FREEDOM C: A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C

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1 FREEDOM C: A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C SR in Combination with an ERA and/or a PDE-5 Inhibitor in Subjects with PAH

2 Study Objectives Primary: Secondary: To assess the effect of UT-15C SR on exercise capacity compared to placebo (as measured by the change in 6MW distance from Baseline to Week 16) in subjects with PAH To assess the effect of UT-15C SR on the following:» Six-minute walk distance at Week 12» Six-minute walk distance at Week 8» Time to clinical worsening» Combined ranking of distance and Borg score from the 6MWT at Week 16» WHO Functional Classification for PAH at Week 16» Borg score from the 6MWT at Week 16» Dyspnea-Fatigue Index at Week 16» Six-minute walk distance at Week 4» Symptoms of PAH at Week 16

3 Clinical Worsening Definition of clinical worsening: 1. Death (all causes excluding accident) 2. Transplantation or atrial septostomy 3. Clinical deterioration as defined by: a. Hospitalization as a result of PAH, OR b. > 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) AND a decrease in WHO functional class AND c. Initiation of new PAH specific therapy (ERA or PDE-5 inhibitor, prostacyclin)

4 Inclusion Criteria Age Baseline 6MWD of meters (initial protocol) Amendment 3: meters Confirmed diagnosis of PAH Idiopathic or Familial Collagen vascular associated disease HIV or Anorexigen associated disease Repaired congenital shunts (repaired 5 years) Receiving background therapy of an approved ERA and/or an approved PDE-5 inhibitor for 3 months prior to enrollment and on a stable dose for 30 days

5 Study Visits Baseline and Weeks 4, 8, 12, and 16 6 minute walk at peak Borg Dyspnea score WHO class PAH signs and symptoms Dyspnea Fatigue Index Clinical worsening assessment Laboratory parameters (Baseline, Wks 8 and 16) Physical Examination (Baseline and Wk 16)

6 Statistical Analysis Plan Primary Analysis: nonparametric ANCOVA testing difference between Active and Placebo in peak 6MWD change from baseline at Week 16, adjusting for baseline 6MWD and background therapy. Treatment effect estimated using the Hodges-Lehmann median difference between treatment groups. 350 patients accounted for in the analysis by imputing missing Week 16 6MW tests. Lowest rank for death or disease progression Last observation carried forward for adverse events or withdrawal of consent

7 Baseline Demographics Characteristic UT-15C SR (n =174) Placebo (n =176) Age in Years: mean (range) Gender: Male / Female (n) PAH Etiology: n (%) IPAH/FPAH CVD Repaired CHD HIV Background PAH Therapy: n (%) ERA PDE-5 Inhibitor Both Baseline WHO Functional Class: II/III (n) Baseline 6MWD: Mean ± SD (m) 51.1 (17-75) 26/ (65%) 49 (28%) 11 (6%) 1 (<1%) 55 (32%) 45 (26%) 74 (43%) 41/ / (15-71) 36/ (68%) 43 (24%) 11 (6%) 3 (2%) 51 (29%) 43 (24%) 82 (47%) 31/ /- 75.5

8 Patient Disposition Study Disposition Completed Study on Drug Treatment n (%) UT-15C SR Placebo n = 174 n = (78%) 152 (86%) Discontinued Study Drug Prematurely Clinical Worsening Adverse Event Other 39 (22%) 8 (5%) 25 (14%) 6 (3%) 24 (14%) 10 (6%) 8 (5%) 6 (3%) Deaths 3 (2%) 3 (2%)

9 6MWD Median Change 20 6MWD Median Change from Baseline (m) p= p= p= p= Week 4 Week 8 Week 12 Week 16 Avg Dose 2.0 +/ / / /- 2.9 Hodges-Lehmann Estimate of Treatment Effect Conducted between 2 and 6 hrs after dose

10 6MWD Median Change Within Group 20 6MWD Median Change from Baseline (m) Week 4 Week 8 Week 12 Week 16 UT-15C SR Placebo Conducted between 2 and 6 hrs after dose

11 Median Change in 6MWD by Dose Achieved at Week MWD Median Change from Baseline (m) AE D/C or dose < or = 1 mg 1.25 mg to 3.25 mg 3.5 mg to 16 mg N (active)

12 Secondary Endpoint Summary Assessment Time to Clinical Worsening Combined 6MWD & Borg Dyspnea Score WHO Functional Class Borg Dyspnea Score Dyspnea Fatigue Index Week 16 Result p=0.46 p=0.013 p=0.94 p=0.06 p=0.01

13 Clinical Worsening Extent of Clinical Worsening No Clinical Worsening* Treatment n (%) UT-15C SR Placebo (n = 174) (n = 176) 166 (95%) 164 (93%) Clinical Worsening 8 (5%) 12 (7%) Death 0 1 (<1%) Transplantation 1 (<1%) 1 (<1%) Clinical Deterioration 7 (4%) 10 (6%) *p=0.49

14 Preliminary Conclusions Primary endpoint finding of change in 6MW distance at Week 16 trended (p=0.072) but did not achieve statistical significance Inability to titrate dose > 1mg BID in 25% of active patients and a 14% discontinuation rate due to intolerance in active patients muted the observed treatment effect Statistically significant treatment effect for 6MWD observed at Week 12 Symptom related secondary endpoints (combined 6MWD/Borg & Dyspnea Fatigue Index) demonstrated a statistically significant difference at Week 16