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― Patient enrollment and site activation progressing in Phase 1b PIONEER trial of pociredir in sickle cell disease (SCD) ― ― Ended the third quarter of 2024 with $257.2 million in cash, cash equivalents, and marketable securities; cash runway into at least 2027 ― ― Conference call and webcast scheduled for 8:00 a.m. ET today ― CAMBRIDGE, Mass., Nov. 13, 2024 (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 2024 as well as a business update. “In the third quarter, we made progress enrolling patients and activating new sites in the Phase 1b PIONEER trial of pociredir in sickle cell disease and advancing our preclinical pipeline,” said Alex C. Sapir, Fulcrum’s president and chief executive officer. “The need for effective therapeutic options for patients with sickle cell disease has become even more urgent due to the recent withdrawal of OXBRYTA® globally. Based on the initial data generated in the Phase 1b trial, we believe that pociredir has the potential to increase fetal hemoglobin to levels that could ameliorate symptoms of sickle cell disease. While we were disappointed with the results of the Phase 3 REACH trial announced in September, we remain committed to improving the lives of patients with genetically defined diseases in areas of high unmet medical need like sickle cell disease. We are focused on progressing the development of pociredir as expeditiously as possible and remain on track to provide data from the PIONEER trial in 2025.” Recent Business Highlights Patient enrollment and site activations continue to progress in the Phase 1b PIONEER trial evaluating pociredir in patients with SCD. Cohort 3 of the Phase 1b trial is evaluating pociredir at the 12 mg once daily dose, which will be followed by Cohort 4 at the 20 mg once daily dose. Each cohort is expected to enroll up to 10 patients. Fulcrum plans to share clinical data from the PIONEER trial in 2025.Following recent interactions with the FDA, Fulcrum plans to initiate Phase 1 clinical studies in healthy volunteers in support of the overall pociredir development program.Following the REACH trial results disclosed in September 2024, Fulcrum suspended development of losmapimod and has focused its research and development activities on advancing pociredir for the treatment of SCD, as well as advancing novel therapeutic agents for the potential treatment of inherited aplastic anemias, such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia, and its early discovery programs. Third Quarter 2024 Financial Results Cash Position: As of September 30, 2024, cash, cash equivalents, and marketable securities were $257.2 million, as compared to $236.2 million as of December 31, 2023. The increase is due to the $80.0 million upfront payment received from Sanofi in the second quarter of 2024, partially offset by cash used to fund operating activities in 2024.Collaboration Revenue: Collaboration revenue was zero for the three months ended September 30, 2024, as compared to $0.8 million for the three months ended September 30, 2023. The decrease of $0.8 million was due to the completion of research services under the collaboration agreement with MyoKardia during the fourth quarter of 2023.R&D Expenses: Research and development expenses were $14.6 million for the three months ended September 30, 2024, as compared to $18.2 million for the three months ended September 30, 2023. The decrease of $3.6 million was primarily due to the reimbursement from the global development cost sharing under the collaboration with Sanofi for losmapimod, partially offset by increased costs related to the advancement of the Phase 1b PIONEER trial.G&A Expenses: General and administrative expenses were $8.4 million for the three months ended September 30, 2024, as compared to $10.0 million for three months ended September 30, 2023. The decrease of $1.6 million was primarily due to decreased employee compensation costs as a result of the reduction in workforce implemented in the third quarter of 2024.Net Loss: Net loss was $21.7 million for the three months ended September 30, 2024, as compared to a net loss of $24.0 million for the three months ended September 30, 2023. Cash Guidance Based on its current operating plans, Fulcrum expects to end 2024 with approximately $240.0 million of cash, cash equivalents, and marketable securities, and expects its cash burn for the full year 2025 will be approximately $55.0 million to $65.0 million. Fulcrum also expects that its cash, cash equivalents, and marketable securities as of September 30, 2024 will be sufficient to fund its current operating requirements into at least 2027. Conference Call and Webcast Fulcrum Therapeutics, Inc. will host a conference call and webcast today at 8:00 a.m. ET to review the third quarter 2024 financial results and recent business highlights. Individuals may register for the conference call by clicking the link here. Once registered, participants will receive dial-in details and unique PIN which will allow them to access the call. An audio webcast will be accessible through the Investor Relations section of Fulcrum's website at www.fulcrumtx.com or by clicking here. Following the live webcast, an archived replay will also be available. About Fulcrum Therapeutics Fulcrum 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 program in clinical development is pociredir, a small molecule designed to increase expression of fetal hemoglobin and in development 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 Twitter/X (@FulcrumTx) and LinkedIn. About Pociredir Pociredir is an investigational oral small-molecule inhibitor of Embryonic Ectoderm Development (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 fetal hemoglobin (HbF). Pociredir is being developed for the treatment of SCD. Initial data in SCD demonstrated proof-of-concept and achieved absolute levels of HbF increases associated with potential overall patient benefit. In clinical trials conducted prior to the clinical hold, which was lifted by the FDA in August 2023, pociredir was generally well-tolerated in people with SCD with up to three months of exposure, with no serious treatment-related adverse events reported. Pociredir has been granted FDA Fast Track designation and Orphan Drug Designation for the treatment of SCD. To learn more about these trials please visit ClinicalTrials.gov. About Sickle Cell Disease Sickle cell disease (SCD) 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 status of enrollment, number of patients per cohort and planned data announcement for such trial; the potential of pociredir to increase fetal hemoglobin to levels that could ameliorate symptoms of SCD; resumption of Phase 1 clinical studies in healthy volunteers ; Fulcrum’s ability to progress its early stage development programs; the effects of the reduction in workforce; and its projected year end cash position, cash runway and cash burn for 2025, 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; 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; realize 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, 2024 December 31, 2023 Cash, cash equivalents, and marketable securities $257,234 $236,221 Working capital(1) 252,980 228,524 Total assets 279,008 257,694 Total stockholders’ equity 257,291 235,193 (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 Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Collaboration revenue $— $759 $80,000 $1,934 Operating expenses: Research and development 14,639 18,238 51,673 52,802 General and administrative 8,424 9,961 28,732 31,804 Restructuring expenses 2,063 — 2,063 — Total operating expenses 25,126 28,199 82,468 84,606 Loss from operations (25,126) (27,440) (2,468) (82,672)Other income, net 3,430 3,423 9,311 10,093 Net (loss) income $(21,696) $(24,017) $6,843 $(72,579)Net (loss) income per share, basic $(0.35) $(0.39) $0.11 $(1.19)Net (loss) income per share, diluted $(0.35) $(0.39) $0.11 $(1.19)Weighted-average common shares outstanding, basic 62,409 61,823 62,200 61,121 Weighted-average common shares outstanding, diluted 62,409 61,823 63,688 61,121 Contact: Chris Calabrese LifeSci Advisors, LLC ccalabrese@lifesciadvisors.com 917-680-5608

此次医博会由同写意策划，以“发展新质生产力，共享健康新未来”为主题，用全新的视角瞄准国内外医药及大健康产业发展前沿。诚邀海内外医药及大健康各界嘉宾齐聚中国医药城，共赴时代之约。 自宣布剥离消费者健康部门一年后，赛诺菲终于走出实质性的一步。 10月，这家法国巨头在市场的猜测中最终证实，将Opella的50%股权出售给美国私募公司CD&R，对价约为174亿美元（160亿欧元）。如果顺利，交易最早将于2025年第二季度完成。 根据媒体报道，赛诺菲打算在未来几年内，出售其消费者健康部门的剩余股份。届时，它便成为一家纯粹的生物制药公司。 转身背后，既是行业的广泛趋势，也是赛诺菲当前亟需变革的题中之义。今年上半年，赛诺菲旗下Dupixent营收首次超过Humira，成为自免赛道的“药王”。但二级市场反响平平，多少透露出投资者对这份“正常发挥”的成绩背后的隐忧——它似乎靠着Dupixent撑起生物制药板块的半壁江山，对于创新热点，实在错失太多了。 前有ADC，后有GLP-1，当一众同行纷纷下场扫货，看起来有些老派的赛诺菲动作迟迟。 实际上，2019年，赛诺菲首席执行官Paul Hudson就启动“全力致胜”战略，加速这家巨头的制药创新进程。 应当承认，着手剥离Opella的同时，赛诺菲已投资不少潜力资产。可创新领域的高风险铁律，意味着它通往肿瘤学、免疫学和疫苗等市场的王者之路，并非光凭破釜沉舟、壮士断腕的魄力就能办到。 辉瑞、诺和诺德、艾伯维都在近期摔了跟头。值得注意，后两者都是收购一年内面临开发挫折，艾伯维87亿美元的加码，更在11月两项临床失败刺激中，一日蒸发近400亿美元市值。 小步快跑的赛诺菲，会把握前车之鉴吗？ 1 10月“三板斧” “全力致胜”战略标志着赛诺菲向生物制药的明确转型。去年宣布剥离Opella的计划时，Hudson强调，他们致力于将变革性药物带向市场。 正如赛诺菲的先行者一样，成为一家纯粹的生物制药公司的关键，是投资。 尽管2023年的并购狂潮中，赛诺菲的身影并不起眼，并且它今年仅有的一次并购还是1月买下Inhibrx，但Opella处理上的实质进展，如同给这家MNC更多的交易底气和魄力。光是10月里，赛诺菲就宣布三笔不同治疗领域的投资。 01 肿瘤核药 10月17日，赛诺菲与Orano Med的战略合作伙伴关系浮出水面。 Orano Med是Orano集团的子公司，专门从事肿瘤靶向α疗法。此次合作旨在利用Orano Med在基于Pb-212的技术方面的专长，开发针对罕见癌症的下一代放射性配体疗法，AlphaMedix。 作为首个获得FDA突破性疗法认定的靶向α疗法，AlphaMedix正处于II/III期开发阶段，用于治疗患有表达生长抑素受体的进行性、不可切除或转移性神经内分泌肿瘤患者。临床上，这类癌症的治疗选择有限。 简言之，放射性配体疗法的原理，是将放射性同位素与针对特定癌细胞分子相结合，在患处实现杀伤效果。Pb-212属于一种发射α射线的同位素，具有能线密度高、电离辐射效应大、射程短等特点，这可以增强对肿瘤细胞的破坏力，同时保护周围的正常细胞。 不同于诺华已把“核药”的标签牢牢跟自己捆绑，也不像阿斯利康、BMS、礼来这样或多或少慢上几拍的跟随者，赛诺菲直到近期才进军放射性配体疗法赛道。 今年前三季度，光是Pluvicto一款产品的总销售额，就给诺华带来10.4亿美元营收。这对整个放射性药物行业，也是迈入“重磅炸弹”级产品的重要节点。所以，赛诺菲的“火急火燎”就不难理解。 上个月，赛诺菲还跟RadioMedix、Orano Med签署了三方协议，以开发另一款放射性配体疗法AlphaMedix。 02 纤维化疗法 10月25日，赛诺菲参与比利时公司Agomab Therapeutics的D轮8900万美元融资，透露出它在制药领域的更广泛探索。 Agomab正在开发慢性疾病中调节纤维化和促进再生的疗法，这些疾病包括纤维狭窄性克罗恩病、特发性肺纤维化等。 一方面，该克罗恩病亚型现有治疗选择有限，诸如类固醇和免疫抑制剂，侧重于控制炎症和缓解症状，并不能直接解决纤维化成分；另一方面，市面上的特发性肺纤维化疗法可能减缓疾病进展，不过效果有限，并伴有潜在副作用。 因此，这两种情况下，患者最终都需要手术干预。 赛诺菲通过对Agomab的战略投资，试图为多种疾病寻找first-in-class药物。Agomab的主要候选药物AGMB-129，是一种针对ALK5（TGFβ1R）的肠道限制性口服小分子抑制剂，目前进行治疗纤维狭窄性克罗恩病的IIa期临床。相关中期数据，预计在2025年第一季度公布。 值得注意，赛诺菲之前，Agomab就得到辉瑞、BI等巨头的入股支持。尽管此次合作让赛诺菲搭上了车，拓展免疫学和炎症领域的布局，但想要赶超其他同行，还需更快地行动。 03 肥胖RNA疗法 10月28日，赛诺菲股权投资方面梅开二度，加码意大利公司Resalis Therapeutics，后者专门从事基于RNA的代谢紊乱疗法。 这项投资旨在通过II期概念验证临床，加速Resalis的主要候选药物RES-010的开发。作为一种潜在first-in-class反义寡核苷酸，RES-010靶向microRNA-22（miR-22），这是与肥胖和相关代谢疾病有关的非编码RNA。 Resalis希望，通过抑制microRNA-22，RES-010重新编程代谢途径，从而帮助持续减轻体重，改善代谢健康。 肥胖问题自前两年就逐渐登上热门，诺和诺德、礼来凭借各自的GLP-1药物，在股价暴涨的同时，进一步刺激着更多资本涌入。亦步亦趋似乎难以超越了，一些在后的MNC和Biotech，正考虑从增肌等细分市场切入。 相比起来，赛诺菲采取的策略有所不同。通过更上游的机制，RNA疗法或许可以解决GLP-1药物面临的挑战，例如供应问题。 2 扩围的基本盘 跨国药企的“VC化”，早已不是什么奇闻逸事。 这个领域，赛诺菲有着漫长的生物技术投资轨迹，乃至追溯到着手拆分Opella之前。迄今为止，该MNC投资版图纳入60家公司，涵盖从早期到成熟阶段不同的技术路线，例如CGT。 现阶段，全球大部分的CGT公司都是初创Biotech。制药巨头常选择与这些Biotech合作来快速切入相关市场。诸如Bluebird Bio、Fate Therapeutics等明星项目背后，亦可见赛诺菲的身影。不过，它的基本盘似乎仍在免疫学上。 宣布剥离消费者健康部门后不久，赛诺菲向临床阶段基因治疗公司MeiraGTx投资了3000万美元。 由此，赛诺菲引进MeiraGTx的核糖开关基因调控技术，用于免疫学和炎症、CNS靶点、GLP-1和其他用于治疗代谢疾病的肠道肽的开发。此外，该巨头也得到MeiraGTx旗下处于II期口干症项目的优先权。 核糖开关是一段RNA，能响应特定小分子来调节基因表达。MeiraGTx称，其核糖开关技术精确控制基因表达，从而实现治疗基因的调节。 赛诺菲希望将核糖开关技术重点应用于免疫学。这项技术有望带来高精度调节免疫反应的疗法，进一步巩固它在自免、炎症疾病上的优势地位。 而8月，赛诺菲还未对外宣布跟CD&R的交易时，就参与了AnaptysBio的1亿美元新股直接发行。 AnaptysBio专注开发用于自免、炎症疾病的免疫细胞调节剂，其中包括几种临床阶段的检查点激动剂：ANB032（BTLA激动剂）处于治疗特应性皮炎的IIb期，Rosnilimab（PD-1激动剂）也处于治疗类风湿性关节炎和溃疡性结肠炎的IIb期。 综合来看，赛诺菲正围绕它的“全力致胜”战略，加快成为一家纯粹生物制药公司的步伐。 通过将50%的Opella股权转让给CD&R，赛诺菲降低当前的营收波动——消费者健康部分拥有Doliprane、Allegra等系列畅销产品，长期为公司贡献不菲的销售额——更重要的是，由此获得超过170亿美元的资金，为持续转型提供保障。 因此，接下来赛诺菲大概率还有其他投资动作，借助不同的生物制药产品线，建立更多协同效应。 3 创新转型隐忧 有目共睹，制药巨头们面临着新的转折点。 从业务布局上看，过于多元化的战略逐渐被抛弃，MNC纷纷聚焦生物制药，寻找和开发“重磅炸弹”产品，以期避开“专利悬崖”，同时获得业绩增长。 消费者健康部门的定位显然与这套叙述冲突。2022年，GSK就将旗下业务剥离，后者最终以新公司Haleon的形式独立运营。强生在2023年，也完成与消费者健康部门Kenvue的分离。 赛诺菲出售Opella，预计为其生物制药研发注入大量资源。按照规划，得益于更多资金投入后期药物开发，赛诺菲的III期管线有望扩大50%。 2030年，赛诺菲对免疫学、肿瘤学和疫苗等核心领域所制定的目标，是超过239.7亿美元（220亿欧元）销售额。对外投资交易的例子表明，这家MNC努力保持风险和回报的平衡，建立一个创新驱动的产品组合。 然而需要指出，赛诺菲必须特别小心。除了并购后的整合压力外，在交易的大年，巨头们通常更容易因为担心错过机会，而轻视后期挑战。 最新教训，发生在艾伯维身上。该公司去年12月斥资87亿美元收购Cerevel Therapeutics，但11月11日公告称，引进的emraclidine在两项重要临床试验中失败。随后，艾伯维股价下跌超过12%。 10月，诺和诺德就宣布终止ocedurenone的开发，距离这款候选产品的引进，也只过了一年。当时，诺和诺德花了13亿美元，设想该药能成为拜耳旗下CKD药物Kerendia的竞争对手。 自从买进ocedurenone，诺和诺德的开发过程却并不顺利。7月，一项针对高血压和晚期CKD的III期临床预定中期分析显示，潜力新药错过主要终点，诺和诺德只好叫停研究。当时，诺和诺德还尝试评估ocedurenone用于其他治疗领域的潜力，结果几个月后，就决定将之彻底放弃。 另一个案例来自辉瑞。9月，辉瑞表示要从全球市场撤回SCD药物Oxbryta。 Oxbryta属于Global Blood Therapeutics的一项核心资产，2022年公司被辉瑞斥资54亿美元并购时，一同进入后者管线。2019年，Oxbryta获FDA加速批准，之后也在多国上市。根据财报，该药2023年贡献了3.28亿美元的销售额。 成熟的商业化产品，为什么不卖了？问题出在安全性上。最新临床试验数据显示，Oxbryta近来牵涉多名患者死亡，临床获益不再超过风险。 其实，赛诺菲也已摔过跟头。今年更早前的4月，赛诺菲被曝出关闭近4亿美元收购的NK细胞疗法公司Kiadis Pharma。2020年，二者曾因为NK细胞疗法走到一起，但四年后，代号为SAR445419的资产I期临床终止。 上述同行与自身的受挫，强化了创新之路难走的现实。 Opella相关交易带来的资金外，赛诺菲启动了成本削减措施，目标是到2025年节省21.8亿美元（20亿欧元）。它表示，这也会投入生物制药转型的各项研发。 手头宽松后，接下来的生物制药交易领域，这家巨头或许变得更加活跃。但最终，赛诺菲还是得拿出实打实的成绩，才能说服投资者。 参考资料： 1.From consumer health to pure biopharma: Inside Sanofi’s strategic shift 2.Sanofi completes the $1.7bn acquisition of Inhibrx 3.手握自免新王股价却难有起色，中国新药资产或成为赛诺菲的“救星” 4.AbbVie’s $9B bet collapses as closely watched schizophrenia drug fails studies 同写意媒体矩阵，欢迎关注↓↓↓