Losmapimod

2025年9月，7岁的脊髓性肌萎缩症（SMA）患儿小石头背着书包走进小学教室，这个曾被医生断言"活不过两岁"的孩子，如今能独立坐在轮椅上朗读课文。改变他命运的，是国家医保谈判中价格从70万元暴跌至3万元的诺西那生钠注射液。但在这份"生命奇迹"背后，全球超3亿罕见病患者中，仍有60%面临无药可治的绝境，38%的在研药物可能倒在临床试验终点线前，基因治疗单剂超千万元的支付难题更是悬在患者头顶的达摩克利斯之剑。研发"九死一生"：38%的失败率与28亿美元的赌注2024年，面肩胛肱型肌营养不良症药物Losmapimod的III期临床试验宣告失败，赛诺菲为此投入的8000万美元合作资金血本无归。这不是个例——据塔夫茨大学研究，一款新药从研发到获批平均成本达28亿美元，而罕见病药物因患者基数小、临床试验难度大，失败率比普通药物高出47%。在210条中国在研罕见病药物管线中，仅5款进入III期临床，绝大多数停留在早期探索阶段。实验室里的蓝色机械臂正在精准分装试剂，XtalPi晶泰科技的智能设备24小时运转，但研发风险无处不在。Sarepta公司的杜氏肌营养不良基因疗法Elevidys上市后，因3起患者死亡事件导致销售额暴跌50%，股价年内蒸发84%。"我们在临床试验中看到90%患者实现零出血，但现实世界中免疫排斥反应完全超出预期。"北京协和医院神经科张教授坦言，罕见病的遗传多样性让药物研发如同在黑暗中射箭。从70万到3万：医保谈判如何创造"中国奇迹""每一个小群体都不该被放弃。"2021年国家医保谈判现场，这句话让诺西那生钠从55万元降至3.3万元。数据显示，纳入医保后该药使用量激增41.5倍，2812名患者像小石头一样获得新生。但蔻德罕见病中心的海报显示，目前仅101种罕见病有药可治，165种上市药物中53种仍未进入医保目录。深圳的创新支付模式提供了新思路：基本医保报销后，"惠民保"再覆盖80%自付部分，年保障额度达205万元。但这种"基本医保+商业保险"的共付模式，在经济欠发达地区难以复制。无锡医惠锡城虽将6种黏多糖贮积症药物纳入保障，但已确诊患者报销比例不足30%，不少家庭仍需卖房凑钱。德国"疗效挂钩"启示：治不好就退钱的支付革命2025年4月，德国医保与CSL公司达成协议：血友病B基因疗法Hemgenix采用"按疗效付费"，患者治疗失败则药企退还全款。这种模式让单次330万美元的天价疗法得以纳入医保，94%患者摆脱终身注射凝血因子的痛苦。美国CMS更创新"三重返利机制"，根据患者5年复发率动态调整支付比例，使镰状细胞病基因疗法净成本降低42%。中国的探索同样值得关注。复星凯特的CAR-T疗法"奕凯达"推出"疗效保险"，患者3个月未缓解可获60万元退款。但基因治疗的复杂性远超预期——国内首款获批的血友病B基因疗法定价279万元，即便分期5年支付，年均费用仍相当于普通家庭15年收入。"我们需要建立疗效追踪系统，让每一分医保钱都花在实处。"复旦大学医保研究专家胡善联强调。真实世界数据：从"孤儿药"到"普惠药"的桥梁在康德弘翼的办公室，数据分析师正通过临界点分析法匹配早衰症患者数据。这家公司曾帮助lonafarnib通过真实世界证据获批，让患者中位生存期从14年延长至26年。如今，中国真实世界研究市场规模已达408亿元，年增速45%，但数据标准化程度不足仍是瓶颈。"传统临床试验需要500例患者，而罕见病可能全国仅100例。"康德弘翼医学总监李博士展示的Kaplan-Meier曲线显示，通过真实世界数据外推，可将试验周期缩短60%。美国FDA已基于真实世界证据批准3款罕见病药物，但中国尚未建立统一的数据共享平台，医院间电子病历互通率不足30%。2425亿美元市场背后：患者的希望与行业的责任2025年全球罕见病药物市场将达2425亿美元，但繁华背后是残酷的现实：脊髓性肌萎缩症患者确诊平均耗时18个月，戈谢病药物年治疗费仍高达200万元。当7岁的小石头在课堂上举起电子手账本时，还有无数患者在等待属于他们的"诺西那生钠时刻"。德国的疗效挂钩模式、美国的分层返利机制、中国的医保谈判经验，正在编织一张全球罕见病保障网。正如《2025中国罕见病行业趋势报告》指出，当政策创新、技术突破与患者参与形成合力，每个"小石头"都能拥有走进教室的权利。但这条路依然漫长——我们需要更多"灵魂砍价"，更需要将2425亿美元的市场规模，真正转化为3亿罕见病患者的生命希望。（文中患者案例均来自公开报道，关键数据引用自沙利文报告、FDA官网及《中国罕见病药物可及性报告》）

― Announced encouraging results in July 2025 from the 12 mg dose cohort of the Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) ― ― Enrollment complete in the 20 mg dose cohort (n=12) of the PIONEER trial; on track to provide data from the 20 mg dose cohort by year-end ― ― Ended Q3 2025 with $200.6 million in cash, cash equivalents, and marketable securities; cash runway into 2028 ― CAMBRIDGE, Mass., Oct. 29, 2025 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.® (Fulcrum) (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases, today reported financial results for the third quarter of 2025 and provided a business update. “We are extremely pleased with the compelling data from the 12 mg dose cohort of the PIONEER trial, which demonstrated that pociredir has the potential to meaningfully improve outcomes for people living with sickle cell disease,” said Alex C. Sapir, Fulcrum’s President and Chief Executive Officer. “The strength of those results has generated significant interest and engagement from investigators and patients, reflected in the over-enrollment of the 20 mg dose cohort. We look forward to sharing results from the 20 mg dose cohort by the end of 2025.” Recent Business Highlights Announced encouraging results from the 12 mg dose cohort of the PIONEER trial, following conclusion of the 12-week treatment period. Results demonstrated a dose-dependent and clinically meaningful increase in fetal hemoglobin (HbF), evidence of pan-cellular induction of HbF, improvements in markers of hemolysis, increases in total hemoglobin, and encouraging trends in vaso-occlusive crisis (VOC) reductions. Pociredir continued to be generally well-tolerated, with no drug-related serious adverse events (SAEs) and no discontinuations due to treatment-emergent adverse events through the completion of the 12 mg dose cohort.Completed patient enrollment in the 20 mg dose cohort of the PIONEER trial, with greater than 90% rates of adherence to study drug to date. The mean and median baseline HbF levels for the 12 evaluable patients (excluding 1 discontinuation that was previously disclosed) enrolled in the 20 mg dose cohort are 7.1% and 7.3%, respectively. Fulcrum plans to present additional clinical data at the 67th American Society of Hematology (ASH) Congress, being held December 6-9, 2025, in Orlando.Initiating an open label extension trial to allow patients to continue receiving pociredir after completing the PIONEER trial, enabling longer-term evaluation of safety and durability of response. Presented real-world data at the 20th Annual Sickle Cell & Thalassemia (ASCAT) Conference demonstrating the quantitative correlation between increased HbF levels and reduced VOC rates in SCD. Read the presentation here.Fulcrum continues to advance its program for the potential treatment of bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), 5q deletion syndrome, Shwachman-Diamond syndrome, and Fanconi anemia, and plans to submit an investigational new drug application (IND) during the fourth quarter of 2025.Presented preclinical data for FTX-6274, an oral embryonic ectoderm development (EED) inhibitor candidate, at the European Society for Medical Oncology (ESMO) Congress 2025, demonstrating robust efficacy in castration resistant prostate cancer models. Read the presentation here. Third Quarter 2025 Financial Results Cash Position: As of September 30, 2025, cash, cash equivalents, and marketable securities were $200.6 million, as compared to $241.0 million as of December 31, 2024. The decrease of $40.4 million is primarily due to cash used to fund operating activities in 2025.R&D Expenses: Research and development expenses were $14.3 million for the three months ended September 30, 2025, as compared to $14.6 million for the three months ended September 30, 2024. The decrease of $0.3 million was primarily due to decreased costs associated with the discontinuation of our losmapimod program and the reimbursement from the global development cost sharing under the now-terminated collaboration with Sanofi, partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial of pociredir.G&A Expenses: General and administrative expenses were $7.6 million for the three months ended September 30, 2025, as compared to $8.4 million for three months ended September 30, 2024. The decrease of $0.8 million was primarily due to decreased professional services costs.Net Loss: Net loss was $19.6 million for the three months ended September 30, 2025, as compared to a net loss of $21.7 million for the three months ended September 30, 2024. Cash Runway Guidance Based on its current operating plans, Fulcrum expects that its current cash, cash equivalents, and marketable securities will be sufficient to fund its operating requirements into 2028. About Fulcrum TherapeuticsFulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on developing small molecules to improve the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s lead clinical program is pociredir, a small molecule designed to increase expression of HbF for the treatment of SCD. Fulcrum uses proprietary technology to identify drug targets that can modulate gene expression to treat the known root cause of gene mis-expression. For more information, visit www.fulcrumtx.com and follow us on X (@FulcrumTx) and LinkedIn. About PociredirPociredir is an investigational oral small-molecule inhibitor of EED that was discovered using Fulcrum’s proprietary discovery technology. Inhibition of EED leads to potent downregulation of key fetal globin repressors, including BCL11A, thereby causing an increase in HbF. Pociredir is being developed for the treatment of SCD. Initial data in SCD in the PIONEER Phase 1b clinical trial showed proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. Through the completion of the 12 mg dose cohort, pociredir was demonstrated to be generally well-tolerated in people with SCD with up to three months of exposure, with no treatment-related SAEs reported. Pociredir has been granted FDA Fast Track designation and Orphan Drug Designation for the treatment of SCD. To learn more about clinical trials of pociredir please visit ClinicalTrials.gov. About Sickle Cell DiseaseSCD is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with SCD typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release are forward-looking statements, including express or implied statements regarding Fulcrum’s Phase 1b PIONEER clinical trial of pociredir, including planned data announcement for such trial; the potential of pociredir to increase HbF to levels that could ameliorate symptoms of SCD and transform the standard of care; Fulcrum’s ability to progress its early stage development programs and planned IND filings related thereto; and its projected cash runway, among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrum’s ability to continue to advance its product candidates in clinical trials, including progressing early stage candidates into the clinic; initiating and enrolling clinical trials on the timeline expected or at all; obtaining and maintaining necessary approvals from the FDA and other regulatory authorities; replicating in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials; obtaining, maintaining or protecting intellectual property rights related to its product candidates; managing expenses; realizing the anticipated benefits of the workforce reduction and strategic realignment and managing risks associated therewith; and raising the substantial additional capital needed to achieve its business objectives, among others. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Fulcrum’s actual results to differ from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties, and other important factors, in Fulcrum’s most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent Fulcrum’s views as of the date hereof and should not be relied upon as representing Fulcrum’s views as of any date subsequent to the date hereof. Fulcrum anticipates that subsequent events and developments will cause Fulcrum’s views to change. However, while Fulcrum may elect to update these forward-looking statements at some point in the future, Fulcrum specifically disclaims any obligation to do so. Fulcrum Therapeutics, Inc.Selected Consolidated Balance Sheet Data(In thousands)(Unaudited) September 30,2025 December 31,2024 Cash, cash equivalents, and marketable securities $200,645 $241,021 Working capital(1) 194,231 238,879 Total assets 214,858 260,718 Total stockholders’ equity 198,366 243,034 (1) Fulcrum defines working capital as current assets minus current liabilities. Fulcrum Therapeutics, Inc.Consolidated Statements of Operations(In thousands, except per share data)(Unaudited) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024 Collaboration revenue — — — 80,000 Operating expenses: Research and development 14,296 14,639 40,687 51,673 General and administrative 7,562 8,424 21,389 28,732 Restructuring expenses — 2,063 — 2,063 Total operating expenses 21,858 25,126 62,076 82,468 Loss from operations (21,858) (25,126) (62,076) (2,468)Other income, net 2,263 3,430 7,530 9,311 Net (loss) income $(19,595) $(21,696) $(54,546) $6,843 Net (loss) income per share, basic $(0.31) $(0.35) $(0.87) $0.11 Net (loss) income per share, diluted $(0.31) $(0.35) $(0.87) $0.11 Weighted-average common shares outstanding, basic 62,597 62,409 62,537 62,200 Weighted-average common shares outstanding, diluted 62,597 62,409 62,537 63,688 Contact: Kevin GardnerLifeSci Advisors, LLCkgardner@lifesciadvisors.com617-283-2856