# Presentation: 134955

## James W. Freston M.D., Ph.D.Professor of Medicine and Clinical PharmacologyUniversity of Connecticut Health Center

**James W. Freston M.D., Ph.D.***Professor of Medicine and Clinical Pharmacology*University of Connecticut Health Center

## Summary of Possibly Related Treatment-Emergent Adverse Events Reported by >5% of Patients

**Nausea**
**Dizziness**
**Somnolence**
**Sweating**
**Headache**
**Yawning**
**Vasodilation**
**Vomiting**
**Asthenia**
**Taste perversion**
**Pallor**

**Adverse Event**

**Placebo**

**2 mg Uprima****®****N=429****n (%)**

**4 mg Uprima****®****N=426****n (%)**

**6 mg Uprima****®****N=262****n (%)**

**5 mg Uprima****®****N=282****n (%)**

**	****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)**
**	****19****	****(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**

- Phase III – CrossoverM96-470, M98-941 & M97-658

*Combined Data – Phase III Crossover Studies*

***Recommended Doses***

***Higher Than ******Recommended Doses***

- Safety-Adverse Events

## Incidence of Nausea by Severity and Dose

**15.6%**

**14.5%**

**0.7%**

**8.0%**

**12.2%**

**0.9%**

**1.2%**

**2 mg**

**4 mg**

**5 mg**

**0.2%**

- None

- Mild

- Moderate

- Severe

**19.1%**

**17.6%**

**2.7%**

**6 mg**

- Phase III – Crossover M96-470, M97-658 & M98-941

**69.2%**

**79.6%**

**97.9%**

**60.6%**

*Combined Data – Phase III Crossover Studies*

***Recommended Doses***

***Higher Than Recommended Doses***

- Safety-Nausea

## Incidence of Nausea and Vomiting per Treatment Administration with 2 and 4 mg

- 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%

- Safety-Nausea

## Percentage of Patients with Related Nausea by Dose Number Patients with at Least 8 Attempts

- Dose Number

- Phase III – Crossover M96-470, M97-658 & M98-941

*Phase III Crossover Studies **Uprima**®** 4 mg*

- Safety - Nausea

## Nausea Conclusion

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

- Safety-Nausea

## Adverse Events Described in Detail in the FDA Briefing Document

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

*Includes Related, Unrelated and Placebo Events*

- Safety-SAEs

## Serious Adverse Event (SAE) Reporting

- 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

- Safety-SAEs

## Serious Adverse Events (SAEs)

- 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

*(2, 4, 5 and 6 mg)*

- Safety-SAEs

## Adverse Events Identified Where Relationshipto Uprima® Questioned by Reviewer

**M96-470****	****68****	****2 mg****	****12-18 hrs****	****Chest pain, unstable angina****	****	****1037****	****	****10th dose****	****	****	****	**
**	****	**
**	**
**M97-658****	****59****	****2 mg****	****Unknown****	****Patient was a passenger.  ****	****	****	**** 1965 ****	****	**** 2nd dose ****	****	****As a result of the accident, lost ****	****	****	**** ****	****	**** ****	****	****consciousness, patient fractured wrist****	****	****	****	****	****	**
**	****	**
**	****	****	****	****	****	****	****	****	****	**** ****	****	****	****	****	****	****	****	****	****	****	**

**Study #****Patient #**

**Age**

**Dose**

**Event Time****Post-Dose**

**SAE – Considered****Unrelated by Investigator**

**Comments**

- Adverse Events Identified Where Relationshipto Uprima® Questioned by Reviewer

- Safety - SAEs

**– ****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**

## Adverse Events Identified Where Relationshipto Uprima® Questioned by Reviewer

**	**** ****M98-941****	****51****	****2 mg****	****4.5 hrs****	****Lightheadedness, nausea, ****	****	****  3294****	****	****9th dose****	****	****temperature 102°F, ventricular ****	**** ****	****	****	****	****	****bigeminy ****	****	**
**	****	****	****	****	****	**
**  ****	****M98-941****	****49****	****5 mg****	****90 mins****	****Diaphoresis, dizziness, nausea,****	****	**** 3361****	****	****15th dose****	****	****syncope****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	****	**

**Study #****Patient #**

**Age**

**Dose**

**Event Time****Post-Dose**

**SAE – Considered****Unrelated by Investigator**

**Comments**

- Adverse Events Identified Where Relationshipto Uprima® Questioned by Reviewer

- Safety - SAEs

**– ****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**

## Overall Incidence of Serious Adverse Events for Patients Treated with Uprima in the Phase I-III Studies

**Treatment**

**Uprima 2 mg**
**Uprima 4 mg**
**Uprima 5 mg**
**Uprima 6 mg**
**TOTAL (N=3035)**

**Related SAEs**
**n (%)**

**	****0****	**
**	****3**
**	****9****	**
**	****3**
**	****15****	****(0.5)**

**Relationship to Study Drug**

**	****8****	**
**	****13****	**
**	****18**
**	****22****	**
**	****61****	****(2.0)**

**Not Related SAEs**
**n (%)**

- Note: Six patients reported unrelated SAEs while on placebo.

- Table 30

## Primary Reasons for Premature Termination from Study

**Lack of Efficacy****	****0-3****	****(0-1)****	****2 (1) ****	****  1 (<1) ****	**** 1 (<1)****	****2 (1)**
**Patient Request****	****3-12****	****(1-3)****	****8 (2) ****	****10 (2) ****	****8 (3)****	****7 (3)**
**Partner Request****	****1-3****	****(<1-1)                  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****	****(<1-1)****	****1 (<1) ****	****5 (1) ****	****2 (1)****	****5 (2)**
**Total****	****14-37****	****(5-10)****	****27 (6) ****	****54 (13) ****	****48 (17)****	**** 57 (22)**

**Reason**

**2 mg Uprima****®**
**N=429****n (%)**

**4 mg Uprima****®**
**N=426****n (%)**

**6 mg Uprima****®**
**N=262****n (%)**

**5 mg Uprima****®**
**N=282****n (%)**

**Placebo**** n (%)**

- Phase III – CrossoverM96-470, M97-658 & M98-941

***Recommended Doses***

***Higher Than ******Recommended Doses***

- Safety -Premature Terminations

## Premature Termination due to Adverse Events

**     ****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)****	**

**Reason**

**2 mg Uprima****®**
**N=429****n (%)**

**4 mg Uprima****®**
**N=426****n (%)**

**6 mg Uprima****®**
**N=262****n (%)**

**5 mg Uprima****®**
**N=282****n (%)**

**Placebo**** n (%)**

- Phase III – CrossoverM96-470, M97-658 & M98-941

***Recommended Doses***

***Higher Than  Recommended Doses***

- Safety-Premature Terminations

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

- Hypertension
- Coronary Artery Disease
- Benign Prostatic Hyperplasia
- Diabetes
- Alcohol Use

- Adverse Events in Subpopulations

- Safety-Subgroups

## Related Treatment-Emergent Adverse Events Reported by 5% of Patients by Subgroups

**COSTART Term**

**Nausea**
**Dizziness**
**Sweating**
**Somnolence**
**Yawning**
**Headache**

**With**
**N=557**

**	****73****	****(13.1)**
**	****35****	****(6.3)**
**	****23****	****(4.2)**
**	****44****	****(7.9)**
**	****34****	****(6.1)**
**	****26****	****(4.7)**

**Hypertension****n (%)**

**Without**
**N=1310**

**	****213****	****(16.3)**
**	****140****	****(10.7)**
**	****86****	****(6.6)**
**	****109****	****(8.3)**
**	****78****	****(6.0)**
**	****75****	****(5.7)**

**With**
**N=273**

**	****32****	****(11.7)**
**	****17****	****(6.2)**
**	****15****	****(5.5)**
**	****20****	****(7.3)**
**	****9****	****(3.3)**
**	****9****	****(3.3)**

**Diabetes****n (%)**

**Without**
**N=1594**

**	****254****	****(15.9)**
**	****158****	****(9.9)**
**	****94****	****(5.9)**
**	****133****	****(8.3)**
**	****103****	****(6.5)**
**	****92****	****(5.8)**

**With**
**N=291**

**	****44****	****(15.1)**
**	****27****	****(9.3)**
**	****17****	****(5.8)**
**	****29****	****(10.0)**
**	****13****	****(4.5)**
**	****18****	****(6.2)**

**CAD****n (%)**

**Without**
**N=1576**

**	****242****	****(15.4)**
**	****148****	****(9.4)**
**	****92****	****(5.8)**
**	****124****	****(7.9)**
**	****99****	****(6.3)**
**	****83****	****(5.3)**

*Phase II/III Studies* *(2 & 4 mg)*

- Safety-Subgroups

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

## Topics Identified in 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

- FDA Briefing Document

## Representative ED 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

- Summary-Patient Population

## Topics Identified in 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

- FDA Briefing Document

## 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

## Topics Identified in 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

- FDA Briefing Document

## Clinical Relevance of 2 mg

- 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

- Summary-2mg

## Topics Identified in 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

- FDA Briefing Document

## 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

- Summary-Diabetes

## Topics Identified in 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

- FDA Briefing Document

## Discontinuations in Long-Term Studies

- 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

- Summary-Long-Term

## Topics Identified in 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

- FDA Briefing Document

## 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

- Summary - Hemodynamics

## Topics Identified in 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

- FDA Briefing Document

## Nitrate Interaction

- 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

- Summary-Nitrates

## Topics Identified in 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

- FDA Briefing Document

## 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 

- 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

- Alcohol Interaction

- Summary-Alcohol

## 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.

## Summary (cont.)

- 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

- Summary

## Summary (cont.)

- 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

- Summary

## Summary (cont.)

- 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

- Summary

## Summary (cont.)

- 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

- Summary

## 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