Uprima E001451 Primary 1 2/21/2016 Summary of Efficacy

UprimaUprima®®

E001451 Primary 105/05/23

Summary of EfficacySummary of Efficacy

E001451 Primary 205/05/23

UprimaUprima®®

EfficacyEfficacy

ErectionErection

IntercourseIntercourse

Timing/onset of actionTiming/onset of action

Couple/physician choiceCouple/physician choice

Clinical Considerations in EDClinical Considerations in ED

Efficacy Assessment

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UprimaUprima®®

EfficacyEfficacy

No standard physical measurementNo standard physical measurement

No accepted means of determining etiologies in most casesNo accepted means of determining etiologies in most cases

Duplex ultra sound, pharmacotesting and Nocturnal Penile Duplex ultra sound, pharmacotesting and Nocturnal Penile Tumescense (NPT) are not used routinelyTumescense (NPT) are not used routinely

The International Index of Erectile Function (IIEF*) and Brief The International Index of Erectile Function (IIEF*) and Brief Sexual Function Inventory (BSFI**) are validated clinical Sexual Function Inventory (BSFI**) are validated clinical trial instrumentstrial instruments

Measurements of ED in Clinical TrialsMeasurements of ED in Clinical Trials

** Rosen et al. Rosen et al. UrologyUrology 49:822-830, 1997. 49:822-830, 1997.**** O’Leary et al. O’Leary et al. UrologyUrology 46:697-706, 1995. 46:697-706, 1995.

Efficacy Assessment

E001451 Primary 405/05/23

UprimaUprima®®

EfficacyEfficacy

Determined after each dose administration (every Determined after each dose administration (every attempt) from the home-use questionnaire attempt) from the home-use questionnaire

– Erection firm enough for intercourse based on Erection firm enough for intercourse based on patientpatient response response

– Erection firm enough for intercourse based on Erection firm enough for intercourse based on partnerpartner response response

– Intercourse rates based on Intercourse rates based on patientpatient//partnerpartner responses responses

Efficacy Assessment

UprimaUprima® ® EndpointsEndpoints

E001451 Primary 505/05/23

UprimaUprima®®

Advantages of Home-Use QuestionnaireAdvantages of Home-Use Questionnairevs. Retrospective Questionnaire (e.g., IIEF)vs. Retrospective Questionnaire (e.g., IIEF)

Direct assessment of efficacy at each dosing attemptDirect assessment of efficacy at each dosing attempt Does not require patient to:Does not require patient to:

– Recall attempts after a 4-week periodRecall attempts after a 4-week period– Create an estimate of average erectile function during that Create an estimate of average erectile function during that

4-week period4-week period

Efficacy Assessment

EfficacyEfficacy

UprimaUprima®®

E001451 Primary 605/05/23

Representative Representative ED Patient Population ED Patient Population

E001451 Primary 705/05/23

UprimaUprima®®

Patient PopulationPatient Population

Heterosexual males, ages 18 – 70Heterosexual males, ages 18 – 70

Partner consentPartner consent

Confirmed presence of ED (inability to attain and maintain erection firm Confirmed presence of ED (inability to attain and maintain erection firm enough for intercourse enough for intercourse 50% of attempts 50% of attempts 3 months prior 3 months prior to study)to study)

Physically able to obtain an erection documented by:Physically able to obtain an erection documented by:

– Ability to attain and maintain an erection sufficient for intercourse on some 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 occasion during 3 months prior to study i.e., nocturnal/morning erections or masturbationmasturbation

– Nocturnal Penile Tumescence (NPT) testing with 55% or greater base 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 testingrigidity for at least 10 minutes on at least 1 of 2 nights of NPT testing

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

Patient Population

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UprimaUprima®®

Patient Population Patient Population (cont.)(cont.)

No uncontrolled diseaseNo uncontrolled disease

Clinically acceptable pre-study laboratory values, including normal Clinically acceptable pre-study laboratory values, including normal testosterone and prolactintestosterone and prolactin

Diabetic patients: fasting glucose values <250 mg/dL, Diabetic patients: fasting glucose values <250 mg/dL, no episode of ketoacidosis within 3 months prior to studyno episode of ketoacidosis within 3 months prior to study

Hypertensive patients: Systolic Blood Pressure (SBP) Hypertensive patients: Systolic Blood Pressure (SBP) <180 mm Hg and Diastolic Blood Pressure (DBP) <100 mm Hg<180 mm Hg and Diastolic Blood Pressure (DBP) <100 mm Hg

Smokers: Smokers: 1/2 pack per day1/2 pack per day

Patients were excluded with a history of allergic reaction to morphine (or Patients were excluded with a history of allergic reaction to morphine (or other opiates) or a history of pharmacotherapy for ED (within 3 months other opiates) or a history of pharmacotherapy for ED (within 3 months prior to study)prior to study)

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

Patient Population

E001451 Primary 905/05/23

UprimaUprima®®

Definition of “No Major Organic Component” Definition of “No Major Organic Component”

This term was used to exclude:This term was used to exclude:

– ProstatectomyProstatectomy

– Spinal cord injurySpinal cord injury

– Parkinson’s diseaseParkinson’s disease

– Multiple sclerosisMultiple sclerosis

– Penile prosthesis, penile deformityPenile prosthesis, penile deformity

– End-stage and unstable disease End-stage and unstable disease

Patient Population

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UprimaUprima®®

Patient DemographicsPatient Demographics

Age (yrs)Age (yrs) 55.155.121 - 7621 - 76 23792379

Weight (lbs)Weight (lbs) 199.9199.9112 - 355112 - 355 23762376

Duration of Erectile DysfunctionDuration of Erectile Dysfunction 4.8 yrs4.8 yrs3 mo. - 47 yrs3 mo. - 47 yrs 17711771

RaceRace CaucasianCaucasian 88.6% 88.6%21072107 BlackBlack 6.3%6.3% 150 150 HispanicHispanic 3.6%3.6% 85 85 Asian/Pacific IslanderAsian/Pacific Islander 0.8%0.8% 20 20 OtherOther 0.7%0.7% 17 17

Range NMean

Phase II/III StudiesPhase II/III Studies

Patient Population

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UprimaUprima®®

Representative ED Patient PopulationRepresentative ED Patient Population

Subgroups with organic diseaseSubgroups with organic disease Baseline ED severity based on IIEF criteriaBaseline ED severity based on IIEF criteria RigiScan values compared with established normsRigiScan values compared with established norms Duration of EDDuration of ED

Patient Population

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UprimaUprima®®

Major SubgroupsMajor Subgroups

HypertensionHypertension 31%31% DiabetesDiabetes 16%16% Coronary Artery DiseaseCoronary Artery Disease 16%16% Benign Prostatic HyperplasiaBenign Prostatic Hyperplasia 16%16% Alcohol UseAlcohol Use 63%63% SmokingSmoking 16%16%

Phase II/III StudiesPhase II/III Studies

Patient Population

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UprimaUprima®®

Baseline ED Severity Based on IIEF*Baseline ED Severity Based on IIEF*

SevereSevere 39.3%39.3% ModerateModerate 35.4%35.4% MildMild 24.9%24.9% No EDNo ED 0.5%0.5%

Phase III Studies Phase III Studies (M97-658, M97-763, M97-804, M98-941 and M98-876)(M97-658, M97-763, M97-804, M98-941 and M98-876)

** <10 <10= Severe= Severe11-1611-16 = Moderate= Moderate17-2517-25 = Mild= Mild

>25>25= No ED= No ED

Patient Population

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UprimaUprima®®

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%

11 Approval Package for ViagraApproval Package for Viagra®® (Sildenafil Citrate). FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/HTM. (Sildenafil Citrate). FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/HTM. Joint Clinical Review Joint Clinical Review p. 14. April 1999.p. 14. April 1999.

22 Johannes et al. Johannes et al. J. UrologyJ. Urology 163: 460-463, 2000. 163: 460-463, 2000.

Uprima® Studies Viagra® Studies1 MMAS2

ED PopulationED PopulationPatient Population

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UprimaUprima®®

Comparison of UprimaComparison of Uprima®® NPT Values NPT Valueswith Values for Normalswith Values for Normals

52.4

37.1

72 0.7 0.9

2016

34

18

94

0

10

20

30

40

50

60

20 20-40 40-60 60-80 80-100 >100

Uprima PatientsNormal Subjects

Maximum Tip RAU ValuesNote:Note: Data from Normals Extrapolated from Graph in Levine and Carroll,Data from Normals Extrapolated from Graph in Levine and Carroll,

Journal of UrologyJournal of Urology, Vol. 152, 1103-1107, Oct. 1994., Vol. 152, 1103-1107, Oct. 1994.

Maximum Tip Rigidity Activity Unit (RAU)Maximum Tip Rigidity Activity Unit (RAU)

®

%

Patient Population

E001451 Primary 1605/05/23

UprimaUprima®®

Comparison of UprimaComparison of Uprima®® NPT Values NPT Valueswith Values for Normalswith Values for Normals

37

45.3

11.3

3.3 1.4 1.7

1215

2420.5 18.5

10

0

10

20

30

40

50

60

20 20-40 40-60 60-80 80-100 >100

Uprima PatientsNormal Subjects

Maximum Base RAU Values

Note:Note: Data from Normals Extrapolated from Graph in Levine and Carroll,Data from Normals Extrapolated from Graph in Levine and Carroll,Journal of UrologyJournal of Urology, Vol. 152, 1103-1107, Oct. 1994., Vol. 152, 1103-1107, Oct. 1994.

Maximum Base RAUMaximum Base RAU

®

%

Patient Population

E001451 Primary 1705/05/23

UprimaUprima®®

Representative ED Patient Population ConclusionRepresentative ED Patient Population Conclusion

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

Patient Population

UprimaUprima®®

E001451 Primary 1805/05/23

Efficacy EndpointsEfficacy Endpoints

E001451 Primary 1905/05/23

UprimaUprima®®

Home-Use Questionnaire Completed AfterHome-Use Questionnaire Completed After Every AttemptEvery AttemptEfficacy Endpoints for Phase III StudiesEfficacy Endpoints for Phase III Studies

Primary EndpointPrimary Endpoint

– Percent of Percent of patientpatient “Yes” responses to the question: “Yes” responses to the question:“Did you attain and maintain an erection firm enough “Did you attain and maintain an erection firm enough for intercourse?”for intercourse?”

Secondary EndpointsSecondary Endpoints

– Percent of Percent of partnerpartner “Yes” responses to the question: “Yes” responses to the question:“Was the erection firm enough for intercourse?”“Was the erection firm enough for intercourse?”

– Percent of Percent of patientpatient//partnerpartner “Yes” responses to the question: “Yes” responses to the question:“Did you have intercourse with “Did you have intercourse with your partner?”your partner?”

– Time to erectionTime to erection

Efficacy Endpoints

E001451 Primary 2005/05/23

UprimaUprima®®

Secondary Secondary (cont.)(cont.)

Efficacy Endpoints for Phase III StudiesEfficacy Endpoints for Phase III Studies

– PatientPatient Brief Sexual Function Inventory (BSFI) data Brief Sexual Function Inventory (BSFI) data

– PartnerPartner Brief Sexual Function Inventory data Brief Sexual Function Inventory data

– PatientPatient International Index of Erectile Function International Index of Erectile Function (IIEF) data(IIEF) data

Efficacy Endpoints

E001451 Primary 2105/05/23

UprimaUprima®®

UprimaUprima®®-Efficacy Endpoints-Efficacy Endpoints

ConsistentConsistent

ClearClear

RelevantRelevant

RigorousRigorous

Efficacy Endpoints

E001451 Primary 2205/05/23

UprimaUprima®®

EfficacyEfficacy

Crossover studiesCrossover studies– Primary endpoint (patient and partner)Primary endpoint (patient and partner)– Subgroup analysesSubgroup analyses– Validated questionnairesValidated questionnaires

Diabetes Diabetes Parallel study (M97-763)Parallel study (M97-763) Long-term studiesLong-term studies

Results are shown from the 3 crossover studies combined, but the results from the individualstudies are consistent with the combined data

Efficacy

E001451 Primary 2305/05/23

UprimaUprima®®

Open-LabelFlexible Dose

Long-Term Study

Baseline

24-96 HoursWashout

2-4 WeekBaseline

4 WeekTreatment Period 1

4 WeekTreatment Period 2

WashoutPeriod

WashoutPeriod

2 mg Placebo

Placebo 2 mg

Uprima®

Uprima®

WashoutPeriod

WashoutPeriod

Placebo4 mg

Placebo 4 mg

Uprima®

Uprima®

WashoutPeriod

WashoutPeriod

Placebo6 mg

Placebo 6 mg

Uprima®

Uprima®

Rand

omiza

tion

WashoutPeriod

WashoutPeriod

Placebo5 mg

Placebo 5 mg

Uprima®

Uprima®

Phase IIIPhase IIIM96-470, M97-658 & M98-941M96-470, M97-658 & M98-941

Crossover Study SchematicCrossover Study SchematicEfficacy-Crossover Studies

E001451 Primary 2405/05/23

UprimaUprima®®

Crossover StudiesCrossover Studies

Suggested by the FDA and provided a powerful designSuggested by the FDA and provided a powerful design

Allows patients to be their own controlAllows patients to be their own control

All patients are exposed to study drugAll patients are exposed to study drug

Appropriate for stable chronic diseasesAppropriate for stable chronic diseases

Rationale for Crossover Study DesignRationale for Crossover Study DesignEfficacy-Crossover Studies

E001451 Primary 2505/05/23

UprimaUprima®®

p<.001 p<.001 p<.001

Patient Response (per attempt)Patient Response (per attempt)“Erection Firm Enough for Intercourse”“Erection Firm Enough for Intercourse”

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

27.5 26.8 25.0 27.333.8 33.8

28.632.2

45.6

54.4 53.960.2

0

10

20

30

40

50

60

70

2 mg (N=388) 4 mg (N=362) 5 mg (N=233) 6 mg (N=199)

BaselinePlaceboUprima

p<.001

%“Yes”

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

®

Efficacy-Crossover

E001451 Primary 2605/05/23

UprimaUprima®®

Patient Response (per attempt) Patient Response (per attempt) “Did Attempt Result in Intercourse”“Did Attempt Result in Intercourse”

p<.001 p<.001

25.9 25.7 24.5 23.8

31.0 30.827.3 25.4

41.5

50.6 52.2 54.1

0

10

20

30

40

50

60

70

2 mg (N=387) 4 mg (N=361) 5 mg (N=233) 6 mg (N=199)


p<.001

%“Yes”

p<.001


®


Efficacy-Crossover

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UprimaUprima®®

Intercourse RatesIntercourse RatesComparison of UprimaComparison of Uprima®® to Viagra to Viagra®®

UprimaUprima®® vs. Viagra vs. Viagra®®

545251

42

29

0

10

20

30

40

50

60

Placebo 2 mg 4 mg 5 mg 6 mg

5048

38

22

0

10

20

30

40

50

60

Placebo 25 mg 50 mg 100 mg

Uprima® Viagra®1

%%

11 Calculated from data provided in the Approval Package for ViagraCalculated from data provided in the Approval Package for Viagra®® (Sildenafil Citrate). FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/HTM. (Sildenafil Citrate). FDA.GOV/CDER/CONSUMERINFO/VIAGRA/VIAGRA/HTM. Joint Clinical ReviewJoint Clinical Review. April 1999.. April 1999.

Phase III Crossover Studies Phase III Studies

Efficacy-Viagra

UprimaUprima®®

E001451 Primary 2805/05/23

PartnerPartner ResponsesResponses

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UprimaUprima®®

Partner Involvement in UprimaPartner Involvement in Uprima®® Studies Studies

PartnerPartner responses were a unique factor for the Uprima responses were a unique factor for the Uprima® ® clinical trials clinical trials PartnerPartner BSFI was developed, utilized and validated BSFI was developed, utilized and validated PartnerPartner consent and participation were required for all studies consent and participation were required for all studies ED is a couple’s issueED is a couple’s issue

Efficacy-Crossover

E001451 Primary 3005/05/23

UprimaUprima®®

p<.001 p<.001 p<.001

PartnerPartner Response (per attempt) Response (per attempt)“Erection Firm Enough for Intercourse”“Erection Firm Enough for Intercourse”


33.030.1 29.8 30.1

33.8 33.027.8

32.0

46.0

54.0 53.960.0

0

10

20

30

40

50

60

70

2 mg (N=384) 4 mg (N=361) 5 mg (N=232) 6 mg (N=199)


p<.001

%“Yes”


®

Efficacy-Crossover

E001451 Primary 3105/05/23

UprimaUprima®®

p<.001 p<.001 p<.001

PartnerPartner Response (per attempt) Response (per attempt) “Did Attempt Result in Intercourse”“Did Attempt Result in Intercourse”

31.128.3 27.5 26.4

30.9 30.527.6 26.2

41.9

50.2 52.4 55.0

0

10

20

30

40

50

60

70

2 mg (N=383) 4 mg (N=360) 5 mg (N=232) 6 mg (N=199)


p<.001

%“Yes”



®

Efficacy-Crossover

E001451 Primary 3205/05/23

UprimaUprima®®

Primary Endpoint Subgroup AnalysesPrimary Endpoint Subgroup Analyses

OrganicOrganic

Non-organicNon-organic

Hypertensive PatientsHypertensive Patients

Diabetic PatientsDiabetic Patients

Coronary Artery DiseaseCoronary Artery Disease

Benign Prostatic HyperplasiaBenign Prostatic Hyperplasia

Alcohol UsersAlcohol Users

SmokersSmokers

Age >65Age >65

ED SeverityED Severity

Efficacy-Crossover/Subgroups

E001451 Primary 3305/05/23

UprimaUprima®®

p<.001



26.1 25.0 24.1 23.9

31.829.0 28.6

35.2

43.348.5 50.5

64.1

0

10

20

30

40

50

60

70

2 mg (N=151) 4 mg (N=136) 5 mg (N=103) 6 mg (N=70)


p<.001

%“Yes”

Subgroup: Documented Organic DiseaseSubgroup: Documented Organic Disease(Hypertension, CAD or Diabetes)(Hypertension, CAD or Diabetes)

®

p<.001 p<.001

Efficacy - Subgroups

E001451 Primary 3405/05/23

UprimaUprima®®

p=.027 p=.002

Patient Response (per attempt) Patient Response (per attempt) “Erection Firm Enough for Intercourse” “Erection Firm Enough for Intercourse”

p<.001

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

p<.001

24.9

32.2

17.120.5

25.1

32.0

19.5 19.7

33.3

53.6

36.8

45.7

0

10

20

30

40

50

60

70

2 mg (N=52) 4 mg (N=38) 5 mg (N=32) 6 mg (N=26)


%“Yes”

Subgroup: Age >65Subgroup: Age >65

®

Efficacy - Subgroups

UprimaUprima®®

E001451 Primary 3505/05/23

ED SeverityED Severity

E001451 Primary 3605/05/23

UprimaUprima®®

Assessment of Effect of ED Severity on EfficacyAssessment of Effect of ED Severity on Efficacy

Analyses were performed in patients with:Analyses were performed in patients with:

– mild, moderate and severe ED severity scores at baselinemild, moderate and severe ED severity scores at baseline

– no success during baselineno success during baseline

– abnormal RigiScan scores at inclusion into studyabnormal RigiScan scores at inclusion into study

Efficacy - ED Severity

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UprimaUprima®®

Definition of ED Severity Based on IIEFDefinition of ED Severity Based on IIEF

ED severity was determined based on the sum of 6 ED severity was determined based on the sum of 6 questions from the IIEF (questions 1-5 and 15)questions from the IIEF (questions 1-5 and 15)

SevereSevere <10<10

ModerateModerate 11-1611-16

MildMild 17-2517-25

No EDNo ED >25>25

Efficacy-ED Severity

IIEF Scoring For Erectile DysfunctionIIEF Scoring For Erectile Dysfunction

E001451 Primary 3805/05/23

UprimaUprima®®

p=.003 p<.001 p<.001


Phase III – Crossover Phase III – Crossover M97-658 & M98-941M97-658 & M98-941

8.012.0 11.0 10.7

17.521.2

15.110.6

25.2

42.336.8

56.8

0

10

20

30

40

50

60

70

2 mg (N=91) 4 mg (N=77) 5 mg (N=74) 6 mg (N=30)


p<.001

%“Yes”

Erectile Dysfunction: Severe* Erectile Dysfunction: Severe* (39% of patients)(39% of patients)

®

* IIEF scores: no ED >25, mild ED 17-25, moderate ED 11-16, severe ED <10.* IIEF scores: no ED >25, mild ED 17-25, moderate ED 11-16, severe ED <10.


E001451 Primary 3905/05/23

UprimaUprima®®

Patient Response (per attempt) Patient Response (per attempt) “Erection Firm Enough for Intercourse”“Erection Firm Enough for Intercourse”


p<.001

16.320.3

16.120.6

25.5

43.739.7

49.0

0

10

20

30

40

50

60

70

2 mg (N=150) 4 mg (N=136) 5 mg (N=98) 6 mg (N=75)

PlaceboUprima

%“Yes”

p<.001p<.001p<.001

For Patients (39%) With No Success During BaselineFor Patients (39%) With No Success During Baseline

®


E001451 Primary 4005/05/23

UprimaUprima®®

24.6 24.018.8

25.430.7 27.9 29.7 27.5

43.1

53.1 50.5

67.7

0

10

20

30

40

50

60

70

2 mg (N=61) 4 mg (N=50) 5 mg (N=35) 6 mg (N=27)



p=.008 p=.002p<.001

%“Yes”

p=.001

®

Phase III – CrossoverPhase III – Crossover

Patients with Maximum Tip RAU Patients with Maximum Tip RAU 9.59.5


E001451 Primary 4105/05/23

UprimaUprima®®

ED Severity ConclusionED Severity Conclusion

UprimaUprima®® is effective in patients with severe ED as is effective in patients with severe ED as evaluated evaluated by:by:

– Baseline IIEF ED severityBaseline IIEF ED severity

– Baseline success rateBaseline success rate

– Abnormal NPT (Tip RAU Abnormal NPT (Tip RAU 9.5)9.5)

UprimaUprima®® is also effective in patients with mild or moderate is also effective in patients with mild or moderate ED ED


UprimaUprima®®

E001451 Primary 4205/05/23

Other EndpointsOther Endpoints

E001451 Primary 4305/05/23

UprimaUprima®®

Other EndpointsOther Endpoints

Home-Use (per attempt) EndpointsHome-Use (per attempt) Endpoints– Timing of erectionsTiming of erections– Treatment Success (% achieving erections sufficient for intercourse in Treatment Success (% achieving erections sufficient for intercourse in

>50% of attempts)>50% of attempts)– Diary Satisfaction Scale (per attempt)Diary Satisfaction Scale (per attempt)

Validated QuestionnairesValidated Questionnaires– PartnerPartner Satisfaction Scale ( Satisfaction Scale (PPBSFI)BSFI)– IIEF (4 point improvement in erectile function)IIEF (4 point improvement in erectile function)

Efficacy-Other Endpoints

E001451 Primary 4405/05/23

UprimaUprima®®

Dose(N placebo, Placebo Minutes Uprima® Minutes N Uprima®) Median (IQR) Median (IQR)

Median Time to ErectionMedian Time to Erection (Using Only Attempts When an Erection Was Achieved) (Using Only Attempts When an Erection Was Achieved)


More erections occurred with UprimaMore erections occurred with Uprima®® than with placebo. than with placebo.IQR = interquartile range.IQR = interquartile range.


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

E001451 Primary 4505/05/23

UprimaUprima®®

Patient Assessment Patient Assessment Percentage of Patients Deemed a Treatment SuccessPercentage of Patients Deemed a Treatment Success

36.1 34.830.9 32.2

47.7

59.4 57.964.3

0

10

20

30

40

50

60

70

2 mg (N=388) 4 mg (N=362) 5 mg (N=233) 6 mg (N=199)

PlaceboUprima

%

p<.001 p<.001 p<.001Definition 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.

p<.001


®



E001451 Primary 4605/05/23

UprimaUprima®®

Percent of Percent of PatientsPatients with Mean Intercourse Attempt with Mean Intercourse Attempt Satisfaction Satisfaction >3 and an Improvement Over Baseline3 and an Improvement Over Baseline


11.28.4

10.813.3

24.3

30.7

36.833.7

0

10

20

30

40

2 mg (N=383) 4 mg (N=358) 5 mg (N=231) 6 mg (N=196)

PlaceboUprima

p<.001 p<.001p<.001 p<.001

®

Combined Data – Phase II/III StudiesCombined Data – Phase II/III Studies

Scale:1=Very dissatisfied2=Mostly dissatisfied3=Neutral or mixed (about equally satisfied and dissatisfied)4=Mostly satisfied5=Very satisfied


E001451 Primary 4705/05/23

UprimaUprima®®

Percent of Percent of PartnersPartners with Mean Intercourse Attempt with Mean Intercourse Attempt Satisfaction Satisfaction >3 and an Improvement Over Baseline3 and an Improvement Over Baseline


12.2 13.1 11.714.4

26.0

31.6

37.7 37.1

0

10

20

30

40

2 mg (N=377) 4 mg (N=351) 5 mg (N=231) 6 mg (N=194)

PlaceboUprima

p<.001 p<.001p<.001 p<.001

®

Combined Data – Phase II/III StudiesCombined Data – Phase II/III Studies

Scale:1=Very dissatisfied2=Mostly dissatisfied3=Neutral or mixed (about equally satisfied and dissatisfied)4=Mostly satisfied5=Very satisfied

Efficacy - Other Endpoints

E001451 Primary 4805/05/23

UprimaUprima®®

p<.001 p<.001

Percent of Patients with 4 Point Improvement Percent of Patients with 4 Point Improvement in the Erectile Function Domain Index of the IIEFin the Erectile Function Domain Index of the IIEF

p<.001

Phase III – Crossover StudiesPhase III – Crossover StudiesM97-658 & M98-941M97-658 & M98-941

p<.001

27.4 27.0 25.0

18.2

44.8

54.0 55.160.2

0

10

20

30

40

50

60

70

2 mg (N=248) 4 mg (N=237) 5 mg (N=236) 6 mg (N=88)

PlaceboUprima

%

®

Combined Data – M97-658 & M98-941Combined Data – M97-658 & M98-941

Based on a scale of 1 to 30, with higher scores being better.Based on a scale of 1 to 30, with higher scores being better.


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Phase III Crossover Studies ConclusionPhase III Crossover Studies Conclusion

Clinical significance has been shown at all dose strengths and Clinical significance has been shown at all dose strengths and demonstrated in all subgroups (organic, non-organic, hypertensive, demonstrated in all subgroups (organic, non-organic, hypertensive, etc.) with these endpointsetc.) with these endpoints

The robustness of the UprimaThe robustness of the Uprima®® efficacy results has been efficacy results has been demonstrated across a variety of home-use efficacy endpoints demonstrated across a variety of home-use efficacy endpoints and is confirmed by the results of validated questionnairesand is confirmed by the results of validated questionnaires

Efficacy-Crossover

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Phase III Crossover Studies Conclusion (cont.)Phase III Crossover Studies Conclusion (cont.)

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 studies for the primary endpoint and virtually all secondary Crossover studies for the primary endpoint and virtually all secondary endpointsendpoints

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

– Statistically significant compared to placebo in patients with moderate to Statistically significant compared to placebo in patients with moderate to severe ED as well as patients with a variety of organic diseases severe ED as well as patients with a variety of organic diseases (hypertension, diabetes, CAD, etc.)(hypertension, diabetes, CAD, etc.)

– Intercourse rates increase from a placebo rate of 29% to 42% for Intercourse rates increase from a placebo rate of 29% to 42% for UprimaUprima®® 2 mg (13% increase) compared to 16% increase seen with 2 mg (13% increase) compared to 16% increase seen with ViagraViagra®® 25 mg 25 mg

Efficacy-Crossover

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EfficacyEfficacy

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

Efficacy

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Efficacy in DiabeticsEfficacy in Diabetics

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UprimaUprima®®Phase III Phase III

4 mg

n (%)

5 mg

n (%)Baseline IIEF Severity Rating*

Severe 61 71.8 42 50.0 103 61.0

Moderate 20 23.5 24 28.6 44 26.0

Mild 4 4.7 18 21.4 22 13.0

Combined**

n (%)

Diabetes Study Baseline ED SeverityDiabetes Study Baseline ED SeverityM97-804M97-804

** Severity rating determined by Erectile Function total.Severity rating determined by Erectile Function total.Severity Score; Mild (17-25), Moderate (11-16), and Severe (<10).Severity Score; Mild (17-25), Moderate (11-16), and Severe (<10).Note: No NPT required for enrollment.Note: No NPT required for enrollment.

**** Due to randomization imbalance, the 4 and 5 mg were combined to represent the overall diabetic population.Due to randomization imbalance, the 4 and 5 mg were combined to represent the overall diabetic population.

Efficacy-Diabetes

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5.1

12.28.1

14.5

27.2

20.424.6

34.1

28.9

0

10

20

30

40

50

4 mg (N=90) 5 mg (N=86) Combined (N=176)

BaselinePlaceboUprima®

Patient Response (per attempt)Patient Response (per attempt)“Did You Achieve an Erection Firm Enough for Intercourse”“Did You Achieve an Erection Firm Enough for Intercourse”

Phase III – DiabeticPhase III – Diabetic

p=.020 p=.179

%“Yes”

p=.009

M97-804M97-804

Efficacy-Diabetes

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p=.038 p=.021

19.6

6.4

13.4 11.5

22.418.3

25.930.0

40.3

29.2

36.2

45.2

0

10

20

30

40

50

2 mg (N=30) 4 mg (N=113) 5 mg (N=111) 6 mg (N=8)

Baseline

Uprima®

p=.004

%“Yes”

p=.090

Patient Response (per attempt) Patient Response (per attempt) “Erection Firm Enough for Intercourse”“Erection Firm Enough for Intercourse”

Phase III – Crossover Phase III – Crossover M96-470, M97-658, M98-941 & M97-804M96-470, M97-658, M98-941 & M97-804

Diabetic Patients– Phase III Crossover StudiesDiabetic Patients– Phase III Crossover Studies(M96-470, M97-658, M98-941 & M97-804)(M96-470, M97-658, M98-941 & M97-804)

Efficacy-Diabetes

Placebo

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Diabetes Efficacy ConclusionDiabetes Efficacy Conclusion

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

Although there was a randomization imbalance, statistically Although there was a randomization imbalance, statistically significant results were noted in the 4 mg arm and both dosing significant results were noted in the 4 mg arm and both dosing groups combined from the M97-804 Diabetes Studygroups combined from the M97-804 Diabetes Study

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 dose efficacy improved approximately 10-20% over placebo in all dose strengthsstrengths

Efficacy-Diabetes

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UprimaUprima®® Efficacy Efficacy


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Open-LabelLong-Term

Extension Study

Placebo

6 mg

Baseline

Baseline

2-4 WeeksDay 1

5 mg

Info

rmed

Con

sent

Rand

omiza

tion

Placebo

6 mg Fixed Dose

VOLUNTARY TITRATION

5 mg Fixed Dose

Week 1 Week 2 Week 3 Week 4 Week 8

2 mg 4 mg 5 mg 6 mg

Optimal Dose

Parallel Study Schematic DesignParallel Study Schematic Design

Phase III – ParallelPhase III – ParallelM97-763M97-763 Efficacy-Parallel

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23.5 21.1

27.5 25.6 25.6

34.7

54.6 53.4 53.9

47.6

0

10

20

30

40

50

60

Placebo 5 mg 6 mg Dose- Optimization

Dose- Optimization

Aver

age

Perc

ent

p<.001p<.001

p<0.001N=114N=112 N=112N=114 N=84N=82 N=232N=230 N=230 N=232

2, 4, 5, 6 mg 2, 4 mgp=.003

Phase III – ParallelPhase III – ParallelM97-763M97-763

Patient Response (per attempt)Patient Response (per attempt)“Erections Firm Enough for Intercourse”“Erections Firm Enough for Intercourse”

BaselinePlaceboUprima ®

Based on last 8 attempts.Based on last 8 attempts.

M97-763M97-763

Efficacy-Parallel

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28.823.7

29.0 26.6 26.6

35.6

54.1 53.6 53.448.4

0

10

20

30

40

50

60


Dose- Optimization

p<.001p<.001

p=.002N=112N=112 N=114N=112 N=80N=84 N=225N=228 N=228 N=224

2, 4, 5, 6 mg 2, 4 mgp=.004


PartnerPartner Response (per attempt)Response (per attempt)“Erections Firm Enough for Intercourse”“Erections Firm Enough for Intercourse”


M97-763M97-763

Aver

age

Perc

ent


Efficacy-Parallel

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22.6 21.0

27.6 26.0 26.0

33.0

52.349.6

52.2

45.1

0

10

20

30

40

50

60


Dose- Optimization

p<.001p<.001

p=.003N=114N=112 N=112N=114 N=84N=82 N=232N=230 N=230 N=232

2, 4, 5, 6 mg 2, 4 mgp=.005


PatientPatient Response (per attempt)Response (per attempt)“Did Attempt Result in Intercourse”“Did Attempt Result in Intercourse”


M97-763M97-763

Aver

age

Perc

ent


Efficacy-Parallel

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EfficacyEfficacy


UprimaUprima®®

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Discontinuations in Discontinuations in Long-Term StudiesLong-Term Studies

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Long-Term StudiesLong-Term Studies

The long-term studies were designed primarily to collect The long-term studies were designed primarily to collect safety informationsafety information

A number of factors contributed to patient discontinuation A number of factors contributed to patient discontinuation in the long-term studiesin the long-term studies– Lack of efficacyLack of efficacy– Adverse eventsAdverse events– Approval of new compounds (MUSEApproval of new compounds (MUSE®®, Viagra, Viagra®®))– Length of studies and stringent patient requirements Length of studies and stringent patient requirements

(office visits, diary completion after every attempt, etc.)(office visits, diary completion after every attempt, etc.)– Competing investigational studiesCompeting investigational studies

Efficacy-Long -Term

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26.2

51.8

66.072.2

78.282.4 83.5

0

10

20

30

40

50

60

70

80

90

100

Baseline Month 1 Month 2 Month 3 Month 4 Month 5 Month 6

Phase III – Long-Term Open-LabelPhase III – Long-Term Open-LabelM96-471, M97-659, M97-682 & M98-936M96-471, M97-659, M97-682 & M98-936

Percentage of Erections Firm Enough for IntercoursePercentage of Erections Firm Enough for Intercourse

N=1,008 N=887 N=728 N=599 N=492 N=426

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

N=1,019

Efficacy-Long -Term

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Long-Term StudiesLong-Term Studies

Short-term studies show that treatment success is achieved Short-term studies show that treatment success is achieved in 50-60% of patients, yet approximately 80% of eligible patients in 50-60% of patients, yet approximately 80% of eligible patients enrolled into long-term studiesenrolled into long-term studies

Dropout rates of 20-30% are not unexpected based on the number Dropout rates of 20-30% are not unexpected based on the number of patients who enrolled from the short-term studies who had no of patients who enrolled from the short-term studies who had no efficacyefficacy

Dropout rates were also influenced by adverse events, approval of Dropout rates were also influenced by adverse events, approval of ViagraViagra®®, other competing ED trials and the burden of patient , other competing ED trials and the burden of patient inconvenience associated with frequent visits, diary completion, etc.inconvenience associated with frequent visits, diary completion, etc.

Despite this, over 42% of patients reached the 6-month time point in Despite this, over 42% of patients reached the 6-month time point in the long-term studies and demonstrated sustained and reliable the long-term studies and demonstrated sustained and reliable efficacyefficacy

Efficacy-Long -Term

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30.5

65.6

78.3 80.984.5 84.7 83.5

0

10

20

30

40

50

60

70

80

90

100


Phase III – Long-Term Open-LabelPhase III – Long-Term Open-LabelM96-471, M97-659 & M97-682M96-471, M97-659 & M97-682


N=417 N=425 N=422 N=425 N=426 N=426

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

Includes only patients who remained on drug for at least 6 months.Includes only patients who remained on drug for at least 6 months.

N=426

Efficacy-Long -Term

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UprimaUprima®®

33.9

82.990.2 90.3 91.6 89.8 89.4

0

10

20

30

40

50

60

70

80

90

100


Phase III – Long-Term Open-LabelPhase III – Long-Term Open-LabelM96-471, M97-659 & M97-682M96-471, M97-659 & M97-682


N=126 N=123 N=117 N=117 N=125 N=128

2 and 4 mg2 and 4 mg

N=129

Includes only patients who remained on drug for at least 6 months.Includes only patients who remained on drug for at least 6 months.

Efficacy-Long -Term

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Efficacy in Long-Term Studies ConclusionEfficacy in Long-Term Studies Conclusion

Patients remaining in long-term studies have sustained and Patients remaining in long-term studies have sustained and reliable response with erections in more than 80% of attemptsreliable response with erections in more than 80% of attempts

Patients obtaining efficacy in the long-term studies are similar Patients obtaining efficacy in the long-term studies are similar to all Uprimato all Uprima® ® patients as evidenced by their baseline success patients as evidenced by their baseline success ratesrates

Efficacy - Long -Term

UprimaUprima®®

E001451 Primary 7005/05/23

Overall Efficacy ConclusionsOverall Efficacy Conclusions

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UprimaUprima®®

Overall Efficacy ConclusionsOverall Efficacy Conclusions

Clinical trials included patients representative of the general ED Clinical trials included patients representative of the general ED population, similar to Viagrapopulation, similar to Viagra®® and MMAS and MMAS

UprimaUprima®® 2 and 4 mg has been shown to be statistically and clinically 2 and 4 mg has been shown to be statistically and clinically significantly better than placebo in large scale controlled studiessignificantly better than placebo in large scale controlled studies

UprimaUprima®® 2 and 4 mg have demonstrated a clinically relevant 2 and 4 mg have demonstrated a clinically relevant improvement in the IIEF Erectile Function Domain (4-point) improvement in the IIEF Erectile Function Domain (4-point) compared to placebocompared to placebo

UprimaUprima®® partnerpartner efficacy data has been shown to be almost identical efficacy data has been shown to be almost identical to Uprimato Uprima®® patientpatient efficacy data efficacy data

Patients remaining in the long-term studies have substantial and Patients remaining in the long-term studies have substantial and reliable responses with erections in more than 80% of attemptsreliable responses with erections in more than 80% of attempts

Efficacy-Conclusions

E001451 Primary 7205/05/23

UprimaUprima®®

Overall Efficacy Conclusions Overall Efficacy Conclusions (cont.)(cont.)

UprimaUprima®® efficacy has been demonstrated in subsets of efficacy has been demonstrated in subsets of patientspatients with: with:– organic diseaseorganic disease - benign prostatic hyperplasia - benign prostatic hyperplasia – hypertensionhypertension - alcohol users - alcohol users – diabetesdiabetes - smokers - smokers– coronary artery diseasecoronary artery disease

UprimaUprima®® efficacy has been demonstrated in all severities of ED efficacy has been demonstrated in all severities of ED UprimaUprima®® has been shown to have a rapid onset of has been shown to have a rapid onset of

erectile responseerectile response UprimaUprima®® has demonstrated significance in all satisfaction and has demonstrated significance in all satisfaction and

erectile function indices (BSFI, IIEF, erectile function indices (BSFI, IIEF, PartnerPartner BSFI) BSFI)

Efficacy-Conclusions

Documents

Uprima E001451 Primary 1 2/21/2016 Summary of Efficacy