Uprima ® E Primary 1 10/10/2015 Uprima ® Presentation TAP Holdings Inc. James W. Freston M.D., Ph.D. Professor of Medicine and Clinical Pharmacology University of Connecticut Health Center

E Primary 2 10/10/2015 Uprima ® 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) 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( ) 1-13( ) 1-7( ) 0-3(0-1.3) 4-10( ) 1-4( ) 1-4( ) 0 0-1(0-0.4) 2-5( ) 0 Phase III – Crossover M96-470, M & M Combined Data – Phase III Crossover Studies Recommended Doses Higher Than Recommended Doses Safety-Adverse Events

E Primary 3 10/10/2015 Uprima ® 15.6% 14.5% 0.7% 8.0 % 12.2% 0.9% 1.2% 2 mg4 mg5 mg 0.2% NoneMildModerateSevere 19.1% 17.6% 2.7% 6 mg Phase III – Crossover M96-470, M & M Incidence of Nausea by Severity and Dose 69.2%79.6%97.9%60.6% Combined Data – Phase III Crossover Studies Recommended DosesHigher Than Recommended Doses Safety-Nausea

E Primary 4 10/10/2015 Uprima ® 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: 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

E Primary 5 10/10/2015 Uprima ® Percentage of Patients with Related Nausea by Dose Number Patients with at Least 8 Attempts Dose Number % of Patients Phase III – Crossover M96-470, M & M Phase III Crossover Studies Uprima ® 4 mg Safety - Nausea

E Primary 6 10/10/2015 Uprima ® Nausea Conclusion No impact on efficacy No impact on efficacy Mostly mild Mostly mild Infrequent anti-emetic use Infrequent anti-emetic use Few patients discontinued Few patients discontinued Incidence declines with continued use Incidence declines with continued use Safety-Nausea

E Primary 7 10/10/2015 Uprima ® Adverse Events Described in Detail in the FDA Briefing Document Syncope Syncope Hypotension Hypotension Serious Adverse Events (SAEs) Serious Adverse Events (SAEs) Premature Terminations Premature Terminations Includes Related, Unrelated and Placebo Events Safety-SAEs

E Primary 8 10/10/2015 Uprima ® Serious Adverse Event (SAE) Reporting The FDA and ICH SAE definition was used in all studies (protocols and case report forms) 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: 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 All SAEs were reported according to the FDA and ICH definition Safety-SAEs

E Primary 9 10/10/2015 Uprima ® Serious Adverse Events (SAEs) Total SAE cases described in FDA Briefing Document - 49 Total SAE cases described in FDA Briefing Document - 49 Cases described twice - 13 Cases described twice - 13 Cases described 3 times - 3 Cases described 3 times - 3 Total actual patients described with SAEs - 30 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

E Primary 10 10/10/2015 Uprima ® M mg1 dayMI 10304th dose M mg12-18 hrsChest pain, unstable angina th dose M mgUnknownPatient was a passenger nd dose As a result of the accident, lost consciousness, patient fractured wrist Study # Patient # AgeDose Event Time Post-Dose SAE – Considered Unrelated by Investigator Comments Adverse Events Identified Where Relationship to 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

E Primary 11 10/10/2015 Uprima ® M mg4 daysViral gastroenteritis, dehydration, 26481st dosesyncope x2, diarrhea, hypotension M mg4.5 hrsLightheadedness, nausea, 32949th dosetemperature 102°F, ventricular bigeminy M mg90 minsDiaphoresis, dizziness, nausea, th dosesyncope Study # Patient # AgeDose Event Time Post-Dose SAE – Considered Unrelated by Investigator Comments Adverse Events Identified Where Relationship to 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

E Primary 12 10/10/2015 Uprima ® 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 (%) (0.5) Relationship to Study Drug (2.0) Not Related SAEs n (%) Note: Six patients reported unrelated SAEs while on placebo. Table 30

E Primary 13 10/10/2015 Uprima ® Adverse Event0-5(0-1)4 (1) 19 (5)23 (8)25 (10) Non-Compliance1-7(<1-2)5 (1) 9 (2)7 (3)6 (2) Lack of Efficacy0-3(0-1)2 (1) 1 (<1) 1 (<1)2 (1) Patient Request3-12(1-3)8 (2) 10 (2) 8 (3)7 (3) Partner Request1-3(<1-1) 0 3 (1) 2 (1)2 (1) Lost to Follow-Up5-8(2)7 (2) 7 (2) 5 (2) 10 (4) Other1-4(<1-1)1 (<1) 5 (1) 2 (1)5 (2) Total14-37(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 – Crossover M96-470, M & M Primary Reasons for Premature Termination from Study Recommended Doses Higher Than Recommended Doses Safety -Premature Terminations

E Primary 14 10/10/2015 Uprima ® Adverse Event0-5 (0-1)4 (1) 19 (5)23 (8)25 (10) Nausea0-1 (0-0.4)1 (0.2)6 (1.4)14 (5.0)15 (5.7) Sweating 0-1 (0-0.4) 06 (1.4)14 (5.0)11 (4.2) Dizziness008 (1.9)11 (3.9)11 (4.2) Hypotension006 (1.4)7 (2.5)4 (1.5) Somnolence004 (0.9)4 (1.4)3 (1.2) Vomiting003 (0.7)6 (2.1)4 (1.5) Syncope01 (0.2)3 (0.7) 1 (0.4)5 (1.9) Asthenia0003 (1.1)5 (1.9) Yawning002 (0.5)4 (1.4)1 (0.4) Bradycardia001 (0.2)0 3 (1.2) Pallor001 (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 – Crossover M96-470, M & M Premature Termination due to Adverse Events Recommended Doses Higher Than Recommended Doses Safety-Premature Terminations

E Primary 15 10/10/2015 Uprima ® No clinically meaningful differences in adverse event rates were observed in patients with: –Hypertension –Coronary Artery Disease –Benign Prostatic Hyperplasia –Diabetes –Alcohol Use Adverse Events in Subpopulations Safety-Subgroups

E Primary 16 10/10/2015 Uprima ® 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= (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) Diabetes n (%) Without N= (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= (15.4) 148(9.4) 92(5.8) 124(7.9) 99(6.3) 83(5.3) Phase II/III Studies(2 & 4 mg) 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

E Primary 17 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 18 10/10/2015 Uprima ® Representative ED Patient Population Reflective of the ED patient population as a whole including both organic and non-organic disease Reflective of the ED patient population as a whole including both organic and non-organic disease Clearly defined and relevant to clinical practice Clearly defined and relevant to clinical practice Consistent with the Viagra ® patient population Consistent with the Viagra ® patient population Consistent with MMAS Consistent with MMAS Included patients with mild, moderate and severe ED Included patients with mild, moderate and severe ED RigiScans abnormal RigiScans abnormal The patient population studied does support the proposed indication The patient population studied does support the proposed indication Summary-Patient Population

E Primary 19 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 20 10/10/2015 Uprima ® Pharmacokinetic Variability Experience with the 5 and 6 mg in Phase III studies provided evidence that even 4 mg patients achieving highest C max would have acceptable safety profiles Experience with the 5 and 6 mg in Phase III studies provided evidence that even 4 mg patients achieving highest C max would have acceptable safety profiles 75,449 treatments at 2 to 6 mg would encompass the extreme ranges of pharmacokinetic variability 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 Clinical use is more relevant than pharmacokinetic profiles in assessing the clinical relevance of variability Pharmacokinetic Variability

E Primary 21 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 22 10/10/2015 Uprima ® Clinical Relevance of 2 mg Statistically superior compared to placebo in all Phase III Crossover studies 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) 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 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 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

E Primary 23 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 24 10/10/2015 Uprima ® Diabetes In diabetic patients enrolled in the Phase III Crossover studies, efficacy improved approximately 10-20% over placebo in all dose strengths 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 Similar to the results seen in the Viagra ® studies, efficacy in diabetic patients is lower than seen in the general population Summary-Diabetes

E Primary 25 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 26 10/10/2015 Uprima ® 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

E Primary 27 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 28 10/10/2015 Uprima ® Hemodynamics Syncope rates at 2 and 4 mg, when the dose is optimized, is 0.6% 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 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. 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 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 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

E Primary 29 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 30 10/10/2015 Uprima ® Nitrate Interaction No syncopal events No syncopal events No Holter monitor changes were associated with Uprima ® except those attributed to a vasovagal effect 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 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 Uprima ® has a notably less hypotensive effect than does Viagra ® in combination with nitrates Summary-Nitrates

E Primary 31 10/10/2015 Uprima ® Topics Identified in FDA Briefing Document FDA Briefing Document

E Primary 32 10/10/2015 Uprima ® Subjects were stressed with high doses of Uprima ®, high doses of ethanol and frequent orthostatic maneuvers and blood draws 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 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 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: 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

E Primary 33 10/10/2015 Uprima ® Summary 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 conditions 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 Drugs with different modes of action are desirable as with other disorders with complex pathophysiology, e.g., hypertension Current therapies are limited 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 Treatment is strongly influenced by couple and physician choice New drugs with different mechanisms offer significant potential benefits New drugs with different mechanisms offer significant potential benefits NIH Consensus Development Panel on Impotence. JAMA 270: 83-90, Summary

E Primary 34 10/10/2015 Uprima ® Summary (cont.) Uprima ® acts through a unique central mechanism 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 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: 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 Both patient population and successful intercourse rates are similar to those seen in Viagra studies Summary

E Primary 35 10/10/2015 Uprima ® 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 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 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: The AE profile was similar in patients with: –Coronary artery disease –Hypertension –Diabetes –Benign prostatic hyperplasia –No known organic disease Summary

E Primary 36 10/10/2015 Uprima ® Summary (cont.) Uprima ® can be taken with alcohol provided patients do not exceed the recommended levels 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 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 There were no pharmacodynamic interactions between Uprima ® and five different classes of antihypertensive drugs Summary

E Primary 37 10/10/2015 Uprima ® Summary (cont.) There were no deaths or major illness (e.g. MI, CVA) related to Uprima ® 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 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 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 (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 Syncope nearly always occurred with a prodrome of vasovagal symptoms Summary

E Primary 38 10/10/2015 Uprima ® Conclusions Uprima is a safe and effective treatment for ED in patients with and without known organic diseases Uprima is a safe and effective treatment for ED in patients with and without known organic diseases Risk-Benefit of Uprima ® 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: 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 Patients, couples and physicians will have another choice of safe and effective non-invasive drug with a different mechanism of action Conclusions