1. Uprima ® E001451 Primary 1 6/4/2016 Timothy Fagan, M.D. Professor of Medicine and Associate Professor of Pharmacology University of Arizona, Tucson, Arizona Uprima ® Presentation TAP Holdings Inc.

2. E001451 Primary 2 6/4/2016 Uprima ® Hemodynamics

3. E001451 Primary 3 6/4/2016 Uprima ® Syncope Definition:A sudden transient loss of consciousness with spontaneous recovery 1 Definition:A sudden transient loss of consciousness with spontaneous recovery 1 Signs:Associated with hypotension, bradycardia or both which occur when a person is in the upright position Signs:Associated with hypotension, bradycardia or both which occur when a person is in the upright position Syncope may occur in up to 40% of the population during lifetime Syncope may occur in up to 40% of the population during lifetime Safety-Syncope 1 Murdock BD. South African Medical Journal. v 57: p.771-774 Williams RL. Aerospace Medicine. v 33. P. 545-551.

4. E001451 Primary 4 6/4/2016 Uprima ® Non-Cardiogenic Etiologies of Syncope Physiological Reflex Syncope (vasovagal) Most common type of syncope (50-80%) 1 Most common type of syncope (50-80%) 1 Biphasic Biphasic –Initial phase: apprehension, anxiety, increased HR –Vasodepressor phase: decreased HR, BP, CO  faint Prompt resolution when supine (self-limiting) Prompt resolution when supine (self-limiting) Accommodation usually occurs (60-85% have only 1 episode) 2 Accommodation usually occurs (60-85% have only 1 episode) 2 Many other types, but represent a small percentage of syncope 1 Wayne, HH Am Journal Med. v30: p. 418-438. 1961 2 Kapoor WN. Am Journal Med. V83: p.700-708. 1987 Safety-Syncope

5. E001451 Primary 5 6/4/2016 Uprima ® Evidence for Non-Cardiogenic Etiology The syncope observed with Uprima ® is vasovagal in origin based on careful review of: –Timing and pattern of syncope in individuals –Absence of association with known markers of CVD –Data from continuous Holter monitoring Safety-Syncope

6. E001451 Primary 6 6/4/2016 Uprima ® Evidence for Non-Cardiogenic Etiology 1,702 Holter monitor recordings in 344 subjects/patients, including those: 1,702 Holter monitor recordings in 344 subjects/patients, including those: –with diabetes –on nitrates –on anti-hypertensives –with and without alcohol ingestion These groups demonstrated a similar incidence of arrhythmias in patients when they received Uprima ® compared to when they received placebo These groups demonstrated a similar incidence of arrhythmias in patients when they received Uprima ® compared to when they received placebo Safety-Syncope

7. E001451 Primary 7 6/4/2016 Uprima ® Dose Fixed DoseDose-Optimization 2 mg0.2% (2/964)N/A 4 mg1.2% (7/590)0.6% (4/690) 5 mg0.8% (7/860)1.1% (6/556) 6 mg2.1% (13/621)0.3% (2/631) Distribution of Syncopal Events for all Uprima ® Studies Recommended Doses Higher Than Recommended Doses Safety-Syncope

8. E001451 Primary 8 6/4/2016 Uprima ® Comparison of Syncope Patients vs. Non-Syncope Patients No apparent difference in age, height, weight or race No apparent difference in age, height, weight or race No association with concurrent medications No association with concurrent medications Prodromal symptoms (moderate or severe nausea, vomiting, sweating/hot flashes/vasodilatation, dizziness/lightheadedness and pallor) occurred in nearly all patients with syncope Prodromal symptoms (moderate or severe nausea, vomiting, sweating/hot flashes/vasodilatation, dizziness/lightheadedness and pallor) occurred in nearly all patients with syncope Any one or more symptoms constitutes the prodrome Any one or more symptoms constitutes the prodrome Safety-Syncope

9. E001451 Primary 9 6/4/2016 Uprima ® Comparison of Prodrome* in Syncope vs. Non-Syncope Patients SyncopalNon-Syncopal Episodes withAdministrations Prodromewith Prodrome Per Administration 2, 4, 5, 6 mg85.4%2.9% 2, 4 mg84.6%1.8% Phase I–III Studies Nearly all patients (85%) who experienced syncope also had one or more of the prodromal vasovagal adverse events Nearly all patients (85%) who experienced syncope also had one or more of the prodromal vasovagal adverse events Among patients who did not experience syncope, only 2.9% of all Uprima ® administrations (1.8% for 2 and 4 mg) resulted in one or more prodromal symptoms Among patients who did not experience syncope, only 2.9% of all Uprima ® administrations (1.8% for 2 and 4 mg) resulted in one or more prodromal symptoms Safety-Syncope with at least 1 prodromal symptom) * ( with at least 1 prodromal symptom)

10. E001451 Primary 10 6/4/2016 Uprima ® Syncope: 2 and 4 mg Of 1,988 patients who received 2 and/or 4 mg of Uprima ®, 13 had syncope (1 per 2,700 doses) Of 1,988 patients who received 2 and/or 4 mg of Uprima ®, 13 had syncope (1 per 2,700 doses) Onset (approximate time post dose): Median= 35 minutes Range= 22 to 54 minutes Onset (approximate time post dose): Median= 35 minutes Range= 22 to 54 minutes Duration (approximate): Median= 60 seconds Range= 1 second to 5 minutes Duration (approximate): Median= 60 seconds Range= 1 second to 5 minutes Occurrence: 7/13 (54%) 1st dose 2/13 (15%) Increase in dose 4/13 (31%) Later dose (range 3rd-11th dose) Occurrence: 7/13 (54%) 1st dose 2/13 (15%) Increase in dose 4/13 (31%) Later dose (range 3rd-11th dose) Rechallenge: 7 patients were rechallenged and took a total of 150 additional doses without syncope Rechallenge: 7 patients were rechallenged and took a total of 150 additional doses without syncope Safety-Syncope

11. E001451 Primary 11 6/4/2016 Uprima ® Uprima Development - Patient Safety Early syncopal events were unexpected and in some cases resulted in interventions; in 2 cases, injury occurred Early syncopal events were unexpected and in some cases resulted in interventions; in 2 cases, injury occurred With patient/physician education (instructions to lie down if lightheaded, dizzy or faint), there have been fewer medical interventions and no serious injuries With patient/physician education (instructions to lie down if lightheaded, dizzy or faint), there have been fewer medical interventions and no serious injuries Safety-Syncope

12. E001451 Primary 12 6/4/2016 Uprima ® Summary of Syncope at 2 - 4 mg Incidence is 0.6% per patient when dose is optimized to 4 mg Incidence is 0.6% per patient when dose is optimized to 4 mg Incidence is 1 syncope per 2,700 administrations of Uprima ® 2 or 4 mg Incidence is 1 syncope per 2,700 administrations of Uprima ® 2 or 4 mg 11 out of 13 patients with syncope had prodromal symptoms 11 out of 13 patients with syncope had prodromal symptoms All syncope occurred within 1 hour of dosing All syncope occurred within 1 hour of dosing The context of usage and instructions to remain recumbent in the event of prodromal symptoms should minimize the risk of syncope. This was further evaluated in the current home-use study with 863 patients submitted to the FDA on March 30, 2000. The context of usage and instructions to remain recumbent in the event of prodromal symptoms should minimize the risk of syncope. This was further evaluated in the current home-use study with 863 patients submitted to the FDA on March 30, 2000. Safety-Syncope

13. E001451 Primary 13 6/4/2016 Uprima ® Syncope Conclusion Of patients who experience syncope, most will experience vasovagal prodromal symptoms before the syncopal event Of patients who experience syncope, most will experience vasovagal prodromal symptoms before the syncopal event When Uprima ® is used, most people will be: When Uprima ® is used, most people will be: –Recumbent –Accompanied by a sympathetic partner –Very unlikely to be driving a car or operating heavy machinery Syncope is reported with other approved drugs Syncope is reported with other approved drugs –Bupropion HCl (Wellbutrin/Zyban)1.2% Depression/smoking cessation –Alpha blockers0.5-1% BPH/hypertension –MUSE ® 0.9%Erectile dysfunction Safety-Syncope

14. E001451 Primary 14 6/4/2016 Uprima ® Hemodynamics

15. E001451 Primary 15 6/4/2016 Uprima ® Definition of Mean Maximum Decrease in Blood Pressure For vital signs measurements at multiple timepoints, the greatest decrease from baseline in each patient is determined For vital signs measurements at multiple timepoints, the greatest decrease from baseline in each patient is determined These changes are then averaged across patients These changes are then averaged across patients These changes will be greater than the mean change at any point in time These changes will be greater than the mean change at any point in time Placebo represents random variation Placebo represents random variation Using the mean maximum decrease in blood pressure provides a conservative (worst-case) estimate of mean changes in blood pressure Using the mean maximum decrease in blood pressure provides a conservative (worst-case) estimate of mean changes in blood pressure Note: Vital signs will be presented both as mean maximum decreases from baseline (tables) and mean changes from baseline over time (graphs) Safety - Hypotension

16. Uprima ® E001451 Primary 16 6/4/2016 Vital Signs and Hypotension in the Phase III Studies

17. E001451 Primary 17 6/4/2016 Uprima ® Supine (mm Hg) Systolic Diastolic Standing (mm Hg) Systolic Diastolic Uprima ® Placebo 4 mg (N = 145) *, **, *** Statistically significant at p = 0.05, 0.01 or 0.001 levels, respectively, compared to placebo. -9.1 -4.9 -8.8 -4.7 -11.7 -5.7 -11.1 -5.4 -9.8 -5.7 -9.8 -5.7 -9.9 -5.3 -10.2 -5.3 Mean Maximum Decrease from Baseline in Blood Pressure 2 mg (N = 148) Placebo Phase III – Crossover M98-941 Uprima ® Placebo 5 mg (N = 138) -15.1*** -7.5* -14.4*** -7.3** -8.2 -5.5 -8.1 -4.8 M98-941 Recommended Doses Higher Than Recommended Dose Safety - Hypotension

18. E001451 Primary 18 6/4/2016 Uprima ® 2 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure Change in SBP (mm Hg) Time — Post-dosing (Minutes) Change in DBP (mm Hg) Phase III – Crossover M98-941 * Statistically significant at the p = 0.05 level. ® ® * * M98-941 Safety - Hypotension

19. E001451 Primary 19 6/4/2016 Uprima ® 4 mg Arm – Mean Change from Baseline in Systolic and Diastolic Blood Pressure Change in SBP (mm Hg) Time — Post-dosing (Minutes) Change in DBP (mm Hg) Phase III – Crossover M98-941 * Statistically significant at the p = 0.05 level. ® ® * * M98-941 Safety - Hypotension

20. E001451 Primary 20 6/4/2016 Uprima ® Change in SBP (mm Hg) Time — Post-dosing (Minutes) ® 4 mg Uprima ® Mean Changes in Supine Systolic Blood Pressure Comparison of Uprima ® to Viagra ® 100 mg Viagra ® Time — Post-dosing (Hours) Change in SBP (mm Hg) ® Pre-dose M98-941 Safety - Hypotension 1 Phase III crossover studies (M96-470, M97-658 & M98-941). 2 Viagra Package Insert, June, 1999. 2 Viagra ® Package Insert, June, 1999.

21. E001451 Primary 21 6/4/2016 Uprima ® Adverse Event of Hypotension In the Phase III Crossover Studies, hypotension was reported as an adverse event in less than 5% of patients overall: In the Phase III Crossover Studies, hypotension was reported as an adverse event in less than 5% of patients overall: Crossover studiesDose-optimization studies Crossover studiesDose-optimization studies 3/429 (0.7%) at 2 mg0/146 (0%) at 2, 4, 5 mg 3/429 (0.7%) at 2 mg0/146 (0%) at 2, 4, 5 mg 18/426 (4.2%) at 4 mg6/242 (2.5%) at 2, 4, 5, 6 mg 14/282 (5.0%) at 5 mg 12/262 (4.6%) at 6 mg Nearly all patients (52 of 53) who had an adverse event of hypotension reported one or more concurrent vasovagal adverse events (prodrome) Nearly all patients (52 of 53) who had an adverse event of hypotension reported one or more concurrent vasovagal adverse events (prodrome) Phase III M96-470, M97-658, M97-763, M98-941 & M98-876

22. E001451 Primary 22 6/4/2016 Uprima ® Phase III Hypotension Summary No clinically significant mean decreases in blood pressure were observed for the recommended dose of 2 mg No clinically significant mean decreases in blood pressure were observed for the recommended dose of 2 mg No clinically significant mean decreases in blood pressure were observed for the recommended dose of 4 mg No clinically significant mean decreases in blood pressure were observed for the recommended dose of 4 mg The higher than recommended dose of 5 mg resulted in statistically significant mean decreases from baseline in standing and supine blood pressure only within the first hour of dosing The higher than recommended dose of 5 mg resulted in statistically significant mean decreases from baseline in standing and supine blood pressure only within the first hour of dosing Mean decreases in BP observed following Viagra ® 100 mg were both larger in magnitude and longer in duration than those seen with Uprima ® 4 mg Mean decreases in BP observed following Viagra ® 100 mg were both larger in magnitude and longer in duration than those seen with Uprima ® 4 mg Hypotension was reported as an adverse event by less than 5% of patients in the Phase III crossover studies, and 98% of these patients experienced one or more prodromal vasovagal adverse events Hypotension was reported as an adverse event by less than 5% of patients in the Phase III crossover studies, and 98% of these patients experienced one or more prodromal vasovagal adverse events Safety-Hypotension Phase III

23. Uprima ® E001451 Primary 23 6/4/2016 Diabetes Study M97-804

24. E001451 Primary 24 6/4/2016 Uprima ® Systolic Diastolic -6.8 -3.9 -6.3 -2.4 -7.9 -3.0 -5.0 -2.5 Mean Maximum Decrease from Baseline in Blood Pressure Phase III – Diabetes Systolic Diastolic -8.4 -3.8 -7.8 -2.9 -6.2 -3.0 -6.9 -3.0 Supine (mm Hg) Standing (mm Hg) M97-804 Uprima ® PlaceboUprima ® Placebo 4 mg Group (N = 74-77) 5 mg Group (N = 67-72) Recommended Dose Higher Than Recommended Dose No significant blood pressure differences between Uprima ® and placebo in diabetic patients No significant blood pressure differences between Uprima ® and placebo in diabetic patients Safety-Diabetes

25. E001451 Primary 25 6/4/2016 Uprima ® Phase III Diabetes Safety Conclusion Adverse event profile at maximum recommended dose or higher in diabetic patients similar to adverse event profile in Phase III studies Adverse event profile at maximum recommended dose or higher in diabetic patients similar to adverse event profile in Phase III studies No abnormalities noted in the subset of patients with Holter monitoring No abnormalities noted in the subset of patients with Holter monitoring Syncope in 3 of 205 patients Syncope in 3 of 205 patients Safety-Diabetes

26. E001451 Primary 26 6/4/2016 Uprima ® Hemodynamics

27. E001451 Primary 27 6/4/2016 Nitrate Interaction Study M98-930

28. E001451 Primary 28 6/4/2016 Uprima ® Antihypertensives and Nitrates Study Objective:To evaluate potential pharmacodynamic interactions between Uprima ® and commonly used cardiovascular medications Objective:To evaluate potential pharmacodynamic interactions between Uprima ® and commonly used cardiovascular medications Study design:Multi-center, double-blind, randomized placebo-controlled, fixed-dose, crossover Study design:Multi-center, double-blind, randomized placebo-controlled, fixed-dose, crossover Dose:Uprima ® 5 mg, chronic therapeutic doses of antihypertensives and/or nitrates Dose:Uprima ® 5 mg, chronic therapeutic doses of antihypertensives and/or nitrates Number of patients:162 with hypertension and/or coronary disease Number of patients:162 with hypertension and/or coronary disease Measurements:Supine and standing blood pressure (BP) by Dinamap ®, Holter monitor recordings and adverse events (AE) Measurements:Supine and standing blood pressure (BP) by Dinamap ®, Holter monitor recordings and adverse events (AE) M98-930

29. E001451 Primary 29 6/4/2016 Uprima ® Uprima ® Antihypertensives and Nitrate Interaction Studies Higher than recommended dose of Uprima ® (5 mg) Higher than recommended dose of Uprima ® (5 mg) Multiple concurrent drugs capable of decreasing blood pressure Multiple concurrent drugs capable of decreasing blood pressure Patients with cardiovascular diseases were subject to frequent orthostatic maneuvers Patients with cardiovascular diseases were subject to frequent orthostatic maneuvers Safety-Nitrates M98-930

30. E001451 Primary 30 6/4/2016 Uprima ® Patients Taking Nitrates Average age of 67.4 years and average weight of 186 lbs. Average age of 67.4 years and average weight of 186 lbs. The majority of patients were on a variety of concurrent cardiovascular medications in addition to nitrates (e.g., 75% on antihypertensives, 12% on digitalis, 52% on lipid lowering agents, 18% on antidiabetic agents) The majority of patients were on a variety of concurrent cardiovascular medications in addition to nitrates (e.g., 75% on antihypertensives, 12% on digitalis, 52% on lipid lowering agents, 18% on antidiabetic agents) Patients had expected CVD risk factors including hypertension, previous MI, previous CABG/angioplasty, previous stroke, diabetes, congestive heart failure and atrial fibrillation Patients had expected CVD risk factors including hypertension, previous MI, previous CABG/angioplasty, previous stroke, diabetes, congestive heart failure and atrial fibrillation Safety-Nitrates M98-930

31. E001451 Primary 31 6/4/2016 Uprima ® Supine (mm Hg) Systolic Diastolic Standing (mm Hg) Systolic Diastolic Uprima ® Placebo Long-Acting Nitrates (N = 20) * Statistically significant at p = 0.05 level compared to placebo. -13.5 -6.0 -22.1 -8.9 -15.1 -6.7 -18.9* -9.9* -11.5 -4.9 -10.6 -5.1 -22.1 -11.6 -22.3 -13.9* M98-930 Nitrates Plus Uprima ® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure Short-Acting Nitrates (N = 20) Placebo Statistically significant differences only occurred in the standing position Statistically significant differences only occurred in the standing position Safety-Nitrates

32. E001451 Primary 32 6/4/2016 Uprima ® Short-Acting Nitrates Mean Change from Baseline in Systolic and Diastolic Blood Pressure 30 minute timepoint = Baseline Change in SBP (mm Hg) Time — Post-dosing (Minutes) M98-930 Change in DBP (mm Hg) ® ® No statistically significant mean changes compared to sublingual nitroglycerin alone (N=20) No statistically significant mean changes compared to sublingual nitroglycerin alone (N=20) Safety-Nitrates

33. E001451 Primary 33 6/4/2016 Uprima ® Long-Acting Nitrates Mean Change from Baseline in Systolic and Diastolic Blood Pressure ***,* Statistically significant at p=0.001, p=0.05 level compared to placebo. Time — Post-dosing (Minutes) * * **** * Change in SBP (mm Hg) Change in DBP (mm Hg) ® ® M98-930 Statistically significant changes occurred only in the standing position (N=20) Statistically significant changes occurred only in the standing position (N=20) Safety-Nitrates

34. E001451 Primary 34 6/4/2016 Uprima ® Short-Acting Nitrates Changes in Systolic Blood Pressure Comparison of Uprima ® to Viagra ® 1 19 on 0.4 mg sublingual nitroglycerin and 1 patient on 0.3 mg sublingual nitroglycerin. 2 Study 148-231: A double-blind, placebo-controlled, randomized, two way crossover study to investigate the effects of a single dose of Sildenafil (50 mg) in patients with stable angina taking sublingual glyceryl trinitrate 0.5 mg. Time Post Dose (hours) Standing Systolic Blood Pressure (mm Hg) Uprima ® 5 mg – Standing (N=20) (higher than recommended dose) Viagra ® 50 mg – Sitting (N=16) Sitting Systolic Blood Pressure (mm Hg) Baseline0.501.001.502.00 Time Post Dose (hours) Sildenafil 50 mg + GTN Placebo + GTN Treatment: Baseline0.170.330.51.01.5 ® 1 1 2 2 Treatment: Safety-Nitrates

35. E001451 Primary 35 6/4/2016 Uprima ® Short-Acting Nitrates Changes in Diastolic Blood Pressure Comparison of Uprima ® to Viagra ® 1 19 on 0.4 mg sublingual nitroglycerin and 1 patient on 0.3 mg sublingual nitroglycerin. 2 Study 148-231: A double-blind, placebo-controlled, randomized, two way crossover study to investigate the effects of a single dose of Sildenafil (50 mg) in patients with stable angina taking sublingual glyceryl trinitrate 0.5 mg. Standing Diastolic Blood Pressure (mm Hg) Sitting Diastolic Blood Pressure (mm Hg) Time Post Dose (hours) Baseline0.170.330.51.01.5 Baseline0.501.001.502.00 Time Post Dose (hours) ® 1 1 Treatment: Sildenafil 50 mg + GTN Placebo + GTN Treatment: 2 2 Uprima ® 5 mg – Standing (N=20) (higher than recommended dose) Viagra ® 50 mg – Sitting (N=16) Safety-Nitrates

36. E001451 Primary 36 6/4/2016 Uprima ® Long-Acting Nitrates Changes in Standing Systolic Blood Pressure Comparison of Uprima ® to Viagra ® 1 16 patients on isosorbide mononitrate and 4 patients on minitran patch. 2 Viagra ® Study 148-231: A double-blind, placebo-controlled, randomized, two way crossover study to investigate the effects of a single dose of Sildenafil (50 mg) in patients with stable angina taking isosorbide mononitrate 20 mg oral therapy. Standing Systolic Blood Pressure (mm Hg) Time Post Dose (hours) Sildenafil 50 mg + ISMN 20 mg Placebo + ISMN 20 mg Treatment: Time Post Dose (hours) Baseline0.170.330.50.670.831.01.52.0 Baseline0.500.751.001.251.501.752.000.25 2 2 ® 1 1 Treatment: Uprima ® 5 mg – Standing (N=20) (higher than recommended dose) Viagra ® 50 mg – Standing (N=16) Safety-Nitrates

37. E001451 Primary 37 6/4/2016 Uprima ® Long-Acting Nitrates Changes in Standing Diastolic Blood Pressure Comparison of Uprima ® to Viagra ® 1 16 patients on isosorbide mononitrate and 4 patients on minitran patch. 2 Viagra ® Study 148-231: A double-blind, placebo-controlled, randomized, two way crossover study to investigate the effects of a single dose of Sildenafil (50 mg) in patients with stable angina taking isosorbide mononitrate 20 mg oral therapy. Standing Diastolic Blood Pressure (mm Hg) Time Post Dose (hours) Baseline0.500.751.001.251.501.752.000.25 Sildenafil 50 mg + ISMN 20 mg Placebo + ISMN 20 mg Treatment: 2 2 1 1 ® Uprima ® 5 mg – Standing (N=20) (higher than recommended dose) Viagra ® 50 mg – Standing (N=16) Baseline0.170.330.50.670.831.01.52.0 Safety - Nitrates

38. E001451 Primary 38 6/4/2016 Uprima ® Nitrate Interaction Conclusion No syncopal events No syncopal events No Holter monitor changes attributed to Uprima ® No Holter monitor changes attributed to Uprima ® Compared to Viagra ®, blood pressure decreases were considerably smaller in magnitude and shorter in duration Compared to Viagra ®, blood pressure decreases were considerably smaller in magnitude and shorter in duration The 4 of 40 patients taking nitrates who had clinically significant decreases in blood pressure also had prodromal symptoms The 4 of 40 patients taking nitrates who had clinically significant decreases in blood pressure also had prodromal symptoms With adequate patient instruction (lie down if you experience prodomal symptoms), Uprima ® can be administered to patients taking nitrates With adequate patient instruction (lie down if you experience prodomal symptoms), Uprima ® can be administered to patients taking nitrates Safety-Nitrates

39. Uprima ® E001451 Primary 39 6/4/2016 Antihypertensive Interaction Study M98-930

40. E001451 Primary 40 6/4/2016 Uprima ® ACE Inhibitors (N = 25) Beta Blockers (N = 26) Calcium Channel Blockers (N = 26) Alpha 1 Blockers (N = 24) Uprima ® -7.1 -14.2 -7.2 Placebo -7.6 -4.8 -13.8 -7.2 Uprima ® -12.0 -6.0 -10.0 -7.2 Placebo -8.5 -3.4 -12.5 -6.2 Uprima ® -9.0 -5.3 -15.9 -8.7 Placebo -6.2 -4.9 -10.8 -6.3 Uprima ® -8.8 -5.1 -10.3 -6.9* Placebo -11.3 -4.2 -6.3 -1.5 Diuretics (N = 21) Uprima ® -9.3 -8.2 -10.6 -5.6 Placebo -11.6 -6.8 -11.1 -7.1 M98-930 Antihypertensives Plus Uprima ® 5 mg Mean Maximum Decrease from Baseline in Blood Pressure Supine (mm Hg) Systolic Diastolic Standing (mm Hg) Systolic Diastolic * Statistically significant at p = 0.05 level compared to placebo. Safety-Antihypertensives

41. E001451 Primary 41 6/4/2016 Uprima ® Antihypertensive Interaction Conclusion No clinically significant mean changes from baseline in blood pressure or pulse rate for patients receiving ACE Inhibitors, beta blockers, calcium channel blockers, alpha 1 blockers, and/or diuretics No clinically significant mean changes from baseline in blood pressure or pulse rate for patients receiving ACE Inhibitors, beta blockers, calcium channel blockers, alpha 1 blockers, and/or diuretics Incidence and type of adverse events reported were similar to other Uprima ® Phase I, II and III studies Incidence and type of adverse events reported were similar to other Uprima ® Phase I, II and III studies No Holter monitor changes attributed to Uprima ® except those consistent with vasovagal effects No Holter monitor changes attributed to Uprima ® except those consistent with vasovagal effects One of 122 patients had syncope (0.8% at 5 mg) One of 122 patients had syncope (0.8% at 5 mg) Safety-Antihypertensives

42. E001451 Primary 42 6/4/2016 Uprima ® Hemodynamics

43. E001451 Primary 43 6/4/2016 Uprima ® History of Alcohol Interaction In an early Phase III trial, a syncopal event occurred in a patient who consumed excessive alcohol. For this reason Uprima ® /ethanol interaction studies were conducted. In an early Phase III trial, a syncopal event occurred in a patient who consumed excessive alcohol. For this reason Uprima ® /ethanol interaction studies were conducted. In the first alcohol interaction study (M97-745) at high doses of Uprima ® (5 mg) and ethanol (0.6 g/kg), two serious adverse event (SAE) occurred. There were no sequelae. However, ethanol interaction studies were redesigned, starting with lower doses of ethanol In the first alcohol interaction study (M97-745) at high doses of Uprima ® (5 mg) and ethanol (0.6 g/kg), two serious adverse event (SAE) occurred. There were no sequelae. However, ethanol interaction studies were redesigned, starting with lower doses of ethanol With 6 mg of Uprima ® and 0.15 g/kg of ethanol (M97-762) there were no SAEs; after experiencing nausea or pallor, 4 subjects received oxygen as a precaution With 6 mg of Uprima ® and 0.15 g/kg of ethanol (M97-762) there were no SAEs; after experiencing nausea or pallor, 4 subjects received oxygen as a precaution Further trials were conducted with 6 mg of Uprima ® and 0.3 g/kg (M98-838) and 0.6 g/kg (M98-891) of ethanol Further trials were conducted with 6 mg of Uprima ® and 0.3 g/kg (M98-838) and 0.6 g/kg (M98-891) of ethanol Safety - Alcohol

44. Uprima ® E001451 Primary 44 6/4/2016 Ethanol Interaction Studies M98-838 & M98-891

45. E001451 Primary 45 6/4/2016 Uprima ® Ethanol Interaction Studies Study Design: Double-blind, randomized, placebo-controlled, three- period crossover studies in healthy male subjects Study Design: Double-blind, randomized, placebo-controlled, three- period crossover studies in healthy male subjects Crossover periods:Ethanol Beverage+Uprima ® Placebo Beverage +Uprima ® Ethanol Beverage +Placebo Crossover periods:Ethanol Beverage+Uprima ® Placebo Beverage +Uprima ® Ethanol Beverage +Placebo Dose:Uprima ® 6 mgM98-838, M98-891 Ethanol0.3 g/kgM98-838 0.6 g/kgM98-891 Dose:Uprima ® 6 mgM98-838, M98-891 Ethanol0.3 g/kgM98-838 0.6 g/kgM98-891 Day 1-3Uprima ® or placebo tablet Day 1-3Uprima ® or placebo tablet Day 3Ethanol or placebo beverage, 1hr. before tablet WashoutFour days Phase I M98-838 & M98-891 Safety-Alcohol

46. E001451 Primary 46 6/4/2016 Uprima ® Ethanol Interaction Studies Higher than recommended dose of Uprima ® (6 mg) Higher than recommended dose of Uprima ® (6 mg) High dose of ethanol (0.6 g/kg in M98-891), equivalent to 5 one- ounce shots, consumed within 30 minutes High dose of ethanol (0.6 g/kg in M98-891), equivalent to 5 one- ounce shots, consumed within 30 minutes Healthy male volunteers were subjected to: Healthy male volunteers were subjected to: –frequent orthostatic maneuvers –frequent blood draws Safety-Alcohol Phase I

47. E001451 Primary 47 6/4/2016 Uprima ® Supine (mm Hg) Systolic Diastolic Standing (mm Hg) Systolic Diastolic Uprima ® Ethanol M98-891 (0.6 g/kg Ethanol) (N=61) * Statistically significant at p = 0.05 level compared to Uprima ® plus ethanol. -14.0 -8.9 -16.6* -9.5* -10.9* -6.5 -21.8 -12.6* -14.7 -8.6 -23.2 -10.6* -13.2 -7.8 -19.3 -12.1 Ethanol Plus Uprima ® 6 mg Mean Maximum Decrease from Baseline in Blood Pressure M98-838 (0.3 g/kg Ethanol) (N=64-66) Ethanol Uprima ® + Ethanol -15.9 -9.1 -26.8 -16.9 -15.2 -7.1 -22.3 -14.2 Changes for Uprima ® + ethanol greater than ethanol alone in the standing position Changes for Uprima ® + ethanol greater than ethanol alone in the standing position Safety-Alcohol Phase I

48. E001451 Primary 48 6/4/2016 Uprima ® Mean Change from Baseline in Systolic Blood Pressure Time — Post-dosing (Minutes) M98-838 Supine SBP (mm Hg) Standing SBP (mm Hg) Uprima ® 6 mg + EtOH 0.3 g/kg Uprima ® 6 mg + Placebo Placebo + EtOH 0.3 g/kg No statistically significant differences from ethanol alone (N=66) No statistically significant differences from ethanol alone (N=66) Safety-Alcohol Phase I

49. E001451 Primary 49 6/4/2016 Uprima ® Mean Change from Baseline in Diastolic Blood Pressure Standing DBP (mm Hg) Time — Post-dosing (Minutes) Supine DBP (mm Hg) * Statistically significant compared to Uprima ® + ethanol at the p = 0.05 levels. * M98-838 Uprima ® 6 mg + EtOH 0.3 g/kg Uprima ® 6 mg + Placebo Placebo + EtOH 0.3 g/kg No clinically meaningful changes (N=66) No clinically meaningful changes (N=66) Phase I Safety-Alcohol

50. E001451 Primary 50 6/4/2016 Uprima ® Mean Change from Baseline in Systolic Blood Pressure Standing SBP (mm Hg) Time — Post-dosing (Minutes) M98-891 Supine SBP (mm Hg) *, **, *** Statistically significant compared to Uprima ® + ethanol at the p = 0.05, 0.01 and 0.001 levels, respectively. * ** * * *** ** * * * * Uprima ® 6 mg + EtOH 0.6 g/kg Uprima ® 6 mg + Placebo Placebo + EtOH 0.6 g/kg Of the statistically significant changes seen, some may be attributable to ethanol alone as well as the combination of Uprima ® and ethanol (N=61) Of the statistically significant changes seen, some may be attributable to ethanol alone as well as the combination of Uprima ® and ethanol (N=61) Phase I Safety-Alcohol

51. E001451 Primary 51 6/4/2016 Uprima ® Of the statistically significant changes seen, some may be attributable to ethanol alone as well as the combination of Uprima ® and ethanol (N=61) Of the statistically significant changes seen, some may be attributable to ethanol alone as well as the combination of Uprima ® and ethanol (N=61) Mean Change from Baseline in Diastolic Blood Pressure Standing DBP (mm Hg) Supine DBP (mm Hg) *, **, *** Statistically significant compared to Uprima ® + ethanol at the p = 0.05, 0.01 and 0.001 levels, respectively. *** ** * * * * * M98-891 Uprima ® 6 mg + EtOH 0.6 g/kg Uprima ® 6 mg + Placebo Placebo + EtOH 0.6 g/kg Time — Post-dosing (Minutes) Phase I Safety-Alcohol

52. E001451 Primary 52 6/4/2016 Uprima ® Possibly Related Treatment-Emergent Adverse Events >5% in Uprima ® (6 mg) Plus Ethanol (0.3 and 0.6 g/kg) Event Nausea 34(50.0)21(31.3) 1(1.6) 31(48.4)23(34.3)2(3.2) Dizziness30(44.1)15(22.4)6(9.4)22(34.4)12(17.9)6(9.5) Pallor 21(30.9)18(26.9) 1(1.6) 19(29.7)10(14.9) 0 Sweating 18(26.5)12(17.9) 0 9(14.1)6(9.0)1(1.6) Vomiting 11(16.2)5 (7.5) 0 17(26.6)13(19.4)1(1.6) Hypotension9(13.2)5(7.5)1(1.6)24(37.5)9(13.4)9(14.3) Headache9(13.2)6(9.0)5(7.8)9(14.1)4(6.0)9(14.3) Asthenia4(5.9)10(14.9)2(3.1)10(15.6)7(10.5)5(7.9) Yawning 3(4.4)6(9.0)2 (3.1) 0 0 0 Somnolence 3(4.4)2(3.0)3(4.7)3(4.7)2(3.0)4(6.4) Vasodilatation 3(4.4)3(4.5) 0 8(12.5)5(7.5) 0 Uprima ® (6 mg) + Ethanol 0.3 g/kg N = 68 Ethanol 0.3 g/kg N = 64 Uprima ® (6 mg) N = 67 Uprima ® (6 mg) + Ethanol 0.6 g/kg N = 64 Uprima ® (6 mg) N = 67 Ethanol 0.6 g/kg N = 63 M98-891M98-838 Phase I Safety-Alcohol

53. E001451 Primary 53 6/4/2016 Uprima ® Patient Instructions in Phase III Trials You should limit yourself to a minimal amount of alcoholic beverages during the six hours prior to taking study medication. For most people, a minimal amount of alcoholic beverages is 2 glasses of beer, or 2 glasses of wine or 1 ounce of hard liquor. Safety-Alcohol

54. E001451 Primary 54 6/4/2016 Uprima ® Related Treatment-Emergent Adverse Events  10% Phase II/III Studies Alcohol Use – Phase II/III Studies Alcohol Users (  1 drink/day) N=350 n (%) Non-Alcohol Users N=685 n (%) Adverse Event Nausea Somnolence Dizziness Sweating Yawning Syncope 2 and 4 mg doses 140(33.8) 70(16.9) 66(15.9) 49(11.8) 43(10.4) 6(1.4) 261(30.4) 101(11.8) 137(16.0) 115(13.4) 77(9.0) 12(1.4) Alcohol Users (  1 drink/day) N=414 n (%) Non-Alcohol Users N=858 n (%) All doses (2, 4, 5, 6 mg) 62(17.7) 32(9.1) 25(7.1) 19(5.4) 22(6.3) 3(0.9) 99(14.5) 50(7.3) 67(9.8) 38(5.5) 35(5.1) 5(0.7) Recommended Dose Includes Higher Than Recommended Dose Safety-Alcohol

55. E001451 Primary 55 6/4/2016 Uprima ® Subjects were stressed with high doses of Uprima ®, high doses of ethanol, frequent orthostatic maneuvers and blood draws Subjects were stressed with high doses of Uprima ®, high doses of ethanol, frequent orthostatic maneuvers and blood draws Between 30 and 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. No clinically meaningful changes in supine blood pressure were noted Between 30 and 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. No clinically meaningful changes in supine blood pressure were noted An increased incidence of adverse events was associated with Uprima ® 6 mg when combined with ethanol An increased incidence of adverse events was associated with Uprima ® 6 mg when combined with ethanol Modest changes in apomorphine pharmacokinetic parameters were observed with ethanol 0.6 g/kg but not 0.3 g/kg. No clinically significant changes were seen in ethanol pharmacokinetics Modest changes in apomorphine pharmacokinetic parameters were observed with ethanol 0.6 g/kg but not 0.3 g/kg. No clinically significant changes were seen in ethanol pharmacokinetics In all Phase II/III studies, the adverse event profiles in alcohol users vs. non-alcohol users were comparable, and the syncope rates were the same In all Phase II/III studies, the adverse event profiles in alcohol users vs. non-alcohol users were comparable, and the syncope rates were the same Ethanol Interaction Conclusion Safety-Alcohol

56. E001451 Primary 56 6/4/2016 Uprima ® No holter monitor changes due to Uprima ® except those attributed to vasovagal effects No increased vasovagal Holter monitor changes with Uprima ® and ethanol compared to Uprima ® alone Ethanol Interaction Conclusion (cont.) Safety-Alcohol