Uprima ® E001451 Primary 1 10/10/2015 Uprima ® Presentation TAP Holdings Inc. James W. Freston...

UprimaUprima®®

E001451 Primary 104/19/23

UprimaUprima®® Presentation Presentation

TAP Holdings Inc.TAP Holdings Inc.

UprimaUprima®® Presentation Presentation

TAP Holdings Inc.TAP Holdings Inc.

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

University of Connecticut Health CenterUniversity of Connecticut Health Center

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

University of Connecticut Health CenterUniversity of Connecticut Health Center

E001451 Primary 204/19/23

UprimaUprima®®

Summary of Possibly Related Treatment-Emergent Summary of Possibly Related Treatment-Emergent Adverse Events Reported by >5% of PatientsAdverse 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=429n (%)

4 mg Uprima®

N=426n (%)

6 mg Uprima®

N=262n (%)

5 mg Uprima®

N=282n (%)

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 – CrossoverPhase III – CrossoverM96-470, M98-941 & M97-658M96-470, M98-941 & M97-658

Combined Data – Phase III Crossover StudiesCombined Data – Phase III Crossover Studies

Recommended DosesHigher Than

Recommended Doses

Safety-Adverse Events

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UprimaUprima®®

15.6%14.5%

0.7%8.0%

12.2%

0.9%1.2%

2 mg 4 mg 5 mg0.2%

None Mild Moderate Severe

19.1%

17.6%

2.7%

6 mg

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

Incidence of Nausea by Severity and DoseIncidence of Nausea by Severity and Dose

69.2%79.6%97.9% 60.6%

Combined Data – Phase III Crossover StudiesCombined Data – Phase III Crossover Studies

Recommended Doses Higher Than Recommended Doses

Safety-Nausea

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UprimaUprima®®

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

In over 35,000 treatment administrations of UprimaIn over 35,000 treatment administrations of Uprima®® 2 and 2 and 4 mg:4 mg:

– the incidence of nausea per administration was 2.2% the incidence of nausea per administration was 2.2%

– the incidence of vomiting per administration was 0.2%the incidence of vomiting per administration was 0.2%

Safety-Nausea

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

Dose Number

10.7

4.6

3.7 3.42.7 2.7 2.7 2.7 3.0 3.0

1.8

0

3.7

2.4 2.5 2.6

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16+

%of Patients

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

Phase III Crossover Studies Phase III Crossover Studies UprimaUprima®® 4 mg 4 mg

Safety - Nausea

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UprimaUprima®®

Nausea ConclusionNausea Conclusion

No impact on efficacyNo impact on efficacy

Mostly mildMostly mild

Infrequent anti-emetic useInfrequent anti-emetic use

Few patients discontinuedFew patients discontinued

Incidence declines with continued useIncidence declines with continued use

Safety-Nausea

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UprimaUprima®®

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

SyncopeSyncope

HypotensionHypotension

Serious Adverse Events (SAEs)Serious Adverse Events (SAEs)

Premature TerminationsPremature Terminations

Includes Related, Unrelated and Placebo EventsIncludes Related, Unrelated and Placebo Events

Safety-SAEs

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Serious Adverse Event (SAE) ReportingSerious Adverse Event (SAE) Reporting

The FDA and ICH SAE definition was used in all studies (protocols The FDA and ICH SAE definition was used in all studies (protocols and case report forms)and case report forms)

An SAE is defined as any adverse drug experience occurring at any An SAE is defined as any adverse drug experience occurring at any dose that results in any of the following outcomes:dose that results in any of the following outcomes:– Life-threateningLife-threatening– DeathDeath– Hospitalization/prolongation of hospitalizationHospitalization/prolongation of hospitalization– Congenital anomalyCongenital anomaly– Persistent or significant disability/incapacityPersistent or significant disability/incapacity– Required intervention to prevent permanent impairment/damageRequired intervention to prevent permanent impairment/damage

All SAEs were reported according to the FDA and ICH definitionAll SAEs were reported according to the FDA and ICH definition

Safety-SAEs

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Serious Adverse Events (SAEs)Serious Adverse Events (SAEs)

Total SAE cases described in FDA Briefing Document - 49Total SAE cases described in FDA Briefing Document - 49

Cases described twice - 13Cases described twice - 13

Cases described 3 times - 3Cases described 3 times - 3

Total actual patients described with SAEs - 30Total actual patients described with SAEs - 30– Possibly related to UprimaPossibly related to Uprima®® per reviewer - 21 per reviewer - 21

– Possibly related to UprimaPossibly related to Uprima®® per investigator - 15 per investigator - 15

– Relationship questioned - 6Relationship questioned - 6

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

Safety-SAEs

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UprimaUprima®®

M96-470 52 2 mg 1 day MI1030 4th dose

M96-470 68 2 mg 12-18 hrs Chest pain, unstable angina1037 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 TimePost-Dose

SAE – ConsideredUnrelated by Investigator Comments

Adverse Events Identified Where RelationshipAdverse Events Identified Where Relationshipto Uprimato Uprima® ® Questioned by ReviewerQuestioned 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 tocar accident

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UprimaUprima®®

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 102°F, ventricular

bigeminy

M98-941 49 5 mg 90 mins Diaphoresis, dizziness, nausea, 3361 15th dose syncope

Study #Patient # Age Dose

Event TimePost-Dose

SAE – ConsideredUnrelated by Investigator Comments

Adverse Events Identified Where RelationshipAdverse Events Identified Where Relationshipto Uprimato Uprima® ® Questioned by ReviewerQuestioned 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 oralglucose, repeat glucose was normal

–No history of diabetes–Completed study

E001451 Primary 1204/19/23

UprimaUprima®®

Overall Incidence of Serious Adverse Events for Overall Incidence of Serious Adverse Events for Patients Treated with Uprima in the Phase I-III StudiesPatients 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 SAEsn (%)

0

3

9

3

15 (0.5)

Relationship to Study Drug

8

13

18

22

61 (2.0)

Not Related SAEsn (%)

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

Table 30Table 30

E001451 Primary 1304/19/23

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Adverse Event 0-5 (0-1) 4 (1) 19 (5) 23 (8) 25 (10)

Non-Compliance 1-7 (<1-2) 5 (1) 9 (2) 7 (3) 6 (2)

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=429n (%)

4 mg Uprima®

N=426n (%)

6 mg Uprima®

N=262n (%)

5 mg Uprima®

N=282n (%)

Placebo n (%)

Phase III – CrossoverPhase III – CrossoverM96-470, M97-658 & M98-941 M96-470, M97-658 & M98-941

Primary Reasons for Premature Termination from StudyPrimary Reasons for Premature Termination from Study

Recommended DosesHigher Than

Recommended Doses

Safety -Premature Terminations

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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)

Reason

2 mg Uprima®

N=429n (%)

4 mg Uprima®

N=426n (%)

6 mg Uprima®

N=262n (%)

5 mg Uprima®

N=282n (%)

Placebo n (%)

Phase III – CrossoverPhase III – CrossoverM96-470, M97-658 & M98-941 M96-470, M97-658 & M98-941

Premature Termination due to Adverse EventsPremature Termination due to Adverse EventsRecommended Doses Higher Than Recommended Doses

Safety-Premature Terminations

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UprimaUprima®®

No clinically meaningful differences in adverse event rates No clinically meaningful differences in adverse event rates were observed in patients with:were observed in patients with:

– HypertensionHypertension

– Coronary Artery DiseaseCoronary Artery Disease

– Benign Prostatic HyperplasiaBenign Prostatic Hyperplasia

– DiabetesDiabetes

– Alcohol UseAlcohol Use

Adverse Events in SubpopulationsAdverse Events in SubpopulationsSafety-Subgroups

E001451 Primary 1604/19/23

UprimaUprima®®

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

COSTART Term

Nausea

Dizziness

Sweating

Somnolence

Yawning

Headache

WithN=557

73 (13.1)

35 (6.3)

23 (4.2)

44 (7.9)

34 (6.1)

26 (4.7)

Hypertensionn (%)

WithoutN=1310

213 (16.3)

140 (10.7)

86 (6.6)

109 (8.3)

78 (6.0)

75 (5.7)

WithN=273

32 (11.7)

17 (6.2)

15 (5.5)

20 (7.3)

9 (3.3)

9 (3.3)

Diabetesn (%)

WithoutN=1594

254 (15.9)

158 (9.9)

94 (5.9)

133 (8.3)

103 (6.5)

92 (5.8)

WithN=291

44 (15.1)

27 (9.3)

17 (5.8)

29 (10.0)

13 (4.5)

18 (6.2)

CADn (%)

WithoutN=1576

242 (15.4)

148 (9.4)

92 (5.8)

124 (7.9)

99 (6.3)

83 (5.3)

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

Safety-Subgroups

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

E001451 Primary 1704/19/23

UprimaUprima®®

Topics Identified in FDA Briefing DocumentTopics Identified in FDA Briefing Document

Representative ED patient populationRepresentative ED patient population

Pharmacokinetic variabilityPharmacokinetic variability

Clinical relevance of 2 mgClinical relevance of 2 mg

Efficacy in diabeticsEfficacy in diabetics

Discontinuations in long-term studiesDiscontinuations in long-term studies

HemodynamicsHemodynamics

Nitrate interactionNitrate interaction

Alcohol interactionAlcohol interaction

FDA Briefing Document

E001451 Primary 1804/19/23

UprimaUprima®®

Representative ED Patient PopulationRepresentative ED Patient Population

Reflective of the ED patient population as a whole including Reflective of the ED patient population as a whole including both organic and non-organic diseaseboth organic and non-organic disease

Clearly defined and relevant to clinical practiceClearly defined and relevant to clinical practice

Consistent with the ViagraConsistent with the Viagra®® patient population patient population

Consistent with MMASConsistent with MMAS

Included patients with mild, moderate and severe EDIncluded patients with mild, moderate and severe ED

RigiScans abnormalRigiScans abnormal

The patient population studied does support the proposed The patient population studied does support the proposed indicationindication

Summary-Patient Population

E001451 Primary 1904/19/23

UprimaUprima®®



Pharmacokinetic variability








E001451 Primary 2004/19/23

UprimaUprima®®

Pharmacokinetic VariabilityPharmacokinetic Variability

Experience with the 5 and 6 mg in Phase III studies provided Experience with the 5 and 6 mg in Phase III studies provided evidence that even 4 mg patients achieving highest Cevidence that even 4 mg patients achieving highest Cmax max would would have acceptable safety profileshave acceptable safety profiles

75,449 treatments at 2 to 6 mg would encompass the extreme 75,449 treatments at 2 to 6 mg would encompass the extreme ranges of pharmacokinetic variability ranges of pharmacokinetic variability

Clinical use is more relevant than pharmacokinetic profiles in Clinical use is more relevant than pharmacokinetic profiles in assessing the clinical relevance of variabilityassessing the clinical relevance of variability

Pharmacokinetic Variability

E001451 Primary 2104/19/23

UprimaUprima®®




Clinical relevance of 2 mg







E001451 Primary 2204/19/23

UprimaUprima®®

Clinical Relevance of 2 mgClinical Relevance of 2 mg

Statistically superior compared to placebo in all Phase III Statistically superior compared to placebo in all Phase III Crossover studiesCrossover studies

Shows a 4-point improvement on IIEF in 45% of patients Shows a 4-point improvement on IIEF in 45% of patients (compared to 27% of placebo) (compared to 27% of placebo)

Statistically significant compared to placebo in subgroups, Statistically significant compared to placebo in subgroups, including patients with organic disease and severe EDincluding patients with organic disease and severe ED

Intercourse rates increase from a placebo rate of 29% to 42% Intercourse rates increase from a placebo rate of 29% to 42% for Uprimafor Uprima®® 2 mg (13% increase) compared to 16% increase 2 mg (13% increase) compared to 16% increase seen with Viagraseen with Viagra®® 25 mg 25 mg

Summary-2mg

E001451 Primary 2304/19/23

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Efficacy in diabetics






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DiabetesDiabetes

In diabetic patients enrolled in the Phase III Crossover studies, In diabetic patients enrolled in the Phase III Crossover studies, efficacy improved approximately 10-20% over placebo in all efficacy improved approximately 10-20% over placebo in all dose strengthsdose strengths

Similar to the results seen in the ViagraSimilar to the results seen in the Viagra®® studies, efficacy in studies, efficacy in diabetic patients is lower than seen in the general populationdiabetic patients is lower than seen in the general population

Summary-Diabetes

E001451 Primary 2504/19/23

UprimaUprima®®











E001451 Primary 2604/19/23

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Discontinuations in Long-Term StudiesDiscontinuations 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

E001451 Primary 2704/19/23

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E001451 Primary 2804/19/23

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Syncope rates at 2 and 4 mg, when the dose is optimized, is Syncope rates at 2 and 4 mg, when the dose is optimized, is 0.6%0.6%

At 2 and 4 mg, there were no clinically significant mean At 2 and 4 mg, there were no clinically significant mean decreases in blood pressuredecreases in blood pressure

When hypotension was reported as an adverse event, nearly When hypotension was reported as an adverse event, nearly all patients had concurrent prodromal symptoms.all patients had concurrent prodromal symptoms.

Mean decreases in blood pressure observed following ViagraMean decreases in blood pressure observed following Viagra® ®

100 mg were both larger in magnitude and longer duration 100 mg were both larger in magnitude and longer duration than those seen with Uprimathan those seen with Uprima® ® 4 mg4 mg

In diabetic patients at 4 or 5 mg, there were no clinically In diabetic patients at 4 or 5 mg, there were no clinically significant mean changes from baseline in blood pressure or significant mean changes from baseline in blood pressure or pulse ratepulse rate

Summary - Hemodynamics

E001451 Primary 2904/19/23

UprimaUprima®®











E001451 Primary 3004/19/23

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Nitrate InteractionNitrate Interaction

No syncopal events No syncopal events

No Holter monitor changes were associated with UprimaNo Holter monitor changes were associated with Uprima® ®

except those attributed to a vasovagal effectexcept those attributed to a vasovagal effect

Significant blood pressure changes were seen only in patients Significant blood pressure changes were seen only in patients with vasovagal symptomswith vasovagal symptoms

UprimaUprima®® has a notably less hypotensive effect than does has a notably less hypotensive effect than does ViagraViagra® ® in combination with nitratesin combination with nitrates

Summary-Nitrates

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Subjects were stressed with high doses of UprimaSubjects were stressed with high doses of Uprima®®, high doses of ethanol , high doses of ethanol and frequent orthostatic maneuvers and blood drawsand frequent orthostatic maneuvers and blood draws

Between 30 to 60 minutes post-dosing, mean decreases in standing Between 30 to 60 minutes post-dosing, mean decreases in standing blood pressure were greater when Uprimablood pressure were greater when Uprima®® 6 mg was combined with 6 mg was combined with ethanol 0.6 g/kg than with ethanol administered aloneethanol 0.6 g/kg than with ethanol administered alone

In all Phase II/III studies, the adverse event profiles in alcohol users vs. In all Phase II/III studies, the adverse event profiles in alcohol users vs. non-alcohol users were comparable, and the syncope rates were identicalnon-alcohol users were comparable, and the syncope rates were identical

Risk can be minimized by using the recommended patient instructions Risk can be minimized by using the recommended patient instructions which include:which include:

– not exceeding recommended alcohol consumption (2 beers or 2 glasses of not exceeding recommended alcohol consumption (2 beers or 2 glasses of wine or 1 ounce of liquor) wine or 1 ounce of liquor)

– lying down if experiencing prodromal events lying down if experiencing prodromal events

Alcohol InteractionAlcohol InteractionSummary-Alcohol

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SummarySummary

ED is a common condition with important health consequences (NIH)ED is a common condition with important health consequences (NIH)

ED is associated with a number of diseases and conditionsED is associated with a number of diseases and conditions

Drugs with different modes of action are desirable as with other Drugs with different modes of action are desirable as with other disorders with complex pathophysiology, e.g., hypertensiondisorders with complex pathophysiology, e.g., hypertension

Current therapies are limitedCurrent therapies are limited– The currently approved agents work by peripheral mechanismsThe currently approved agents work by peripheral mechanisms

– Each drug has its own adverse event profileEach drug has its own adverse event profile

– There is no one appropriate treatment for every patientThere is no one appropriate treatment for every patient

Treatment is strongly influenced by couple and physician choiceTreatment is strongly influenced by couple and physician choice

New drugs with different mechanisms offer significant New drugs with different mechanisms offer significant potential benefitspotential benefits

NIH Consensus Development Panel on Impotence. NIH Consensus Development Panel on Impotence. JAMAJAMA 270: 83-90, 1993. 270: 83-90, 1993.

Summary

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Summary Summary (cont.)(cont.)

UprimaUprima®® acts through a unique central mechanism acts through a unique central mechanism

Efficacy has been evaluated using consistent and Efficacy has been evaluated using consistent and relevant end-points after each attempt plus supporting partner datarelevant end-points after each attempt plus supporting partner data

Efficacy of 2 and 4 mg was demonstrated in all studies with all Efficacy of 2 and 4 mg was demonstrated in all studies with all endpoints in patients with:endpoints in patients with: – Mild, moderate and severe EDMild, moderate and severe ED– Coronary artery diseaseCoronary artery disease– Hypertension Hypertension – DiabetesDiabetes– Benign prostatic hypertrophyBenign prostatic hypertrophy– No known organic diseaseNo known organic disease

Both patient population and successful intercourse rates are similar Both patient population and successful intercourse rates are similar to those seen in Viagra studiesto those seen in Viagra studies

Summary

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The safety of UprimaThe safety of Uprima®® has been evaluated in 27 studies, including has been evaluated in 27 studies, including 3,035 patients taking 75,449 doses (treatment episodes) in 3,035 patients taking 75,449 doses (treatment episodes) in Phase I, II and III trialsPhase I, II and III trials

The duration of treatment has exceeded one year in 127 patients The duration of treatment has exceeded one year in 127 patients and 6 months in 461 patients at time of NDAand 6 months in 461 patients at time of NDA

The AE profile was similar in patients with:The AE profile was similar in patients with:– Coronary artery diseaseCoronary artery disease

– HypertensionHypertension

– DiabetesDiabetes

– Benign prostatic hyperplasiaBenign prostatic hyperplasia

– No known organic diseaseNo known organic disease

Summary

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UprimaUprima®® can be taken with alcohol provided patients do not exceed can be taken with alcohol provided patients do not exceed the recommended levels the recommended levels

UprimaUprima®® can be taken with nitrates using the recommended patient can be taken with nitrates using the recommended patient instructions instructions

There were no pharmacodynamic interactions between UprimaThere were no pharmacodynamic interactions between Uprima®® and five different classes of antihypertensive drugsand five different classes of antihypertensive drugs

Summary

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There were no deaths or major illness (e.g. MI, CVA) related There were no deaths or major illness (e.g. MI, CVA) related to Uprimato Uprima®®

Nausea was the most frequent adverse event: 15.5% of patients Nausea was the most frequent adverse event: 15.5% of patients with 2 and 4 mg doses, 2.2% of treatment administrationswith 2 and 4 mg doses, 2.2% of treatment administrations

Accommodation to nausea occurred with subsequent dosesAccommodation to nausea occurred with subsequent doses

Syncope (vasovagal in nature) occurred in 0.8% of patients at 2 and Syncope (vasovagal in nature) occurred in 0.8% of patients at 2 and 4 mg doses (only 0.04% of treatment administrations); with dose-4 mg doses (only 0.04% of treatment administrations); with dose-optimization to 4 mg, syncope occurred in 0.6% of patientsoptimization to 4 mg, syncope occurred in 0.6% of patients

Syncope nearly always occurred with a prodrome of Syncope nearly always occurred with a prodrome of vasovagal symptomsvasovagal symptoms

Summary

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ConclusionsConclusions Uprima is a safe and effective treatment for ED in patients with and Uprima is a safe and effective treatment for ED in patients with and

without known organic diseaseswithout known organic diseases

Risk-Benefit of UprimaRisk-Benefit of Uprima® ®

– 2 mg - rare adverse events, efficacy in all Phase III studies2 mg - rare adverse events, efficacy in all Phase III studies

– 4 mg - few adverse events, robust efficacy4 mg - few adverse events, robust efficacy

– no deaths, MIs, CVAsno deaths, MIs, CVAs

Uprima is a useful and needed addition to the treatment of ED because Uprima is a useful and needed addition to the treatment of ED because it has a:it has a:– unique central mechanism of actionunique central mechanism of action

– novel delivery systemnovel delivery system

– rapid onsetrapid onset

Patients, couples and physicians will have another choice of safe and Patients, couples and physicians will have another choice of safe and effective non-invasive drug with a different mechanism of actioneffective non-invasive drug with a different mechanism of action

Conclusions

Uprima ® E001451 Primary 1 10/10/2015 Uprima ® Presentation TAP Holdings Inc. James W. Freston...

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