Aliskiren Fumarate

FDA grants Priority Review for sNDA to convert FILSPARI® (sparsentan) from accelerated approval to full approval for the treatment of IgAN in the U.S.; PDUFA target action date of September 5, 2024 Received 511 new patient start forms (PSFs) for FILSPARIin Q1 2024; Total of 1,963 PSFs received since launch Net product sales of FILSPARI totaled $19.8 million for the first quarter of 2024 European Commission recently granted conditional marketing authorization (CMA) to FILSPARI for the treatment of IgAN in Europe; first launch in European markets anticipated in H2 2024 First patients dosed in pivotal Phase 3 HARMONY Study of pegtibatinase in classical homocystinuria (HCU); topline data anticipated in 2026 Cash, cash equivalents, and marketable securities as of March 31, 2024, totaled $441.0 million SAN DIEGO, May 06, 2024 (GLOBE NEWSWIRE) -- Travere Therapeutics Inc. (NASDAQ: TVTX) today reported its first quarter 2024 financial results and provided a corporate update. “We are off to an excellent start to 2024. We are reporting new highs in both demand and revenue for FILSPARI in IgAN during the first quarter, with continuing strong trends into the second quarter. Additionally, the FDA recently granted Priority Review to our sNDA seeking the conversion of accelerated approval of FILSPARI to full approval for IgAN in the U.S., and FILSPARI recently received conditional marketing authorization for IgAN in Europe. Our strong performance and achievement of these key regulatory milestones furthers our confidence in being able to deliver significant growth in 2024 and beyond,” said Eric Dube, Ph.D., president and chief executive officer of Travere Therapeutics. “Additionally, we remain on track with the other priorities to expand our growth, including dosing the first patients with HCU in our pivotal program designed to deliver pegtibatinase as the only disease modifying therapy for HCU. We also continue to review our data from the DUPLEX Study and engage with the nephrology community to facilitate our planned engagement with FDA on potential regulatory pathways for sparsentan in FSGS.” Financial Results for Continuing Operations for the Quarter Ended March 31, 2024 The following financial results discussion compares Travere’s continuing operations. All periods unless otherwise specified have been adjusted to exclude discontinued operations related to the divestiture of the bile acid product portfolio completed on August 31, 2023. Net product sales for the first quarter of 2024 were $40.0 million, compared to $24.2 million for the same period in 2023. The difference is attributable to an increase in sales from the ongoing commercial launch of FILSPARI. Research and development (R&D) expenses for the first quarter of 2024 were $49.4 million, compared to $58.2 million for the same period in 2023. The reduction in expense is largely attributable to decreased personnel costs and lower development costs related to FILSPARI as the Phase 3 programs advance towards completion. On a non-GAAP adjusted basis, R&D expenses were $45.8 million for the first quarter of 2024, compared to $51.3 million for the same period in 2023. Selling, general, and administrative (SG&A) expenses for the first quarter of 2024 were $64.2 million, compared to $66.0 million for the same period in 2023. The reduction in expense is largely attributable to a decrease in personnel and support costs. On a non-GAAP adjusted basis, SG&A expenses were $48.2 million for the first quarter of 2024, compared to $49.5 million for the same period in 2023. The Company recognized a $65 million IPR&D milestone expense during the first quarter of 2024 as a result of achieving the first patient dosed in the pivotal HARMONY Study of pegtibatinase in HCU. The milestone payment is expected to occur in the second quarter of 2024. Total other income, net, for the first quarter of 2024 was $3.5 million, compared to $0.9 million for the same period in 2023. The difference is largely attributable to an increase in interest income during the period. Net loss including discontinued operations for the first quarter of 2024 was $136.1 million, or $1.76 per basic share, compared to a net loss of $86.3 million, or $1.27 per basic share for the same period in 2023. On a non-GAAP adjusted basis, net loss including discontinued operations for the first quarter of 2024 was $116.2 million, or $1.51 per basic share, compared to a net loss of $62.9 million, or $0.92 per basic share for the same period in 2023. As of March 31, 2024, the Company had cash, cash equivalents, and marketable securities of $441.0 million. During the first quarter of 2024, the Company had non-recurring cash use of approximately $61 million related to the previously announced strategic restructuring, first quarter compensation expense, delivery of inventory and transfer of receivables related to the divestiture of the bile acid product portfolio. The Company continues to anticipate that operating cash use will decline throughout 2024. Program Updates and Anticipated Milestones FILSPARI® (sparsentan) – IgAN On February 17, 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval to FILSPARI to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g. FILSPARI became commercially available the week of February 27, 2023. Commercial progress in the ongoing launch has resulted in: 511 new patient start forms (PSFs) received in the first quarter of 2024; as of March 31, 2024, a total of 1,963 PSFs had been received since approval. Net product sales of $19.8 million during the first quarter, bringing the total to $49.0 million in net product sales since the beginning of the launch. In May 2024 the FDA granted Priority Review of the Company’s supplemental New Drug Application (sNDA) to convert FILSPARI from accelerated approval to full approval for the treatment of IgAN in the U.S. The FDA assigned a PDUFA target action date of September 5, 2024. In April 2024, the Company and its commercial partner CSL Vifor announced the European Commission granted conditional marketing authorization (CMA) for FILSPARI for the treatment of adults with primary IgAN with a urine protein excretion ≥1.0 g/day (or urine protein-to-creatinine ratio ≥0.75 g/g). The CMA is granted for all member states of the European Union, as well as in Iceland, Liechtenstein and Norway. The Company expects to receive a $17.5 million milestone payment from CSL Vifor upon conversion of the CMA to full approval, and the Company anticipates receiving an additional milestone payment in 2025 upon achievement of market access milestones in certain countries. The first launch of FILSPARI by CSL Vifor is expected in the second half of 2024. With the CMA approval, the Company expects to pay a $5.8 million milestone to Ligand Pharmaceuticals in the second quarter of 2024. In January 2024, the Company announced that it had entered into an exclusive licensing agreement with Renalys Pharma, Inc., to bring sparsentan to patients in Japan and other countries in Asia. Following successful meetings with the Pharmaceuticals and Medical Devices Agency (PMDA), Renalys Pharma announced in April 2024 that it has submitted an Investigational New Drug (IND) Application for a Phase 3 clinical trial in Japan. The Phase 3 study will be a multicenter, open-label, single arm study in Japanese patients with IgA nephropathy, and is planned to confirm the efficacy and safety of sparsentan in approximately 30 Japanese patients. Topline data from the study are expected in the second half of 2025. At the World Congress of Nephrology (April 13-16), the Company presented five abstracts, including a late-breaking oral presentation on subgroup analyses of the Phase 3 PROTECT Study of FILSPARI in IgAN, demonstrating a consistent treatment benefit in absolute eGFR change across baseline urine protein-to-creatinine ratio subgroups. Presentations also included preliminary findings from the SPARTAN Study which demonstrated an approximate 80 percent reduction in proteinuria and stable eGFR out to 36 weeks in newly diagnosed patients with IgAN, as well as the early clinical experience from the PROTECT open-label extension illustrating that the addition of sodium-glucose cotransporter-2 inhibitors (SGLT2i) to ongoing FILSPARI treatment is generally well-tolerated with additive benefit on proteinuria reduction in patients with IgAN. At the American Nephrology Nurses Association (ANNA) National Symposium (April 14-17), the Company presented four abstracts on the additional insights from the HONUS trial, including health-related quality of life (HRQoL) data and the humanistic burden experienced by patients with IgAN and FSGS. In 2024, the Company anticipates inclusion of FILSPARI into the draft Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases. Sparsentan – Focal Segmental Glomerulosclerosis (FSGS) In 2024, the Company is conducting additional analyses of FSGS data with plans to engage with regulators to evaluate potential regulatory pathways for a sparsentan FSGS indication. Pegtibatinase – Classical HCU In December 2023, the Company initiated the pivotal Phase 3 HARMONY Study to support the potential approval of pegtibatinase for the treatment of HCU. The HARMONY Study is a global, randomized, multi-center, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate the efficacy and safety of pegtibatinase as a novel treatment to reduce total homocysteine (tHcy) levels. The trial is expected to enroll approximately 70 patients with a diagnosis of classical HCU and tHcy levels ≥50 μM while maintaining their standard-of-care treatment. The primary endpoint is relative geometric mean change in plasma tHcy levels from baseline compared to weeks 6 through 12. Durability of treatment response through 24 weeks of treatment will also be measured as a secondary endpoint. Topline results from the HARMONY Study are expected in 2026. During the first quarter of 2024, the Company dosed the first patient in the Phase 3 HARMONY Study. The Company is nearing initiation of the ENSEMBLE Study, a Phase 3b, open-label, long-term extension, that will evaluate the ongoing efficacy and long-term safety of pegtibatinase in participants with HCU following their completion of the Phase 1/2 COMPOSE Study or the HARMONY Study. ENSEMBLE will include an optional protein tolerance modification sub-study that will evaluate if patients can increase their natural dietary protein intake and maintain an acceptable level of metabolic control while receiving pegtibatinase. At the Society for Inherited Metabolic Disorders (SIMD) annual meeting (April 14-17) and Genetic Metabolic Dieticians International (GMDI) conference (April 17-20), the Company presented eight abstracts covering the previously reported positive results from cohort 6 in the placebo-controlled Phase 1/2 COMPOSE Study, the trial design of the pivotal Phase 3 HARMONY Study, insights on the development of an innovative tool used for dietary management and monitoring in the Phase 3 HARMONY Study and open-label extension ENSEMBLE Study, as well as economic and clinical burdens of classical HCU in the U.S., and the association between homocysteine and clinical outcomes in patients with classical HCU. Conference Call Information Travere Therapeutics will host a conference call and webcast today, Monday, May 6, 2024, at 4:30 p.m. ET to discuss company updates as well as first quarter 2024 financial results. To participate in the conference call, dial +1 (888) 224-1005 (U.S.) or +1 (323) 794-2575 (International), confirmation code 2471523 shortly before 4:30 p.m. ET. The webcast can be accessed on the Investor page of Travere’s website at ir.travere.com/events-presentations. Following the live webcast, an archived version of the call will be available for 30 days on the Company’s website. Use of Non-GAAP Financial Measures To supplement Travere’s financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP adjusted financial measures in this press release and the accompanying tables. The Company believes that these non-GAAP financial measures are helpful in understanding its past financial performance and potential future results. They are not meant to be considered in isolation or as a substitute for comparable GAAP measures and should be read in conjunction with the consolidated financial statements prepared in accordance with GAAP. Travere’s management regularly uses these supplemental non-GAAP financial measures internally to understand, manage and evaluate its business and make operating decisions. In addition, Travere believes that the use of these non-GAAP measures enhances the ability of investors to compare its results from period to period and allows for greater transparency with respect to key financial metrics the Company uses in making operating decisions. Investors should note that these non-GAAP financial measures are not prepared under any comprehensive set of accounting rules or principles and do not reflect all of the amounts associated with the Company’s results of operations as determined in accordance with GAAP. Investors should also note that these non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time to time in the future the Company may exclude other items, or cease to exclude items that it has historically excluded, for purposes of its non-GAAP financial measures; because of the non-standardized definitions, the non-GAAP financial measures as used by the Company in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by the Company’s competitors and other companies. As used in this press release, (i) the historical non-GAAP net loss measures exclude from GAAP net loss, as applicable, stock-based compensation expense, amortization and depreciation expense, and income tax; (ii) the historical non-GAAP SG&A expense measures exclude from GAAP SG&A expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense; (iii) the historical non-GAAP R&D expense measures exclude from GAAP R&D expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense. About Travere Therapeutics At Travere Therapeutics, we are in rare for life. We are a biopharmaceutical company that comes together every day to help patients, families, and caregivers of all backgrounds as they navigate life with a rare disease. On this path, we know the need for treatment options is urgent – that is why our global team works with the rare disease community to identify, develop, and deliver life-changing therapies. In pursuit of this mission, we continuously seek to understand the diverse perspectives of rare patients and to courageously forge new paths to make a difference in their lives and provide hope – today and tomorrow. For more information, visit travere.com. About FILSPARI (sparsentan) FILSPARI (sparsentan) is a once-daily, oral medication designed to selectively target two critical pathways in the disease progression of IgAN (endothelin-1 and angiotensin II) and is the first and only non-immunosuppressive therapy approved for the treatment of this condition. FILSPARI is a prescription medicine indicated to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a UPCR ≥1.5 g/g. FILSPARI (sparsentan) U.S. Indication FILSPARI is an endothelin and angiotensin II receptor antagonist indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a UPCR ≥1.5 g/g. This indication is granted under accelerated approval based on reduction in proteinuria. It has not been established whether FILSPARI slows kidney function decline in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. FILSPARI (sparsentan) Important Safety Information BOXED WARNING: HEPATOTOXICITY AND EMBRYO-FETALTOXICITY Becauseoftherisksof hepatotoxicity and birthdefects,FILSPARIisavailableonlythrougharestrictedprogramcalled the FILSPARI REMS. Under the FILSPARI REMS, prescribers, patients and pharmacies must enroll in the program. Hepatotoxicity Some Endothelin Receptor Antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3-times the Upper Limit of Normal (ULN) have been observed in up to 2.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3x Upper Limit of Normal (ULN). FILSPARI should generally be avoided in patients with elevated aminotransferases (>3x ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity FILSPARI can cause major birth defects if used by pregnant patients based on animal data. Therefore, pregnancy testing is required before the initiation of treatment, during treatment and one month after discontinuation of treatment with FILSPARI. Patients who can become pregnant must use effective contraception before the initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI. Contraindications: FILSPARI is contraindicated in patients who are pregnant. Do not coadminister FILSPARI with angiotensin receptor blockers (ARBs), endothelin receptor antagonists (ERAs), or aliskiren. WarningsandPrecautions Hepatotoxicity: Hepatotoxicity: Elevations in ALT or AST of at least 3-fold ULN have been observed. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment, monthly for the first 12 months, then every 3 months during treatment. Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended. Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity. Avoid initiation of FILSPARI in patients with elevated aminotransferases (>3x ULN) prior to drug initiation. Embryo-FetalToxicity: FILSPARI can cause fetal harm. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test and advise patients who can become pregnant to use effective contraception prior to, during, and one month after discontinuation of FILSPARI treatment. FILSPARIREMS: FILSPARI is available only through a restricted program under a REMS called the FILSPARI REMS. Important requirements include: — Prescribers must be certified with the FILSPARI REMS by enrolling and completing training. — All patients must enroll in the FILSPARI REMS prior to initiating treatment and comply with monitoring requirements. — Pharmacies that dispense FILSPARI must be certified with the FILSPARI REMS and must dispense only to patients who are authorized to receive FILSPARI. Further information is available at or 1-833-513-1325. Please see Full Prescribing Information for FILSPARI here. Forward-Looking Statements This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, these statements are often identified by the words “on-track,” “positioned,” “look forward to,” “will,” “would,” “may,” “might,” “believes,” “anticipates,” “plans,” “expects,” “intends,” “potential,” or similar expressions. In addition, expressions of our strategies, intentions or plans are also forward-looking statements. Such forward-looking statements include, but are not limited to, references to: statements regarding the continuing commercial launch of FILSPARI and trends related thereto; the potential for FILSPARI to receive full approval for the treatment of IgAN in the U.S. and the anticipated timing thereof; statements related to the anticipated launch of FILSPARI for the treatment of IgAN in certain European markets and the anticipated timing thereof; statements relating to clinical studies, including but not limited to the anticipated timing for topline data for the Phase 3 HARMONY Study and topline data from Renalys Pharma’s study in Japanese patients with IgA nephropathy; statements regarding the potential to deliver significant growth in 2024 and beyond; statements regarding plans to engage with the FDA on potential regulatory pathways for sparsentan in FSGS and the anticipated timing thereof; statements regarding the potential for pegtibatinase to become the only disease modifying therapy for HCU; statements regarding future milestone payments; and the potential inclusion of FILSPARI into the KDIGO guidelines. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks and uncertainties associated with the regulatory review and approval process, as well as risks and uncertainties associated with the Company’s business and finances in general, the success of its commercial products and risks and uncertainties associated with the Company’s preclinical and clinical stage pipeline. Specifically, the Company faces risks associated with the ongoing commercial launch of FILSPARI, market acceptance of its commercial products including efficacy, safety, price, reimbursement, and benefit over competing therapies, as well as risks associated with the successful development and execution of commercial strategies for such products, including FILSPARI. The risks and uncertainties the Company faces with respect to its preclinical and clinical stage pipeline include risk that the Company’s clinical candidates will not be found to be safe or effective and that current or anticipated future clinical trials will not proceed as planned. Specifically, the Company faces risks related to the timing and potential outcome of the studies described herein, and the timing and potential outcome of the FDA’s review of the Company’s sNDA submission for full approval of FILSPARI in IgAN. There is no guarantee that regulators will grant full approval of sparsentan for IgAN or FSGS. The Company also faces the risk that it will be unable to raise additional funding that may be required to complete development of any or all of its product candidates, including as a result of macroeconomic conditions; risks relating to the Company’s dependence on contractors for clinical drug supply and commercial manufacturing; uncertainties relating to patent protection and exclusivity periods and intellectual property rights of third parties; risks associated with regulatory interactions; and risks and uncertainties relating to competitive products, including current and potential future generic competition with certain of the Company’s products, and technological changes that may limit demand for the Company’s products. The Company also faces additional risks associated with global and macroeconomic conditions, including health epidemics and pandemics, including risks related to potential disruptions to clinical trials, commercialization activity, supply chain, and manufacturing operations. You are cautioned not to place undue reliance on these forward-looking statements as there are important factors that could cause actual results to differ materially from those in forward-looking statements, many of which are beyond our control. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investors are referred to the full discussion of risks and uncertainties, including under the heading “Risk Factors”, as included in the Company’s most recent Form 10-K, Form 10-Q and other filings with the Securities and Exchange Commission. TRAVERE THERAPEUTICS, INC. CONSOLIDATED BALANCE SHEETS (in thousands, except share amounts) March 31, 2024 December 31, 2023 Assets (unaudited) Current assets: Cash and cash equivalents $ 43,251 $ 58,176 Marketable debt securities, at fair value 397,793 508,675 Accounts receivable, net 22,731 21,179 Inventory 4,532 9,410 Prepaid expenses and other current assets 12,769 19,335 Total current assets 481,076 616,775 Long-term inventory 37,774 31,494 Property and equipment, net 6,943 7,479 Operating lease right of use assets 17,271 18,061 Intangible assets, net 101,182 104,443 Other assets 19,301 10,661 Total assets $ 663,547 $ 788,913 Liabilities and Stockholders' Equity Current liabilities: Accounts payable $ 16,725 $ 41,675 Accrued expenses 139,580 118,991 Deferred revenue, current portion 6,460 7,096 Operating lease liabilities, current portion 5,036 4,909 Other current liabilities 5,428 5,237 Total current liabilities 173,229 177,908 Convertible debt 377,693 377,263 Deferred revenue, less current portion 888 1,835 Operating lease liabilities, less current portion 21,287 22,612 Other non-current liabilities 16,379 8,485 Total liabilities 589,476 588,103 Stockholders' Equity: Preferred stock $0.0001 par value; 20,000,000 shares authorized; 0 issued and outstanding as of March 31, 2024 and December 31, 2023 — — Common stock $0.0001 par value; 200,000,000 shares authorized; 76,108,829, and 75,367,117 issued and outstanding as of March 31, 2024 and December 31, 2023, respectively 8 7 Additional paid-in capital 1,337,638 1,327,881 Accumulated deficit (1,261,683 ) (1,125,622 ) Accumulated other comprehensive loss (1,892 ) (1,456 ) Total stockholders' equity 74,071 200,810 Total liabilities and stockholders' equity $ 663,547 $ 788,913 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC. CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except share and per share data) (unaudited) Three Months Ended March 31, 2024 2023 (unaudited) Net product sales: Tiopronin products $ 20,150 $ 21,174 FILSPARI 19,834 3,004 Total net product sales 39,984 24,178 License and collaboration revenue 1,390 6,710 Total revenue 41,374 30,888 Operating expenses: Cost of goods sold 1,504 4,145 Research and development 49,420 58,162 Selling, general and administrative 64,223 65,950 In-process research and development 65,205 — Restructuring 259 — Total operating expenses 180,611 128,257 Operating loss (139,237 ) (97,369 ) Other income (expenses), net: Interest income 6,032 3,646 Interest expense (2,800 ) (2,850 ) Other income, net 238 87 Total other income, net 3,470 883 Loss from continuing operations before income tax provision (135,767 ) (96,486 ) Income tax provision on continuing operations (191 ) (78 ) Loss from continuing operations, net of tax (135,958 ) (96,564 ) (Loss) income from discontinued operations, net of tax (103 ) 10,233 Net loss $ (136,061 ) $ (86,331 ) Per share data: Net loss per common share $ (1.76 ) $ (1.27 ) Weighted average common shares outstanding 77,136,493 68,174,099 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC. RECONCILIATION OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATION (in thousands, except share and per share data) (unaudited) Three Months Ended March 31, 2024 2023 GAAP operating loss $ (139,237 ) $ (97,369 ) R&D operating expense (49,420 ) (58,162 ) Stock compensation 3,657 4,481 Amortization & depreciation — 2,394 Subtotal non-GAAP items 3,657 6,875 Non-GAAP R&D expense (45,763 ) (51,287 ) SG&A operating expense (64,223 ) (65,950 ) Stock compensation 6,100 9,283 Amortization & depreciation 9,880 7,152 Subtotal non-GAAP items 15,980 16,435 Non-GAAP SG&A expense (48,243 ) (49,515 ) Subtotal non-GAAP items 19,637 23,310 Non-GAAP operating loss $ (119,600 ) $ (74,059 ) GAAP net income (loss) $ (136,061 ) $ (86,331 ) Non-GAAP operating loss adjustments 19,637 23,310 Income tax provision 191 78 Non-GAAP net income (loss)(1) $ (116,233 ) $ (62,943 ) Per share data: Net loss per common share $ (1.51 ) $ (0.92 ) Weighted average common shares outstanding 77,136,493 68,174,099 (1) Non-GAAP net income (loss) includes income from discontinued operations but excludes non-GAAP adjustments for the effect of discontinued operations. Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. Contact: Investors: Media: 888-969-7879 888-969-7879 ir@travere.com mediarelations@travere.com

▲5月30-31日 第八届广州生物医药创新者峰会 扫码立即报名 注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。近40年首例！FDA批准新机制降压药Aprocitentan上市2024年3月20日，美国食品药品监督管理局（FDA）批准由瑞士Idorsia制药公司与强生联合研发的降压新药阿普昔腾坦（aprocitentan，商品名Tryvio）上市。FDA批准该药与其他降压药物联合，用于治疗难治性高血压。该药的获批，引起业内人士的广泛关注，原因主要有两方面：（1）阿普昔腾坦通过抑制内皮素（ET）-1与ETA和ETB两种亚型受体的结合而降低血压，是FDA近40年来第一个批准的全新降压机制的药物；（2）可以有效地治疗血压控制不佳的难治性高血压。市场潜力巨大！人口老龄化驱动高血压用药需求飙升高血压是最常见的慢性非传染性疾病之一，是脑卒中、冠心病、心力衰竭、慢性肾病等多种疾病的危险因素。流行病学调查显示，截止到2012年，我国年龄≥18岁的成人高血压发病率升高至25.2%。随着社会老龄人口的增多，高血压发病率逐年升高，但高血压控制率仍然很低。高血压病的发生发展与交感神经系统亢进、肾素-血管紧张素-醛固酮系统（RAAS）激活、肾脏排泄功能障碍、血管内皮损害、胰岛素抵抗及家族遗传等多种因素相关。目前，高血压的治疗仍以药物治疗为主，已上市的抗高血压药物主要包括利尿剂、钙离子通道阻滞剂（CCB）、β 受体阻滞剂、血管紧张素转换酶抑制剂（ACEI）和血管紧张素Ⅱ受体阻断剂（ARB）等。根据药融云数据统计，2015-2019年国内高血压市场持续扩容，至2019年达到690.92亿元（未统计中药），2020年以后，受疫情、集采等因素影响，整体市场有一定萎缩，但销量基本稳中有升。从细分市场来看，钙通道阻断剂、血管紧张素Ⅱ拮抗剂为市场份额较高品类，2022年市场占比分别达到40.13%、31.03%，β受体阻断剂近年来市场份额逐步提升。未来，随着人口老龄化加剧、生活习惯进一步改变等因素影响下，以高血压为代表的慢病患者人数不断增加，抗高血压用药需求仍将稳步增长。2015-2022年国内抗高血压药物销售额数据来源：药融云全产业链数据库&药融咨询整理2015-2022年国内抗高血压药物主要品类市场占比数据来源：药融云全产业链数据库&药融咨询整理 新机制降压药涌现，高血压治疗领域迎来曙光目前高血压的治疗仍以药物治疗为主，足剂量、长效制剂、个体化、联合应用抗高血压药物是治疗高血压的基本原则。但我国高血压患者血压达标率不高，与单药治疗疗效欠佳、药物的可耐受性及患者依从性差等因素有关，因此研发新型和新作用靶点的降压药对提高血压达标率具有重要的临床意义。目前，抗高血压药物的研发重点在于对传统降压药物的改进（如新型双通道阻断型钙通道阻滞剂、直接肾素抑制剂、双重内皮素受体拮抗剂、内皮素A型受体/血管紧张素受体亚型1拮抗剂）以及探索新作用靶点的降压药物（如新型氨基肽酶A抑制剂、钠钾离子通道转换酶抑制剂、利钠肽受体激动剂、多巴胺β-羟化酶抑制剂、膜金属内肽酶抑制剂、可溶性鸟苷酸环化酶刺激剂）等方面。高血压领域主流在研作用机制及代表药物数据来源：药融云全产业链数据库&药融咨询整理根据药融云数据统计，目前全球共有1176款高血压相关研发药物（按高血压适应症统计，不包含上市阶段），其中研发活跃状态药物共计310款，占比达26.36 % ，IND及以上阶段药物112款，占比达9.52% ，值得一提的是，处于研究终止、研究暂停、无后续进展报道、撤市等非活跃状态的药物共866款，占比高达73.64%。然而，近年来，随着高血压基础研究和治疗等方面的不断深入，国内外诸多对新型降压药物靶点的研究已取得较大进展，并陆续有用于高血压治疗的新药获批，为该领域的发展带来新的曙光。因篇幅有限，本文总结和归纳了几种值得关注的新作用机制的药物研发进展，供参考。 01ETA/ETB双重内皮素受体拮抗剂 内皮素（ET）是由 21 个氨基酸组成的血管收缩肽，有三种类型，即 ET-1、ET-2、ET-3，作用于血管平滑肌受体ETA 和 ETB，这两种受体具有非常明显的相互拮抗效应。ET-1 作用于 ETA 既能引起人和哺乳动物体内强烈的血管收缩，也能激活 RAAS，刺激儿茶酚胺释放。ETA 激活后会诱导血管收缩，而ETB 激活后能够激发内皮舒张因子释放，产生血管舒张效应，抵消ETA的缩血管作用。目前关于ET受体拮抗剂（ERAs）相关研究显示，ERAs可以分为两种类型，即选择性ERAs和非选择性 ERAs。目前临床已在使用的内皮素受体拮抗剂包括波生坦（非选择性 ERA）、安立生坦（选择性ERA）、马昔腾坦（选择性ERA），以上药物主要用于治疗肺动脉高压，而并非高血压。单纯阻断ETA可能导致ETB受体的过度刺激，引起非选择性血管舒张、血管通透性增加、外周水肿加重以及血浆加压素和醛固酮水平升高。研究显示，与安慰剂相比，ETA阻断药物能够显著降低收缩压和舒张压，但水肿和液体潴留风险也显著增加。因此，研究者把目光转向选择性靶向ETB受体而非ETA受体的药物。前文所述的Aprocitentan 是 Quantum Genomics SA 公司研发的新型口服 ETA/ETB 双重受体拮抗剂，其对ETB受体的亲和力高出16倍，半衰期长达44 h，既不会干扰胆盐分泌，也不具有肝毒性，为难治性高血压患者的降压治疗提供了新思路。02直接肾素抑制剂 RAAS 在高血压的发生发展中具有重要作用，肾球囊细胞分泌的肾素可将肝脏合成的血管紧张素原转变为血管紧张素Ⅰ（AngⅠ），后者在血管紧张素转化酶（ACE）的活化作用下转化为血管紧张素Ⅱ（Ang Ⅱ）。Ang Ⅱ主要作用于血管紧张素受体亚型1（AT1），具有促进血管收缩、水钠潴留、增强交感系统的活性、导致血压上升的作用。直接肾素抑制剂能够直接抑制肾素的产生，降低体内Ang Ⅱ浓度，拮抗Ang Ⅱ的升压作用。阿利吉伦是目前惟一上市的直接肾素抑制剂，其单独使用或与其他药物联用治疗高血压均安全有效。但是，阿利吉伦的口服生物利用度相对较低，合成途径较长，在临床实践中患者可能会出现严重的不良反应。中央研究院、上海医药控股有限公司（中国）和三菱田边制药公司（日本）联合研发得到新一代的直接肾素抑制剂 SPH3127，于2023年5月达到III期临床试验确证性研究（SPH3127-301第二阶段）方案预设的主要研究终点指标。研究共入组828例患者，实验方案为SPH3127片100mg/次，口服，每日一次，连续用药12周。试验结果显示，SPH3127可降低原发性高血压患者msDBP，安全有效，提示SPH312片可为原发性高血压患者提供一种新的治疗途径和更丰富的治疗组合。此外，研发团队还积极拓展SPH3127新适应症，其中糖尿病肾病适应症正在中国开展Ⅱ期临床试验，溃疡性结肠炎适应症也正在中国、美国开展Ⅱ期临床试验。 03钠钾离子通道转换酶抑制剂 在肾小管的基底外侧，Na+-K+泵是肾脏钠重吸收的驱动器，改变Na+-K+泵功能能够改变全身血容量，进而引发高血压。因此，肾小管Na+-K+泵是潜在的治疗高血压的新靶点。研究表明，在人类和大鼠中存在两种影响肾脏 Na+-K+泵功能的因子，即盐调节激素内源性哇巴因和突变的细胞骨架蛋白 α-内收蛋白。以上两种因子通过异常激活Na+-K+离子泵，促进水钠潴留，引发高血压。因此，针对这两种作用靶点开发的药物能够抵抗哇巴因和突变型α内收蛋白对Na+-K+泵功能的影响。Rostafuroxin 是一种安全有效的洋地黄毒苷衍生物，目前处于临床Ⅱ期，李氏大药厂已于今年1月获得在大中华地区开发和商业化Rostafuroxin的许可。Rostafuroxin作用于Src-SH2域，能够选择性抑制Src活化，通过抑制相关信号通路来抑制肾小管对Na+的重吸收，从而发挥降低血压作用。PEARL-HT临床试验结果显示，与安慰剂相比，Rostafuroxin 对中国受试者收缩压的影响不明显；因此 Rostafuroxin可能用于指导白种人原发性高血压的药物治疗，但针对中国原发性高血压患者的靶向治疗药物仍需要更进一步的研究。 04新型氨基肽酶A（APA）抑制剂 APA和氨基肽酶 N（APN）是两种膜结合的锌金属蛋白酶，分别参与脑Ang Ⅱ和Ang Ⅲ的代谢，APA从 Ang Ⅱ切割 N 末端天冬氨酸形成 Ang Ⅲ，而 APN从 Ang Ⅲ切割 N 末端精氨酸形成血管紧张素Ⅳ（Ang Ⅳ）。Ang Ⅱ和 Ang Ⅲ与脑 Ang Ⅱ受体的亲和力相似，均可通过激活交感神经活性、在孤束核水平抑制压力反射，以及增加血液中精氨酸加压素浓度而引起血压升高。在动物实验中，脑室注射选择性 APA 抑制剂 EC33 能够引起血压下降，提示EC33 可阻滞 Ang Ⅲ的压力反射，相较于脑中 AngⅡ，Ang Ⅲ的升压作用更强。新型氨基肽酶 A 抑制剂 Firibastat 是美国 Quantum Genomics 制药公司开发的一种首创降压药，该药物通过在大脑中递送EC33产物，特异地抑制氨基肽酶 A，从而减少 Ang Ⅲ的产生，起到降低血压作用。研究表明，它可以通过降低全身加压素水平、降低交感神经张力和刺激压力反射来降低血压。一项多中心、开放标签2b期研究纳入256名原发性高血压患者，证明Firibastat是有效的。然而，在一项多中心（11个国家，75家中心）、随机、双盲、安慰剂对照、Ⅲ期研究（FRESH试验）中，未能证实Firibastat能够有效降低难治性高血压患者AOBP结果；所有亚组与次要终点的结果是一致的；Firibastat组患者耐受性良好，最常见的不良反应为皮肤反应，发生率为5.1%。结语随着老龄化的加剧，我国高血压的发病率将越来越高，国家已通过带量采购降价、加快纳入医保目录的速度及鼓励新药研发等举措提高高血压药物的可及性。总体来看，近年开展的带量采购对抗高血压仿制药市场影响巨大，而目前该领域仍存在未满足临床需求，Aprocitentan 的成功获批，标志着高血压治疗领域新药研发曙光初现，未来可期。版权声明：本文转自药融云，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 活动推荐  5月 • 第八届大湾区生物医药创新者峰会  关键词：  小分子，XDC，多肽及GLP-1热点话题，80+行业专家（点击下方图片查看详情）▼【关于药融圈】药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。