Neonatal diabetes mellitus

Amglidia® has been approved by the European Medicines Agency (EMA) and is commercially available in EuropeStrong strategic fit with Eton’s existing pediatric endocrinology focusAmglidia has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA)Potential New Drug Application (NDA) submission in 2026 DEER PARK, Ill., Nov. 25, 2024 (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 announced that it has acquired the U.S. rights to Amglidia (glyburide oral suspension, known as glibenclamide in Europe) for the treatment of neonatal diabetes mellitus from AMMTeK. “This exciting transaction adds another attractive, patented product candidate to our growing pediatric endocrinology portfolio. In addition, the product aligns with Eton’s expertise and wealth of experience in bringing to market liquid and precision dose formulations for pediatric patients,” said Sean Brynjelsen, CEO of Eton Pharmaceuticals. “Currently, there are no FDA-approved oral treatments for neonatal diabetes mellitus. Amglidia has been used successfully to treat European patients for years, and families and pediatric endocrinologists have expressed to us the significant need for this treatment in the United States. We look forward to working with AMMTeK to bring the product to U.S. patients as quickly as possible,” concluded Brynjelsen. Amglidia is a proprietary, patented liquid product that was developed for the treatment of neonatal diabetes mellitus by AMMTeK, a French biotechnology company. The product was approved by the EMA in 2018. The product has already been granted Orphan Drug Designation by the U.S. FDA. Neonatal diabetes mellitus is a rare condition estimated to impact approximately 300 patients in the United States. Currently, there are no FDA-approved oral treatment options and as a result, U.S. patients frequently either rely on compounded products that are not FDA-approved or administer products off-label by making homemade suspensions. AMMTeK has conducted a post-approval study tracking five years of real-world safety and efficacy in European patients, which will be used to support Eton’s NDA submission. Eton plans to hold a meeting with the FDA in the first quarter of 2025 and anticipates submitting an NDA for the product in 2026. About Eton Pharmaceuticals Eton is an innovative pharmaceutical company focused on developing and commercializing treatments for rare diseases. The Company currently has five commercial rare disease products: ALKINDI SPRINKLE®, PKU GOLIKE®, Carglumic Acid, Betaine Anhydrous, and Nitisinone. The Company has three additional product candidates in late-stage development: ET-400, ET-600, and ZENEO® hydrocortisone autoinjector. For more information, please visit our website at www.etonpharma.com. Forward-Looking Statements Statements 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

Neonatal diabetes mellitus affects an estimated 300 individuals in the US. Credit: July Semianovich/Shutterstock. Eton Pharmaceuticals has acquired the US rights to Amglidia, a treatment developed for neonatal diabetes mellitus, from France-based biotechnology company AMMTeK. Amglidia, also known as glibenclamide in Europe, is a patented liquid product and was approved by the European Medicines Agency in 2018. The move is set to align with Eton Pharmaceuticals’ focus on paediatric endocrinology. The product also holds an orphan drug designation from the US Food and Drug Administration (FDA). AMMTeK’s post-approval study, which includes five years of real-world data on efficacy and safety from European subjects, is set to back Eton Pharmaceuticals’ new drug application submission. Eton Pharmaceuticals plans to meet with the FDA in the first quarter of 2025 and submit the NDA in 2026. Eton Pharmaceuticals CEO Sean Brynjelsen stated: “This exciting transaction adds another attractive, patented product candidate to our growing paediatric endocrinology portfolio. “The product aligns with Eton’s expertise and wealth of experience in bringing to market liquid and precision dose formulations for paediatric patients. Currently, there are no FDA-approved oral treatments for neonatal diabetes mellitus. “Amglidia has been used successfully to treat European patients for years, and families and paediatric endocrinologists have expressed to us the significant need for this treatment.” Neonatal diabetes mellitus affects an estimated 300 individuals in the US. Eton Pharmaceuticals acquired the US rights to PKU GOLIKE from Relief Therapeutics in March 2024. PKU GOLIKE is a medical formula product for the dietary management of phenylketonuria (PKU), using patented Physiomimic technology. In November 2021, the FDA approved Eton Pharmaceuticals and Azurity Pharmaceuticals’ Eprontia (topiramate) oral solution for seizures and migraine treatment.

CDS微专辑 扫描二维码 可查看更多内容 编者按 单基因糖尿病作为早发糖尿病中的一个重要类别，其患病率正在逐步攀升，而针对这一疾病的流行病学研究仍需进一步深化。在诊治早发糖尿病的过程中，识别单基因糖尿病至关重要，以便能够及时做出准确的诊断，并制定出适合患者的个性化治疗方案。近日，中华医学会糖尿病学分会第二十六次学术会议顺利召开，北京协和医院内分泌科肖新华教授就早发糖尿病人群单基因糖尿病的流行病学进行分析，旨在为单基因糖尿病的防治提供指导！ 肖新华 教授 北京协和医院内分泌科 医学博士 主任医师 教授 博士导师 中国研究型医院学会糖尿病学专委会主任委员 中华医学会糖尿病学分会常委兼副秘书长，糖尿病营养学组组长 中国老年保健协会糖尿病分会会长 北京医学会糖尿病分会候任主任委员 中国代谢病防治协同创新平台副理事长 中国中西医结合学会内分泌专业委员会副主任委员 荣获2020年首届“人民好医生-科技创新典范奖”  荣获2021年度医师报中国十大医学影响力专家 兼任《中华糖尿病杂志》副总编辑，《医学参考报 . 内分泌专刊》副主编、《Diabetes Research and Clinical Practice》中文版副主编 在PNAS, Diabetes Care和Metabolism 等发表Sci文章150余篇，主持申请多项国家级科研课题，获省部级科技成果奖5次 任国家科技奖评审专家，国家自然基金评审专家，北京市科学技术奖励评审专家 主要研究方向糖尿病发病机制及早期防治，特殊糖代谢异常分子遗传学研究。 一、与晚发糖尿病相比，早发糖尿病病理生理机制存在差异 根据国际糖尿病联盟（IDF）发布的地图数据，2021年全球约有5.37亿成年人（20至79岁）患有糖尿病，患病率高达10.5%[1]。值得注意的是，早发糖尿病患者的比例也不容小觑，全球20~39岁人群中糖尿病的患病率从2013年的2.9%上升到了2021年的3.8%，而我国2018年18~39岁人群的糖尿病患病率约为6.0%[2]。 早发糖尿病指的是40岁之前被诊断的糖尿病。与晚发糖尿病相比，早发糖尿病人群的β细胞功能下降更快，每年β细胞功能损失约25%~30%；遗传背景更强，罕见变异相关性增加5倍，常见变异相关性增加3.4倍；微血管并发症、大血管并发症和死亡风险更高；生活方式干预或二甲双胍单药治疗血糖控制率均较低（图1）[3-9]。早发糖尿病的危险因素众多，包括遗传、心理健康、活动量下降和环境等，可根据病因学将其分为1型糖尿病（T1DM）、2型糖尿病（T2DM）和单基因糖尿病等[10,11]。 图1. 早发糖尿病与晚发糖尿病的病理生理机制存在差异 二、单基因糖尿病是早发糖尿病的重要组成部分 单基因糖尿病是在胰岛β细胞发育、功能或胰岛素信号通路中起关键作用的单个基因突变导致的一种特殊类型糖尿病[11]，约占所有糖尿病的1%~5%，在我国大约有800万人患病。约80%单基因糖尿病患者被误诊为T1DM或T2DM，且近70%单基因糖尿病患者没有得到有效的治疗[12,13]。单基因糖尿病主要包括4类——青少年起病的成人型糖尿病（MODY)、新生儿糖尿病（NDM)、线粒体糖尿病（MDM）和糖尿病相关遗传综合征[14]，且不同类型单基因糖尿病致病基因不同（图2）[11]。 图2. 单基因糖尿病相关基因 三、探究相关流行病学，助力早期识别单基因糖尿病 临床发现，糖尿病具有重叠的多基因易感性和潜在病因（图3），很难定义对治疗具有巨大影响的离散临床亚型，因此从早发糖尿病人群中识别单基因糖尿病对于患者的个体化精准治疗至关重要。 图3. 单基因糖尿病发病机制相关基因具有重叠性 01 早发糖尿病中MODY的流行病学研究 美国一项纵向队列研究（SEARCH研究），分析了<20岁的糖尿病患者中MODY的患病率、临床特征及治疗情况。研究结果显示，8%的患者被诊断为MODY，而93.6%的MODY患者被误诊，其中36%误诊为T1DM，51%误诊为T2DM。MODY患者诊断年龄较小，BMI Z值、腰围、黑棘皮症率、空腹C肽和CRP等均较低，但胰岛素敏感性指数较高[14]。美国另一项纵向队列研究（TODAY研究），分析了10-17岁临床诊断T2DM且肥胖的患者中单基因糖尿病的患病率、临床特征及治疗情况。结果显示，4.5%的患者被诊断为MODY，且BMI Z值和空腹胰岛素更低，空腹血糖和总胆固醇更高，其中HNF4A-MODY患者在两年的随访中治疗失败率*（85.7%）最高[15]。此外，美国最新的纵向队列研究（ProDiGY研究）也分析了单基因糖尿病的患病率、临床特征及治疗情况。研究结果显示，2.8%的患者被诊断为MODY，且诊断年龄较小，空腹C肽更低，HDL-C更高（图4），高血压风险更低（5.9% vs 17.5%），同胞患糖尿病的比例增加（17.1% vs 9.8%）。其中65.2%的GCK-MODY患者已接受药物治疗，89.7%的HNF1A-MODY和HNF4A-MODY患者接受胰岛素/二甲双胍治疗[16]。 *治疗失败定义为连续6个月糖化血红蛋白≥8.0 %或因急性代谢失代偿治疗后3个月内无法停用胰岛素 图4. ProDiGY研究中MODY患者的基因突变谱和临床特征 此外，中国的几项研究也探究了早发糖尿病中MODY的流行病学。一项队列研究发现，在1个月~18岁的糖尿病或空腹血糖受损儿童中，3.1%的患者被诊断为MODY，其中83%为GCK-MODY[17]。而另一项横断面研究则显示，在15~45岁临床诊断T2DM的患者中，0.74%的患者被诊断为MODY，其中HNF1A-MODY、GCK-MODY和HNF4A-MODY占77.8%，且仅27.8%MODY患者≤35岁，38.9%有糖尿病家族史[18]。香港糖尿病登记册（HKDR研究）显示，早发糖尿病中单基因糖尿病患病率为2.2%，在30岁以下起病的患者中，单基因糖尿病患病率为4.1%，而在20岁以下起病的患者中，单基因糖尿病患病率为10.6%，其中HNF1A-MODY、GCK-MODY和HNF4A-MODY占81.8%。单基因糖尿病患者诊断年龄更小，代谢特征更好，BMI、LDL-C和TG更低，但在性别分布和糖尿病家族史方面与非单基因糖尿病患者没有显著差异，且2例（9.1%）单基因糖尿病患者GAD抗体阳性。在17年的中位随访期间，单基因糖尿病患者发生心血管疾病、终末期肾病和全因死亡的风险与非单基因糖尿病患者相似（图5）[19]。 图5. HKDR研究中单基因糖尿病患者的临床结局 02 早发糖尿病中MDM的流行病学研究 MDM是由于线粒体功能缺陷引起的糖尿病，包括线粒体基因突变型糖尿病和核基因突变型糖尿病，又名母系遗传糖尿病伴耳聋（MIDD）。MDM患病率较低，约占全球糖尿病患者的3%。MDM患者常表现为发病年龄<40岁，体型消瘦，病程短，病程中出现胰岛β细胞分泌功能进行性减退，需要尽快进行胰岛素治疗，合并其他多系统表现（中枢神经系统病变、心肌病、骨骼肌肌力减低），存在母系遗传家族史[20,21]。 早期精准诊断MDM可尽早给予患者针对性治疗，对其他并发症（如耳聋、神经肌肉病等）进行筛查和治疗，对家庭成员进行产前诊断及遗传咨询。中国MDM研究结果显示，早发T2DM且具有糖尿病家族史的患者中，m.3243A>G突变携带率为1.8%，当限定母亲患有糖尿病后，m.3243A>G突变携带率升高至3%[22]。芬兰的两项研究显示，2007年儿童中MDM估计最低患病率为18.4人/10万人；2013年，在18~45岁糖尿病患者中，1%诊断为MDM（均为m.3243A>G）[23,24]。 四、探究聚类分型的遗传学基础，深化聚类分型为导向的精准医疗 为了探究聚类分型的遗传学基础，深化聚类分型为导向的精准医疗，北京协和医院肖新华教授团队牵头了北京市科委项目“早发糖尿病的病因学研究”，从北京9所医院招募1000例新诊断早发糖尿病患者，收集临床信息，留取血液样本，随机选择其中350例患者进行全外显子组测序，并进行聚类分析和生物信息学分析[25]。 基于年龄、BMI、HbA1c、HOMA2-IR、HOMA2-β、谷氨酸脱羧酶抗体（GADA）等指标进行聚类分型，将早发糖尿病人群分为5种： 严重自身免疫型（SAID）：GADA阳性、发病年龄较小、BMI较低、胰岛功能较差、代谢控制差 严重胰岛素缺乏型（SIDD）：GADA阴性、BMI较低、胰岛功能差、代谢控制差、视网膜病变风险高 严重胰岛素抵抗型（SIRD）：HOMA2-IR最高、BMI较高、非酒精性脂肪肝及慢性肾病风险高 轻度肥胖相关型（MOD）：BMI较高、代谢控制较好 轻度年龄相关型（MARD）：年龄较大、代谢控制较好 生物信息学分析发现，单基因糖尿病检出率为2.57%，MODY检出率为1.7%。SAID组和SIRD组均未检出致病或可疑致病的单基因糖尿病相关突变，MARD组致病或可疑致病的单基因糖尿病相关突变检出率最高。共检出3例MDM，均来自SIDD组，提示可能需在此类患者中关注糖尿病家族史及耳聋等合并疾病，以及时识别线粒体糖尿病。 传统的MODY诊断标准为发病年龄小于25岁、具有糖尿病家族史、体型非肥胖且不依赖胰岛素治疗[26]。最新ADA指南则指出，对于儿童期或者成年早期发病的以下糖尿病患者均需要考虑单基因糖尿病的可能[27]：起病年龄在6月龄前；无典型T1DM或T2DM特点；表现为轻度空腹血糖升高（5.6~8.5 mmol/L），HbA1c 5.6%~7.6%，特别是非肥胖的患者。因此，尽早识别早发糖尿病患者中的单基因糖尿病尤为重要，以便能够及时做出准确的诊断，并制定出适合患者的个性化治疗方案。 单基因糖尿病是早发糖尿病的重要组成部分，患病率逐渐升高。基于国内外单基因糖尿病流行病学研究结果，对于起病年龄早、有糖尿病家族史、不符合典型T1DM或T2DM疾病特点的患者，需要考虑单基因糖尿病。早期正确诊断单基因糖尿病，对于选择合理的个体化治疗方案、提高患者生活质量及改善预后至关重要。 参考文献 （上下滑动可查看） 1.IDF Diabetes Atlas, 10th ed; The Lancet Diabetes & Endocrinology, 2023, 11(10):768-782. 2.IDF Diabetes Atlas, 10th ed; JAMA, 2021, 326(24):2498-2506. 3.Diabetes Care, 2021, 44(9):1938-1947. 4.Diabetes, 2021, 70: 996–1005.  5.Nephrol Dial Transplant, 2020, 35(1):115-121. 6.Diabetes Res Clin Pract, 2011, 94(2):207-211. 7.Diabetes Care, 2021, 44(6):1426-1432. 8.Circulation, 2019, 139(19):2228-2237. 9.Diabetologia, 2021, 64(2):275-287.  10.The Lancet Diabetes & Endocrinology, 2023, 11(10):768-782.  11.Nat Rev Dis Primers. 2023;9(1):12. 12.Diabetologia, 2010, 53(12):2504–2508. 13.Diabetes Care, 2016, 39(11): 1879–1888.   14.J Clin Endocrinol Metab. 2013;98(10):4055-4062. 15.Genet Med, 2018, 20(6):583-590. 16.Diabetes care. 2021; 44(10):2312–2319. 17.Pediatr Diabetes, 2020, 21(3):431-440. 18.Chin Med J (Engl). 2023;136(1):56-64. 19.Diabetes Metab Res Rev. 2024;40(5):e3823.  20.中国2型糖尿病防治指南(2020年版),  中华糖尿病杂志, 2021, 13(4):315-409; 21.线粒体糖尿病临床检验诊断专家共识, 中华糖尿病杂志, 2021, 13(9):846-851. 22.Clin Endocrinol (Oxf), 2000, 52(5):557-564. 23.Ann Neurol, 2007, 62(3):278-287. 24.Acta Diabetol, 2013, 50(5):737-741. 25.Lancet Diabetes Endocrinol, 2018. 26.Diabetologia, 2012, 55(5):1231-4. 27.Diabetes Care, 2024, 47(Supplement_1): S20-S42. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！ （来源：《国际糖尿病》编辑部） 版权声明 版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。