Brincidofovir

近日，Jazz Pharmaceuticals斥资9.35亿美元收购了Chimerix公司，这次收购的主要目标是为了Chimerix公司即将上市的管线Dordaviprone（ONC201）。 早先我们曾经介绍过这款核心管线，本文将简单对此进行回顾，并结合Dordaviprone的传奇经历来说明Chimerix这家当初核心管线折戟的公司是怎么起死回生的。 Dordaviprone的峰回路转 Chimerix最初并不开发Dordaviprone，Dordaviprone是这家公司从另外一家私营Biotech Oncoceutics手中买下的。 从一些更早期的信息来看，Dordaviprone（ONC201）最早可以追溯到Boehringer Ingelheim 1973年的小分子化合物TIC10。Dordaviprone本身是一种多巴胺受体D2/D3抑制剂和线粒体酪蛋白水解蛋白酶P（CIpP）变构激动剂。 因为多巴胺受体抑制剂的性质，最初是打算将用于精神相关疾病的（比如说癫痫），但后续的研究人员发现这种小分子还可以穿透血脑屏障，因此他们就将其用于脑瘤开发。 滨州州立大学得到TIC10后，将其转让给了Oncoceutics交给他们开发脑瘤。 比较有趣的是，Boehringer Ingelheim在当初申请专利的时候搞错了分子结构，专利申请的化合物本身是没有抗肿瘤活性的，但后续其他研究团队发现，实际上用Boehringer Ingelheim的工艺会得到另外一种有抗肿瘤活性的化合物，而这种化合物才是真正的ONC201。虽然这一问题造成了专利战的波澜，但是最终无伤大雅。 在临床开发中，ONC201选择了脑瘤中占据不小比例的胶质母细胞瘤（GBM）作为适应症，但临床最终失败，并没能改善患者的无进展生存期（PFS）。 好在天无绝人之路。 在这项试验的两个GBM组中，四名偶然入选的H3K27M突变患者中有两名表现出多处病变的持续消退。后续的多项在H3K27M突变患者中的临床轶事和肿瘤消退也证明了其疗效。这就使得研究人员将注意力转移到H3K27M突变上。 不过Oncoceutics还没开发完，21年年初就被这次收购的主角Chimerix买下了。实际上Chimerix买下Oncoceutics可以说是抓住了救命稻草。 抗病毒制药公司的转生 Chimerix的成立时间其实很早，2000年。这家公司最初致力于利用其专有脂质缀合技术开发抗病毒药物。 公司早先侧重的是CMX001（brincidofovir），这是Cidofovir（西多福韦）的一种衍生物，通过抑制病毒DNA聚合酶来阻止病毒DNA的复制。它是Cidofovir的亲脂性形式，具有更好的细胞内吸收和更少的肾毒性。 CMX001最初在严重腺病毒感染和巨细胞病毒感染等临床研究开发失败。后续相关合作方美国生物医学高级研究与开发管理局（BARDA）找上门来，主打开发天花。不过Chimerix走的基本上是对外授权的路子，权益出售给了Emergent BioSolutions。CMX001（brincidofovir）虽然上市，Chimerix并没有拿到什么资金大头。 几乎是与此同时，Chimerix开始主打开发公司另外一款管线dociparstat sodium (DSTAT) ，同样这也是从另外一家公司Cantex制药手中买来的，DSTAT本身是一种低抗凝肝素，具有多种作用机制，包括抑制 CXCR4/CXCL12 轴、阻断 HMGB1 和结合血小板因子 4 (PF-4)。 Chimerix最初是对DSTAT抱有很大期待的，时值新冠疫情爆发，DSTAT被开发用于新冠紧急损伤和AML，但是后续开发就相当令人失望。推进到III期临床后，2022年第一季度突然就放弃开发了。 公司股价当时大跌60%。而2021年初买下的ONC201这时候接过大棒，成为公司主推。而现在，随着Dordaviprone上市在即，Chimerix公司成功实现了溢价变现，这对于成立多年的Chimerix也算是个好结局。 参考来源： https://ir.chimerix.com/news-releases/news-release-details/chimerix-reports-fourth-quarter-and-year-end-2021-financial 绝命脑癌的一线生机 Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL DOI:10.1002/anie.201402133

Brain cancers are notoriously difficult to treat, with surgery and radiation continuing to be the main options for these malignancies. A rare and aggressive type of brain tumor driven by a particular genetic signature could soon have its first approved drug treatment. Jazz Pharmaceuticals is now committing $935 million to add this prospect to its pipeline. The drug, dordaviprone, was developed by Durham, North Carolina-based Chimerix. The cancer is H3 K27M-mutant diffuse glioma, a high-grade glioma that affects children and young adults. While surgery is a treatment option for brain cancers, it’s usually risky for H3 K27M gliomas because these tumors affect critical parts of the brain and spinal cord. Meanwhile, radiation introduces complication risks and is not curative. “This is a very high unmet need,” Jazz Chief Medical Officer Robert Iannone said, speaking during the company’s presentation Wednesday at TD Cowen’s annual health care conference in Boston. “I’m a pediatric oncologist by training. There really has been no progress in this area. I know from treating these patients, it’s been a very sad situation to have only radiation and surgery as the effective therapy.” Sponsored Post Tackling Messy Provider Data with an NPI-Forward Approach Mike Wirth of ProviderTrust shares insights about the company in this interview at the ViVE 2025 conference in Nashville last month. By ProviderTrust and MedCity News About 2,000 patients are affected by H3 K27M-mutant gliomas annually in the U.S., according to a Chimerix estimate. Dordaviprone is part of a new class of cancer drugs called imipridones. These small molecules target certain G protein-coupled receptors and enzyme targets, altering their activity to lead to cancer cell death. Dordaviprone, known earlier in its development as ONC201, is designed to selectively target mitochondrial protease ClpP and dopamine receptor D2. Phase 2 results showed tumor regression in patients with glioblastoma who exhibited the H3 K27M mutation. In the 50 patients included in the primary efficacy analysis, Chimerix reported a 28% objective response rate and a median duration of response of 10.4 months. A Phase 3 test enrolling patients newly diagnosed with this type of brain cancer could support first-line use of the drug; interim results are expected in the third quarter of 2025. But based on the Phase 2 data, Chimerix is seeking accelerated approval of dordaviprone for recurrent H3 K27M-mutant diffuse glioma. Last month, the FDA accepted the new drug application under priority review, setting an Aug. 18 target date for a regulatory decision. Though cancer is the therapeutic focus of Chimerix, it’s a relatively new area for the company, one of the older biotechs in North Carolina’s Research Triangle. Dordaviprone came from Chimerix’s 2021 cash and stock acquisition of Oncoceutics, a clinical-stage developer of imipridones. Besides the lead drug candidate, the deal also brought ONC206, an imipridone that Chimerix has advanced to Phase 1 testing in central nervous system tumors. Per terms of the Oncoceutics acquisition, that company’s shareholders could receive up to $360 million in milestone payments plus royalties from sales. Chimerix, founded in 2000, began as an antiviral drug developer. For most of the biotech’s history, its focus was brincidofovir, a molecule initially developed for treating cytomegalovirus infection. It failed in that indication, but won FDA approval in 2021 as a treatment for smallpox and is now known by the brand name Tembexa. In 2022, Chimerix sold that drug’s rights to Emergent BioSolutions for $225 million up front and up to $100 million in milestone payments. Chimerix applied the cash toward clinical development of dordaviprone in brain cancer. Sponsored Post Webinar: Tips To Have Your Practice Succeed This Year This on-demand webinar will offer insights and share tips on helping practices run more efficiently. By Elation Health and MedCity News In the past year, Chimerix’s stock price has mostly traded below the $1 mark. Those shares got a significant lift in December after the biotech announced it would seek accelerated approval for dordaviprone. According to acquisition terms disclosed Wednesday, Dublin-based Jazz will pay $8.55 in cash for each Chimerix share, representing a 72% premium to the biotech’s closing stock price on Tuesday. There’s potential for additional financial upside. Because Chimerix’s drug is under priority review, it’s eligible for a rare pediatric disease priority review voucher if the drug is approved. Such vouchers are typically sold to big pharma companies, and they once fetched prices in the range of $100 million. Recent voucher sales have been in the neighborhood of $150 million. The Jazz portfolio currently has five cancer drugs. Chief Financial Officer Philip Johnson described dordaviprone as a “great fit with our oncology business,” adding that the drug can leverage Jazz’s commercial capabilities and offers a patent life extending into 2037 and potentially longer. The Chimerix acquisition fits Jazz’s strategy of acquiring assets for rare opportunities in niche markets, Leerink Partners analyst Marc Goodman wrote in a note to investors. Beyond addressing a high unmet medical need, the deal leverages Jazz’s expertise in rare diseases and oncology. Jazz prefers acquiring late-stage assets that have a potential near-term commercial launch, Goodman said. Leerink is still researching the H3 K27M market opportunity, but he noted that given the size of the patient population for this ultra-rare type of cancer, it makes sense for dordaviprone to fall within the $300,000 to $800,000 price range for orphan drug products. The acquisition has been approved by the boards of both Jazz and Chimerix, but still must meet customary closing conditions including the tender of the majority of the outstanding shares of Chimerix. The companies expect the deal to close in the second quarter of this year.