CYP2C8

SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--( BUSINESS WIRE )--United Therapeutics Corporation (Nasdaq: UTHR ), a public benefit corporation, announced full enrollment of the TETON 1 study evaluating the use of Tyvaso® (treprostinil) inhalation solution ( nebulized Tyvaso ) for the treatment of idiopathic pulmonary fibrosis ( IPF ). The TETON 1 study enrolled 598 patients and is part of the three-study global TETON clinical trial program evaluating the use of inhaled treprostinil in IPF and a similar condition, progressive pulmonary fibrosis ( PPF ). TETON 1 is evaluating the use of inhaled treprostinil in IPF in patients in the United States and Canada. TETON 2 is evaluating the use of inhaled treprostinil in IPF in patients outside the United States and Canada. TETON PPF is evaluating the use of inhaled treprostinil in PPF in patients globally. Patients in any of the TETON program studies may use nebulized Tyvaso alone as a monotherapy or in combination with one background therapy approved for the treatment of IPF or PPF. Enrollment in TETON 2 completed in July 2024 and top-line data for that study is expected in the second half of 2025. Enrollment in TETON PPF is ongoing. “Completing enrollment in this trial brings us one step closer to potentially delivering a transformative and much needed treatment option for this vulnerable group of patients living with IPF,” said Peter Smith, Pharm. D. , Vice President, Product Development at United Therapeutics and the lead for the global TETON program. “Each of the participants in this study represents someone seeking better outcomes and improved quality of life. Their willingness to participate, along with the commitment of our investigators, moves us forward in our mission to deliver novel therapies that address significant challenges for patients and meaningfully impact the standard of care.” The TETON program in IPF and PPF was prompted by data from the INCREASE study of nebulized Tyvaso for the treatment of pulmonary hypertension associated with interstitial lung disease ( PH-ILD ), which demonstrated in a post-hoc analysis that treatment with nebulized Tyvaso resulted in significant improvements in percent predicted forced vital capacity ( FVC ) at weeks 8 and 16, with subjects having an underlying etiology of IPF showing the greatest improvement (week 8: 2.5%; p=0.038 and week 16: 3.5%; p=0.015). Further, open label extension data published in 2023 showed these improvements in FVC were sustained for at least 64 weeks. For those patients who received placebo during the INCREASE study, marked improvements in FVC were observed following transition to nebulized Tyvaso during the open-label extension study. These data points, combined with substantial preclinical evidence of antifibrotic activity of treprostinil, suggest that nebulized Tyvaso may offer a treatment option for patients with IPF and PPF. The TETON program is evaluating the use of nebulized Tyvaso, which is approved to improve exercise ability in patients with pulmonary arterial hypertension and PH-ILD. Tyvaso DPI ® (treprostinil) Inhalation Powder is not being evaluated in the TETON program, but United Therapeutics intends to seek U.S. Food and Drug Administration ( FDA ) approval to expand the Tyvaso DPI label to include IPF and PPF following completion of the TETON studies and any FDA-required bridging studies. Tyvaso Inhalation Solution and Tyvaso DPI are not approved in any jurisdiction for the treatment of IPF or PPF. If the TETON 1 and TETON 2 trials are successful, United Therapeutics intends to use the data from the studies to support a regulatory filing with the FDA to add IPF to the labeled indications for nebulized Tyvaso. In Europe, where Tyvaso is not an approved product, we plan to work with our international distributor, Grupo Ferrer Internacional, S.A., to support a marketing authorization application with the European Medicines Agency ( EMA ) for nebulized Tyvaso to treat IPF. About TETON 1 The TETON 1 study is a 598-patient, multicenter, randomized, double-blind, placebo-controlled phase 3 registration study to evaluate the safety and efficacy of nebulized Tyvaso in subjects with IPF over a 52-week period at sites in the United States and Canada. The study reached full enrollment in January 2025 and top-line data is expected in the first half of 2026. Subjects will be randomly allocated 1:1 to receive nebulized Tyvaso or placebo. All subjects will initiate nebulized Tyvaso or placebo at a dose of three breaths administered four times daily ( QID ) and will titrate to a target dosing regimen of 12 breaths QID. Study drug doses may be titrated up as tolerated, until the target dose or maximum clinically tolerated dose is achieved. The primary endpoint of the study is the change in FVC from baseline to week 52. Secondary endpoints include: (1) time to clinical worsening; (2) time to first acute exacerbation of IPF; (3) overall survival at week 52; (4) change in percent predicted FVC from baseline to week 52; and (5) change in the King’s Brief Interstitial Lung Disease questionnaire. Other data collected in the study will include the plasma N-terminal pro-brain natriuretic peptide ( NT-proBNP ) concentration, supplemental oxygen use, and lung diffusion capacity. Safety assessments include the development of adverse events, serious adverse events, vital signs, clinical laboratory parameters, and electrocardiogram parameters. About IPF Idiopathic pulmonary fibrosis, or IPF, is a scarring disease of the lungs of an unknown (idiopathic) cause and is the most common of the idiopathic interstitial pneumonias. IPF is characterized by the progressive loss of the ability of the lungs to transfer oxygen into the blood, ultimately resulting in respiratory failure and death. While the precise causes of IPF remain unknown, IPF rarely presents before age 50 and can be associated with cigarette smoking and certain genetic dispositions. In addition, some evidence suggests that gastroesophageal reflux (acid reflux, or heartburn), certain viral infections, air pollution, and some exposures in the workplace may be risk factors for IPF. According to recent research , IPF is estimated to affect between 0.33 and 4.51 people per 10,000 persons worldwide. Further, United Therapeutics estimates there are over 100,000 IPF patients in the United States alone. Just two therapies are approved in the United States to treat IPF, and studies for both therapies have shown only a reduction in the rate of forced vital capacity, or FVC, decline in IPF patients. About Tyvaso® Inhalation Solution and Tyvaso DPI® Inhalation Powder INDICATION TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration. Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension. Both products inhibit platelet aggregation and increase the risk of bleeding. Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness. Like other inhaled prostaglandins, TYVASO and TYVASO DPI may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with TYVASO and TYVASO DPI. DRUG INTERACTIONS/SPECIFIC POPULATIONS The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8. Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production. Safety and effectiveness in pediatric patients have not been established. Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. ADVERSE REACTIONS Pulmonary Arterial Hypertension (WHO Group 1) In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea. In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%). Pulmonary Hypertension Associated with ILD (WHO Group 3) In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH. Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO® Inhalation System and TYVASO DPI® Inhalation Powder, and additional information at www.TYVASOHCP.com or call 1 844 UNITHER (1-844-864-8437). TYVISIhcpSEP2024 United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun, we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation ( PBC ). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs. You can learn more about what it means to be a PBC here: unither.com/pbc . Forward-Looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, our plans concerning the TETON program, including our plans to release top-line data from the TETON 1 and TETON 2 studies in the first half of 2026 and the second half of 2025, respectively, our plans to seek FDA approval of nebulized Tyvaso and Tyvaso DPI to treat IPF and PPF, our plan to work with our international distributor to support a marketing authorization application with the EMA for nebulized Tyvaso to treat IPF, the potential for the TETON program to deliver a transformative therapy for patients, our progress toward our mission of deliverying novel therapies that address significant challenges for patients and meaningfully impact the standard of care, our efforts to innovate for the unmet medical needs of our patients, to benefit our other stakeholders, and to pursue our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language, and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of February 4, 2025, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events or any other reason. TYVASO and TYVASO DPI are registered trademarks of United Therapeutics Corporation.

Posters include real-world dosing of Tyvaso DPI® in pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, and data from the BREEZE open-label extension study of Tyvaso DPI detailing its long-term outcomes and dosing in patients with pulmonary arterial hypertension United Therapeutics is sponsoring the Women in PH Luncheon and the Career Catalyst Luncheon: Speed Mentoring for Early Career PH Professionals SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)-- United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, today announced that five posters across its commercial and development portfolio in pulmonary hypertension (PH) will be presented at the Pulmonary Vascular Research Institute (PVRI) 2025 Annual Congress taking place January 29 through February 1, 2025 in Rio de Janeiro. In addition, professionals from United Therapeutics will participate in two speaking events associated with the congress. United Therapeutics is also proud to sponsor the Women in PH Luncheon and the Career Catalyst Luncheon: Speed Mentoring for Early Career PH Professionals. “At this year’s annual congress, we are delighted to share further findings that support long-term outcomes and dosing of Tyvaso DPI, as well as interim data from our PHINDER study that is beginning to reveal clues that could help to efficiently detect pulmonary hypertension associated with interstitial lung disease,” said Andrew Nelsen, PharmD, Vice President, Global Medical Affairs at United Therapeutics. “PVRI is a cornerstone event for the field of pulmonary vascular disease and provides an invaluable platform for collaboration and scientific exchange. We look forward to engaging with the scientific and medical communities about these latest developments.” Posters include: Burger, C., El-Kersh, K., Parikh, R., Wu, B., Thrasher, C., & Broderick, M. Real-World Dosing of Tyvaso DPI in Pulmonary Arterial Hypertension and Pulmonary Hypertension Associated with Interstitial Lung Disease. Spikes, L., Bajwa, A., Burger, C., Ramani, G., Palevsky, H., Mehta, J., Joly, J., El-Kersh, K., Fisher, M., Eggert, M., Restrepo-Jaramillo, R., Sahay, S., Desai, S., Johri, S., Shah, T., Shapiro, S., Thrasher, C., Deng, C.Q., Smith, P., & Broderick, M. BREEZE Optional Extension Phase: Long-Term Outcomes with Tyvaso DPI in Patients with Pulmonary Arterial Hypertension. Beck, E., Broderick, M., Chavarria, M.C., DerSarkissian, M., Kiely, D.G., Lee, D., Maher, K., Paxton, K., Sahay, S., Scholand, M.B., Shen. E., Shlobin, O., & Zisman, D. Interim Results from PHINDER: Pulmonary Hypertension Screening in Patients with Interstitial Lung Disease for Earlier Detection. Argula, R., El-Kersh, K., Estrada, R., McLaughlin, V., Hong, T., Thrasher, C., & Broderick, M. Inhaled treprostinil for the treatment of pulmonary arterial hypertension in intermediate-high risk patients: a sub-group analysis of the TRIUMPH study. Tomson, M.L., Gunzenhauser, D., Daczkowski, N., McGovern, A., Orozco, L., Clark, K., Mintz, A., O’Toole, B., Derma, A., Sista, P., & Rahaghi, F. Patient Reported Experience of Participants in the ARTISAN study for PAH. Speaking events include: Session 3: Real World Evidence/Real World Data, Wednesday, January 29, 10:40 to 11:15: 2nd Floor, Oceania IX. Co-chaired by Kellie Morland, PharmD, United Therapeutics. Session 6: Challenges of Clinical Trial Design, Conduct & Endpoints, Wednesday, January 29, 12:22 to 12:30: 2nd Floor, Oceania IX – Insights on clinical trial design from the perspective of industry.Presented by C.Q. Deng, M.D., Ph.D., MPH, United Therapeutics. Sponsored events include: The Women in PH Luncheon, Friday, January 31, 11:15 to 13:00. Women in PH began as a way to support educational opportunities for women in PH and strengthen their professional network, aimed at building an inclusive, diverse community. The Career Catalyst Luncheon: Speed Mentoring for Early Career PH Professionals, Thursday, January 30, 11:10 to 13:00. This event will offer micro-mentoring opportunities to early-career PH professionals and trainees, facilitating networking and connection-building between early-career PH professionals and providing opportunities to connect with renowned senior and mid-career PH researchers in a welcoming and informal setting. About Tyvaso® Inhalation Solution and Tyvaso DPI® Inhalation Powder INDICATION TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration. Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension. Both products inhibit platelet aggregation and increase the risk of bleeding. Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness. Like other inhaled prostaglandins, TYVASO and TYVASO DPI may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with TYVASO and TYVASO DPI. DRUG INTERACTIONS/SPECIFIC POPULATIONS The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8. Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production. Safety and effectiveness in pediatric patients have not been established. Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. ADVERSE REACTIONS Pulmonary Arterial Hypertension (WHO Group 1) In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea. In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%). Pulmonary Hypertension Associated with ILD (WHO Group 3) In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH. Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO® Inhalation System and TYVASO DPI® Inhalation Powder, and additional information at www.TYVASOHCP.com or call 1 844 UNITHER (1-844-864-8437). TYVISIhcpSEP2024 United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun, we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation (PBC). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs. You can learn more about what it means to be a PBC here: unither.com/pbc. Forward-Looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, our goals of innovating for the unmet medical needs of our patients and to benefit our other stakeholders, furthering our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of January 21, 2025, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events, or any other reason. TYVASO and TYVASO DPI are registered trademarks of United Therapeutics Corporation. View source version on businesswire.com: https://www.businesswire.com/news/home/20250121855504/en/ For Further Information Contact: Dewey Steadman at (202) 919-4097 (media/investors) Harry Silvers at (301) 578-1401 (investors) https://ir.unither.com/contact-uthr/ Source: United Therapeutics Corporation

Results from BRUIN CLL-321 show Lilly's pirtobrutinib reduced the risk of disease progression or death by 46% compared to idelalisib plus rituximab or bendamustine plus rituximab Pirtobrutinib prolonged the time to next treatment or death by a median of 23.9 months compared to 10.9 months in the control arm BRUIN CLL-321 is the first randomized Phase 3 study in CLL ever conducted exclusively in patients previously treated with a BTK inhibitor INDIANAPOLIS, Dec. 9, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced results from the Phase 3 BRUIN CLL-321 trial evaluating pirtobrutinib, a non-covalent (reversible) Bruton's tyrosine kinase (BTK) inhibitor in adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) previously treated with a covalent BTK inhibitor. The study's primary endpoint of progression-free survival (PFS) was met at primary analysis1, demonstrating pirtobrutinib was superior to investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR), based on independent review committee (IRC) assessment. Today's updated results corresponding to the final prespecified analysis, demonstrate consistent improvement in PFS for patients treated with pirtobrutinib, with a reduction in risk of relapse, disease or death by 46% compared to IdelaR or BR. These data will be presented in an oral presentation at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition. "These results demonstrate the ability of pirtobrutinib to deliver clinically meaningful outcomes in a post-covalent BTK inhibitor setting, which is especially remarkable given the poor prognosis for the patient population enrolled in BRUIN CLL-321," said Jeff Sharman, M.D., Disease Chair, Lymphoma Research Executive Committee, SCRI at Willamette Valley Cancer Institute and Research Center, and one of the principal investigators of the BRUIN CLL-321 trial. "These data also show that pirtobrutinib can significantly prolong the time to next treatment with a median of approximately two years. Coupled with the safety results, the BRUIN CLL-321 data are important as we consider treatment sequencing for this setting." BRUIN CLL-321 enrolled 238 patients who were randomized to receive pirtobrutinib monotherapy (n=119) or investigator's choice of IdelaR or BR (n=119). Patients across both arms received a median of three prior lines of therapy, with all patients having received at least one prior covalent BTK inhibitor. Approximately half of the patients had also received a venetoclax-containing regimen. Reflective of the poor prognosis of patients enrolled in this study, a high proportion of patients presented with high-risk features indicative of aggressive disease, including TP53 mutation and/or 17p deletion, unmutated IGHV status and complex karyotype. Efficacy results are based on IRC assessment of the intent-to-treat (ITT) population and utilize an Aug. 29, 2024 data cutoff date. Crossover to the pirtobrutinib arm was allowed after IRC-confirmed disease progression. At median follow-up of approximately 19 months, median PFS was 14.0 months for the pirtobrutinib arm compared to 8.7 months for the control arm (HR=0.54 [95% CI, 0.39-0.75]). PFS results were consistent across key subgroups associated with a poor prognosis, including patients who received prior venetoclax and those with TP53 mutations and/or 17p deletions, unmutated IGHV status and complex karyotype. Pirtobrutinib also demonstrated clinically meaningful improvements in other secondary endpoints such as investigator-assessed PFS (median PFS: 15.3 vs. 9.2 months; HR=0.48 [95% CI, 0.34-0.67]), event-free survival (EFS) (median EFS: 14.1 vs. 7.6 months; HR=0.39 [95% CI, 0.28-0.53]), and time to next treatment (TTNT) or death (median TTNT: 23.9 vs. 10.9 months; HR=0.37 [95% CI, 0.25-0.52]). Specifically, among patients in the control arm who were eligible for crossover, 76% (n=50/66) crossed over to receive pirtobrutinib. Multiple analyses that adjust for the effect of crossover demonstrate trends in favor of pirtobrutinib (Inverse Probability Censored Weighting methodology: HR= 0.89 [95% CI, 0.52-1.53]; two-stage Accelerated Failure Time methodology: HR=0.77 [95% CI, 0.45-1.26]). The overall safety profile for patients treated with pirtobrutinib in BRUIN CLL-321 was consistent with safety data from the Phase 1/2 BRUIN study, including adverse events of special interest. In the Phase 3 study, pirtobrutinib treatment was associated with fewer grade 3 or higher treatment-emergent adverse events (TEAEs) and fewer treatment discontinuations due to adverse events compared to IdelaR or BR. When adjusting for exposure, the incidence rate of TEAEs was overall lower in patients receiving pirtobrutinib compared to IdelaR or BR. "BRUIN CLL-321 is the only randomized CLL or SLL study ever conducted exclusively in the BTK-inhibitor pre-treated population, where there is significant need for new treatment options, and these data illustrate pirtobrutinib's ability to meaningfully delay disease progression and time to next treatment in this setting," said David Hyman, M.D., chief medical officer, Lilly. "This is the first in our suite of randomized Phase 3 trials for pirtobrutinib to readout and we look forward to continuing to build the body of evidence supporting the role of pirtobrutinib in advancing care for people with B-cell malignancies." Lilly is committed to the ongoing investigation of pirtobrutinib in people living with hematologic malignancies. The BRUIN clinical trial program consists of six clinical studies, four of which are Phase 3 studies evaluating pirtobrutinib in CLL/SLL. For more information on the BRUIN Phase 3 clinical trial program, please visit clinicaltrials.gov. Pirtobrutinib is approved as Jaypirca® under the U.S. Food and Drug Administration's (FDA) Accelerated Approval pathway for the treatment of adult patients with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor and adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. About BRUIN CLL-321 BRUIN CLL-321 is a Phase 3, randomized, open-label study of pirtobrutinib versus investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pre-treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). The trial enrolled 238 patients, who were randomized 1:1 to receive pirtobrutinib (200 mg orally, once daily) or investigator's choice of either IdelaR or BR per labeled doses. This trial's primary endpoint is progression-free survival (PFS) per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria, as assessed by blinded independent review committee (IRC). Secondary endpoints include PFS, as assessed by investigator; overall response rate (ORR) and duration of response (DoR); event-free survival; overall survival (OS) and time to next treatment (TTNT); safety and tolerability; and patient-reported outcomes (PRO). About Pirtobrutinib Pirtobrutinib is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK.2 BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation, and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).3,4 Pirtobrutinib was developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma CLL and SLL are forms of slow-growing non-Hodgkin lymphoma that develop from white blood cells known as lymphocytes.5,6 CLL is one of the most common types of leukemia in adults.5 In the U.S., CLL accounts for about one-quarter of the new cases of leukemia and there will be approximately 20,700 new cases of CLL diagnosed this year.5,7 SLL is identical to CLL from a pathologic and immunophenotypic standpoint, with the main difference between them being the location of the cancer cells.5 In CLL, the cancer cells are present in the blood, and in SLL, the cancer cells are found in the lymph nodes.5 INDICATIONS FOR JAYPIRCA® Jaypirca® is a kinase inhibitor indicated for the treatment of Adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. IMPORTANT SAFETY INFORMATION FOR JAYPIRCA® (pirtobrutinib) Infections: Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred (4.4%). Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included Pneumocystis jirovecii pneumonia and fungal infection. Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients at increased risk for infection, including opportunistic infections. Monitor patients for signs and symptoms, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Hemorrhage: Fatal and serious hemorrhage has occurred with Jaypirca. Major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred in 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred (17%). Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) antithrombotic agents. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca. Monitor patients for signs of bleeding. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Consider benefit/risk of withholding Jaypirca 3-7 days pre- and post-surgery depending on type of surgery and bleeding risk. Cytopenias: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). Patients with cardiac risk factors such as hypertension or previous arrhythmias may be at increased risk. Monitor for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Second Primary Malignancies: Second primary malignancies, including non-skin carcinomas, developed in 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor for development of second primary malignancies. Hepatotoxicity, Including Drug-Induced Liver Injury (DILI): Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, has occurred in patients treated with BTK inhibitors, including Jaypirca. Evaluate bilirubin and transaminases at baseline and throughout Jaypirca treatment. For patients who develop abnormal liver tests after Jaypirca, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Jaypirca. Upon confirmation of DILI, discontinue Jaypirca. Embryo-Fetal Toxicity: Jaypirca can cause fetal harm in pregnant women. Administration of pirtobrutinib to pregnant rats caused embryo-fetal toxicity, including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended 200 mg/day dose. Advise pregnant women of potential fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose. Adverse Reactions (ARs) in Patients Who Received Jaypirca The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%). Mantle Cell Lymphoma Serious ARs occurred in 38% of patients. Serious ARs occurring in ≥2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal ARs within 28 days of last Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients). Dose Modifications and Discontinuations: ARs led to dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dosage modification in >5% of patients included pneumonia and neutropenia. ARs resulting in permanent discontinuation in >1% of patients included pneumonia. Most common ARs ( ≥ 15%), excluding laboratory terms (all Grades %; Grade 3-4 %): fatigue (29; 1.6), musculoskeletal pain (27; 3.9), diarrhea (19; -), edema (18; 0.8), dyspnea (17; 2.3), pneumonia (16; 14), bruising (16; -). Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥ 10% of Patients: hemoglobin decreased (42; 9), platelet count decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte count decreased (32; 15), creatinine increased (30; 1.6), calcium decreased (19; 1.6), AST increased (17; 1.6), potassium decreased (13; 1.6), sodium decreased (13; -), lipase increased (12; 4.4), alkaline phosphatase increased (11; -), ALT increased (11; 1.6), potassium increased (11; 0.8). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10), platelets decreased (7), lymphocytes decreased (6). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%). Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis. Most common ARs ( ≥ 20%), excluding laboratory terms (all Grades %; Grade 3-4 %): fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9). Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥ 20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23). Drug Interactions Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to approved labeling. Strong or Moderate CYP3A Inducers: Concomitant use with Jaypirca decreased pirtobrutinib systemic exposure, which may reduce Jaypirca efficacy. Avoid concomitant use of Jaypirca with strong or moderate CYP3A inducers. If concomitant use with moderate CYP3A inducers is unavoidable, increase Jaypirca dosage according to approved labeling. Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: Concomitant use with Jaypirca increased their plasma concentrations, which may increase risk of adverse reactions related to these substrates for drugs that are sensitive to minimal concentration changes. Follow recommendations for these sensitive substrates in their approved labeling. Use in Special Populations Pregnancy and Lactation: Due to potential for Jaypirca to cause fetal harm, verify pregnancy status in females of reproductive potential prior to starting Jaypirca and advise use of effective contraception during treatment and for one week after last dose. Presence of pirtobrutinib in human milk is unknown. Advise women not to breastfeed while taking Jaypirca and for one week after last dose. Geriatric Use: In the pooled safety population of patients with hematologic malignancies, patients aged ≥65 years experienced higher rates of Grade ≥3 ARs and serious ARs compared to patients <65 years of age. Renal Impairment: Severe renal impairment increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling. PT HCP ISI MCL_CLL AA JUN2024 Please see Prescribing Information and Patient Information for Jaypirca. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY Jaypirca® is a registered trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates. © Lilly USA, LLC 2024. ALL RIGHTS RESERVED. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Jaypirca® (pirtobrutinib) as a potential treatment for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) previously treated with a covalent BTK inhibitor and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that studies will be completed as planned, that future study results will be consistent with the results to date, that Jaypirca will prove to be a safe and effective treatment for relevant indications, or that Jaypirca will receive additional regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. Sharman JP, Munir T, Grosicki S, et al. 886 BRUIN CLL-321: Randomized Phase III Trial of Pirtobrutinib Versus Idelalisib Plus Rituximab (IdelaR) or Bendamustine Plus Rituximab (BR) in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Abstract presented at: American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, CA. Session 642. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5 Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. Published 2020 Jun 17. doi:10.1186/s13045-020-00914-1 Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies. J Hematol Oncol. 2021;14(1):40. Published 2021 Mar 6. doi:10.1186/s13045-021-01049-7 Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic Lymphocytic Leukemia. [Updated 2023 Feb 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: The Leukemia and Lymphoma Society. NHL Subtypes. Access here: . Accessed on October 25, 2023. NIH National Cancer Institute. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). Access here: . Accessed on October 3, 2023. SOURCE Eli Lilly and Company WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED