Bosentan

Approximately 200,000 patients in the United States have PPF, with limited treatment options Topline data expected in the second half of 2027 SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)--United Therapeutics Corporation (Nasdaq: UTHR ) announced full enrollment of its TETON-PPF study evaluating the use of Tyvaso ® (treprostinil) inhalation solution ( nebulized Tyvaso ) for the treatment of progressive pulmonary fibrosis ( PPF ). The TETON-PPF study enrolled 754 patients. “The rapid pace of enrollment underscores both the significant unmet need for new treatment options in PPF and the strong interest in nebulized Tyvaso’s potential in addressing the burden of this disease, particularly following the highly successful results observed in our TETON-1 and TETON-2 studies in idiopathic pulmonary fibrosis ( IPF ),” said Peter Smith, Pharm. D. , Senior Vice President, Product Development at United Therapeutics and the lead for the global TETON program. “Due to the similarities in the mechanism of fibrosis between IPF and PPF, we are optimistic that anti-fibrotic therapies, such as inhaled treprostinil, will impact disease progression similarly in patients with these conditions. We are deeply grateful to the participants, investigators, and study teams whose commitment made this milestone possible.” If the TETON-PPF trial is successful, United Therapeutics intends to use the data from the study to support a supplemental New Drug Application ( sNDA ) to the U.S. Food and Drug Administration ( FDA ) to add PPF to the labeled indications for nebulized Tyvaso. Nebulized Tyvaso has not been approved by the FDA for PPF and remains investigational for this indication. United Therapeutics is currently seeking priority review of an sNDA submitted to the FDA in June 2026 to add IPF to the labeled indications for nebulized Tyvaso based on data from the TETON-1 and TETON-2 studies. Data from these studies were published in the New England Journal of Medicine , available here and here , respectively. About TETON-PPF The TETON-PPF study is a 754-patient, multinational, randomized, double-blind, placebo-controlled phase 3 registration study to evaluate the safety and efficacy of nebulized Tyvaso in subjects with PPF over a 52-week period. The study reached full enrollment in August 2026 and topline data is expected in the second half of 2027. Subjects were 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 absolute forced vital capacity ( FVC ) from baseline to week 52. Secondary endpoints include: (1) time to first clinical worsening; (2) time to first acute exacerbation of ILD; (3) overall survival at week 52; (4) change in percent predicted FVC from baseline to week 52; (5) change in the King’s Brief Interstitial Lung Disease questionnaire score from baseline to week 52; and (6) change in diffusing capacity of the lungs for carbon monoxide from baseline to week 52. Other data collected in the study will include the plasma N-terminal pro-brain natriuretic peptide concentration and supplemental oxygen use. Safety assessments include the development of adverse events, serious adverse events, vital signs, clinical laboratory parameters, and electrocardiogram parameters. Subjects who complete the Week 52 visit may be offered the opportunity to enter an open-label extension study after completing the final study visit. About PPF PPF occurs in interstitial lung diseases ( ILD ) and exhibits progressive, self-sustaining fibrosis, and a similar disease course to IPF. PPF includes idiopathic interstitial pneumonias, autoimmune ILDs, chronic fibrosing hypersensitivity pneumonitis, and fibrotic ILDs related to environmental/occupational exposure. It is estimated that 13% to 40% of patients with these various ILDs will go on to develop PPF. Patients with PPF exhibit decreased lung function, poor quality of life, and increased mortality despite usual treatments for the underlying ILD. Estimates for median transplant free survival and overall survival are approximately 2.9 years and 3.7 years, respectively. While estimates vary, we believe the size of the U.S. PPF population is approximately 200,000 patients. About Tyvaso ® (treprostinil) Inhalation Solution INDICATION TYVASO (treprostinil) Inhalation Solution is a prostacyclin mimetic 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 is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, TYVASO may produce symptomatic hypotension. TYVASO inhibits platelet aggregation and increases 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 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. DRUG INTERACTIONS/SPECIFIC POPULATIONS The concomitant use of TYVASO 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 pro 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. 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, the TD-300 TYVASO ® Inhalation System Instructions for Use manual, and additional information at or call 1 844 UNITHER (1-844-864-8437). About United Therapeutics Founded by CEO Martine Rothblatt to discover a cure for her daughter's life-threatening rare disease, pulmonary arterial hypertension, United Therapeutics transforms the treatment of rare diseases and pioneers alternatives to expand the supply of transplantable organs. From our innovative therapies to our groundbreaking manufactured organs, we are bold and unconventional. We move quickly from scientific theory to practical technologies that can save lives. As a public benefit corporation, even our legal structure reflects our commitments. We serve patients, act with integrity, create long-term shareholder value, and operate with sustainable practices that protect the future we are working to build. Visit us at and follow us on LinkedIn , Facebook , and Instagram . 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, statements regarding: the potential timing and outcome of the TETON-PPF study; our plans to obtain FDA approval of sNDAs to add PPF and IPF to the labeled indications for nebulized Tyvaso; the potential benefits of nebulized Tyvaso for patients with PPF; and our goals of expanding the supply of transplantable organs, developing practical technologies that can save lives, creating long-term shareholder value, and operating with sustainable practices. 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 August 17, 2026, and assume no obligation to update or revise the information contained in this press release whether because of new information, future events or any other reason. TYVASO is a registered trademark of United Therapeutics Corporation. Contacts For Further Information Contact: Investor Inquiries Media Inquiries communications@unither.com

国际顶尖系统性硬化（硬皮病）领域权威专家，伦敦大学学院（UCL） 皇家自由医院风湿病与结缔组织病中心负责人Christopher P. Denton教授，2026年8月在nature reviews rheumatology发表了《Navigating evidence‑based recommendations for the management of systemic sclerosis》，一篇重量级系统性硬化的诊断与治疗方法综述。 作者聚焦系统性硬化（SSc，硬皮病）临床诊断分层、器官评估体系以及循证治疗策略，区分证据等级、推荐强度与临床现实局限，梳理从初筛、分型、多器官评估到分靶点治疗的完整临床路径。综述反复强调：系统性硬化异质性极强，很多干预措施缺乏大型 RCT 证据，指南 “强推荐” 不等于拥有 Ⅰ 级高质量证据，部分强推荐来自观察性研究与专家共识，临床不能机械套用条文，需要结合患者个体情况权衡获益风险。一、系统性硬化的诊断与全面评估体系 综述没有重新制定新的分类标准，沿用当前通用的 ACR‑EULAR 系统性硬化分类标准，同时重点强调：SSc 诊断不是单一疾病确诊，而是分型 + 多器官受累的完整评估过程，诊断完成只是起点，器官损伤筛查是决定后续治疗方案的核心。 1. 临床分型诊断 分为局限型系统性硬化（lcSSc）与弥漫型系统性硬化（dcSSc）两大亚型，二者治疗侧重点截然不同。 弥漫型 SSc（dcSSc）：皮肤硬化快速广泛进展，躯干、四肢近端受累，发生皮肤纤维化、间质性肺病、肾危象风险更高，需要更加积极的免疫抑制干预。 局限型 SSc（lcSSc）：皮肤硬化主要局限于肢体远端，皮肤进展风险相对低；但血管并发症风险突出，雷诺现象、反复指端溃疡、肺动脉高压发生率高，该类患者治疗重点不在于强力免疫抑制，而在于血管并发症的长期筛查与对症处理。 综述特别提醒：部分患者早期仅有雷诺现象，皮肤硬化尚未显现，此时不能直接确诊 SSc，需要借助自身抗体、甲襞毛细血管镜进行风险分层，识别向系统性硬化转化的高危人群。2. 血清学与微血管辅助诊断自身抗体检测 抗着丝点抗体多见于局限型 SSc，与肺动脉高压、雷诺、指端缺血相关；抗 Scl‑70 抗体多见于弥漫型 SSc，提示间质性肺病、严重皮肤病变风险升高。抗体用于风险预判，不能单独作为确诊依据，需要结合临床表型。甲襞毛细血管镜 是综述重点强调的无创微血管评估手段。出现巨型毛细血管、毛细血管缺失、微出血，提示结缔组织病相关雷诺，预示未来发生指端溃疡风险升高。它可以区分原发性雷诺与 SSc 相关雷诺；原发性雷诺毛细血管镜基本正常，SSc‑RP 存在明确微血管结构破坏。该检查不只是辅助诊断，也用于长期随访微血管损伤进展。3. 系统化器官受累评估（诊断后必须完成） 综述提出，SSc 的诊断价值在于识别潜在内脏损害，所有确诊患者均需要完成基线多器官评估，部分无症状患者依然存在隐匿脏器损伤。 皮肤系统：采用改良 Rodnan 皮肤评分（mRSS）量化皮肤硬化程度，作为皮肤治疗的主要随访指标。 血管系统：评估雷诺发作频率、持续时间、疼痛程度，检查指端有无凹陷瘢痕、溃疡、坏疽。 肺部评估：肺功能（FVC、DLCO）、胸部高分辨 CT 筛查硬皮病相关间质性肺病（SSc‑ILD）；DLCO 下降需要进一步排查肺动脉高压，必要时心脏超声初筛右心负荷，高危患者完善右心导管检查。 肾脏：监测血压、肾功能、尿常规，警惕硬皮病肾危象，即使血压正常也不能排除肾危象风险。 心脏：超声心动图、心电图，排查心肌纤维化、心律失常。 消化道：询问反流、吞咽困难、腹胀、肠道动力障碍；很多患者消化道症状突出，但缺少特异性实验室指标，主要依靠临床症状诊断。 关节肌肉：评估关节痛、腱鞘炎、肌病相关表现。 综述指出，很多内脏损伤早期无明显临床症状，仅依靠患者主诉会漏诊，基线评估和定期复查是 SSc 诊疗的重要组成部分。二、分系统循证治疗方法 综述严格区分每一项治疗的证据来源、治疗目标、适用人群，同时明确药物能够做到什么、不能做到什么，纠正临床常见超适应症用药误区。（一）皮肤纤维化治疗 治疗核心目标：抑制皮肤硬化继续进展，无法逆转已经形成的晚期纤维化瘢痕。已经形成的皮肤纤维化瘢痕，现有药物不能使之恢复正常，临床需要避免对治疗效果过度期待。弥漫型系统性硬化（dcSSc） 吗替麦考酚酯、环磷酰胺：拥有 RCT 证据，EULAR 强推荐，用于改善进行性皮肤硬化。 托珠单抗：临床试验可见 mRSS 轻度下降，但整体获益有限，不作为一线选择。 JAK 抑制剂：二期研究观察到皮肤指标改善，但缺少大型 Ⅲ 期确证 RCT，不推荐常规使用，仅用于其他方案效果差的难治病例，谨慎选用。局限型系统性硬化（lcSSc） 皮肤进展风险低，一般不需要强化免疫抑制。不盲目使用大剂量免疫抑制剂，重点转向血管并发症的防控。（二）血管病变：雷诺现象与指端溃疡 综述反复强调关键病理：SSc 相关雷诺现象，不只是功能性血管痉挛，后期合并小动脉内膜增生、管腔狭窄、微血管丢失的结构性损伤。因此部分患者即使足量扩血管药物，效果依旧不理想，属于疾病本身病理改变，并非药物失效。同时明确：免疫抑制剂、生物制剂不能直接改善雷诺血管痉挛，不要为治疗雷诺而使用免疫抑制。雷诺现象的治疗 一线：二氢吡啶类钙通道阻滞剂（硝苯地平缓释剂），高级别证据，减少发作频率、减轻严重程度；对已经出现结构性微血管闭塞效果有限。 二线：PDE‑5 抑制剂（西地那非、他达拉非），用于 CCB 不耐受或者疗效不足，可与 CCB 联合，注意低血压叠加风险。 非药物干预（共识推荐）：全身保暖、戒烟，戒烟为最高优先级干预，吸烟会加重微血管损伤，抵消扩血管药物疗效；避免寒冷、情绪应激、手部外伤、振动刺激。 证据较弱手段：局部硝酸甘油凝胶，存在头痛、皮肤刺激，证据不一致；A 型肉毒素注射仅小样本队列，无安慰剂 RCT，仅限难治病例。指端溃疡治疗，区分 “促进现有溃疡愈合” 与 “预防新发溃疡” 两大目标 促进溃疡愈合：静脉伊洛前列素，用于多发活动性指端溃疡，改善局部缺血、减轻疼痛、促进溃疡愈合；缺点需要静脉输注，不良反应头痛、面部潮红常见，停药后症状易反弹。 预防新发溃疡：波生坦，不改善雷诺发作症状，核心作用是降低新的指端溃疡发生风险，用于反复溃疡复发的高危患者。 外科手段：掌交感神经切除短期改善缺血症状，但远期复发率高，仅用于濒临指端坏疽其他手段无效的极端情况，不作为常规治疗。SSc 以弥漫微血管病变为主，大血管重建手术适用人群极少。（三）内脏器官受累治疗硬皮病相关间质性肺病 SSc‑ILD 吗替麦考酚酯、环磷酰胺为免疫抑制一线选择；尼达尼布抗纤维化治疗，可以延缓 FVC 下降。免疫抑制剂联合抗纤维化药物临床可以使用，但需要严密监测骨髓抑制、肝肾功能等多重不良反应。治疗目标是延缓肺功能下降，不能彻底逆转已经形成的肺纤维化。系统性硬化相关肺动脉高压 SSc‑PAH 强调早期筛查，一旦确诊肺动脉高压，不能单独依靠免疫抑制剂，必须启动肺高压靶向药物。依据风险分层选择内皮素受体拮抗剂、PDE‑5 抑制剂、前列环素通路药物，可单药或联合治疗。硬皮病肾危象 SRC 属于危及生命急症。血管紧张素转换酶抑制剂（ACEI）是核心治疗药物；综述重点指出，即使患者血压正常，发生肾危象时也应当使用 ACEI，不能等待血压升高再用药。同时需要严格规避大剂量糖皮质激素，大剂量激素会显著升高肾危象发病风险。胃肠道受累 胃食管反流、吞咽困难、肠道动力紊乱在 SSc 中十分常见，但几乎没有高质量 RCT 证据，治疗方案大多来自专家共识。以对症处理为主：质子泵抑制剂控制反流；促动力药物改善胃肠动力。尚无可以逆转胃肠道纤维化的特效药物。关节、肌肉骨骼受累 关节痛、肌痛可酌情小剂量糖皮质激素短期使用；严格限制大剂量激素长期使用，警惕肾危象风险。非甾体抗炎药对症缓解疼痛，注意肾功能、胃肠道不良反应。（四）综述明确的证据不足、不推荐常规使用的方案 JAK 抑制剂：皮肤方面有二期数据，但缺乏 Ⅲ 期确证；对雷诺、指端溃疡无充分证据，禁止超适应症用于血管病变。 各类生物制剂（托珠单抗除外）：主要针对皮肤纤维化，对雷诺现象没有明确获益。 口服前列环素类似物：雷诺相关证据偏弱，不作为首选。三、该综述传递的重要循证治疗原则 分清推荐强度和证据等级：EULAR 强推荐不等于有高质量 RCT；部分干预虽然证据等级低，但获益远大于风险，依旧为强推荐，临床阅读指南不能只看结论，要回溯证据来源。 分清药物的治疗边界：部分病变可以延缓进展（皮肤纤维化、间质性肺病）；部分只能控制症状（雷诺、胃肠道症状）；晚期结构性损伤（微血管闭塞、纤维化瘢痕）药物无法逆转，避免过度治疗。 分型决定治疗方向：弥漫型重点抑制免疫纤维化；局限型重点防控血管并发症，避免过度免疫抑制。 警惕超适应症用药：临床经常将免疫抑制剂、JAK 抑制剂用于改善雷诺现象，现有证据不支持该用法。四、现有证据缺口（原文指出的临床现实局限） 大量治疗缺少头对头大型 RCT，很多治疗建议来自观察性队列与专家意见。 雷诺局部治疗、胃肠道并发症、疾病相关疲劳，高质量临床试验稀缺。 早期 SSc 最优起始治疗方案尚无统一答案。 多器官同时受累，多种药物联合使用的真实世界安全性数据不足。 系统性硬化的诊疗，是 “证据‑指南‑患者个体” 三者结合的过程，诊断阶段做好分型和全面器官筛查，治疗阶段明确药物能实现的目标，规避超适应症用药，实现个体化循证管理。