Flucytosine

SAN DIEGO, April 30, 2024 /PRNewswire/ -- Denovo Biopharma LLC (Denovo), a pioneer in applying precision medicine to the development of innovative therapies, today announced that the California Institute for Regenerative Medicine (CIRM) has awarded a $11.8M grant for further development of DB107, Denovo's DGM7™ biomarker–guided late–stage gene therapy, for high–grade glioma (HGG) including glioblastoma (GBM), a malignant brain cancer. CIRM has awarded the grant to Dr. Noriyuki Kasahara, MD, PhD, at the University of California San Francisco (UCSF) and a group of investigators at California universities to conduct a Phase 1/2 clinical trial studying DB107 in patients with newly–diagnosed HGG. Continue Reading The trial, titled "A Phase I/IIa Study to Evaluate the Efficacy of DB107–RRV, Administered to Subjects at Time of Resection and Intravenously Thereafter, in Combination with DB107–FC and Radiation Therapy or DB107–FC, Temozolomide (TMZ) and Radiation Therapy in Patients with Newly–Diagnosed High–Grade Glioma," plans to enroll up to 70 patients. The trial aims to demonstrate improvements in progression–free survival. We are thrilled to continue the clinical development of our biomarker-guided DB107 gene therapy in HGG including GBM. Post this DB107 consists of two components: DB107–RRV (vocimagene amiretrorepvec) as a prodrug activator gene therapy and DB107–FC (extended-release 5–fluorocytosine [5–FC]) as an oral prodrug. DB107–RRV, a retroviral replicating vector (RRV) administered intratumorally and intravenously, converts the orally administered 5–FC into the potent chemotherapy agent 5–fluorouracil (5–FU) locally at the tumor sites. This enables intratumoral concentrations 30–50 times of those achievable by 5–FU systemic administration, killing tumor cells while minimizing the systemic exposure and off–target toxicities of 5–FU. Using its proprietary biomarker discovery platform including whole genome sequencing (WGS) and artificial intelligence (AI), Denovo discovered the novel germline genetic biomarker, Denovo Genomic Marker 7 (DGM7), which is located in the SHROOM3 gene intron. Retrospective analysis of an earlier randomized clinical trial in patients with recurrent HGG suggested improved overall survival in DGM7–positive patients treated with DB107. "We are excited to conduct this novel trial which will be investigating several new approaches for the first time in patients with newly–diagnosed high–grade glioma. In addition to DB107–RRV being administered both intratumorally and intravenously to provide more exposure, this study will also use the RRV in conjunction with radiation therapy and chemotherapy with temozolomide. In addition to the direct therapeutic effect of gene therapy, glioma cells will be sensitized to these standard therapies by 5–FU generated directly within the patient's tumor from DB107–FC. We are also excited to test the DGM7 biomarker to see if we can identify patients who may benefit the most from this unique gene therapy approach," said Dr. Kasahara. DGM7 status will be determined at the time of enrollment to prospectively assess the effect of the biomarker on clinical outcomes. The study will be conducted at UCSF (Dr. Noriyuki Kasahara, MD, PhD, and Dr. Nicholas Butowski, MD), University of Southern California (USC) (Dr. Thomas Chen, MD, PhD), and University of California San Diego (UCSD) (Dr. David Piccioni, MD, PhD), and will be managed by Anova Enterprises, Inc. "We are thrilled to continue the clinical development of our biomarker–guided DB107 gene therapy in patients with HGG including GBM, a major unmet medical need with less than 5% of GBM patients surviving 5 years," said Dr. Matthew A. Spear, MD, Denovo's Chief Medical Officer and Chief Development Officer. "Alongside our recent announcement of positive results in a Phase 2b clinical trial of our DGM4 biomarker–guided DB104 drug (liafensine) in treatment–resistant depression, the CIRM grant provides continued validation of Denovo's approach to discovering new genetic biomarkers and developing biomarker–guided therapies." About HGG and GBM The most common type of high–grade glioma (HGG) is glioblastoma (GBM), which is also the most common type of adult primary brain cancer, with 18,000 newly–diagnosed patients in the US and 13,000 deaths annually. Standard treatments for patients with newly–diagnosed GBM can include surgery followed by radiation and chemotherapy, but treatment options are limited. The 5–year survival rate of patients with GBM is less than 5%. About DB107 and the DGM7™ Biomarker DB107 is an investigational combination product consisting of the DB107–RRV (vocimagene amiretrorepvec) gene therapy and DB107–FC (extended–release 5–fluorocytosine) oral prodrug. DB107–RRV, an innovative proprietary retroviral replicating vector (RRV), is combined with DB107–FC to selectively infect and kill cancer cells while stimulating a robust and durable anti–cancer immune response against a tumor with minimal toxicity. DB107 has been tested clinically in solid tumors including recurrent high–grade glioma (rHGG) and colorectal cancer, most recently in a randomized 403–patient Phase 2/3 trial in rHGG including glioblastoma (GBM). Using its proprietary biomarker discovery platform, Denovo discovered the novel genetic biomarker, DGM7, which has been shown to be associated with treatment response to DB107 in patients with rHGG including GBM. DB107 has received Fast Track Designation and Breakthrough Therapy Designation from the FDA, as well as Orphan Drug Designations from the FDA and EMA. About Denovo Biopharma Denovo Biopharma LLC (Denovo) is a clinical–stage biopharmaceutical company that uses a novel biomarker discovery platform including whole genome sequencing (WGS) and artificial intelligence (AI) to find new genetic biomarkers predictive of drug efficacy, and then uses these biomarkers to execute efficient clinical trials in targeted patient populations to increase the probability of success. Denovo has eight late–stage drugs in its pipeline addressing major unmet medical needs in oncology and central nervous system diseases; most of the pipeline are first–in–class drugs with global rights. Denovo recently announced a major breakthrough in treatment–resistant depression (TRD) with its DGM4™ biomarker–guided DB104 drug (liafensine, a potential first–in–class triple reuptake inhibitor for TRD). The global Phase 2b clinical trial of DB104 in DGM4–positive patients with TRD demonstrated strikingly positive results, with highly significant improvements in symptoms of depression seen in DGM4–positive patients. Visit for additional information. Contact Michael F. Haller, Chief Business Officer Denovo Biopharma LLC [email protected] SOURCE Denovo Biopharma LLC

未经授权，不得转载氢氯噻嗪-氟胞嘧啶共晶的制备、表征及溶解性考察Preparation, Characterization and Solubility Investigation ofHydrochlorothiazide-flucytosine Cocrystal邓雪珍，陈乐乐，谭雨梦，钱 坤*，杨 婕(江西中医药大学药学院，江西南昌 330004)摘要：为提高氢氯噻嗪(1) 的水溶性和改善氟胞嘧啶(2) 的引湿性，该文制备了1-2 共晶。应用单晶X 射线衍射、粉末X 射线衍射、傅里叶变换红外光谱、热重和差示扫描量热等方法对其进行了表征，并研究了1-2 共晶的溶解性和引湿性。结果表明，与1 相比，1-2 共晶中的1 在盐酸(pH 1.2)、磷酸盐缓冲液(pH 6.8) 和纯水(pH 7.0) 中的平衡溶解度和特性溶出速率均得到提高。并且，1-2 共晶在25 ℃和相对湿度95％的条件下未发生增重。研究结果表明所制备的1-2 共晶增加了1 的溶解性，并减轻了2 的引湿性，为提高难溶性药物溶解性的研究提供了参考。关键词：氢氯噻嗪；氟胞嘧啶；共晶；溶解性；引湿性以下为文章节选药物共晶是由API 与其他一种或一种以上的共晶形成物(cocrystal former，CCF) 或药物以一定比例通过非共价键结合于一个晶格内并堆积而成的物质状态[1]。自首个用于治疗心脑血管疾病的共晶药物“沙库巴曲+ 缬沙坦”获FDA 批准上市以来，药物共晶受到了广泛关注[2—3]。随着对药物共晶及API 理化性质的深入研究，共晶技术被广泛用于改善API 因其原有结构而导致的生物利用度低、渗透性差、溶解性差、稳定性低等的研究之中[4—5]。氢氯噻嗪(hydrochlorothiazide，1，图1A) 是一种利尿性抗高血压药，被广泛用于治疗浮肿和高血压，属于低溶解性和低渗透性的BCS Ⅳ类药物，体内生物利用度低[6—7]。氟胞嘧啶(flucytosine，2，图1B) 是一种常用的抗真菌药，可用于治疗念珠菌和隐球菌感染，但其稳定性较差，易因水合作用导致晶型改变，不利于生产和贮存[8—9]。本研究采用溶剂挥发法制备1-2 共晶，并通过平衡溶解度、特性溶出速率(intrinsic dissolution rate，IDR) 和引湿性试验考察共晶是否改善了1 的溶解性和2 的引湿性，以期为提高难溶性药物1 的溶解性和增加2 的片剂成药性研究提供数据参考。↑长按二维码阅读全文基金项目：国家自然科学基金资助项目(22165014)、江西省2022年度研究生创新专项资金项目(YC2022-s856)、中药炮制技术的传承与创新项目(CXTD22003)作者简介：邓雪珍(1998—)，女，硕士研究生，专业方向：药物化学。通信作者：钱 坤(1979—)，男，副教授，博士，从事药物共晶的研究。E-mail：qiankun@jxutcm.edu.cn文章详情欢迎登录《中国医药工业杂志》官网查看。END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001