Praliciguat

近日，知名“变废为宝”的二手商Roivant携带着新公司Pulmovant亮相欧洲呼吸学会大会，新公司Pulmovant手握肺动脉高压药mosliciguat，是从拜耳处收购得来。 Roivant公司的战略一直以来是收购其他人不要的管线，再将其开发，此次交易也不例外，拜耳在2022年上半年放弃了处于I期临床的mosliciguat的开发，而如今Roivant以1400万美元的预付款从拜耳获得了mosliciguat的全球许可权，未来里程碑付款高达2.8亿美元，拜耳还有资格获得专利使用费。 sGC通路的开发历程 Mosliciguat，前称BAY 1237592，是一款吸入剂型可溶性鸟苷酸环化酶（sGC）激动剂，靶向的是一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-环鸟苷酸（cGMP）途径。 这是1998年诺奖获得者Ferid Murad等三位科学家首次发现的通路，这位美国三院院士的团队最初在研究爆炸物硝化甘油为何能够治疗心脏病。他们意外发现硝化甘油释放的一氧化氮会作为信号分子刺激sGC，进而产生cGMP舒张血管。 具体而言，sGC本身是NO的受体，在接收到NO信号后，会发生构象变化，由静息状态转变为高活力激活状态，进而催化GTP生成cGMP。cGMP作为第二信使，能够激活下游的效应蛋白，如PKG（蛋白激酶G），从而调节多种生理过程，如血管舒张、神经信号传递、血小板凝集等。 在肺动脉高压和一些心血管疾病中，sGC通路受到抑制，这导致血管紧缩。因此靶向NO/sGC/cGMP途径被广泛认为是治疗心血管疾病，包括慢性心力衰竭、肺动脉高压等疾病的重要靶标。 值得一提的是，“伟哥”西地那非同样也是在这一机制背景下开发的药物（“伟哥”西地那非是一种PDE-5抑制剂，PDE-5能够降解cGMP，而抑制PDE-5有利于血管舒张），因此亲自参与“伟哥”临床的Ferid Murad可以说是“伟哥”之父。“伟哥”为代表的PDE-5抑制剂同样也可以用于肺动脉高压。 sGC激动剂药物的困境 从药物机制来看，Mosliciguat并不是非常新颖的，毕竟已经有上市药物在先。 mosliciguat的老东家拜耳正是sGC激动剂领域的研发大牛，2013年首款在美上市sGC激动剂Riociguat（利奥西呱）就是由拜耳开发的，Mosliciguat这款后续开发的吸入剂型是拜耳在诸多sGC激动剂中的尝试之一。 利奥西呱的劣势主要在于可替代性，是西地那非等PDE-5抑制剂的下位替代，临床实践中常常是患者对西地那非无反应才使用利奥西呱，而且虽然是同一通路的不同机制，但是不能一同使用，否则可能造成严重低血压。 考虑到相比之下西地那非价格也不贵，这也难怪，在商业上，利奥西呱并不算太成功，半衰期短，价格贵，又要经常服用，市场起步还晚，市场渗透率自然相对较低，增长也相对比较缓慢。 而事实上，后续业内的sGC激动剂迭代产品开发也不顺利。Cyclerion Therapeutics公司想要将praliciguat用于保留射血分数的心衰、糖尿病肾病，但是19年I期临床的概念验证就失败了。开发的另外一款分子Olinciguat在镰状细胞性贫血中的临床也宣告失败，Cyclerion Therapeutics后续打算开发中枢神经系统中的sGC激动剂Zagociguat和CY3018，不过也已经出售给了Tisento Therapeutics公司，Cyclerion Therapeutics现在是待价而沽，寻求股东价值最大化的状态。 拜耳方面，vericiguat在2021年以心衰适应症上市，但市场并不看好这一药物的未来市场前景，疗效看起来似乎不如诺华的Entresto和阿斯利康的达格列净，普遍给出的较低销售额预测。 2022年H1拜耳放弃了mosliciguat的开发，其实纵向对比Riociguat，mosliciguat已经将原本12h但半衰期提升到40h了。但横向对比，合作伙伴默沙东的肺动脉高压新药Sotatercept机制完全不相同，服药间隔长，三周一支，虽然价格贵，年治疗费用能达到24.2万美元，但效果好，市场普遍看好Sotatercept未来该是个重磅炸弹。 2024年上半年放弃了runcaciguat用于慢性肾病的开发，转而投入药效和药动更优化的BAY3283142。 和上述的开发途径相比，此次Roivant倒是另辟蹊径。 Roivant的算盘 拜耳的出售固然有拜耳新CEO上任改革的缩影，Roivant的收购也有自己的算盘。 此次Roivant表示观察到Mosliciguat能够使肺动脉高压患者的肺血管阻力（PVR）持续降低高达38%，降幅确实是史无前例的，但值得指出的是，Roivant选择的适应症是与间质性肺病（PH-ILD）相关的肺动脉高压，选择的是存在巨大未满足临床需求中的药物，而他们认为这一患者群体在欧美可能有20万人。 如果确实存在这样的一个市场，那么Roivant在这场博弈中可能确实找准了位置，未来默沙东新药Sotatercept可能会取代利奥西呱的位置，实际可能会反映在Sotatercept放量后利奥西呱的销售额变化。 Mosliciguat在这一空白市场的开发，可能为这类sGC激动剂药物找到出路。 参考来源： Friebe A, Kraehling JR, Russwurm M, Sandner P, Schmidtko A. The 10th International Conference on cGMP 2022: recent trends in cGMP research and development-meeting report. Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug;396(8):1669-1686. doi: 10.1007/s00210-023-02484-8. Epub 2023 Apr 20. 周婷婷,刘潇.可溶性鸟苷酸环化酶刺激药的研究现状[J].中国临床药理学杂志,2023,39(21):3178-3182.DOI:10.13699/j.cnki.1001-6821.2023.21.029.

– Dr. Graul will lead the rebuild of Cyclerion, bringing more than two decades of drug making experience, R&D portfolio leadership, and a deep expertise in company strategy – – Peter Hecht, Ph.D., will continue to work closely with Cyclerion leadership as a strategic consultant and longstanding board member; steps down from CEO role – CAMBRIDGE, Mass., Dec. 04, 2023 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a biopharmaceutical company on a mission to develop treatments for serious diseases, today announced that Regina Graul, Ph.D., has joined the company as president, effective immediately. As Cyclerion’s president, she will lead the organization and will work closely with, and report directly to, the board of directors. She will be responsible for creating, implementing, and executing strategy as well as building a uniquely talented cross-functional management team. With Graul’s arrival, transitional commitments under the asset purchase agreement with Tisento Therapeutics completed, and general expense reductions largely in place, founding chief executive officer Peter Hecht, Ph.D. has completed his transitional assignment. As a result, he is stepping away from an operational role at Cyclerion, effective immediately, and will continue to work with Dr. Graul and her team as a strategic consultant and board director going forward. “I am thrilled to be joining Cyclerion at this pivotal moment. The recent additions of Dina Katabi and Michael Higgins as board members and the evolution of Cyclerion’s board and management team provide a key inflection point to re-envision the company’s future,” said Dr. Graul. “As we evaluate our existing assets and identify external value-creating opportunities, cutting-edge innovation and addressing unmet patient needs will be central tenets. Together with our outstanding board of directors, I look forward to building Cyclerion’s capabilities for its next chapter to bring meaningful medicines to the patients who need them most.” “I am optimistic about the future of Cyclerion with Regina shepherding the company, a top-notch board of directors, promising existing assets, and a strategy for growth and evolution through external innovation,” said Dr. Hecht. “Having worked with Regina personally for years at Microbia, Ironwood, and Cyclerion, I can attest to her effective leadership style, savvy sense of strategy, and ability to identify and advance promising science. I look forward to working with her and the rest of the board as we build the next phase of the company and seek to make important progress on behalf of patients.” Regina most recently served as vice president, program executive at EQRx, where she led cross-functional development teams in oncology, using the latest in clinical innovation to create and deliver sustainable solutions. Previously, she served as olinciguat program lead at Cyclerion where she oversaw all aspects of olinciguat research and development. She began her industry career at Ironwood Pharmaceuticals (formerly Microbia Inc.) after completing a postdoctorate at MIT. She received her Ph.D. in synthetic organic chemistry from Rice University and her B.A. in chemistry from Saint Anselm College. About Cyclerion Therapeutics Cyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments for serious diseases. Cyclerion acquired 10 percent equity ownership in Tisento Therapeutics as part of an asset sale agreement in which Tisento acquired the brain-penetrant soluble guanylate cyclase (sGC) stimulators zagociguat and CY3018 acquired from Cyclerion. Cyclerion’s current portfolio includes novel sGC stimulators, namely praliciguat and olinciguat, as well as multiple research stage molecules. Praliciguat is a systemic sGC stimulator that is exclusively licensed to Akebia. Olinciguat is a vascular sGC stimulator that Cyclerion intends to out-license for cardiovascular diseases. Concurrently, Cyclerion is also evaluating other activities aimed at enhancing shareholder value, which potentially include collaborations, licenses, mergers, acquisitions and/or other targeted investments. Forward Looking Statement Certain matters discussed in this press release are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should”, “positive”, or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements involve risks, uncertainties and other factors that may cause actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained in this press release, we caution you that these statements are based on a combination of facts and factors currently known by us and our projections of the future, about which we cannot be certain. Forward-looking statements in this press release include, but are not limited to, statements about pursuing collaborations, licenses, mergers, acquisitions and/or other targeted investments aimed at enhancing shareholder value. We cannot assure you that the forward-looking statements in this press release will prove to be accurate. Furthermore, if the forward-looking statements prove to be inaccurate, the inaccuracy may be material. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties, including, those under the heading “Risk Factors” in our Annual Report on Form 10-K filed with the SEC on March 22, 2023 and in our Form 10-Q filed with the SEC on July 28, 2023, as well as our subsequent SEC filings. In light of the significant uncertainties in these forward-looking statements, you should not regard these statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame, or at all. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances. Contacts Investor & Media Relations Phone: 857-327-8778 Email: IR@cyclerion.com