ORAL TREPROSTINIL AS PART OF A TRIPLE-THERAPY REGIMEN FOR PULMONARY ARTERIAL HYPERTENSION: ANALYSIS FROM THE FREEDOM-EV OPEN-LABEL EXTENSION

SESSION TITLE: PAH Assessment, Treatment, and Outcomes AnalysesSESSION TYPE: Rapid Fire Original InvPRESENTED ON: 10/17/2022 12:15 pm - 1:15 pmPURPOSE: FREEDOM-EV was an event-driven trial demonstrating that oral treprostinil (TRE) delayed disease progression in pulmonary arterial hypertension (PAH) participants when added to oral monotherapy. Participants could enroll in an open-label extension (OLE) study after experiencing a clinical worsening event (CWE) or at closure of FREEDOM-EV. Participants could add a third class of PAH therapy after enrolling in the OLE. Because triple therapy is commonly used in managing PAH, participants who added a third class of PAH therapy during the OLE were analyzed.METHODS: Only participants who were initially randomized to oral TRE in FREEDOM-EV and subsequently added a third class of PAH therapy (ERA, PDE-5i and/or sGC) after enrolling in the OLE are included in this analysis. Safety and efficacy were assessed at baseline (start of OLE) and every 12 weeks until voluntary discontinuation or study closure. Efficacy measures included 6-minute walk distance (6MWD), WHO functional class (FC), and N-terminal pro-brain natriuretic peptic (NT-proBNP) levels (the latter at Week 48).RESULTS: Of the 346 participants initially assigned oral TRE in FREEDOM-EV, 212 enrolled in the OLE; 50 of these 212 (23.6%) added an additional, non-prostacyclin PAH therapy after enrolling in the OLE and are included in these analyses. Of these participants, 25 had had a CWE in FREEDOM-EV which likely influenced the clinical decision to add a third agent. Participants were on an additional PAH therapy (triple therapy) in the OLE for an average of 384+-452 days (mean+-SD), and 66% of participants added the additional PAH therapy within a year of OLE enrollment. Eight of these 50 participants subsequently died during the OLE. At baseline, participants who added a third PAH therapy had 6MWD of 411 m (270, 465) [median (IQR), (n = 49)]. Change in 6MWD [median (IQR)] from baseline to Week 48 was +21 m (0, 60) (n = 34) and change from baseline to Week 72 was +28 m (-23, 63) (n = 33). At baseline, NT-proBNP [median (IQR)] was 1906 pg/mL (249, 3377) (n = 48) and change from baseline to Week 48 was -17 pg/mL (-331, 168) (n = 36). At Week 48, FC was improved compared to baseline for 28% of participants and FC remained stable for 69% of participants. Adverse effects (AEs), especially diarrhea, attributed to oral TRE were more common in those on triple therapy compared to those on dual therapy (n = 156); AEs were more likely to be severe and lead to oral TRE discontinuation.CONCLUSIONS: A substantial minority of OLE participants added a third PAH therapy. Participants on sequential triple combination therapy including oral TRE demonstrated improvements in clinical parameters. Overall, AE burden was greater.CLINICAL IMPLICATIONS: This long-term, prospective data adds to the previously published experiences demonstrating that oral TRE can be safely utilized in patients as part of a triple therapy PAH regimen. Sponsored by United Therapeutics.DISCLOSURES: Employee relationship with United Therapeutics Corporation Please note: 2011-Current by Meredith Broderick, value=SalaryEmployee relationship with United Therapeutics Please note: >$100000 by C.Q. Deng, value=SalaryAdvisory Committee Member relationship with United Therapeutics Please note: $5001 - $20000 Added 04/06/2022 by Jean Elwing, value=Consulting feeAdvisory Committee Member relationship with Liquidia, Altavant, Bayer, Gossamer Bio, Acceleron, Aerovate Please note: $1001 - $5000 Added 04/06/2022 by Jean Elwing, value=Consulting feeResearch - Paid directly to employer relationship with Acceleron, Actelion, Reata, United Therapeutics, Liquidia, Aerovate, Altavant Please note: $1-$1000 Added 04/06/2022 by Jean Elwing, value=Grant/ResearchResearch - Paid directly to employer relationship with Phase Bio, Janssen, Gossamer Bio, Bayer Please note: $1-$1000 Added 04/06/2022 by Jean Elwing, value=Grant/Research SupportNo relevant relationships by Ekkehard GrünigNo relevant relationships by Antoine HageEmployee relationship with United Therapeutics Corporation Please note: 2018-present Added 04/05/2022 by Louis Holdstock, value=SalaryConsultantSpeaker/Speaker's Bureau relationship with Janssen PH Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=HonorariaConsultant relationship with Bayer Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting feeSpeaker/Speaker's Bureau relationship with Bayer Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=HonorariaConsultant relationship with United Therapeutics Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting feeSpeaker/Speaker's Bureau relationship with United Therapeutics Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=HonorariaConsultant relationship with Merck Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting feeEmployee relationship with United Therapeutics Corporation Please note: 9/20/2021-present Added 04/05/2022 by Scott Seaman, value=SalaryNo relevant relationships by Carmine VizzaNo relevant relationships by Kuo WangPrincipal Investigator relationship with United Therapeutics Please note: >$100000 by R. James White, value=Grant/Research SESSION TITLE: PAH Assessment, Treatment, and Outcomes Analyses SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: FREEDOM-EV was an event-driven trial demonstrating that oral treprostinil (TRE) delayed disease progression in pulmonary arterial hypertension (PAH) participants when added to oral monotherapy. Participants could enroll in an open-label extension (OLE) study after experiencing a clinical worsening event (CWE) or at closure of FREEDOM-EV. Participants could add a third class of PAH therapy after enrolling in the OLE. Because triple therapy is commonly used in managing PAH, participants who added a third class of PAH therapy during the OLE were analyzed. METHODS: Only participants who were initially randomized to oral TRE in FREEDOM-EV and subsequently added a third class of PAH therapy (ERA, PDE-5i and/or sGC) after enrolling in the OLE are included in this analysis. Safety and efficacy were assessed at baseline (start of OLE) and every 12 weeks until voluntary discontinuation or study closure. Efficacy measures included 6-minute walk distance (6MWD), WHO functional class (FC), and N-terminal pro-brain natriuretic peptic (NT-proBNP) levels (the latter at Week 48). RESULTS: Of the 346 participants initially assigned oral TRE in FREEDOM-EV, 212 enrolled in the OLE; 50 of these 212 (23.6%) added an additional, non-prostacyclin PAH therapy after enrolling in the OLE and are included in these analyses. Of these participants, 25 had had a CWE in FREEDOM-EV which likely influenced the clinical decision to add a third agent. Participants were on an additional PAH therapy (triple therapy) in the OLE for an average of 384+-452 days (mean+-SD), and 66% of participants added the additional PAH therapy within a year of OLE enrollment. Eight of these 50 participants subsequently died during the OLE. At baseline, participants who added a third PAH therapy had 6MWD of 411 m (270, 465) [median (IQR), (n = 49)]. Change in 6MWD [median (IQR)] from baseline to Week 48 was +21 m (0, 60) (n = 34) and change from baseline to Week 72 was +28 m (-23, 63) (n = 33). At baseline, NT-proBNP [median (IQR)] was 1906 pg/mL (249, 3377) (n = 48) and change from baseline to Week 48 was -17 pg/mL (-331, 168) (n = 36). At Week 48, FC was improved compared to baseline for 28% of participants and FC remained stable for 69% of participants. Adverse effects (AEs), especially diarrhea, attributed to oral TRE were more common in those on triple therapy compared to those on dual therapy (n = 156); AEs were more likely to be severe and lead to oral TRE discontinuation. CONCLUSIONS: A substantial minority of OLE participants added a third PAH therapy. Participants on sequential triple combination therapy including oral TRE demonstrated improvements in clinical parameters. Overall, AE burden was greater. CLINICAL IMPLICATIONS: This long-term, prospective data adds to the previously published experiences demonstrating that oral TRE can be safely utilized in patients as part of a triple therapy PAH regimen. Sponsored by United Therapeutics. DISCLOSURES: Employee relationship with United Therapeutics Corporation Please note: 2011-Current by Meredith Broderick, value=Salary Employee relationship with United Therapeutics Please note: >$100000 by C.Q. Deng, value=Salary Advisory Committee Member relationship with United Therapeutics Please note: $5001 - $20000 Added 04/06/2022 by Jean Elwing, value=Consulting fee Advisory Committee Member relationship with Liquidia, Altavant, Bayer, Gossamer Bio, Acceleron, Aerovate Please note: $1001 - $5000 Added 04/06/2022 by Jean Elwing, value=Consulting fee Research - Paid directly to employer relationship with Acceleron, Actelion, Reata, United Therapeutics, Liquidia, Aerovate, Altavant Please note: $1-$1000 Added 04/06/2022 by Jean Elwing, value=Grant/Research Research - Paid directly to employer relationship with Phase Bio, Janssen, Gossamer Bio, Bayer Please note: $1-$1000 Added 04/06/2022 by Jean Elwing, value=Grant/Research Support No relevant relationships by Ekkehard Grünig No relevant relationships by Antoine Hage Employee relationship with United Therapeutics Corporation Please note: 2018-present Added 04/05/2022 by Louis Holdstock, value=Salary Consultant Speaker/Speaker's Bureau relationship with Janssen PH Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Honoraria Consultant relationship with Bayer Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting fee Speaker/Speaker's Bureau relationship with Bayer Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Honoraria Consultant relationship with United Therapeutics Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting fee Speaker/Speaker's Bureau relationship with United Therapeutics Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Honoraria Consultant relationship with Merck Please note: 2019-2022 Added 04/06/2022 by Franck Rahaghi, value=Consulting fee Employee relationship with United Therapeutics Corporation Please note: 9/20/2021-present Added 04/05/2022 by Scott Seaman, value=Salary No relevant relationships by Carmine Vizza No relevant relationships by Kuo Wang Principal Investigator relationship with United Therapeutics Please note: >$100000 by R. James White, value=Grant/Research