Losmapimod

近日，Fulcrum公布了核心管线losmapimod治疗面肩肱型肌营养不良症（FSHD）Ⅲ期临床试验REACH顶线结果。 与安慰剂相比，losmapimod未能达到的主要终点—相较基线的RSA变化，此外，次要终点也没有达到统计学差异，安全性和耐受性与先前报道的研究一致。 鉴于该结果，Fulcrum计划暂停losmapimod项目的开发。公司将对收集到的数据进行全面评估，并计划在即将召开的医学会议上分享结果。 对于憧憬losmapimod上市的FSHD患者而言，这仍是令人深感遗憾的失败。FSHD目前没有任何有效的治疗手段，losmapimod是备受期待的候选药物，被认为将是全球首个获批FSHD治疗药物。 最初，公司计划在REACH取得了积极结果后，便与赛诺菲在美国、欧洲、日本等国家/地区提交新药上市申请。 该消息发出后，Fulcrum的股价也下跌了约61%。 REACH具体的数据如下： 可及工作区（RWS）： 在第48周时，与安慰剂患者相比，losmapimod组的RSA（衡量肌肉功能指标）改善了0.013，而安慰剂组RWS改善了0.010。 肌肉脂肪浸润 (MFI)： 在第48周时，与接受安慰剂相比，losmapimo组的MFI（衡量肌肉健康指标）增加了0.42%，而安慰剂组增加了0.576%。 肩外展肌力: 在第48周时，losmapimod组的外展肌强度提高了9.63%，而安慰剂组提高了2.24%。 患者自我报告(PRO): REACH的两个次要终点上—患者整体印象变化(PGIC)和上肢神经质量(Neuro QoL)，相较于安慰剂组，losmapimod组均未显示出统计学差异。 Losmapimod是一种口服选择性p38α/β丝裂原活化蛋白激酶（MAPK）抑制剂，最早由葛兰素史克开发，2019年4月，Fulcrum从GSK手中收购了losmapimod的所有权益。 有约95%的FSHD患者因肌肉细胞中DUX4基因异常表达所引起。DUX4基因的异常激活会引发一系列的病理过程，其转录和表达产物会导致肌肉细胞内的炎症反应和肌肉细胞凋亡，最终造成肌肉组织的不可逆损伤。 而p38 MAPK在DUX4诱导肌肉炎症损伤的过程中起关键作用，Losmapimod通过抑制p38 MAPK信号通路，来降低DUX4基因的表达水平，减少其对肌肉组织的毒性效应，阻止或延缓病情的恶化。Losmapimod先前已获FDA用于治疗FSHD的快速通道指定和孤儿药指定。 2024年5月13日，赛诺菲还引进了Losmapimod美国区以外独家开发和商业化权益，代价是8000万美元的首付款，以及9.75亿美元的未来实现里程碑付款，以及十位数以上的销售分成。并且双方还是平分其全球研发成本。 不过，后面的里程碑付款Fulcrum是收不到了，终止合作协议的消息可能很快从赛诺菲那发出来。同时，这将又在赛诺菲长长的失败项目名单新增一员。 停止Losmapimod项目后，Fulcrum将重点推进治疗SCD项目pociredr，Diamond-Blackfan贫血(DBA)项目，以及早期发现项目。 截至2024年6月30日，Fulcrum拥有现金、现金等价物以及有价证券约2.738亿美元。 参考出处： https://www.globenewswire.com/news-release/2024/09/12/2945039/0/en/Fulcrum-Therapeutics-Announces-Topline-Results-from-Phase-3-REACH-Clinical-Trial-of-Losmapimod-in-Facioscapulohumeral-Muscular-Dystrophy-FSHD.html

Fulcrum Therapeutics said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. Just four months after Sanofi bet $80 million in upfront cash on Fulcrum Therapeutics’ losmapimod, the program has ended in a phase 3 failure.The licensing deal with the Big Pharma was agreed upon while counting down to the release of late-stage data in the progressive muscle wasting disorder facioscapulohumeral muscular dystrophy (FSHD) which, if successful, could have opened the door to the p38 inhibitor becoming the first approved therapy for the disease.But the results are just in, and it looks like a wipeout. Not only did the 260-patient study miss its primary endpoint of showing an improvement in an individual’s arm reach when taking a 15-mg losmapimod tablet twice a day compared to placebo, but the study’s secondary endpoints like muscle fat infiltration and patient-reported improvements “did not achieve nominal statistical significance,” Fulcrum explained in a Sept. 12 premarket release.Specifically, the primary endpoint of reachable workspace (RWS)—an analysis of how far an individual can reach—saw a 0.013 improvement among patients receiving losmapimod at Week 48 compared to a 0.010 improvement among those who received placebo. Fulcrum’s chief medical officer Pat Horn, M.D., Ph.D., blamed the results on the lack of deterioration among the placebo cohort.“These results in patients receiving losmapimod when compared to baseline were similar to those observed in our phase 2 study,” Horn said. “However, in contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status as measured by RWS and shoulder dynamometry over the 48 weeks of the study.”The safety and tolerability of losmapimod was consistent with previously reported studies, according to Fulcrum, which said it will fully evaluate the data before sharing the results at an upcoming medical meeting.“We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the phase 2 ReDUX4 trial,” Fulcrum’s CEO Alex Sapir said in the release. “In light of these results, we plan to suspend the losmapimod program in FSHD.”The biotech’s stock plummeted 70% in premarket trading Thursday morning to $2.60 from a Wednesday closing price of $8.85.Massachusetts-based Fulcrum said it would use its $273.8 million in cash and equivalents to swiftly pivot to its remaining pipeline. This is headed up by pociredir, a phase 1-stage small molecule designed to treat sickle cell disease by increasing expression of fetal hemoglobin. Today’s results mark a fork in the road for Fulcrum, which could have been on track to get the first-ever FSHD drug to market if the phase 3 data had shown promise. Losmapimod had a two- to three-year head start on Roche’s myostatin inhibitor that is being targeted at FSHD, while Avidity Biosciences and Arrowhead Pharmaceuticals both have antibody-oligonucleotide complexes in clinical development for the condition.It also means Fulcrum can wave goodbye to potentially $975 million in milestone payments that were tied to the Sanofi licensing deal. When the French Pharma secured the ex-U.S. rights to losmapimod in May, the drugmaker’s global head of rare disease Burcu Eryilmaz pointed to “meaningful clinical benefits” shown in phase 2 studies that “underscore the disease-modifying potential and opportunity to address the high unmet need for a safe and effective drug that slows disease progression.”But losmapimod already had a number of clinical misses on its scorecard. Fulcrum rescued the molecule in 2019 from the vault of GSK, where losmapimod had failed a phase 3 trial in patients with acute coronary syndrome and a midstage study in chronic obstructive pulmonary disease. Under its new owner, it had also failed a phase 2 trial in FSHD in 2021, although Fulcrum was heartened by phase 2b data showing losmapimod could still slow disease progression and improve function in FSHD patients.