Voxelotor

来源：环球市场播报 　　美国生物制药公司Fulcrum Therapeutics（股票代码：FULC.O）2日宣布，因美国食品和药物管理局（FDA）对潜在致癌风险提出严重关切，公司决定终止其实验性镰状细胞贫血症治疗药物Pociredir的研发工作，并全面启动包括寻求公司出售或合并在内的战略转型。受此利好出尽及重组消息影响，Fulcrum当日股价暴跌52%。 　　Pociredir是一款在研口服药物，旨在通过作用于PRC2蛋白复合体中的关键亚基来提高胎儿血红蛋白水平，从而缓解镰状细胞贫血症患者的贫血、疼痛及器官损伤症状。尽管Fulcrum强调该药物在临床试验中疗效显著且未出现新的安全问题，但美国食品和药物管理局最终认定，所有作用于该蛋白复合体的在研或在售药物均存在诱发恶性肿瘤的类似系统性风险。 　　导致美方监管机构态度转向的诱因，是另一家制药企业益普生（Ipsen）旗下同样靶向PRC2复合体的抗癌药物Tazverik，因存在引发继发性血液癌症的风险，于今年早些时候在全球范围内遭到撤市。Fulcrum此前曾向监管部门提交对比数据，试图证明Pociredir与Tazverik作用于不同的亚基结构，具备独特的安全特征，但未获采纳。 　　投行Truist分析师格雷戈里·伦扎（Gregory Renza）指出，美国食品和药物管理局并未对PRC2复合体的具体亚基进行差异化区分，而是将其视为一个整体的致癌风险源。Stifel分析师詹姆斯·孔杜利斯（James Condulis）则对该项目的终止感到意外，认为该药此前展现出的强劲临床疗效本有望填补巨大的临床空白。目前，华尔街至少有三家券商在消息公布后下调了Fulcrum的股票评级和目标价。 　　鉴于核心研发管线断裂，Fulcrum公司表示已开始实施紧缩政策以维持现金流，并将正式评估潜在的出售、合并或其他资产重组等战略替代方案。这也是继2024年辉瑞公司（Pfizer）因安全隐患撤回已上市药物Oxbryta并停止相关研究后，全球镰状细胞贫血症药物研发领域遭遇的又一次重大挫折。

Fulcrum Therapeutics has begun a strategic review that may result in it getting sold, a move made after the companys main medicine hit a possibly insurmountable obstacle.On Tuesday, Fulcrum disclosed that, late last month, it received the official record from a recent meeting with the Food and Drug Administration. The meeting revolved around next steps for pociredir, an experimental treatment for sickle cell disease that Fulcrum had ushered through early-stage human testing.According to the company, FDA staff were worried about pociredirs safety, given emerging data that showed higher-than-expected rates of secondary blood cancers in patients who had received an Ipsen drug, Tazverik, which was pulled from the market in March. Fulcrums drug works in a similar-but-different way, and the company tried to make the case that these differences are important to assessing overall benefits and risks. The FDA, though, still concluded the potential hazards were too great and left no viable regulatory path forward.Fulcrum has therefore made the very difficult decision to discontinue development of pociredir, said CEO Alex Sapir. The company is now exploring strategic alternatives, including potentially merging or selling either assets or the entire business. Its also started efforts to significantly reduce operating expenses and preserve capital, though specific details werent provided. Fulcrum had a third of a billion dollars in cash, cash equivalents, and marketable securities as of March 31.Fulcrums stock price, which had already fallen significantly since late last year, cratered following Tuesdays update. Shares were down more than 50%, to just above $3 apiece.With limited visibility into future value creation beyond strategic alternatives and cost-cutting initiatives, we are moving to the sidelines, wrote Leerink Partners analyst Joseph Schwartz, who also downgraded his rating on Fulcrums stock to Market Perform.Schwartz noted, however, that his team was surprised by this outcome due to the effects pociredir demonstrated in that early-stage study. There, the drug boosted fetal hemoglobin levels one of the most proven methods for treating sickle cell and improved red blood cell health in adults with severe disease. Schwartz highlighted how the trial also hadnt reported any new clinical safety signals.Pociredir is designed to inhibit a large protein complex, PRC2, that helps turn off fetal hemoglobin production. It does this by latching onto a specific piece of the protein that, notably, is distinct from where Tazverik binds. Recent clinical data pointing to an increased incidence of hematologic malignancies among patients given Tazverik appears to have led the FDA to draw a hard line regarding the risk/benefit profile of all PRC2 inhibitors regardless of mechanistic differences, Schwartz wrote.The FDA previously put a so-called full clinical hold on Fulcrums program in early 2023, in part because of concerns with the wider class of PRC2-targeting drugs. The hold was lifted that summer, with Fulcrum agreeing to tailor the type of patients who were eligible to participate in its Phase 1 study. Schwartz argues the FDA position regarding pociredir seems to have been biased by malignancy observations seen in preclinical testing.Luca Issi, an analyst at RBC Capital Markets, claims his team wasnt entirely surprised by this outcome. While its unfortunate for the many [sickle cell] patients looking for therapeutic alternatives, we do believe that discontinuing the program is the right pragmatic decision given the FDA clearly believes that this is a class effect, Issi wrote in his own note to clients.Fulcrums is the latest in a string of setbacks for sickle cell drugmakers. In 2023, development was discontinued for three experimental treatments from Intellia Therapeutics, Sangamo Therapeutics and Graphite Bio. Two years later, Pfizer and Agios Pharmaceuticalseach delivered disappointing clinical results.Pfizers study was for a drug that the pharmaceutical giant picked up through the $5.4 billion acquisition of Global Blood Therapeutics. In 2024, Pfizer removed from the market another asset from that deal, the approved sickle cell therapy Oxbryta, because of safety concerns.The year prior, Novartis withdrew Adakveo from the European market after authorities there formally revoked the sickle cell disease drugs authorization.The World Health Organization estimates that, as of 2021, close to 8 million people had sickle cell. The disease causes “vaso-occlusive crises,“ a sudden, brutal wave of pain brought on by the crescent-shaped blood cells block small blood vessels. It can also make patients more vulnerable to infections and trigger chronic damage. Often, the life expectancy for people with sickle is 20 or so years less than their peers. '