Efficacy of oral treprostinil in patients with pulmonary arterial hypertension with and without cardiovascular comorbidities

SESSION TITLE: Pulmonary Vascular Disease Posters 3 SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2023 12:00 pm - 12:45 pm PURPOSE: FREEDOM-EV (NCT01560624) was a global, event-driven trial which demonstrated that oral treprostinil (TRE) reduced the risk of clinical worsening compared to placebo (PBO) when added to oral monotherapy in pulmonary arterial hypertension (PAH) participants. Many patients with PAH have cardiovascular comorbidities, and the recent 2022 ESC/ERS guidelines highlight a need to evaluate for comorbid conditions when making therapy decisions. Here, we performed a post-hoc analysis of the FREEDOM-EV data to determine whether comorbid conditions influence oral TRE efficacy. METHODS: FREEDOM-EV participants (n = 346 oral TRE, n = 344 PBO) were classified as having 0, 1+, and 2+ defined cardiovascular comorbidities (e.g. coronary artery/heart disease, obesity, diabetes, hypertension) using source-monitored data from the original study. The risk of clinical worsening was compared between treatment groups for 0, 1+, and 2+ comorbidity cohorts. As in the primary analysis, we adjusted for the baseline imbalance in mortality risk (number of French non-invasive low-risk factors) between oral TRE and PBO participants. Hazard ratios, 95% confidence intervals, and p-values were calculated from a Cox proportional hazards regression model. RESULTS: Of the 346 initially assigned oral TRE participants, 174 (50%) had 0 defined cardiovascular comorbidities, 172 (50%) had 1+ defined cardiovascular comorbidities; 88 (25%) had 2+ defined cardiovascular comorbidities. Of the 344 initially assigned PBO participants, 187 (54%) had 0 defined comorbidities,157 (46%) had 1+ defined comorbidities; 84 (24%) had 2+ defined comorbidities. At baseline, participants with comorbidities were on average older, had higher body mass indices, and were more likely to be male compared to participants without comorbidities. Additionally, at baseline, participants with comorbidities had lower average 6-minute walk distances, higher functional class, and fewer low-risk variables (French non-invasive). For participants without cardiovascular comorbidities, clinical worsening occurred in 26% of oral TRE participants and 34% of PBO participants; there was a 37% reduction in risk for clinical worsening (HR 0.63, 95% CI 0.43-0.93, P = 0.021) after adjusting for baseline mortality risk. For participants with at least one cardiovascular comorbidity, clinical worsening occurred in 26% of oral TRE participants and 38% of PBO participants; there was a 40% reduction in risk for clinical worsening (HR 0.60, 95% CI 0.40-0.90, P = 0.013) after adjusting for baseline risk. In the population with 2+ comorbidities an even greater treatment effect was observed with a 48% reduction in risk for clinical worsening (HR 0.52, 95% CI 0.30-0.91, P = 0.022). CONCLUSIONS: The clinical worsening data for each cohort very closely mirror the overall FREEDOM-EV population data (baseline risk adjusted HR 0.61, 95% CI 0.46-0.81, P < 0.001) suggesting that oral TRE benefits in patients with PAH with and without cardiovascular morbidities, including patients with high cardiovascular comorbidity burden. CLINICAL IMPLICATIONS: Oral TRE can reduce the risk of clinical worsening irrespective of the presence of cardiovascular comorbidities. Sponsored by United Therapeutics. DISCLOSURES: Employee relationship with United Therapeutics Corporation Please note: 2011-Current by Meredith Broderick, value=Salary Advisory Committee Member relationship with United Therapeutics Please note: Ongoing Added 03/31/2023 by Jean Elwing, value=Consulting fee Advisor / Grant Reviewer (Ongoing 3/23) relationship with Bayer Please note: Ongoing Grant Review Added 03/27/2023 by Jean Elwing, source=Web Response, value=Consulting Fee and Honoraria Advisory Committee Member relationship with Bayer Please note: Complete 11/22 Added 03/28/2023 by Jean Elwing, source=Web Response, value=Consulting fee Removed 03/28/2023 by Jean Elwing, source=Web Response unknown relationship with United Therapeutics Please note: Intermittent Added 03/28/2023 by Jean Elwing, source=Web Response, value=Consulting fee Removed 03/28/2023 by Jean Elwing, source=Web Response Advisory Committee Member relationship with United Therapeutics (ongoing advising / education with speaking) Please note: Intermittent Added 03/28/2023 by Jean Elwing, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Altavant, Aerovate, Gossamer Bio (complete 12/21), Janssen (complete 3/23), Insmed (complete 12/22) Please note: Complete 3/23 Added 03/28/2023 by Jean Elwing, source=Web Response, value=Consulting fee Research - Paid directly to employer relationship with Altavant, Aerovate, Tenax, Pharmosa Please note: Ongoing Research Added 03/31/2023 by Jean Elwing, value=Grant/Research Support Research - Paid directly to employer relationship with Janssen, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron/Merck Please note: Ongoing Research Added 03/31/2023 by Jean Elwing, value=Grant/Research Advisory Committee Member relationship with Altavant, Aerovate, Bayer, Gossamer Bio, Liquida, Acceleron/Merck, Janssen, Insmed Please note: All complete before 4/23 Added 03/31/2023 by Jean Elwing, value=Consulting fee Advisory Committee Member relationship with Liquida, Acceleron/Merck Please note: To complete 5/23 Added 03/28/2023 by Jean Elwing, source=Web Response, value=Consulting fee Research - Paid directly to UC relationship with Altavant, Aerovate, Tenax, Pharmosa, Actelion/Janssen, Lung Please note: Ongoing Added 03/27/2023 by Jean Elwing, source=Web Response, value=Grant/Research Support Research - Paid directly to UC relationship with United Therapeutics, Gossamer Bio, Bayer, Acceleron/Merck Please note: Ongoing Added 03/27/2023 by Jean Elwing, source=Web Response, value=Grant/Research Support Speaker/Speaker's Bureau relationship with United Therapeutics Please note: 2022-2023 Added 03/31/2023 by Jean Elwing, source=Web Response, value=Honoraria Removed 03/31/2023 by Jean Elwing, source=Web Response NonCME Speaker (Complete 4/23) relationship with United Therapeutics Please note: End 4/23 Added 03/31/2023 by Jean Elwing, source=Web Response, value=Honoraria No relevant relationships by Veronica Franco No relevant relationships by Hyoshin Kim research grant relationship with MSD Please note: 2022-2023 Added 03/31/2023 by Joanna Pepke-Zaba, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with MSD Please note: 2023 Added 03/31/2023 by Joanna Pepke-Zaba, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Ferrer Please note: 2022 Added 03/31/2023 by Joanna Pepke-Zaba, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with United Therapeutic s Please note: 2022 Added 03/31/2023 by Joanna Pepke-Zaba, source=Web Response, value=Honoraria Advisory relationship with Janssen Pharmaceutical Companies of Johnson & Johnson, Please note: 2021-2-23 Added 03/31/2023 by Joanna Pepke-Zaba, source=Web Response, value=Travel
$100K Added 04/01/2023 by R. James White, value=Grant/Research Removed 04/01/2023 by R. James White, source=Web Response Research relationship with United Therapeutics Please note: 1/1/2005-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Research relationship with Merck Please note: 1/1/2016-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Merck Please note: 1/1/2013-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Consulting fee Research relationship with Bayer Please note: 1/1/2015-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research