
• no success during baseline
• abnormal RigiScan scores at inclusion into study

37
Definition of ED Severity Based on IIEF
Efficacy-ED Severity
IIEF Scoring For Erectile Dysfunction

• ED severity was determined based on the sum of 6
  questions from the IIEF (questions 1-5 and 15)
• Severe
• Moderate 11-16
• Mild 17-25
• No ED 25

38
Patient Response (per attempt)Erection Firm
Enough for Intercourse
Phase III Crossover M97-658 M98-941
Efficacy-ED Severity
Erectile Dysfunction Severe (39 of patients)

Yes
p.003
ppp IIEF scores no ED 25, mild ED 17-25, moderate
ED 11-16, severe ED 39
Patient Response (per attempt) Erection Firm
Enough for Intercourse
Phase III Crossover M96-470, M97-658 M98-941
Efficacy-ED Severity
For Patients (39) With No Success During Baseline

Yes
pppp 40
Patient Response (per attempt)Erection Firm
Enough for Intercourse
Phase III Crossover
Efficacy-ED Severity
Patients with Maximum Tip RAU 9.5

Yes
p.008
p.002
pp.001
41
ED Severity Conclusion
Efficacy-ED Severity

• Uprima is effective in patients with severe ED
  as evaluated by
• Baseline IIEF ED severity
• Baseline success rate
• Abnormal NPT (Tip RAU 9.5)
• Uprima is also effective in patients with mild
  or moderate ED

42
Other Endpoints
43
Other Endpoints
Efficacy-Other Endpoints

• Home-Use (per attempt) Endpoints
• Timing of erections
• Treatment Success ( achieving erections
  sufficient for intercourse in 50 of attempts)
• Diary Satisfaction Scale (per attempt)
• Validated Questionnaires
• Partner Satisfaction Scale (PBSFI)
• IIEF (4 point improvement in erectile function)

44
Median Time to Erection (Using Only Attempts
When an Erection Was Achieved)
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Other Endpoints
Combined Data Phase III Crossover Studies
Dose(N placebo, Placebo Minutes Uprima
Minutes N Uprima) Median (IQR) Median (IQR)
2 mg (271, 309) 16.3 (10 25) 17.5 (10 25) 4
mg (271, 318) 15.0 (9 25) 16.4 (10 28)

• Erection firm enough for intercourse 33.8 on
  placebo and 54.4 on 4 mg
• Natural time course (in context of clinical
  trial)
• Not dose related

More erections occurred with Uprima than with
placebo. IQR interquartile range.
45
Patient Assessment Percentage of Patients Deemed
a Treatment Success
Phase III CrossoverM96-470, M97-658 M98-941
Efficacy-Other Endpoints
Combined Data Phase III Crossover Studies


ppppDefinition of Success A treatment is deemed a
success for a patient if at least 50 of all
attempts while using the treatment resulted in
erections firm enough for intercourse.
46
Percent of Patients with Mean Intercourse Attempt
Satisfaction 3 and an Improvement Over Baseline
Phase III Crossover M96-470, M97-658 M98-941
Efficacy-Other Endpoints
Combined Data Phase II/III Studies

Scale 1Very dissatisfied 2Mostly
dissatisfied 3Neutral or mixed (about
equally satisfied and dissatisfied) 4Mostly
satisfied 5Very satisfied
pppp 47
Percent of Partners with Mean Intercourse Attempt
Satisfaction 3 and an Improvement Over Baseline
Phase III Crossover M96-470, M97-658 M98-941
Efficacy - Other Endpoints
Combined Data Phase II/III Studies

Scale 1Very dissatisfied 2Mostly
dissatisfied 3Neutral or mixed (about
equally satisfied and dissatisfied) 4Mostly
satisfied 5Very satisfied
pppp 48
Percent of Patients with 4 Point Improvement in
the Erectile Function Domain Index of the IIEF
Phase III Crossover StudiesM97-658 M98-941
Efficacy-Other Endpoints
Combined Data M97-658 M98-941


ppppBased on a scale of 1 to 30, with higher scores
being better.
49
Phase III Crossover Studies Conclusion
Efficacy-Crossover

• Clinical significance has been shown at all dose
  strengths and demonstrated in all subgroups
  (organic, non-organic, hypertensive, etc.) with
  these endpoints
• The robustness of the Uprima efficacy results
  has been demonstrated across a variety of
  home-use efficacy endpoints and is confirmed by
  the results of validated questionnaires

50
Phase III Crossover Studies Conclusion (cont.)
Efficacy-Crossover

• Clinical Relevance of 2 mg
• Statistically superior compared to placebo in all
  Phase III Crossover studies for the primary
  endpoint and virtually all secondary endpoints
• Shows a 4-point improvement on IIEF in 45 of
  patients (compared to 27 of placebo)
• Statistically significant compared to placebo in
  patients with moderate to severe ED as well as
  patients with a variety of organic diseases
  (hypertension, diabetes, CAD, etc.)
• Intercourse rates increase from a placebo rate of
  29 to 42 for Uprima 2 mg (13 increase)
  compared to 16 increase seen with Viagra 25 mg

51
Efficacy
Efficacy

• Crossover studies
• Diabetes
• Parallel study (M97-763)
• Long-term studies

52

Efficacy in Diabetics
53
Diabetes Study Baseline ED Severity
Phase III
Efficacy-Diabetes
M97-804
4 mg n ()
5 mg n ()
Combined n ()
Baseline IIEF Severity Rating
Severe 61 71.8 42 50.0 103 61.0 Moderate 20 23.5 2
4 28.6 44 26.0 Mild 4 4.7 18 21.4 22 13.0
Severity rating determined by Erectile
Function total. Severity Score Mild (17-25),
Moderate (11-16), and Severe (NPT required for enrollment. Due to
randomization imbalance, the 4 and 5 mg were
combined to represent the overall diabetic
population.
54
Patient Response (per attempt)Did You Achieve
an Erection Firm Enough for Intercourse
Phase III Diabetic
Efficacy-Diabetes
M97-804
Baseline
Placebo
Uprima
50
40
34.1
28.9
27.2
30
Yes
24.6
20.4
20
14.5
12.2
8.1
10
5.1
0
4 mg (N90)
5 mg (N86)
Combined (N176)
p.020
p.179
p.009
55
Patient Response (per attempt) Erection Firm
Enough for Intercourse
Phase III Crossover M96-470, M97-658, M98-941
M97-804
Efficacy-Diabetes
Diabetic Patients Phase III Crossover
Studies(M96-470, M97-658, M98-941 M97-804)
Baseline
Placebo
Uprima
50
45.2
40.3
40
36.2
30.0
29.2
Yes
30
25.9
22.4
19.6
18.3
20
13.4
11.5
10
6.4
0
2 mg (N30)
4 mg (N113)
5 mg (N111)
6 mg (N8)
p.038
p.021
p.004
p.090
56
Diabetes Efficacy Conclusion
Efficacy-Diabetes

• Similar to the results seen in the Viagra
  studies, efficacy in diabetic patients is lower
  than seen in the general population
• Although there was a randomization imbalance,
  statistically significant results were noted in
  the 4 mg arm and both dosing groups combined from
  the M97-804 Diabetes Study
• In diabetic patients enrolled in the Phase III
  Crossover studies, efficacy improved
  approximately 10-20 over placebo in all dose
  strengths

57
Uprima Efficacy

• Crossover studies
• Diabetes
• Parallel study (M97-763)
• Long-term studies

58
Parallel Study Schematic Design
Phase III ParallelM97-763
Efficacy-Parallel
Placebo
Placebo
Informed Consent
Randomization
5 mg
5 mg Fixed Dose
Open-Label Long-Term Extension Study
Baseline
6 mg Fixed Dose VOLUNTARY TITRATION
6 mg
Optimal Dose
2 mg
4 mg
5 mg
6 mg
Baseline 2-4 Weeks
Day 1
Week 1
Week 2
Week 3
Week 4
Week 8
59
Patient Response (per attempt)Erections Firm
Enough for Intercourse
Phase III ParallelM97-763
Efficacy-Parallel
M97-763

Average Percent
N114
N112
N112
N114
N84
N82
N232
N230
N230
N232
pp2, 4, 5, 6 mg
2, 4 mg
Based on last 8 attempts.
pp.003
60
Partner Response (per attempt)Erections Firm
Enough for Intercourse
Phase III ParallelM97-763
Efficacy-Parallel
M97-763

Average Percent
N112
N112
N114
N112
N80
N84
N225
N228
N228
N224
pp.002
2, 4, 5, 6 mg
2, 4 mg
Based on last 8 attempts.
pp.004
61
Patient Response (per attempt)Did Attempt
Result in Intercourse
Phase III ParallelM97-763
Efficacy-Parallel
M97-763

Average Percent
N114
N112
N112
N114
N84
N82
N232
N230
N230
N232
pp.003
2, 4, 5, 6 mg
2, 4 mg
Based on last 8 attempts.
pp.005
62
Efficacy

• Crossover studies
• Diabetes
• Parallel study (M97-763)
• Long-term studies

63
Discontinuations in Long-Term Studies
64
Long-Term Studies
Efficacy-Long -Term

• The long-term studies were designed primarily to
  collect safety information
• A number of factors contributed to patient
  discontinuation in the long-term studies
• Lack of efficacy
• Adverse events
• Approval of new compounds (MUSE, Viagra)
• Length of studies and stringent patient
  requirements (office visits, diary completion
  after every attempt, etc.)
• Competing investigational studies

65
Percentage of Erections Firm Enough for
Intercourse
Phase III Long-Term Open-LabelM96-471,
M97-659, M97-682 M98-936
Efficacy-Long -Term
All Doses (2, 4, 5, and 6 mg)
N1,008
N887
N728
N599
N492
N426
N1,019
66
Long-Term Studies
Efficacy-Long -Term

• Short-term studies show that treatment success is
  achieved in 50-60 of patients, yet
  approximately 80 of eligible patients enrolled
  into long-term studies
• Dropout rates of 20-30 are not unexpected based
  on the number of patients who enrolled from the
  short-term studies who had no efficacy
• Dropout rates were also influenced by adverse
  events, approval of Viagra, other competing ED
  trials and the burden of patient inconvenience
  associated with frequent visits, diary
  completion, etc.
• Despite this, over 42 of patients reached the
  6-month time point in the long-term studies and
  demonstrated sustained and reliable efficacy

67
Percentage of Erections Firm Enough for
Intercourse
Phase III Long-Term Open-LabelM96-471, M97-659
M97-682
Efficacy-Long -Term
All Doses (2, 4, 5, and 6 mg)
N417
N425
N422
N425
N426
N426
N426
Includes only patients who remained on drug for
at least 6 months.
68
Percentage of Erections Firm Enough for
Intercourse
Phase III Long-Term Open-LabelM96-471, M97-659
M97-682
Efficacy-Long -Term
2 and 4 mg
N126
N123
N117
N117
N125
N128
N129
Includes only patients who remained on drug for
at least 6 months.
69
Efficacy in Long-Term Studies Conclusion
Efficacy - Long -Term

• Patients remaining in long-term studies have
  sustained and reliable response with erections in
  more than 80 of attempts
• Patients obtaining efficacy in the long-term
  studies are similar to all Uprima patients as
  evidenced by their baseline success rates

70
Overall Efficacy Conclusions

71
Overall Efficacy Conclusions
Efficacy-Conclusions

• Clinical trials included patients representative
  of the general ED population, similar to Viagra
  and MMAS
• Uprima 2 and 4 mg has been shown to be
  statistically and clinically significantly better
  than placebo in large scale controlled studies
• Uprima 2 and 4 mg have demonstrated a clinically
  relevant improvement in the IIEF Erectile
  Function Domain (4-point) compared to placebo
• Uprima partner efficacy data has been shown to
  be almost identical to Uprima patient efficacy
  data
• Patients remaining in the long-term studies have
  substantial and reliable responses with erections
  in more than 80 of attempts

72
Overall Efficacy Conclusions (cont.)
Efficacy-Conclusions

• Uprima efficacy has been demonstrated in subsets
  of patients with
• organic disease - benign prostatic hyperplasia
  
• hypertension - alcohol users
• diabetes - smokers
• coronary artery disease
• Uprima efficacy has been demonstrated in all
  severities of ED
• Uprima has been shown to have a rapid onset of
  erectile response
• Uprima has demonstrated significance in all
  satisfaction and erectile function indices (BSFI,
  IIEF, Partner BSFI)