The University of Texas Southwestern Medical Center

For the second time in five years, an FDA advisory committee voted against endorsing the benefit-risk profile of Lexicon’s drug sotagliflozin. The Endocrinologic and Metabolic Drugs Advisory Committee voted 11-3 against the drug, an SGLT2 inhibitor the company has proposed as an adjunct to insulin to improve glycemic control in adults with type 1 diabetes and chronic kidney disease. The same adcomm in January 2019 voted 8-8 on the benefit-risk profile of sotagliflozin in type 1 diabetes, and the FDA rejected the application about three months later, saying it found an unacceptable level of risk of diabetic ketoacidosis (DKA) compared with the drug’s benefit. Kicking off the meeting, Lexicon CMO Craig Granowitz explained that the indication the company is seeking is a slight tweak from the last time around, this time for a “high-risk population where the benefit-risk assessment is different” than type 1 diabetics. FDA’s Justin Penzenstadler presented part of the agency’s side, discussing how the available data “do not provide reassurance that the magnitude of the DKA risk observed” in the clinical trial program applies to patients with type 1 diabetes and chronic kidney disease. Committee members voting against Lexicon questioned whether there were enough new data. Panelist Prabir Roy-Chaudhury, co-director of the University of North Carolina Kidney Center, was one of three votes in favor of sotagliflozin because he said he thinks “it’s important to live in a big bubble, and I do believe risk mitigation strategies will work.” Earlier in the day, following the FDA’s and Lexicon’s presentations, committee members’ discussions generally expressed uncertainties on DKA risks and the magnitude of clinical benefit. Committee panelist Thomas Wang of the University of Texas Southwestern Medical Center said he didn’t see enough new prospective data from Lexicon. There’s an unmet clinical need but there’s so much uncertainty on the benefit and risk side, he said. The FDA in its briefing documents similarly raised repeat safety and efficacy questions , questioning the use of post-hoc analyses from three Phase 3 clinical trials. Since the rejection five years ago, the FDA and Lexicon have gone back and forth over a path forward in type 1 diabetes. In May 2022, the drug was approved for use in adults with type 2 diabetes who have chronic kidney disease and other cardiovascular risk factors, to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visits. It’s sold under the brand name Inpefa. In December, the FDA told Lexicon that for the new indication it needed to provide a rationale for its proposed chronic kidney disease population, “with statistically and clinically meaningful evidence of glycemic control.” The FDA often follows the advice of its adcomms although it isn’t required to.

想象一下，如果有一种技术能够直接修改我们的DNA，从而治愈或预防那些目前无法治疗的遗传性疾病，那该有多好？这不再是科幻小说中的情节，而是现实中的基因编辑疗法。通过精确地编辑基因组，我们可以修正或消除有问题的基因，为遗传性疾病提供长效的治疗方法。 去年，美国食品药品管理局（FDA）批准了一种使用CRISPR技术治疗镰状细胞病的基因编辑疗法，这是基因编辑领域的一个重要里程碑。然而，大多数这类疗法都需要进行昂贵且耗时的干细胞移植过程：从患者体内提取干细胞，对其进行基因修饰以修复缺陷，然后再将这些经过修饰的干细胞重新输回患者体内。这种方法虽然有效，但成本高昂且操作复杂。 那么，有没有一种方法可以直接在患者体内对干细胞进行基因修饰，而不需要将它们取出呢？德克萨斯大学西南医学中心的研究人员正在为此努力，并取得了一些令人兴奋的进展。 他们在Science期刊上发表了题为“In vivo editing of lung stem cells for durable gene correction in mice”的研究成果。 研究人员开发了一种新型脂质纳米颗粒（Lipid Nanoparticles, LNP），这种纳米颗粒可以有效地将基因编辑分子递送到特定器官，特别是肺部。他们发现，使用这种纳米颗粒进行一次性治疗后，小鼠肺部的基因编辑效果可持续近两年时间。此外，这项技术还有望校正囊性纤维化中的一种无法治疗的突变。 选择性器官靶向纳米颗粒 由于mRNA COVID-19疫苗的成功，脂质纳米颗粒成为一种流行的药物递送方法。传统脂质纳米颗粒通常由四种不同的脂质组成，包裹着治疗货物。然而，这些纳米颗粒在输注到人体后，往往会集中在肝脏中。这是因为传统的脂质纳米颗粒与低密度脂蛋白（Low-Density Lipoprotein, LDL）非常相似，而LDL会自然进入肝脏被分解。 为了克服这一局限，Siegwart及其团队开发了一种新型纳米颗粒，称为选择性器官靶向（Selective Organ Targeting, SORT）纳米颗粒。除了传统的四种脂质外，SORT纳米颗粒还含有一种特殊的第五种脂质，这种脂质可以引导纳米颗粒到达特定器官。第五种脂质改变了SORT纳米颗粒的物理和化学特性，并吸引不同的血浆蛋白附着在其表面，从而影响不同组织对纳米颗粒的摄取。 长期肺部编辑 将脂质纳米颗粒送到正确的器官只是第一步，更重要的是要确保它们能够靶向正确的细胞类型，尤其是干细胞和祖细胞。这些细胞可以分化成多种类型的细胞，因此对它们进行基因编辑可以实现持久的效果。 为了验证SORT纳米颗粒是否能在肺部实现持久的基因编辑，研究人员使用了一种基因工程小鼠模型。这种小鼠具有制造红色荧光蛋白的能力，但前提是其基因组以特定方式被编辑。通过注射充满基因编辑分子的SORT纳米颗粒，并在注射后的多个时间点评估肺组织，研究人员发现，在每个时间点，红色荧光均匀分布在肺部，表明基因编辑持续存在。 在铜绿假单胞菌感染小鼠的肺部中SORT脂质纳米颗粒介导的基因编辑 在囊性纤维化模型中进行评估 有了这种实现长期基因编辑的方法，研究人员将目光转向了囊性纤维化。囊性纤维化是由氯泵（一种调节细胞内外盐浓度的蛋白质）突变引起的。当这种蛋白质发生故障时，会导致肺部积聚黏稠的粘液，引发一系列呼吸问题、感染和持续性肺损伤。 大约90%的囊性纤维化患者可以通过一种突破性的药物来改善症状，但对于某些基因突变导致无功能截短蛋白的患者来说，目前还没有有效的治疗方法。研究人员使用SORT纳米颗粒装载了一种基因编辑器，可以校正这种突变，将截短的氯泵变成正常的版本。实验结果显示，这种纳米颗粒可以在近50%的肺干细胞中实现基因校正，恢复氯泵50%以上的功能。 未来展望 这些早期研究结果表明，这种技术有朝一日可能彻底改变囊性纤维化患者的日常生活。尽管还需要更多的动物模型研究和临床试验，但这项技术为遗传病患者带来了新的希望。正如美国国家生物医学成像与生物工程研究所的Jermont Chen博士所说：“通过对标准脂质纳米颗粒的巧妙改良，该团队为肺部体内基因编辑平台奠定了基础，并有可能将其应用于其他组织。这项研究中描述的方法有可能为遗传病患者带来长效治疗。” 总之，这项研究不仅展示了基因编辑技术的巨大潜力，还为未来的医疗创新提供了新的方向。随着更多研究的推进，我们有望看到更多遗传性疾病得到根治，为患者带来更健康、更美好的生活。 参考资料： Yehui Sun et al. In vivo editing of lung stem cells for durable gene correction in mice. Science, 2024, doi:10.1126/science.adk9428. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

Chaired by founder Stephen Birrell, MD PhD, group includes experts in breast cancer biology, endocrine signaling and biomarker-driven risk reduction strategies BOULDER, Colo.--(BUSINESS WIRE)--Havah Therapeutics, a clinical stage biopharmaceutical company developing innovative, proprietary hormonal implant therapies for prevention and treatment of breast cancers, announced the formation of their Clinical Advisory Board Chaired by Havah Therapeutics founder Stephen Birrell, MD, PhD. “The scientific and clinical guidance of this esteemed group will be invaluable as we advance our androgen targeted therapy into late-stage clinical studies for Ductal Carcinoma In-Situ (DCIS) and investigator-sponsored combination studies in more advanced disease,” said, Matthew Brewer, CEO of Havah Therapeutics. Shelley Hwang, MD, MPH, Breast Cancer Research Foundation (BCRF) Investigator and internationally recognized expert in pre-invasive disease and DCIS, added: “I am thrilled to be involved with Havah Therapeutics at this critical stage of their development. Insights gained from their ongoing Phase 2 study ( RECAST DCIS ), coupled with my experience as the principal investigator of the COMET Study , will potentially enable the company’s androgen receptor targeting therapy to provide a much needed treatment alternative to invasive surgery and radiation treatment.” The members of Havah Therapeutics’ Clinical Advisory Board include: Stephen Birrell, MD, PhD (Chair), is founder of Havah Therapeutics and Chief Medical Officer of Wellend Health, an Australia-wide clinic that specializes in breast hormone-health, women at high-risk breast cancer and clinical trials. He is a Clinical Affiliate academic at the University of Adelaide Dame Roma Mitchell Cancer Research Laboratories. Shelley Hwang, MD, MPH is the Mary and Deryl Hart Distinguished Professor of Surgical Oncology and Radiology, Vice Chair of Research and Disease Group Leader for the Breast Cancer Program at Duke University Comprehensive Cancer Center. Her research focus includes breast cancer prevention, identifying less invasive treatments for early-stage breast cancers including DCIS and addressing and mitigating health care disparities in breast cancer. Seema A. Khan, MD is Professor of Surgery in the Feinberg School of Medicine at Northwestern University, and the Bluhm Family Professor of Cancer Research. She is the Co-Leader of the Cancer Prevention Research Program at the Robert H. Lurie Comprehensive Cancer Center. Her research focuses on applying biomarker knowledge to improve breast cancer risk stratification and develop preventive interventions for high-risk women. Her research is funded by the National Institutes of Health, The Breast Cancer Research Foundation, the Avon Foundation, and the Susan G. Komen Foundation Professor Wayne Tilley, PhD is the Inaugural Director of the Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide. He completed a Fellowship at UT Southwestern in Dallas Texas in the late 1980s where he was one of the first to clone the human androgen receptor (AR) with Professor Jean Wilson, MD. A current major research focus of Professor Tilley’s lab is the development of new treatments for breast cancer that stimulate the tumor suppressive activity of the AR in the breast (Nature Medicine 2021; Lancet Oncology 2024) to counter the proliferative effects of estrogen. Additional background information on the CAB members can be found on the company’s website: About RECAST DCIS Havah Therapeutics is currently participating in the Re-Evaluating Conditions for Active Surveillance Suitability as Treatment: Ductal Carcinoma In Situ (RECAST DCIS), a Phase 2 platform study aimed at preventing the progression of DCIS to breast cancer. Havah Therapeutics’ HAVAH T+Ai™, a proprietary combination of testosterone (T) and anastrozole (Ai) that targets the androgen and estrogen receptor pathways, is being evaluated alongside two other endocrine therapy arms. About Havah Therapeutics Havah Therapeutics is developing a novel therapeutic implant for treating hormonally sensitive cancers and other breast conditions. This groundbreaking method relies on stimulating (agonizing) the androgen receptor in breast tissue, utilizing natural hormonal mechanisms to treat patients safely and with greatly reduced side effects. The product is a combination of two registered agents (testosterone and anastrozole, a low dose aromatase inhibitor) that when dosed, provides three months of continuous medication enabling a superior product pro compliance, safety and efficacy. For more information, visit . Contacts Media Contacts: Matthew Brewer mb@havahtx.com Danielle Clark-Brown dcb@havahtx.com