TAFAZZIN

In 2 Months, Petition Garnered Nearly 20,000 Signatures from Individuals in All 50 U.S. States BOSTON, Dec. 21, 2023 /PRNewswire/ -- The Barth Syndrome Foundation (BSF), the only patient advocacy organization dedicated to Barth syndrome and saving lives around the world through education, advances in treatment and finding a cure, today announced that it is petitioning the U.S. Food and Drug Administration (FDA) to review the New Drug Application (NDA) for elamipretide, the only potential treatment for Barth syndrome, in a fair, equitable and appropriate manner. Despite compelling evidence that elamipretide has been well-tolerated and has demonstrated clinical benefit in Barth syndrome, and despite ongoing efforts by the Barth Syndrome Foundation and other advocates to engage with regulators, the FDA has refused to review an NDA to date. The petition ran from mid-September to mid-November, and in just two months, garnered nearly 20,000 signatures from individuals across all 50 U.S. states, plus Washington, DC, Puerto Rico, the U.S. Virgin Islands and deployed military personnel. Continue Reading Kate McCurdy, board chair of Barth Syndrome Foundation, poses for a portrait, while holding a petition with nearly 20,000 signatures requesting the U.S. Food and Drug Administration (FDA) to review the New Drug Application (NDA) for elamipretide, the only potential treatment for Barth syndrome, at the FDA White Oak Campus in Silver Spring, Maryland, USA, on Thursday, December 21, 2023. (Barth Syndrome Foundation/Eric Lee) Learn more at nottooraretocare.org Barth syndrome is an ultra-rare, life-threatening, genetic disease primarily affecting males. Eighty-five percent of deaths due to Barth syndrome occur by age 5. There are currently no FDA-approved treatments for Barth syndrome, and there are no other potential therapies in clinical development. "For many Barth syndrome families, elamipretide represents their only hope for an affected child to have an increased chance to live into adulthood and to enjoy a life with reduced debilitating weakness and fatigue that precludes them from going to school, playing with friends, or holding a job," said Kate McCurdy. As co-founder and Chair of the Board of BSF, she hand-delivered the petition to Dr. Norman Stockbridge, Director of the Division of Cardiology and Nephrology, and Dr. Hylton Joffe, Director of the Office of Cardiology, Hematology, Endocrinology and Hematology at FDA, which refused to review the elamipretide NDA in 2021. McCurdy continued: "We lost our son, Will, to this devastating disease in 2014, the same year BSF approached Stealth to ask that they initiate development efforts. During the 10 years, 2 clinical trials, and 2 dozen FDA meetings since then, over 10% of our global patient population have died as the result of this disease. Meanwhile, elamipretide has been shown to be well-tolerated and has demonstrated clear, statistically significant improvements relative to the natural history of the disease. Patients who have no approved treatment options deserve access to this medicine. It is unconscionable that the FDA refuses to even fully review the data. We implore them to be fair and equitable and to utilize the appropriate flexibility that has been granted to them by the US Congress for cases just like ours." The Barth Syndrome Foundation and leading scientific thought leaders lobbied for the development of elamipretide for Barth syndrome beginning in 2014. After completing promising nonclinical studies, and publication of extensive natural history studies characterizing the disease in more than 50% of the U.S. Barth syndrome patient population, the sponsor, Stealth BioTherapeutics, agreed to start development efforts in 2016. Since Barth Syndrome Foundation and the sponsor met with FDA to discuss the clinical data in 2019, FDA has moved the program through four different FDA review divisions, rejected multiple proposed new trial protocols, and most recently this summer said there is no feasible path forward for development because there are too few patients to enroll in clinical trials. "People with Barth syndrome have experienced greater than 40% improvement in heart function, greater than 25% improvement in exercise tolerance, and greater than 40% improvement in muscle function, none of which is expected in the natural course of Barth syndrome," said Emily Milligan, Executive Director of BSF. "This has helped make transformational and meaningful changes in their lives. There simply aren't enough people with Barth syndrome, though, to meet the impossible statistical requirements of the FDA to give elamipretide a full drug review. In our many meetings with Congress, we have been assured that the FDA has the regulatory flexibility to review these data, yet they have not used it. This is a systemic problem affecting all who seek treatments for ultra-rare diseases. Every patient – no matter how rare their disease – deserves a chance at fulfilling, longer life. We are not too rare for care." The patient community is also concerned that the boys and young men currently receiving elamipretide under an expanded access protocol will lose access to the drug if the FDA fails to act. For Jamie Dubuque, a young mother whose one-year-old son Declan experienced an unprecedented heart recovery while receiving elamipretide treatment through emergency access, the prospect of losing access is incredibly frightening. "At 11 months old, my son Declan experienced life-threatening acute heart failure. He was admitted to a pediatric intensive care unit, placed on a ventricular assist device that helped pump blood for his failing heart, and was listed for a heart transplant. His doctors indicated his native heart would not recover sufficiently and a transplant was the only course of action," said Jamie Dubuque. Dubuque continued: "To help him survive until the transplant could take place, Declan was placed on emergency access elamipretide. Less than three months after starting elamipretide, Declan's heart structure and function improved more than doctors ever expected, and he regained strength and energy. After nearly eight months on elamipretide, Declan's ventricular assist device was removed, and he was discharged from the hospital without requiring a heart transplant. His doctors credit elamipretide with making the difference. For Declan, now nearly 2 years old, and other clinical trial patients who are still on elamipretide, we need the FDA to act now and see the inevitable pain we'd face otherwise." In addition to delivering the petition to FDA, BSF is spearheading a grassroots advocacy campaign called "Not Too Rare to Care" to raise awareness about Barth syndrome and the community's advocacy for a fair review of the only potential treatment for this rare condition. Barth syndrome is a rare, X-linked genetic disorder with an estimated incidence of only 1 in 1 million live births. Caused by a mutation in the TAFAZZIN gene, also called G4.5, that results in an inborn error of phospholipid metabolism, Barth syndrome affects many systems of the body and is characterized by cardiac abnormalities often leading to heart failure and reduced life expectancy, recurrent infections, muscle weakness and delayed growth. Barth syndrome can be fatal in childhood due to heart failure or uncontrollable infection, with approximately 50 percent of deaths due to Barth syndrome occurring within the first year of life and 85 percent before the fifth year of life. Those who survive to adulthood have a severely reduced life expectancy and typically experience compromised physical health with medical conditions that can become life-threatening with little or no warning. About Barth Syndrome Foundation (BSF) Barth Syndrome Foundation and our international affiliates comprise the only global network of families, healthcare providers, and researchers solely driven by the mission to save lives through education, advances in treatment and finding a cure for Barth syndrome. Considered a role model in rare disease advocacy, BSF has funded $6.2M USD and catalyzed over $33M USD in funding from other sources to advance global scientific discoveries to end the suffering and loss of life from Barth syndrome. Additionally, BSF provides a lifeline to families and individuals living with Barth syndrome around the world, offering individualized support, educational conferences, a patient registry and collaborations with specialist healthcare providers to define standards of care, treatment and rapid diagnosis. SOURCE Barth Syndrome Foundation

在发表于《自然代谢》的一篇论文中，匹兹堡大学的研究人员详细介绍了一个潜在的新靶点和一种小分子候选药物，可以用于治疗巴氏综合征。这是一种罕见的、危及生命且目前无法治愈的遗传性疾病，具有毁灭性的后果。 全球每30-40万名新生儿中，就约有1人患有巴氏综合征。该疾病患者的肌肉和心脏都很虚弱，会感到疲劳和反复感染。 匹兹堡大学的研究人员发现，有缺陷的线粒体是导致该疾病的部分“罪魁祸首”。他们通过研究，确定了一个有望逆转疾病进程的分子靶点。 该项研究的资深作者、匹兹堡大学公共卫生学教授Valerian Kagan博士解释说，在健康人体内存在一种被称为心磷脂（CL）的脂质，会在线粒体内经历一系列转变，即重塑。 然而，在患有巴氏综合征的人体内，线粒体内的一个重要基因——tafazzin（TAZ）发生了突变。没有TAZ，CL的重塑就会停止，带来有害脂质的积聚。 在这项最新研究中，研究小组使用了计算机模型，并对小鼠成肌细胞和巴氏综合征患者的人类心脏组织样本进行了体外研究。 Valerian Kagan说：“我们发现，溶血心磷脂是一种在TAZ缺陷突变细胞中积累的中间体，它与线粒体细胞色素c蛋白相互作用，将其转化为一种可以氧化周围一切的酶。” 事实证明，TAZ缺陷细胞中的过度氧化是可以预防的。研究小组表明，一种咪唑类化合物（IOA，imidazole-substituted oleic acid）可以阻止这种过度氧化现象，并改善巴氏综合征果蝇模型的运动功能和耐力。 未来，这一发现可能为纠正遗传性TAZ缺陷和通过小分子疗法改善线粒体功能铺平道路。 参考文献：Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome, Nature Metabolism (2023). DOI: 10.1038/s42255-023-00926-4 内容来源于网络，如有侵权，请联系删除。

Sarah Silbiger/Getty Images On Tuesday, Stealth Biotherapeutics announced that it plans to meet with the U.S. Food and Drug Administration to discuss a potential New Drug Application (NDA) for its therapeutic, elamipretide, which is intended to treat Barth syndrome. The development comes amid a rocky journey. In August 2021, Stealth submitted an NDA for elamipretide, a small mitochondrially-targeted tetrapeptide, for the treatment of Barth syndrome. The FDA had granted the therapy orphan drug designation, rare pediatric designation and fast track designation. Barth syndrome is a rare, genetic disorder that causes an enlarged and weakened heart, weakness in muscles and small numbers of white blood cells due to mutations in the gene TAFAZZIN which creates the protein tafazzin. This protein is important to the function of mitochondria. Those with the condition produce tafazzin proteins with little or no function, causing dysfunction in mitochondrial cells. There are currently no FDA-approved treatments for the condition, lending to elamipretide’s multiple designations. The NDA submission was based on data from a Phase III clinical trial in which the drug met its primary and secondary endpoints and produced clinically meaningful improvements in biomarkers of cardiac function, exercise tolerance and strength. The trial compared data from treated patients to natural history controls, a method that uses retrospective data collected from patients, usually from medical records, rather than collecting data from controls that participated in the clinical trial. At the time of the submission, the FDA recommended additional controlled data be generated to support NDA review, but Stealth stated that neither the company nor the regulatory agency had identified a suitable trial design. Stealth forged ahead with the data submission, namely because conducting additional clinical trials in the population would prove difficult as less than 130 people in the U.S. are diagnosed with the condition. The additional data needed would prove to be Stealth’s downfall in October 2021 when the company received a Refusal to File letter from the FDA. The agency stated that the NDA the company had submitted was not sufficiently complete to warrant a substantive review, citing again the lack of an adequate and well-controlled trial that provides efficacy evidence. At the time, Stealth stated that the FDA did not provide reasoning as to why its retrospective controls were not considered adequate. Now, the FDA has granted Stealth a pre-NDA meeting to discuss new clinical data collected over 3.5 years from its open-label extension period of a Phase II study. The meeting is set to take place sometime in the third quarter. "We welcome the opportunity to meet with FDA to discuss our promising new clinical data and a potential NDA submission," Reenie McCarthy, CEO of Stealth said. "We look forward to working with the Agency toward our goal of securing the regulatory review and approval necessary to make elamipretide available to patients with Barth Syndsararome. We are eager to present our new clinical data at an upcoming scientific meeting."