James W. Freston M.D., Ph.D. Professor of Medicine and Clinical Pharmacology University of Connectic

1
James W. Freston M.D., Ph.D.Professor of
Medicine and Clinical PharmacologyUniversity of
Connecticut Health Center
Uprima PresentationTAP Holdings Inc.
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Summary of Possibly Related Treatment-Emergent
Adverse Events Reported by gt5 of Patients
Phase III CrossoverM96-470, M98-941 M97-658
Safety-Adverse Events
Combined Data Phase III Crossover Studies
Higher Than Recommended Doses
Recommended Doses
2 mg UprimaN429n ()
4 mg UprimaN426n ()
6 mg UprimaN262n ()
5 mg UprimaN282n ()
Adverse Event
Placebo
Nausea Dizziness Somnolence Sweating Headache Yawn
ing Vasodilation Vomiting Asthenia Taste
perversion Pallor
9 (2.1) 13 (3.0) 9 (2.1) 7 (1.6) 15 (3.5) 13
(3.0) 4 (0.9) 3 (0.7) 4 (0.9) 12 (2.8) 1 (0.
2)
87 (20.4) 59 (13.9) 45 (10.6) 42 (9.9) 22 (5.
2) 36 (8.5) 12 (2.8) 11 (2.6) 18 (4.2) 28 (6.
6) 9 (2.1)
87 (30.9) 57 (20.2) 33 (11.7) 45 (16.0) 13 (4
.6) 37 (13.1) 18 (6.4) 24 (8.5) 11 (3.9) 19 (
6.7) 19 (6.7)
103 (39.3) 52 (19.9) 37 (14.1) 53 (20.2) 18 (
6.9) 29 (11.1) 26 (9.9) 29 (11.1) 27 (10.3) 1
9 (7.3) 8 (3.1)
4-8 (1.2-2.3) 1-13 (0.4-3.0) 1-7 (0.4-1.6) 0-3 (0-
1.3) 4-10 (0.2-3.4) 1-4 (0.4-1.5) 1-4 (0.2-0.9) 0
0-1 (0-0.4) 2-5 (0.5-2.1) 0
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Incidence of Nausea by Severity and Dose
Phase III Crossover M96-470, M97-658 M98-941
Safety-Nausea
Combined Data Phase III Crossover Studies
Recommended Doses
Higher Than Recommended Doses
2 mg
4 mg
5 mg
6 mg
1.2
0.9
2.7
0.7
8.0
0.2
15.6
17.6
14.5
12.2
69.2
79.6
97.9
60.6
19.1
None
Mild
Moderate
Severe
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Incidence of Nausea and Vomiting per Treatment
Administration with 2 and 4 mg
Safety-Nausea

• In over 35,000 treatment administrations of
  Uprima 2 and 4 mg
• the incidence of nausea per administration was
  2.2
• the incidence of vomiting per administration was
  0.2

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Percentage of Patients with Related Nausea by
Dose Number Patients with at Least 8 Attempts
Phase III Crossover M96-470, M97-658 M98-941
Safety - Nausea
Phase III Crossover Studies Uprima 4 mg
Dose Number
6
Nausea Conclusion
Safety-Nausea

• No impact on efficacy
• Mostly mild
• Infrequent anti-emetic use
• Few patients discontinued
• Incidence declines with continued use

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Adverse Events Described in Detail in the FDA
Briefing Document
Safety-SAEs
Includes Related, Unrelated and Placebo Events

• Syncope
• Hypotension
• Serious Adverse Events (SAEs)
• Premature Terminations

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Serious Adverse Event (SAE) Reporting
Safety-SAEs

• The FDA and ICH SAE definition was used in all
  studies (protocols and case report forms)
• An SAE is defined as any adverse drug experience
  occurring at any dose that results in any of the
  following outcomes
• Life-threatening
• Death
• Hospitalization/prolongation of hospitalization
• Congenital anomaly
• Persistent or significant disability/incapacity
• Required intervention to prevent permanent
  impairment/damage
• All SAEs were reported according to the FDA and
  ICH definition

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Serious Adverse Events (SAEs)
Safety-SAEs
(2, 4, 5 and 6 mg)

• Total SAE cases described in FDA Briefing
  Document - 49
• Cases described twice - 13
• Cases described 3 times - 3
• Total actual patients described with SAEs - 30
• Possibly related to Uprima per reviewer - 21
• Possibly related to Uprima per investigator - 15
  
• Relationship questioned - 6

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Adverse Events Identified Where Relationshipto
Uprima Questioned by Reviewer
Safety - SAEs
Study Patient
Event TimePost-Dose
SAE ConsideredUnrelated by Investigator
Age
Dose
Comments
M96-470 52 2 mg 1 day MI 1030 4th
dose M96-470 68 2 mg 12-18 hrs Chest pain,
unstable angina 1037 10th dose M97-6
58 59 2 mg Unknown Patient was a passenger.
1965 2nd dose As a result of the accident,
lost consciousness, patient fractured
wrist
Hospitalized, underwent angioplasty Prior
history of hypercholesterolemia, sleep
apnea No additional doses were taken,
patient discontinued study Hospitalized,
given Imdur, Monopril, Norvasc, prior history of
angina, MI 8 months prior Completed study, one
more dose taken Patient discontinued study
due to car accident
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Adverse Events Identified Where Relationshipto
Uprima Questioned by Reviewer
Safety - SAEs
Study Patient
Event TimePost-Dose
SAE ConsideredUnrelated by Investigator
Age
Dose
Comments
Hospitalized, multiple lab tests, IV
fluids Continues on study at 5
mg Hospitalized Prior history of MI,
hypertension, diabetes and this type of
arrhythmia Completed study, no additional doses
taken ER, blood glucose 15 mg/dL, given
oral glucose, repeat glucose was normal No
history of diabetes Completed study
M97-793 56 4 mg 4 days Viral gastroenteritis,
dehydration, 2648 1st dose syncope x2,
diarrhea, hypotension M98-941 51 2 mg 4.5
hrs Lightheadedness, nausea, 3294 9th
dose temperature 102F, ventricular
bigeminy M98-941 49 5 mg 90
mins Diaphoresis, dizziness, nausea,
3361 15th dose syncope
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Overall Incidence of Serious Adverse Events for
Patients Treated with Uprima in the Phase I-III
Studies
Table 30
Relationship to Study Drug
Related SAEs n ()
Not Related SAEs n ()
Treatment
0 3 9 3 15 (0.5)
Uprima 2 mg Uprima 4 mg Uprima 5 mg Uprima 6
mg TOTAL (N3035)
8 13 18 22 61 (2.0)
Note Six patients reported unrelated SAEs while
on placebo.
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Primary Reasons for Premature Termination from
Study
Phase III CrossoverM96-470, M97-658 M98-941
Safety -Premature Terminations
Higher Than Recommended Doses
Recommended Doses
2 mg Uprima N429n ()
4 mg Uprima N426n ()
6 mg Uprima N262n ()
5 mg Uprima N282n ()
Placebo n ()
Reason
Adverse Event 0-5 (0-1) 4 (1) 19 (5) 23 (8) 25
(10)Non-Compliance 1-7 (lt1-2) 5 (1) 9 (2) 7
(3) 6 (2) Lack of Efficacy 0-3 (0-1) 2 (1) 1
(lt1) 1 (lt1) 2 (1) Patient Request 3-12 (1-3) 8
(2) 10 (2) 8 (3) 7 (3) Partner
Request 1-3 (lt1-1) 0 3 (1) 2
(1) 2 (1) Lost to Follow-Up 5-8 (2) 7 (2) 7 (2)
5 (2) 10 (4) Other 1-4 (lt1-1) 1 (lt1) 5 (1) 2
(1) 5 (2) Total 14-37 (5-10) 27 (6) 54 (13) 48
(17) 57 (22)
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Premature Termination due to Adverse Events
Phase III CrossoverM96-470, M97-658 M98-941
Safety-Premature Terminations
Recommended Doses
Higher Than Recommended Doses
2 mg Uprima N429n ()
6 mg Uprima N262n ()
5 mg Uprima N282n ()
4 mg Uprima N426n ()
Placebo n ()
Reason
Adverse Event 0-5 (0-1) 4 (1) 19 (5) 23 (8) 25
(10) Nausea 0-1 (0-0.4) 1 (0.2) 6 (1.4) 14
(5.0) 15 (5.7) Sweating 0-1 (0-0.4) 0 6
(1.4) 14 (5.0) 11 (4.2) Dizziness 0 0 8
(1.9) 11 (3.9) 11 (4.2) Hypotension 0 0 6
(1.4) 7 (2.5) 4 (1.5) Somnolence 0 0 4
(0.9) 4 (1.4) 3 (1.2) Vomiting 0 0 3 (0.7) 6
(2.1) 4 (1.5) Syncope 0 1 (0.2) 3 (0.7) 1
(0.4) 5 (1.9) Asthenia 0 0 0 3 (1.1) 5
(1.9) Yawning 0 0 2 (0.5) 4 (1.4) 1
(0.4) Bradycardia 0 0 1 (0.2) 0 3
(1.2) Pallor 0 0 1 (0.2) 8 (2.8) 4 (1.5)
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Adverse Events in Subpopulations
Safety-Subgroups

• No clinically meaningful differences in adverse
  event rates were observed in patients with
• Hypertension
• Coronary Artery Disease
• Benign Prostatic Hyperplasia
• Diabetes
• Alcohol Use

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Related Treatment-Emergent Adverse Events
Reported by ³5 of Patients by Subgroups
Safety-Subgroups
Phase II/III Studies (2 4 mg)
Hypertensionn ()
Diabetesn ()
CADn ()
With N557
Without N1310
With N273
Without N1594
With N291
Without N1576
COSTART Term
Nausea Dizziness Sweating Somnolence Yawning Heada
che
73 (13.1) 35 (6.3) 23 (4.2) 44 (7.9) 34 (6.1)
26 (4.7)
213 (16.3) 140 (10.7) 86 (6.6) 109 (8.3) 78 (
6.0) 75 (5.7)
32 (11.7) 17 (6.2) 15 (5.5) 20 (7.3) 9 (3.3)
9 (3.3)
254 (15.9) 158 (9.9) 94 (5.9) 133 (8.3) 103 (
6.5) 92 (5.8)
44 (15.1) 27 (9.3) 17 (5.8) 29 (10.0) 13 (4.5
) 18 (6.2)
242 (15.4) 148 (9.4) 92 (5.8) 124 (7.9) 99 (6
.3) 83 (5.3)

• Patients with hypertension, diabetes, and
  coronary artery disease do not show any increases
  in adverse events

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Representative ED Patient Population
Summary-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

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Pharmacokinetic Variability
Pharmacokinetic Variability

• Experience with the 5 and 6 mg in Phase III
  studies provided evidence that even 4 mg patients
  achieving highest Cmax would have acceptable
  safety profiles
• 75,449 treatments at 2 to 6 mg would encompass
  the extreme ranges of pharmacokinetic variability
  
• Clinical use is more relevant than
  pharmacokinetic profiles in assessing the
  clinical relevance of variability

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Clinical Relevance of 2 mg
Summary-2mg

• Statistically superior compared to placebo in all
  Phase III Crossover studies
• Shows a 4-point improvement on IIEF in 45 of
  patients (compared to 27 of placebo)
• Statistically significant compared to placebo in
  subgroups, including patients with organic
  disease and severe ED
• 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

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Diabetes
Summary-Diabetes

• In diabetic patients enrolled in the Phase III
  Crossover studies, efficacy improved
  approximately 10-20 over placebo in all dose
  strengths
• Similar to the results seen in the Viagra
  studies, efficacy in diabetic patients is lower
  than seen in the general population

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Discontinuations in Long-Term Studies
Summary-Long-Term

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

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Hemodynamics
Summary - Hemodynamics

• Syncope rates at 2 and 4 mg, when the dose is
  optimized, is 0.6
• At 2 and 4 mg, there were no clinically
  significant mean decreases in blood pressure
• When hypotension was reported as an adverse
  event, nearly all patients had concurrent
  prodromal symptoms.
• Mean decreases in blood pressure observed
  following Viagra 100 mg were both larger in
  magnitude and longer duration than those seen
  with Uprima 4 mg
• In diabetic patients at 4 or 5 mg, there were no
  clinically significant mean changes from baseline
  in blood pressure or pulse rate

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Nitrate Interaction
Summary-Nitrates

• No syncopal events
• No Holter monitor changes were associated with
  Uprima except those attributed to a vasovagal
  effect
• Significant blood pressure changes were seen only
  in patients with vasovagal symptoms
• Uprima has a notably less hypotensive effect
  than does Viagra in combination with nitrates

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Topics Identified in FDA Briefing Document
FDA Briefing Document

• Representative ED patient population
• Pharmacokinetic variability
• Clinical relevance of 2 mg
• Efficacy in diabetics
• Discontinuations in long-term studies
• Hemodynamics
• Nitrate interaction
• Alcohol interaction

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Alcohol Interaction
Summary-Alcohol

• Subjects were stressed with high doses of
  Uprima, high doses of ethanol and frequent
  orthostatic maneuvers and blood draws
• Between 30 to 60 minutes post-dosing, mean
  decreases in standing blood pressure were greater
  when Uprima 6 mg was combined with ethanol 0.6
  g/kg than with ethanol administered alone
• In all Phase II/III studies, the adverse event
  profiles in alcohol users vs. non-alcohol users
  were comparable, and the syncope rates were
  identical
• Risk can be minimized by using the recommended
  patient instructions which include
• not exceeding recommended alcohol consumption (2
  beers or 2 glasses of wine or 1 ounce of liquor)
• lying down if experiencing prodromal events

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Summary
Summary

• ED is a common condition with important health
  consequences (NIH)
• ED is associated with a number of diseases and
  conditions
• Drugs with different modes of action are
  desirable as with other disorders with complex
  pathophysiology, e.g., hypertension
• Current therapies are limited
• The currently approved agents work by peripheral
  mechanisms
• Each drug has its own adverse event profile
• There is no one appropriate treatment for every
  patient
• Treatment is strongly influenced by couple and
  physician choice
• New drugs with different mechanisms offer
  significant potential benefits

NIH Consensus Development Panel on Impotence.
JAMA 270 83-90, 1993.
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Summary (cont.)
Summary

• Uprima acts through a unique central mechanism
• Efficacy has been evaluated using consistent and
  relevant end-points after each attempt plus
  supporting partner data
• Efficacy of 2 and 4 mg was demonstrated in all
  studies with all endpoints in patients with
• Mild, moderate and severe ED
• Coronary artery disease
• Hypertension
• Diabetes
• Benign prostatic hypertrophy
• No known organic disease
• Both patient population and successful
  intercourse rates are similar to those seen in
  Viagra studies

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Summary (cont.)
Summary

• The safety of Uprima has been evaluated in 27
  studies, including 3,035 patients taking 75,449
  doses (treatment episodes) in Phase I, II and
  III trials
• The duration of treatment has exceeded one year
  in 127 patients and 6 months in 461 patients at
  time of NDA
• The AE profile was similar in patients with
• Coronary artery disease
• Hypertension
• Diabetes
• Benign prostatic hyperplasia
• No known organic disease

36
Summary (cont.)
Summary

• Uprima can be taken with alcohol provided
  patients do not exceed the recommended levels
• Uprima can be taken with nitrates using the
  recommended patient instructions
• There were no pharmacodynamic interactions
  between Uprima and five different classes of
  antihypertensive drugs

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Summary (cont.)
Summary

• There were no deaths or major illness (e.g. MI,
  CVA) related to Uprima
• Nausea was the most frequent adverse event 15.5
  of patients with 2 and 4 mg doses, 2.2 of
  treatment administrations
• Accommodation to nausea occurred with subsequent
  doses
• Syncope (vasovagal in nature) occurred in 0.8 of
  patients at 2 and 4 mg doses (only 0.04 of
  treatment administrations) with
  dose-optimization to 4 mg, syncope occurred in
  0.6 of patients
• Syncope nearly always occurred with a prodrome of
  vasovagal symptoms

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Conclusions
Conclusions

• Uprima is a safe and effective treatment for ED
  in patients with and without known organic
  diseases
• Risk-Benefit of Uprima
• 2 mg - rare adverse events, efficacy in all Phase
  III studies
• 4 mg - few adverse events, robust efficacy
• no deaths, MIs, CVAs
• Uprima is a useful and needed addition to the
  treatment of ED because it has a
• unique central mechanism of action
• novel delivery system
• rapid onset
• Patients, couples and physicians will have
  another choice of safe and effective non-invasive
  drug with a different mechanism of action