THE BEAT COMBINATION STUDY. Jordan Shin MD, PhD Medical Director, Lung Biotechnology PBC

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1 THE BEAT COMBINATION STUDY Jordan Shin MD, PhD Medical Director, Lung Biotechnology PBC

2 2 SAFE HARBOR STATEMENT Remarks today concerning United Therapeutics may include forward-looking statements which represent United Therapeutics expectations or beliefs regarding future events. We caution that such statements involve risks and uncertainties that may cause actual results to differ materially from those in the forward-looking statements. Consequently, all such forward-looking statements are qualified by the cautionary language and risk factors set forth in United Therapeutics periodic and other reports filed with the SEC. There can be no assurance that the actual results, events or developments referenced in such forward-looking statements will occur or be realized. United Therapeutics assumes no obligation to update these forward-looking statements to reflect actual results, changes in assumptions or changes in factors affecting such forward-looking statements. This presentation and any related discussions or statements are intended to educate investors about our company. Sometimes that process includes reporting on the progress and results of clinical trials or other developments with respect to our products. This presentation and any related discussions or statements are not intended to promote our products, to suggest that our products are safe and effective for any use other than what is consistent with their FDA-approved labeling, or to provide all available information regarding the products, their risks, or related clinical trial results. Anyone seeking information regarding the use of one of our products should consult the full prescribing information for the product available on our website at Tyvaso is a registered trademark of United Therapeutics Corporation.

3 3 BEAT: ORAL ESUBERAPROST AS AN ADD-ON TO TYVASO Esuberaprost Tyvaso

4 4 DEVELOPMENT BACKGROUND BERAPROST SODIUM (BPS): ORALLY AVAILABLE PROSTACYCLIN ANALOGUE TWO FORMULATIONS OF BERAPROST SODIUM (BPS) AVAILABLE APAC BPS=RACEMIC MIX OF 4 STEREOISOMERS (314d,-l, & 315d, -l) GEN 3 ESUBERAPROST = BPS-314d-MR Patented by Toray Industries (Japan) + licensed to UT/Lung Biotech Gen 1: BPS-IR (approved in Japan 1999) Gen 2: BPS-MR (2007) Extensive safety database and clinical experience 314d isomer accounts for >90% of BPS activity»» Primary activity of BPS in a cleaner formulation

5 5 SCIENTIFIC RATIONALE UNDERLYING BEAT COMBINATION THERAPY (ESUBERAPROST + TYVASO ) COMBINATION APPROACHES ZERO-ORDER RELEASE POTENTIAL TO TARGET INACCESSIBLE TISSUE COMPARTMENTS CAUSED BY DEFECTS IN GAS EXCHANGE PHARMACOLOGICAL TARGETING OF TWO PROSTACYCLIN SIGNALING PATHWAYS

6 6 ZERO ORDER PK: INTRAVENOUS DELIVERY TIME

7 7 TYVASO Tyvaso B P S d LEVEL Time

8 8 ESUBERAPROST Esuberaprost B P S d LEVEL Time

9 9 COMBINED THERAPY Tyvaso Esuberaprost B P S d LEVEL Time

10 10 ESUBERAPROST / TYVASO / EFFECTIVE PROSTANOID Tyvaso Esuberaprost Effective prostanoid B P S d LEVEL Time

11 11 RESULT: MORE CONSISTENT PROSTANOID EXPOSURE Effective prostanoid B P S d LEVEL Time

12 12 POTENTIAL TO TARGET INACCESSIBLE TISSUE COMPARTMENTS...Precapillary gas exchange contributes importantly to blood oxygenation at rest, but is attenuated in remodeled lung arterioles, which may be of relevance in pulmonary hypertension... Am J Respir Crit Care Med 2013; 188: Arata Tabuchi 1,2,*, Beata Styp-Rekowska 1*, Arthur S.Slutsky 2,3, Peter D. Wagner 4, Alex R. Pries 1, and Wolfgang M. Kuebler 1,2,5,6,7

13 13 PRECAPILLARY OXYGENATION NORMOXIA HYPOXIA HYPOXIA-INDUCED WALL THICKENING

14 14 ENHANCED EFFICACY MAY RESULT FROM DIFFERENTIAL TISSUE COMPARTMENT ACCESSIBILITY IV INHALED ORAL BEAT PRECAPILLARY ARTERIOLAR INTERFACE ++ +_ +_ ++? ALVEOLAR- CAPILLARY INTERFACE _ ++?

15 15 TARGETING TWO PROSTACYCLIN SIGNALING PATHWAYS TREPROSTINIL & ESUBERAPROST: DISTINCT BINDING AFFINITIES AT HUMAN PROSTANOID RECEPTORS: TRE: has highest affinity for DP1=EP2 > IP Esuberaprost: greatest affinity for IP receptor (L Clapp) Combination of esuberaprost added to TRE provides a broader range of receptor activity KEY POINT: ESUBERAPROST COMPLEMENTS AND MAY SYNERGIZE WITH TREPROSTINIL

16 16 COMBINATION PROSTANOID THERAPY CAN ACTIVATE MORE IMPORTANT CELLULAR PATHWAYS PROSTANOIDS IP G S AC ATP camp PKA PPAR PPARβ/δ

17 17 BEAT STUDY DESIGN OVERVIEW ESUBERAPROST + TYVASO NCT ENRICHMENT TRIAL: FC III + IV N=240 SUBJECTS WITH PAH RANDOMIZE 1:1 DOUBLE-BLIND 79 SITES US + ISRAEL PRIMARY EFFICACY ENDPOINT TIME TO THE FIRST CLINICAL WORSENING (MORTALITY/ MORBIDITY) EVENT PLACEBO + TYVASO TREATMENT PERIOD CONTINUED UNTIL THE 113TH ADJUDICATED CW EVENT

18 18 BEAT STUDY DESIGN OVERVIEW KEY CLINICAL ASSESSMENTS PRIMARY ENDPOINT CLINICAL WORSENING (MORTALITY/MORBIDITY) EVENT Death (all causes) Hospitalization due to worsening PAH Initiation of an infused prostacyclin Disease progression Unsatisfactory long-term clinical response SECONDARY ENDPOINT 6 minutes Walk Distance Borg Dyspnea Score WHO-Functional Class NT-pro-BNP levels Safety

19 19 FULLY ENROLLED MAX PATIENTS ENROLLED

20 20 NEXT STOP 113 EVENTS LAST EVENT EXPECTED 2018

21 THANK YOU