Nitisinone

▎药明康德内容团队编辑疟疾是由疟原虫引起的致命传染病，通过雌性按蚊叮咬传播。据世界卫生组织统计，2021年全球有约61.9万人死于疟疾，这些不起眼的蚊子仍然是全球致死人数最多的动物。近年来，随着蚊子抗药性和疟原虫药物耐受性的增长，疟疾防控面临着新的挑战。例如在疟疾高发地区，蚊子对拟除虫菊酯类杀虫剂的抗性显著增加；疟原虫对青蒿素的耐药性也逐渐显现。在与蚊子的漫长斗争历史中，科学家们提出了一系列旨在减少蚊子数量、降低疟疾传播风险的策略。例如，清华合作团队就在一项《科学》研究中提出，可以通过向环境或蚊子吸食的植物中添加Rosenbergiella_YN46菌给蚊子“调理肠胃”，让蚊子变得“洁身自好”，避免携带和传播病毒。还有研究提出，可以通过阻断相应转运蛋白的功能，让蚊子停留在幼虫阶段，永远无法性成熟、繁殖后代。图片来源：123RF此外，科学家们也在探索体内外杀虫剂（endectocide）的灭蚊思路。这类可以同时对抗体内和体外寄生虫的药物通过口服或注射进入人体或动物体内，这时血液对蚊子来说就产生了毒性。当蚊子吸食了“有毒”的血液，它们的生理功能会受到干扰。这种策略不仅能直接减少蚊子的数量，还能阻断疟原虫在按蚊体内的发育周期，抑制疟疾传播。在本周的一篇《科学-转化医学》论文中，由利物浦热带医学院领衔的研究团队从一种诞生20多年的“老药”中，找到了高效、持久地抑制蚊子数量、帮助控制疟疾传播的潜在新药。尼替西农（nitisinone）在2002年获得美国FDA批准上市，用于治疗一种罕见的遗传疾病——1型遗传性酪氨酸血症（hereditary tyrosinemia type 1, HT-1）。这些患者缺乏酪氨酸降解途径中的最终酶，因此自身难以代谢酪氨酸。其中，中间产物的积累和进一步分解会导致肾脏与肝脏损伤。随着疾病的进展，HT-1患者可能出现肝细胞癌。如果不及时接受治疗，患者往往在24个月内面临死亡。尼替西农可以抑制4-羟基苯丙酮酸双加氧酶（HPPD），阻断酪氨酸代谢途径，避免有毒副产物在人体内积累。此外，尼替西农的“超适应症用药”（off-label use）还包括尿黑酸尿症（一种常染色体隐性遗传病）。之所以将这种老药与灭蚊联系在一起，是因为此前有研究发现，HPPD对吸血昆虫（如锥蝽、蜱虫）的生存至关重要，而尼替西农恰好可以通过干扰这一途径杀死昆虫。因此，研究团队提出猜想：尼替西农或许能成为更高效、持久的杀虫剂，帮助控制疟疾传播。为此，研究团队设计了一系列实验，从多个角度评估尼替西农的灭蚊效果。▲含有荧光染料的冈比亚按蚊（图片来源：Lee R. Haines）研究团队首先分析了不同浓度的尼替西农和体内外杀虫剂“黄金标准”——伊维菌素（ivermectin）对实验室培养的冈比亚按蚊的致死效果。尼替西农的绝对效力较低，但其血药浓度维持时间更长，也就是说杀蚊活性在人体内有着更长的循环时间。老年蚊子因寿命更长，更可能携带感染人类的成熟疟原虫。然而，传统杀虫剂对老年蚊子的效果通常较差。接下来的实验检验了两种杀虫剂对不同年龄蚊子的致死效果，发现尼替西农对老年蚊子的致死效果与年轻蚊子无显著差异，而伊维菌素对老年蚊子的效力明显下降。此外，研究团队还检验了尼替西农对抗药性按蚊的杀伤效果，这些蚊子对拟除虫菊酯、DDT等多种传统杀虫剂耐药。结果显示，尼替西农对耐药蚊子的致死率与敏感品系相当，表明其作用机制与传统杀虫剂不同，不易产生交叉抗性。为了评估尼替西农的实际应用潜力，研究团队模拟了低剂量给药方案。结果显示，单次口服0.1 mg/kg的尼替西农即可维持5天以上的灭蚊效果，而伊维菌素在同等剂量下几乎无效。研究团队还获得了服用低剂量尼替西农的尿黑酸尿症患者的血液样本。实验表明，这些患者的血液对蚊子具有显著毒性，即使稀释5倍仍能有效杀灭蚊子。由此，这一系列实验证实，尼替西农在人体血液中有着更长的半衰期，不仅能杀死最有可能传播疟疾的老年蚊子，还能杀死对传统杀虫剂有抗药性的蚊子。此外，即使是低剂量的尼替西农，也能产生良好的灭蚊效果。在研究团队看来，通过交替使用尼替西农和伊维菌素，或许能带来更加安全、有效的控蚊策略。当然，对于安全记录有限的尼替西农，还需要更多研究才能将其实际应用于疟疾高发地区。参考资料：[1] Lee R. Haines et al., Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone. Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adr4827本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

Management to Hold Investor Day Conference Call Today at 10:00am ET Reported record product revenue of $11.6 million in Q4 2024, an increase of 59% over Q4 2023, representing the 16th straight quarter of sequential product sales growthClosed the transformational acquisition of pediatric endocrinology biologic Increlex® and relaunched the product in JanuaryAcquired and relaunched ultra rare disease product Galzin®Licensed U.S. rights to late-stage pipeline candidate Amglidia®, further boosting the Company’s pediatric endocrinology pipelineAnnounced positive pivotal clinical study results for ET-600; preparing for an April 2025 NDA submissionManufactured ET-400 launch inventory in preparation for a potential approval on its PDUFA goal date of May 28Management to hold Investor Day conference call today at 10:00am ET to discuss its recent acquisitions and review its product portfolio, market opportunities, and 2025 and long-term financial outlook DEER PARK, Ill., March 18, 2025 (GLOBE NEWSWIRE) -- Eton Pharmaceuticals, Inc (“Eton” or “the Company”) (Nasdaq: ETON), an innovative pharmaceutical company focused on developing and commercializing treatments for rare diseases, today reported financial results for the quarter ended December 31, 2024. “The fourth quarter of 2024 was the most transformational in Eton’s history. We closed the pivotal acquisition of Increlex, acquired another high-value rare disease product in Galzin, and boosted our product pipeline with the license of Amglidia and initiation of two exciting new internal development projects, ET-700 and ET-800. We completed all this while continuing to execute on our base business, delivering record product sales and our 16th straight quarter of sequential revenue growth,” said Sean Brynjelsen, CEO of Eton Pharmaceuticals. “We are poised for an acceleration of growth in 2025. Increlex was relaunched in January with our now fully dedicated pediatric endocrinology sales force and is already adding new patients at a pace well ahead of our expectations. Galzin was relaunched in March with our newly deployed metabolic sales force and has been well received by the Wilson disease community. Launch inventory for ET-400 has been manufactured and our team stands ready to launch the product within days of its PDUFA goal date of May 28, if approved. Finally, ET-600’s successful pivotal study results allow us to file an additional high-value NDA in the coming weeks.” concluded Brynjelsen. Fourth Quarter and Recent Business Highlights Delivered 16th straight quarter of sequential growth in product sales. Eton reported fourth quarter 2024 net sales of $11.6 million, an increase of 59% over the prior year period, driven primarily by strong growth of ALKINDI SPRINKLE® and Carglumic Acid. The company expects sequential growth in quarterly product revenue to continue through 2025 and beyond. Relaunched Increlex, which is tracking ahead of expectations. Increlex is a highly durable, complex biologic used for the treatment of an ultra-rare pediatric endocrinology condition that is estimated to impact approximately 200 children in the U.S. Eton closed the acquisition in late December and relaunched the product in the United States in January. The Company intends to leverage its existing sales team and relationships in the pediatric endocrinology community to promote the product and increase awareness of this underdiagnosed and undertreated condition. The launch has seen strong initial results, with numerous new patients added in January, February, and the first half of March. Awarded second patent for ET-400 and preparing for potential launch. During the fourth quarter, Eton was granted an additional patent for ET-400 by the United States Patent & Trademark Office (USPTO). The patent, which expires in 2043, covers hydrocortisone oral liquid formulations and is expected to be listed in the FDA’s Orange Book upon approval. The Company has successfully manufactured launch quantities for the product and its sales and promotional campaigns are ready to go live. If approved on its May 28 Prescription Drug User Fee Act (PDUFA) goal date, the Company anticipates being in position to quickly launch the product. Acquired and re-launched Galzin. In January, Eton added the ultra-rare disease commercial product Galzin to its metabolic portfolio. Seeing the need for improved patient experience, increased awareness, and broader access and affordability, the Company relaunched Galzin on March 3 with its newly deployed metabolic sales force and robust Eton Cares patient support service. The Eton Cares patient support program ensures patients can access Galzin with $0 co-pays, patient assistance, reimbursement support, and overnight shipments. Announced positive pivotal study results for ET-600 and the issuance of a patent. ET-600 passed its pivotal bioequivalence study, successfully demonstrating pharmacokinetic equivalence to the reference product. In addition, the Company was issued a patent covering the product’s proprietary formulation of desmopressin oral solution. The patent expires in 2044 and is expected to be listed in the FDA’s Orange Book upon the product’s approval. Eton is preparing to submit an NDA for ET-600 in April, which could allow for approval in the first quarter of 2026. Disclosed two new internal development programs, ET-700 and ET-800. The Company has two new, high-value product candidates under development internally. More details regarding these previously undisclosed programs will be shared during Eton’s Investor Day conference call. Acquired U.S. rights to Amglidia (glyburide oral suspension). Amglidia, which has been approved in the E.U. since 2018, is under development in the U.S. for the treatment of neonatal diabetes mellitus and has been granted Orphan Drug Designation by the FDA. Amglidia is a strong strategic fit with Eton’s existing pediatric endocrinology portfolio, and the Company is scheduled to meet with the FDA in April 2025 to discuss the product’s clinical pathway. Fourth Quarter Financial Results Net Revenue: Total net revenues for the fourth quarter of 2024 increased 59% to $11.6 million compared to $7.3 million in the prior year period, driven primarily by growth in ALKINDI SPRINKLE and Carglumic Acid. The Increlex and Galzin acquisitions closed in late December and contributed less than $0.2 million of revenue during the fourth quarter. Gross Profit: Gross profit for the fourth quarter of 2024 was $6.5 million, compared to gross profit of $3.6 million for the fourth quarter of 2023. The increase was primarily due to increased product sales. In addition, fourth quarter 2023 gross profit was negatively impacted by $1.0 million as a result of ALKINDI SPRINKLE net sales triggering a one-time commercial success-based milestone under the terms of the product’s licensing agreement. Research and Development (R&D) Expenses: R&D expenses for the fourth quarter of 2024 were $(0.9) million compared to $1.0 million in the prior year period. During the fourth quarter of 2024, Eton’s ET-400 product was granted Orphan Drug Designation by the FDA, which resulted in Eton receiving a refund of the NDA filing fee that was paid and expensed in the second quarter of 2024. General and Administrative (G&A) Expenses: G&A expenses for the fourth quarter of 2024 were $6.7 million compared to $4.6 million in the prior year period. The increase was primarily due to personnel additions and increased sales and marketing investments that were initiated in the fourth quarter of 2024 to support the 2025 launches of Increlex, Galzin, and ET-400, as well as Increlex related transaction costs. Net Loss: Net loss for the fourth quarter of 2024 was $0.6 million or $0.02 per basic and diluted share compared to a net loss of $2.3 million or $0.09 per basic and diluted share in the prior year period. Cash Position: As of December 31, 2024, Eton had cash and cash equivalents of $14.9 million. Conference Call and Webcast InformationAs previously announced, Eton Pharmaceuticals will hold a virtual Investor Day and report fourth quarter 2024 financial results on Tuesday, March 18, 2025, beginning at 10:00 a.m. ET (9:00 a.m. CT).To participate, please click here to register. An archived webcast will be available on the Investors section of Eton’s website approximately two hours after the completion of the event and for 30 days thereafter.In addition to taking live questions from participants on the conference call, management will be answering emailed questions from investors. Investors can email questions to: investorrelations@etonpharma.com. About Eton PharmaceuticalsEton is an innovative pharmaceutical company focused on developing and commercializing treatments for rare diseases. The Company currently has seven commercial rare disease products: INCRELEX®, ALKINDI SPRINKLE®, GALZIN®, PKU GOLIKE®, Carglumic Acid, Betaine Anhydrous, and Nitisinone. The Company has six additional product candidates in late-stage development: ET-400, ET-600, Amglidia®, ET-700, ET-800 and ZENEO® hydrocortisone autoinjector. For more information, please visit our website at www.etonpharma.com. Forward-Looking StatementsStatements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements associated with the expected ability of Eton to undertake certain activities and accomplish certain goals and objectives. These statements include but are not limited to statements regarding Eton’s business strategy, Eton’s plans to develop and commercialize its product candidates, the safety and efficacy of Eton’s product candidates, Eton’s plans and expected timing with respect to regulatory filings and approvals, and the size and growth potential of the markets for Eton’s product candidates. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “believes,” “anticipates,” “plans,” “expects,” “intends,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Eton’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. These and other risks concerning Eton’s development programs and financial position are described in additional detail in Eton’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Eton undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Investor Relations:Lisa M. Wilson, In-Site Communications, Inc.T: 212-452-2793E: lwilson@insitecony.com Eton Pharmaceuticals, Inc.STATEMENTS OF OPERATIONS(In thousands, except per share amounts) For the three months ended For the years ended (Unaudited) December 31, December 31, December 31, December 31, 2024 2023 2024 2023 Revenues: Licensing revenue $— $— $500 $5,500 Product sales and royalties, net 11,647 7,313 38,511 26,142 Total net revenues 11,647 7,313 39,011 31,642 Cost of sales: Licensing revenue — 1,000 270 1,000 Product sales and royalties 5,171 2,683 15,330 9,581 Total cost of sales 5,171 3,683 15,600 10,581 Gross profit 6,476 3,630 23,411 21,061 Operating expenses: Research and development (871) 1,047 3,255 3,322 General and administrative 6,718 4,575 22,753 18,931 Total operating expenses 5,847 5,622 26,008 22,253 Income (loss) from operations 629 (1,992) (2,597) (1,192) Other (expense) income: Interest and other (expense) income, net (1,140) (17) (1,211) 503 Loss before income tax expense (511) (2,009) (3,808) (689) Income tax expense 87 247 15 247 Net loss $(598) $(2,256) $(3,823) $(936)Net loss per share, basic and diluted $(0.02) $(0.09) $(0.15) $(0.04) Weighted average number of common shares outstanding, basic and diluted 26,136 25,741 25,895 25,645 Eton Pharmaceuticals, Inc.BALANCE SHEETS(in thousands, except share and per share amounts) December 31, December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $14,936 $21,388 Accounts receivable, net 5,361 3,411 Inventories, net 15,232 911 Prepaid expenses and other current assets 5,492 1,129 Total current assets 41,021 26,839 Property and equipment, net 34 58 Intangible assets, net 34,881 4,739 Operating lease right-of-use assets, net 175 92 Other long-term assets, net 12 12 Total assets $76,123 $31,740 Liabilities and stockholders’ equity Current liabilities: Accounts payable $4,167 $1,848 Current portion of long-term debt, net of discount — 5,380 Accrued Medicaid rebates 6,866 3,627 Accrued liabilities 8,914 5,386 Total current liabilities 19,947 16,241 Long-term debt, net of discount and including accrued fees 29,811 — Operating lease liabilities, net of current portion 107 22 Other long-term liabilities 1,830 — Total liabilities 51,695 16,263 Commitments and contingencies Stockholders’ equity Common stock, $0.001 par value; 50,000,000 shares authorized; 26,709,084 and 25,688,062 shares issued and outstanding at December 31, 2024 and 2023, respectively 27 26 Additional paid-in capital 132,294 119,521 Accumulated deficit (107,893) (104,070)Total stockholders’ equity 24,428 15,477 Total liabilities and stockholders’ equity $76,123 $31,740 Eton Pharmaceuticals, Inc.STATEMENTS OF CASH FLOWS(In thousands) For the three months ended For the years ended (Unaudited) December 31, December 31, December 31, December 31, 2024 2023 2024 2023 Cash flows from operating activities Net loss $(598) $(2,256) $(3,823) $(936) Adjustments to reconcile net loss to net cash from operating activities: Stock-based compensation 782 750 3,165 3,137 Depreciation and amortization 355 325 1,146 901 Non-cash lease expense 17 17 70 67 Debt discount amortization 1,039 27 1,109 117 Changes in operating assets and liabilities, net of impact of product acquisitions: — — Accounts receivable (939) 84 (3,118) (1,559)Inventories (34) 140 (1,061) (354)Prepaid expenses and other assets (3,520) (655) (3,349) 94 Accounts payable 1,482 105 2,318 53 Accrued Medicaid rebates (1,181) 476 3,239 2,818 Accrued liabilities 2,043 1,374 1,484 2,477 Other non-current assets and liabilities 38 — 38 — Net cash from operating activities (516) 387 1,218 6,815 Cash from investing activities Purchases of property and equipment (12) — (26) — Acquisition of business (30,000) — (30,000) — Purchase of product licensing rights (8,369) (775) (10,237) (775)Net cash from investing activities (38,381) (775) (40,263) (775) Cash flows from financing activities Net proceeds from the issuance of long-term debt 25,309 — 25,309 — Repayment of long-term debt — (385) (1,155) (1,155)Common stock issued in private placement offering 7,000 — 7,000 — Proceeds from stock option exercises 1,015 — 1,191 148 Payment of tax withholding related to net share settlement of stock option exercises — — — (180)Employee stock purchase plan 108 91 248 229 Stock warrant exercises — — — — Net cash from financing activities 33,432 (294) 32,593 (958) Change in cash and cash equivalents (5,465) (682) (6,452) 5,082 Cash and cash equivalents at beginning of period 20,401 22,070 21,388 16,305 Cash and cash equivalents at end of period $14,936 $21,388 $14,936 $21,388 Supplemental disclosures of cash flow information Cash paid for interest $140 $204 $665 $842 Cash paid for income taxes $(99) $247 $82 $247 Supplemental disclosures of non-cash investing and financing activities: Debt issuance costs $386 $— $386 $— Fair value of warrants issued in connection with debt agreement $— $— $1,171 $— Right-of-use assets obtained in exchange for lease liabilities $66 $— $219 $29