Tasurgratinib

-01-引言成纤维细胞生长因子（FGF）通过FGF受体（FGFR1-4）发出信号，协调胎儿发育，有助于组织和全身稳态，但FGFR基因的融合、重排或突变也可能促进肿瘤发生。FGFR融合可分为I型（非受体型，由融合伴侣的N端置换引起，如BCR-FGFR1和ZYM2-FGFR1）、IIa型（受体型，也由融合伴侣N端置换产生；如FN1-FGFR1、KLK2-FGFR2）或IIb型（受体型，由融合伴侣C端置换产生；如FGFR2-BICC1、FGFR3-TACC3）。在实体瘤中检测到的FGFR变化包括非小细胞肺癌中的FGFR1扩增（20%）、乳腺癌中的FGFR 1/2扩增（7-23%）、尿路上皮癌中的FGFR3突变（10-60%）或FGFR3融合（6%）、肝内胆管癌中的FGFR2融合（10-20%）、子宫内膜癌中的FGFR2突变（12%）和胃癌中FGFR2的扩增（5-10%）。在约7.0%的未经选择的癌症患者中可以检测到FGFR基因的改变。目前，已经开发出了多种FGFR靶向药物，包括泛FGFR抑制剂（erdafitinib和futibatinib）、FGFR1/2/3抑制剂（infigratinib和pemigatinib），以及一系列更具特异性的药物，其中一些已进入临床使用。Erdafitinib已被批准用于携带FGFR2/3突变的尿路上皮癌患者，futibatinib和pemigatinib被批准治疗携带FGFR2融合或重排的胆管癌患者。这些药物的临床益处在一定程度上受到高磷血症的限制，这是由于FGFR1的脱靶抑制以及FGFR基因中耐药性突变的出现。下一代小分子抑制剂，如lirafugratinib和LOXO-435，以及FGFR2特异性抗体bemarituzumab，有望降低高磷血症的风险，并有能力克服某些耐药性突变。-02-一、FGFR的结构和信号通路FGFs由具有球状或非典型β三叶结构的保守核心结构域组成，可分为典型FGFs（FGF1-10、FGF16-18、FGF20和FGF22）、内分泌型FGF（FGF19/FGF15、FGF21和FGF23）以及FGF同源因子（FGF11-14）。全长FGF受体（FGFR1-4）是I型跨膜蛋白，具有三个细胞外免疫球蛋白样结构域和一个胞内酪氨酸激酶结构域。典型的FGF与硫酸乙酰肝素辅因子一起通过FGFR传递信号，而内分泌型FGF与klotho共受体（KLA和KLB）和硫酸乙酰肝素辅助因子一起通过FGFR传递信号。FGF–FGFR信号传导参与细胞存活、增殖、代谢、迁移和分化，包括生理作用，如协调胎儿发育和维持组织和/或全身稳态。这些受体也可以驱动肿瘤的发展。FGFR中配体依赖性二聚化或病理改变通过自身抑制机制释放而导致内源性激酶激活。FGFR激活导致FRS2依赖性激活PI3K–AKT、RAS–ERK和磷脂酶Cγ（PLCγ）依赖性二酰基甘油（DAG）–PKC和IP3–Ca2+信号。癌症患者的FGFR改变通过异常的FGFR信号传导促进肿瘤发生：FGFR扩增导致FGFR过度表达和下游信号通路过度激活；FGFR融合或重排导致融合伴侣介导的FGFR二聚化、磷酸化改变和异常的下游信号传导；细胞外区或跨膜结构域中的FGFR突变通过改变对FGF配体的特异性或亲和力，以及配体非依赖性二聚化来激活FGFR；酪氨酸激酶结构域中的FGFR突变由于自身抑制机制的破坏而结构性性地激活FGFR。-03- 二、小分子FGFR抑制剂几种小分子FGFR抑制剂已被开发用于治疗具有FGFR改变的癌症患者，如尿路上皮癌、乳腺癌、胃癌、肝癌、肺癌、卵巢癌和宫颈癌。能够与酪氨酸激酶结构域的ATP结合位点结合的FGFR抑制剂通常分为多激酶FGFR抑制剂或选择性FGFR抑制剂。Derazatinib、dovitinib、tasurgratinib、lenvatinib、lucitanib、nintedanib和ponatinib都是多激酶FGFR抑制剂，对FGFR以外的多种RTK具有活性。然而，由于其广泛的活性，与选择性FGFR抑制剂相比，多激酶FGFR抑制剂的作用机制和不良反应都很复杂。选择性FGFR抑制剂包括泛FGFR、FGFR1/2/3和FGFR2/3抑制剂以及选择性FGFR2、FGFR3或FGFR4抑制剂。泛FGFR抑制剂包括 erdafitinib, futibatinib, rogaratinib和resigratinib；FGFR1/2/3抑制剂包括pemigatinib, infigratinib, fexagratinib和zoligratinib；Lirafugratinib是一种选择性FGFR2抑制剂，LOXO-435是一种选择FGFR3抑制剂，roblitinib和fissotioninib是选择性FGFR4抑制剂。目前，根据在II期试验中观察到的疗效和耐受性，美国食品药品监督管理局（FDA）在这些适应症的二线或更后线的治疗中加速批准erdafitinib、futibatinib、infigratinib和pemiginib。在erdafitinib的临床研究（BLC2001）中，根据FGFR3或FGFR2/FGFR3融合物中至少一种突变的存在，选择局部晚期和/或不可切除的尿路上皮癌患者。整体队列的ORR为40%，中位无进展生存期（mPFS）和中位总生存期（mOS）分别为5.5个月和13.8个月。46%的患者出现≥3级不良事件，在初步分析中包括低钠血症（11%）、口腔炎（10%）和乏力（7%），以及长期随访的指甲（15%）、口炎（14%）和皮肤事件（8%）。在FIGHT-203的II期研究中，在携带I型FGFR1融合（如ZMYM2–FGFR1或BCR–FGFR2）的MLN患者中测试了pemiginib的药效和安全性。其中77%（24/31）的患者对pemiginib有完全响应。常见的≥3级不良事件包括贫血（18%）、口腔炎和四肢疼痛（均为12%）。2022年8月，FDA批准了pemiginib用于携带FGFR1融合的复发性和/或难治性MLN患者。任何级别的高磷血症都发生在大多数接受泛FGFR抑制剂或FGFR1/2/3抑制剂的患者中。这种不良反应很可能反映了泛FGFR或FGFR1/2/3抑制剂对FGF23信号传导的抑制，因为这种分泌蛋白依赖于与近端小管上皮细胞膜上的FGFR1和klotho的结合。该复合物通过抑制磷酸钠协同转运蛋白（NPT2a/c）调节肾脏中的磷酸盐吸收。FGFR1在这一过程中的作用得到证实，因此，开发FGFR2特异性和FGFR3特异性抑制剂有望避免或降低这种不良反应的发生率。-04-三、FGFR抑制性单克隆抗体在靶向FGF/FGFR信号的生物制剂中，bemarituzumab是目前正在III期试验中评估的唯一药物。bemarituzumab是一种人源化抗FGFR2b抗体，其抑制FGF7、FGF10和FGF22的结合，从而抑制癌细胞中配体诱导的FGFR2b信号传导，并且由于修饰的Fc结构域对自然杀伤细胞上的人FcγRIIIA受体的亲和力增加，因此具有诱导抗体依赖性细胞介导的细胞毒性（ADCC）的能力。在一项涉及晚期FGFR2b过表达胃和胃食管交界腺癌（GEA）患者的I期试验中，bemarituzumab单药治疗显示出可接受的耐受性，ORR为18%（5/28）。随后，在携带FGFR2扩增或FGFR2过表达的GEA患者的II期FIGHT试验中，将bemarituzumab与mFOLFOX6（包括氟嘧啶、亚叶酸和奥沙利铂）联合测试。bemarituzumab联合化疗组和安慰剂联合化疗组患者的ORR分别为53%和40%，mPFS分别为9.5个月和7.4个月（P=0.073)。bemarituzumab的其他几项试验，包括评估bemarituzumab联合mFOLFOX6加(NCT0511626) 或不加(NCT050252801) nivolumab在先前未经治疗的晚期GEA患者中的研究正在进行中。-05-四、新型FGFR靶向疗法蛋白水解靶向嵌合体（PROTAC）、嵌合抗原受体（CAR）T细胞、抗体偶联药物（ADC）、放射免疫偶联物（RICs）和可溶性受体是能够靶向FGF–FGFR信号级联的潜在新治疗模式，其中一些已经或正在临床试验中进行测试。PROTACPROTAC具有双重部分，使其能够与靶蛋白和E3泛素连接酶相互作用，从而诱导靶蛋白的泛素化介导的蛋白酶体降解。LC-MB12是一种基于infigratinib的PROTAC，能够优先降解FGFR2，并抑制表达TEL–FGFR2融合的Ba/F3细胞和FGFR2扩增的SNU16癌细胞的增殖。相比之下，DGY-09-192是另一种基于 infigratinib的PROTAC，旨在募集von Hippel–Lindau蛋白（VHL），从而优先降解FGFR1和FGFR2。这些药物目前仍处于临床前开发阶段。CAR-T细胞由于PAX3–FOXO1的下游作用，FGFR4在儿科横纹肌肉瘤中普遍过表达。然而，N535K和V550L等耐药性突变通常在治疗前出现，这可能会限制小分子抑制剂的有效性。因此，研究人员开发了靶向FGFR4的CAR-T细胞，如RJ154-HL和3A11，具有不同的靶向FGFR4的scFv。目前，靶向FGFR的CAR-T细胞也仍处于临床前开发阶段。基于抗体的药物Aprutumab是一种全人源抗FGFR2抗体，它识别FGFR2b和FGFR2c亚型共同N末端区域P23、L27和E29周围的表位，并已被证明能诱导这些变体的内化和运输至溶酶体降解。Aprutumab和bemarituzumab在I期临床试验中均显示出良好的安全性和耐受性。目前，bemarituzumab已作为联合疗法进行II期和III期临床试验，而Aprutumab用于开发ADCs和RICs。Aprutumab ixadotin（前身为BAY-1187982）是具有不可裂解连接子的抗FGFR2 ADC，LY3076226是具有可裂解连接子的抗FGFR3 ADC。然而，测试这两种药物的第一阶段试验(nct22368951)由于耐受性差和活性有限而终止。此外，Aprutumab和抗FGFR3抗体vofatamab分别用于FGFR2靶向的RIC（227Th-Aprutumab，BAY 2304058）和FGFR3靶向的RIC，225Ac-vofatamab（FPI-1966）和111In vofatamab（FPI-1967）。BAY 2304058仍处于临床前开发阶段，而FPI-1966（用于放射免疫疗法）和FPI-1967（用于放射成像）目前正在I/II期试验(NCT05363605)中进行测试，用于表达FGFR3的晚期实体瘤患者。可溶性FGFR受体可溶性FGFR受体，如衍生自FGFR1c的细胞外结构域的FP-1039和衍生自FGFR 3c的细胞外区域的Recifecept，是另一类通过充当诱饵受体来捕获FGFR配体的重组蛋白药物。FP-1039已显示对促有丝分裂FGF配体具有高亲和力，并且在FGFR1扩增的肺癌和FGFR2突变的子宫内膜癌的小鼠异种移植模型中具有抗肿瘤作用。FP-1039在一期试验中具有可接受的耐受性。测试FP-1039与各种化疗联合用药的Ib期试验(NCT01868022) 显示同时接受紫杉醇和卡铂治疗的鳞状非小细胞肺癌患者的ORR为47%，同时接受培美曲塞和顺铂治疗的恶性胸膜间皮瘤患者的ORR为39%。-06-结语目前，小分子FGFR抑制剂和FGFR靶向抗体药物已在临床后期试验中进行开发和测试，其中几种小分子FGFR抑制剂已被批准用于FGFR改变的癌症患者。尽管如此，某些不良事件，如FGFR1脱靶抑制引起的高磷血症和获得性耐药性，仍然限制了这些药物的临床益处。选择性第三代抑制剂，如特异性靶向FGFR2或FGFR3的抑制剂，正在临床开发中，这些药物可能避免或显著降低高磷血症的风险，并可能克服突变介导的耐药性。参考资料：1.FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. 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In February 2025, the global pharmaceutical industry witnessed a series of milestone post-marketing collaboration deals, highlighting a deep integration of pharmaceutical innovation and market expansion that transcends geographical boundaries. From treatments for rare diseases to cancer management, and from improving sleep quality to alleviating chronic pain, drug development and distribution partnerships are advancing at an unprecedented pace. In February, Eisai joined forces with SciClone Pharmaceuticals to advance the application of tasurgratinib in the Greater China region, offering new hope to patients with cholangiocarcinoma. Meanwhile, Nxera Pharma’s partnership with Holling Bio-Pharma Corp. aims to introduce daridorexant to the Taiwanese market, providing a novel treatment option for insomnia sufferers. In another example of global collaboration, Bavarian Nordic and Biological E Limited announced a partnership to expand global supply of the chikungunya vaccine, underscoring the cooperative spirit of multinational companies in addressing public health challenges. 1. Eisai and SciClone Partner to Advance the Development and Distribution of Tasurgratinib in Greater China On February 28, 2025, Eisai announced a significant licensing agreement with a subsidiary of SciClone Pharmaceuticals. The agreement grants SciClone exclusive rights to develop and commercialize tasurgratinib in Greater China, including Mainland China, Hong Kong, Macau, and Taiwan. Tasurgratinib is a novel tyrosine kinase inhibitor that selectively inhibits FGFR1, FGFR2, and FGFR3. It has already been approved in Japan for the treatment of unresectable cholangiocarcinoma with FGFR2 gene fusions or rearrangements that have progressed after chemotherapy, and it was successfully launched in November 2024. Through this collaboration, Eisai aims to leverage SciClone’s strong market presence and commercialization capabilities in the region to accelerate the local deployment of tasurgratinib, bringing hope to more patients. Under the terms of the agreement, Eisai will receive an upfront payment in recognition of the licensing rights. In addition, milestone payments will be made as the drug progresses through development stages and secures regulatory approvals. Following product launch, Eisai will also receive royalties based on net sales, providing a return on its R&D investment and reflecting confidence in the drug’s market performance. This financial structure is designed to promote close collaboration between both parties and maximize the value of tasurgratinib. Tasurgratinib, as an orally bioavailable tyrosine kinase inhibitor, exerts its effects through selective inhibition of FGFR1, FGFR2, and FGFR3. This selectivity allows tasurgratinib to target specific types of cancer cells effectively without interfering with other essential physiological processes. In particular, tumors associated with FGFR abnormalities—such as cholangiocarcinoma and certain breast cancers—present promising therapeutic targets. In addition to its approved use in cholangiocarcinoma in Japan, tasurgratinib is currently undergoing a Phase I clinical trial in Japan for patients with estrogen receptor-positive, HER2-negative breast cancer, further exploring its potential in broader oncology indications. 2. Nxera Pharma and Holling Collaborate to Commercialize Daridorexant in Taiwan On February 28, 2025, Tokyo- and Cambridge-based Nxera Pharma announced it had signed a licensing, supply, and commercialization agreement with Holling Bio-Pharma Corp., Taiwan’s largest pharmaceutical distributor, to bring daridorexant to the Taiwanese market. The collaboration seeks to address the growing demand for effective insomnia treatments in the region. Daridorexant is a new oral dual orexin receptor antagonist (DORA) that helps regulate overactive wakefulness signals by selectively binding to and inhibiting orexin receptors OX1R and OX2R, thereby promoting better sleep onset and maintenance. Under the agreement, Nxera will supply the drug product, while Holling will handle regulatory approval, commercialization, and distribution activities, retaining all regulatory rights. Holling is expected to submit a New Chemical Entity (NCE) application to the Taiwan Food and Drug Administration by mid-2025. If approved, daridorexant could be launched in Taiwan by mid-2026. Nxera will receive an upfront payment upon signing, along with additional milestone payments based on regulatory progress and sales performance. Nxera is also entitled to royalties on net sales from product supply, reflecting the mutual confidence in daridorexant’s market potential and supporting further development efforts. Daridorexant works by blocking the binding and activity of orexins—neuropeptides that promote wakefulness—through dual inhibition of their receptors. The drug has already been launched in Japan under the brand name QUVIVIQ™ following approval in September 2024 and a subsequent market launch in December 2024 by Nxera Pharma Japan in collaboration with Shionogi. Nxera is also conducting a Phase III clinical trial in South Korea to evaluate daridorexant’s efficacy and safety in adults with insomnia. Notably, QUVIVIQ™ has also received regulatory approval in the United States, Europe, and several other countries, where Idorsia Pharmaceuticals Ltd. is responsible for marketing activities. This broad international recognition further supports daridorexant’s status as a best-in-class treatment option. The development of daridorexant continues to progress positively. In addition to its successful launch in Japan, the Phase III trial in South Korea is ongoing, aiming to confirm the drug’s safety and efficacy in improving insomnia symptoms in adults. Given the significant number of insomnia patients in Taiwan, the introduction of daridorexant is expected to have a meaningful impact on clinical practice in the region. Furthermore, this collaboration is part of Nxera’s broader strategy to enhance access to innovative medicines across Japan and the wider Asia-Pacific region by partnering with leading regional commercial players, thus reaching a larger patient population while leveraging the company’s internal expertise in specialty and rare disease medicines. 3. Bavarian Nordic Partners with Biological E Limited to Expand Global Access to Chikungunya Vaccine On February 28, 2025, Bavarian Nordic announced a strategic partnership with Indian biopharmaceutical company Biological E Limited to enhance the global supply of its Chikungunya vaccine. This collaboration underscores both companies’ commitment to improving access to this important vaccine in developing countries. Through this partnership, Bavarian Nordic and Biological E Limited plan to co-invest in the further development of the vaccine and ensure its availability across more countries and regions. The product at the center of this agreement is a vaccine specifically designed to prevent Chikungunya virus infection. This innovative vaccine mimics the structural features of the virus—particularly its surface proteins—to induce a specific antibody response from the human immune system. These antibodies can recognize and neutralize the actual Chikungunya virus during infection, thereby preventing disease onset. Utilizing virus-like particle (VLP) technology, the vaccine delivers robust immune protection without containing live virus, significantly enhancing its safety profile. This Chikungunya VLP vaccine has already received its first regulatory approval in the United States for the prevention of Chikungunya fever. It has also been granted multiple special regulatory designations in both the U.S. and the European Union, including Accelerated Approval, Breakthrough Therapy Designation, Fast Track, and Priority Review—highlighting the recognized public health value of the vaccine. Beyond U.S. approval, additional clinical trials and regulatory submissions are underway in various other countries and regions to expand its global reach. Originally developed by PaxVax Holding Co., Ltd., the vaccine has achieved several critical development milestones. After Bavarian Nordic acquired the program, it advanced the clinical research and secured the initial U.S. approval. Through its new collaboration with Biological E Limited, the vaccine is expected to gain more rapid market access in Asia and other developing regions. Biological E Limited's deep market knowledge and extensive distribution network in these areas make it a key partner in achieving this objective. Moreover, early-stage development efforts were supported by Emergent BioSolutions, Inc. and the U.S. National Institute of Allergy and Infectious Diseases (NIAID), laying a solid foundation for the vaccine’s success. This partnership marks a significant step toward broader protection against Chikungunya fever worldwide. 4. RedHill and Hyloris Sign Global (Excluding North America) Commercialization Agreement for RHB-102 to Improve Quality of Life for Cancer and Gastrointestinal Patients On February 25, 2025, RedHill Biopharma Ltd. announced the signing of an exclusive development and commercialization licensing agreement with Hyloris Pharmaceuticals SA for RHB-102 (Bekinda®). Under this agreement, Hyloris gains the rights to develop and commercialize RHB-102 in all global markets except the United States, Canada, and Mexico. This collaboration reflects the shared commitment of both companies to provide effective treatment options to more patients worldwide, particularly those suffering from chemotherapy/radiation-induced nausea and vomiting (CINV/RINV), acute gastroenteritis, gastritis, and diarrhea-predominant irritable bowel syndrome (IBS-D). As part of the agreement, Hyloris will pay RedHill an upfront fee and milestone payments of up to $60 million based on the achievement of specific commercial targets. Additionally, Hyloris will pay mid-to-high double-digit percentage royalties on net sales, subject to certain cost deductions and inclusive of minimum annual payments. This financial structure not only provides RedHill with necessary funding support but also incentivizes Hyloris to actively promote RHB-102 and ensure its success in global markets. RHB-102 is a once-daily, dual-release, proprietary oral tablet formulation of ondansetron, a 5-HT3 receptor antagonist used to treat nausea and vomiting. It is available in two dosage strengths: 12 mg and 24 mg, aimed respectively at IBS-D and other indications such as acute gastroenteritis and gastritis. The extended-release profile allows for 24-hour symptom control, representing a significant therapeutic advancement for cancer patients undergoing chemotherapy or radiotherapy, as well as for those with gastrointestinal disorders. RHB-102 has completed multiple key clinical trials, including a Phase III study in the United States for acute gastroenteritis and gastritis (24 mg dose) and a Phase II study for IBS-D (12 mg dose), both of which met their primary endpoints. Recently, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a positive opinion, paving the way for a Marketing Authorization Application (MAA) in the UK. If approved, RHB-102 would become the first 24-hour extended-release oral ondansetron formulation indicated for CINV/RINV. RedHill also plans to continue pursuing FDA approval for RHB-102 in the United States. 5. Pharmanovia and Er-Kim Reach Exclusive Distribution Agreement for Sunosi® in Eastern Europe In February 2025, Pharmanovia announced that it had entered into an exclusive distribution agreement with Er-Kim, a leading Turkish pharmaceutical company, for Sunosi® (solriamfetol) in Eastern Europe. This collaboration brings Sunosi® to the Eastern European market to meet the treatment needs of patients suffering from narcolepsy and obstructive sleep apnea (OSA). Although specific financial details have not been fully disclosed, it can be inferred that the agreement involves an upfront payment, milestone payments, and a royalty structure based on sales performance. This arrangement not only supports further development and marketing efforts for the product but also reflects both parties' confidence in the commercial potential of Sunosi®. Sunosi® is a medication indicated for the treatment of excessive daytime sleepiness associated with narcolepsy and OSA. Its active ingredient, solriamfetol, is a selective dopamine and norepinephrine reuptake inhibitor (DNRI). By increasing the concentrations of these neurotransmitters in the brain, Sunosi® effectively enhances wakefulness and alertness, helping patients regain a normal daily rhythm. This mechanism of action makes it an important treatment option, particularly for patients who do not respond well to or cannot tolerate traditional therapies. Sunosi® has been approved and is commercially available in several countries and regions. Originally developed by Jazz Pharmaceuticals, it received FDA approval in the United States in 2019 for the treatment of excessive daytime sleepiness in adults with narcolepsy or OSA. Since then, Sunosi® has gradually expanded its market presence globally. The partnership between Pharmanovia and Er-Kim marks a significant step toward deeper penetration into the Eastern European market, allowing more patients to benefit from the treatment. Ongoing monitoring of Sunosi®'s long-term safety and efficacy continues to ensure the provision of optimal treatment options for patients. Beyond its current indications, Sunosi® may also demonstrate potential efficacy in treating other types of excessive daytime sleepiness disorders, providing new directions for future research. Pharmanovia will continue to monitor the accumulation of clinical data for Sunosi® and explore broader application possibilities. Through its collaboration with Er-Kim, Pharmanovia aims to establish a strong market position in Eastern Europe while raising awareness of the disease and available treatment options. Furthermore, as the understanding of the pathophysiology of excessive daytime sleepiness deepens, Sunosi® is expected to introduce new research findings in the coming years, offering a stronger scientific foundation for its use. This partnership between Pharmanovia and Er-Kim not only enhances the accessibility of Sunosi® in Eastern Europe but also highlights both companies' shared commitment to improving public health. Leveraging Er-Kim's strong local presence and extensive distribution network will be key to achieving this goal. Such cross-border collaborations accelerate the entry of innovative therapies into emerging markets, offering patients more treatment choices. With increasing recognition and support for Sunosi® across more countries and regions, the medication is expected to significantly improve the quality of life for patients with excessive daytime sleepiness worldwide in the coming years. 6. Apotex Partners with Grünenthal to Bring Qutenza® to the Canadian Market On February 24, 2025, Apotex Inc., Canada’s largest pharmaceutical company, and Grünenthal, a global leader in pain management and related diseases, announced a strategic licensing agreement. Under the agreement, Apotex will obtain exclusive rights to Qutenza® in Canada. This partnership aims to introduce Qutenza® as an innovative treatment option for patients suffering from neuropathic pain in Canada. Although specific financial terms have not been fully disclosed, it can be inferred that Grünenthal will receive an upfront payment, additional milestone payments upon achieving specific regulatory milestones, and royalties based on sales. This financial arrangement not only supports further development and commercialization of the product but also reflects both parties’ confidence in the commercial potential of Qutenza®. Qutenza® is a topical, non-systemic, non-opioid pain treatment patch indicated for the management of neuropathic pain. Its active ingredient is high-concentration capsaicin (8%), a naturally occurring compound that is applied directly to the skin to alleviate pain. Capsaicin works by activating and subsequently desensitizing the TRPV1 receptors in sensory nerves, which play a key role in the transmission of pain signals. Through this mechanism, Qutenza® provides effective relief from chronic pain caused by nerve damage without causing systemic side effects or the risk of addiction. This treatment is particularly beneficial for patients who do not respond well to or cannot tolerate traditional therapies. Since acquiring global rights to Qutenza® in 2018, Grünenthal has continued to invest resources in the product’s development and expansion. Qutenza® has been commercialized in the European Union and the United States, with its indication broadened through relaunch and label expansion efforts. In the U.S. market, Qutenza® has experienced a significant brand resurgence, laying a strong foundation for its further promotion worldwide. Apotex’s subsidiary, Searchlight Pharma, will be responsible for seeking marketing authorization for Qutenza® in Canada and for its subsequent commercialization and distribution upon regulatory approval. This partnership is expected to further enhance the global availability and impact of Qutenza®. Since 2017, Grünenthal has invested over €2 billion in successful mergers and acquisitions, continually creating synergies across manufacturing, logistics, and commercial activities by integrating acquired brands into its infrastructure. For Apotex, this partnership not only strengthens its ability to meet patient needs but also expands its global portfolio, which includes more than 550 branded, generic, and biosimilar products. With the launch of Qutenza® in the Canadian market, an effective new treatment option will soon be available for many patients suffering from neuropathic pain. 7. Daré Bioscience Partners with Theramex to Develop the First Biodegradable Long-Acting Contraceptive Implant, Casea S On February 20, 2025, Daré Bioscience, a company focused on innovation in women’s health, announced a co-development and licensing agreement with Theramex, a global specialty pharmaceutical company dedicated to women’s health. This collaboration aims to advance the development of a first-in-class, biodegradable, long-acting contraceptive implant based on etonogestrel. The agreement marks a significant partnership in promoting women’s health management. Etonogestrel is a small-molecule drug used for contraception. It was first approved on July 17, 2006, in the United States for contraceptive use. As the current Phase 1 study is foundation-funded, there are no direct development costs for either Daré or Theramex at this stage. Under the agreement, Daré receives a royalty-free, exclusive, fully paid-up, and sublicensable license to the U.S. patent for Casea S, recently acquired by Theramex. If Phase 1 results are positive, Daré will take responsibility for conducting Phase 2 studies in the U.S., and funding for future Phase 3 trials in the U.S. will be negotiated between Daré and Theramex based on market opportunity. Etonogestrel is a synthetic progestin that primarily works by inhibiting ovulation to prevent pregnancy. It also thickens cervical mucus, making it harder for sperm to reach the egg, and alters the endometrium to reduce the likelihood of implantation. As a long-acting reversible contraceptive (LARC), etonogestrel is typically delivered via a subdermal implant that can continuously release the hormone for up to three years, offering extended contraceptive protection. Due to its high efficacy and convenience, etonogestrel has become one of the preferred contraceptive options for many women. Since its initial approval, etonogestrel has been authorized for contraceptive use in multiple countries and regions worldwide. It has also been studied for other indications such as dysmenorrhea, bleeding disorders, lower urinary tract symptoms, and benign prostatic hyperplasia. Although some indications are no longer under investigation, the use of etonogestrel in contraception continues to evolve. Companies such as Organon NV are actively working to expand its applications and improve efficacy through ongoing research. 8. SK Chemicals Partners with Jeil Health Science to Boost Pharmacy Sales of Ginexin and Trast On March 17, 2025, SK Chemicals announced a co-marketing agreement with Jeil Health Science, a leading South Korean manufacturer of over-the-counter (OTC) pharmaceuticals. The partnership is aimed at increasing pharmacy sales of two SK Chemicals products—Ginexin-F Soft Cap 120mg and Trast Patch 30—by leveraging Jeil Health Science’s extensive distribution network. Previously, these products were distributed through general pharmaceutical wholesalers. Ginexin-F Soft Cap 120mg: This product is a circulation enhancer formulated with ginkgo biloba extract and comes in a soft capsule format, sold exclusively through pharmacies. Ginkgo biloba extract is renowned for its antioxidant properties and is widely used to improve blood circulation and alleviate symptoms related to poor circulation. Trast Patch 30: This is a pain relief patch available in packs of 7, 10, and 30 units, with the 30-pack being particularly suited for patients requiring repeated use. The patch is applied directly to the skin and delivers active ingredients to relieve localized pain, making it suitable for conditions such as muscle aches and arthritis. Both products are already on the market and have established brand recognition and customer bases. Ginexin enjoys a strong reputation as a natural-origin blood circulation booster, while Trast is favored by consumers for its convenient application and effective pain relief. The goal of the partnership is to further expand the market share of these two products in the pharmacy channel and to enhance consumer awareness and trust through more targeted marketing strategies. Through this collaboration, SK Chemicals aims to take advantage of Jeil Health Science’s powerful sales network—serving over 12,000 pharmacies directly—and its proven track record in promoting OTC products, especially in pain management with successful brands like Kefentech and Jeil Cool Pap. Han Sang-chul, CEO of Jeil Health Science, expressed his enthusiasm for the partnership, stating that they are honored to work with SK Chemicals to promote products that have earned long-term trust in the fields of blood circulation and pain relief. Together, the two companies hope to strengthen Ginexin and Trast’s positions as leading brands in their respective markets and to provide more therapeutic options for patients. This partnership not only aims to enhance the market standing of both companies but also to deliver higher-quality products and services to a broader consumer base. 9. X4 Pharmaceuticals and Taiba Rare Enter Exclusive Agreement to Advance Distribution and Commercialization of XOLREMDI® (Mavorixafor) in Select Middle Eastern Countries On February 19, 2025, X4 Pharmaceuticals, a company committed to improving the lives of patients with rare immunodeficiency diseases, announced an exclusive agreement with Taiba Rare, a division of Taiba Healthcare. The agreement grants Taiba Rare exclusive rights to distribute and commercialize XOLREMDI® (mavorixafor) in Saudi Arabia, the United Arab Emirates, Qatar, Oman, Kuwait, Bahrain, and Egypt, contingent upon obtaining local regulatory approvals. Although specific financial terms have not been disclosed, agreements of this nature typically include upfront payments, sales-based milestone payments, and royalties. These arrangements align the interests of both parties and incentivize Taiba Rare to actively promote XOLREMDI®. Given that XOLREMDI® is the first and only treatment approved for WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis), the therapy holds significant market potential, making the partnership attractive to both companies. XOLREMDI® (mavorixafor) is an oral, once-daily treatment approved by the U.S. Food and Drug Administration (FDA) in April 2024 for patients aged 12 and older with WHIM syndrome. It works by increasing the number of circulating mature neutrophils and lymphocytes, thereby enhancing the body's ability to fight infections. Mavorixafor functions by inhibiting the CXCR4 receptor, promoting the release of white blood cells from the bone marrow into the bloodstream. While XOLREMDI® has already received FDA approval in the U.S., its Marketing Authorization Application (MAA) is currently under review by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). The collaboration with Taiba Rare will accelerate the product's introduction into Middle Eastern markets, offering new treatment options for patients with WHIM syndrome. Under the agreement, Taiba Rare will be responsible for XOLREMDI®’s distribution, promotion, marketing, and sales in the designated region and will jointly develop key strategic decisions with X4 Pharmaceuticals. 10. Beihai Biotechnology Partners with Zydus Lifesciences to Commercialize BEIZRAY® (BH009) in the U.S. On February 18, 2025, Beihai Biotechnology announced a strategic partnership with Zydus Lifesciences. Under the agreement, Beihai grants Zydus exclusive commercialization rights for its novel oncology drug BEIZRAY® in the United States. Following the agreement, Beihai will receive an upfront payment of USD 15 million, with an additional USD 10 million upon the first product delivery—amounting to nearly RMB 200 million in total. Beihai will also benefit from future sales-based milestone payments and a high double-digit percentage share of profits. This payment structure not only provides Beihai with early financial support but also motivates both parties to ensure the commercial success of the product. BEIZRAY® (BH009) is a proprietary, improved formulation of docetaxel developed by Beihai Biotechnology for the treatment of various solid tumors, including breast cancer, non-small cell lung cancer, prostate cancer, gastric cancer, and head and neck squamous cell carcinoma. It acts by stabilizing microtubules and preventing their depolymerization, arresting the cell cycle in the mitotic phase and thereby inhibiting tumor cell proliferation. BEIZRAY® is distinguished by its use of targeted molecular delivery technology that eliminates the use of polysorbate 80—a common component in traditional docetaxel formulations—significantly reducing adverse reactions and improving patient safety. BEIZRAY® received FDA approval in October 2024, making it the first clinically validated and demonstrably superior docetaxel reformulation approved in nearly 30 years. Clinical trials have shown that BEIZRAY® reduces the risk of hematologic toxicity and severe allergic reactions, thereby enhancing the benefit-risk profile for patients. This partnership will leverage Zydus Lifesciences’ robust sales infrastructure in the U.S. to expedite market access and deliver this innovative treatment to a broader patient population. 11. Baheal Pharmaceutical Partners with Roche to Advance Commercialization of Rituximab in China On February 13, 2025, Baheal Pharmaceutical announced that it had entered into a collaboration agreement with Roche. Under this agreement, Baheal has obtained the exclusive rights to promote Roche’s well-known oncology-targeted therapy Rituximab in mainland China. According to the agreement, Roche will pay Baheal a quarterly service fee for its promotional efforts. This arrangement ensures that while Baheal bears the promotional costs, it also receives a corresponding economic return based on sales performance. Additionally, the agreement stipulates that Roche may not appoint any third party to promote the product in the region without prior notice to Baheal, ensuring Baheal’s exclusivity in the market. Rituximab is the world’s first monoclonal antibody specifically targeting the CD20 antigen and marked the beginning of a new era in targeted cancer therapy. It is primarily used for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and other related diseases. Rituximab binds to the CD20 antigen on the surface of B lymphocytes, inducing immune responses against the cancer cells and promoting their apoptosis, thereby inhibiting tumor growth. Since its initial approval in the U.S. in 1997, Rituximab has accumulated over two decades of clinical use and has benefited more than 6.8 million patients worldwide. In China, Rituximab was approved in April 2000, and with approvals for multiple indications—including maintenance therapy for treatment-naïve follicular lymphoma and combination chemotherapy for chronic lymphocytic leukemia—its market potential continues to grow. 12. Chong Kun Dang Secures Exclusive Distribution and Sales Rights for Bayer’s Nexavar and Stivarga in South Korea Chong Kun Dang Pharmaceutical has announced that it has reached an agreement with German pharmaceutical giant Bayer to exclusively distribute and sell two of Bayer’s key oncology drugs—Nexavar and Stivarga—in the South Korean market. This partnership aims to leverage Chong Kun Dang’s robust market network and sales capabilities to expand the local market share of both therapies. Although the specific financial terms have not been disclosed, such agreements typically involve an upfront payment, milestone payments based on sales performance, and profit-sharing arrangements. These structures align the interests of both parties and incentivize Chong Kun Dang to actively promote the products and expand their market presence. Nexavar: A multi-kinase inhibitor indicated for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-refractory differentiated thyroid cancer. It works by inhibiting several intracellular protein kinases involved in tumor growth and angiogenesis. Stivarga: Also a multi-kinase inhibitor, Stivarga is indicated for metastatic colorectal cancer, gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma. It shares a similar mechanism of action with Nexavar but is approved for different indications and is sometimes used as a follow-up treatment after Nexavar. Both Nexavar and Stivarga are globally approved and have been widely used in clinical practice across many countries and regions. They have demonstrated significant efficacy in treating specific types of cancer and have accumulated extensive real-world usage data. With Chong Kun Dang now taking over the distribution and sales of these two drugs in South Korea, the accessibility of these innovative therapies for local patients is expected to increase substantially. For Chong Kun Dang, this partnership strengthens its presence in the oncology sector by adding two well-recognized therapeutic options to its portfolio, potentially creating new growth drivers for the company. For Bayer, choosing Chong Kun Dang as its local partner reflects confidence in the latter’s commercial capabilities and market expertise in South Korea. This strategic alliance is expected to accelerate market penetration of Nexavar and Stivarga in South Korea, ultimately benefiting more patients with access to advanced cancer treatments. Furthermore, it highlights the growing trend of multinational pharmaceutical companies partnering with strong local firms to optimize resource allocation and achieve mutually beneficial outcomes in global market expansion. 13. Lotus Pharmaceutical Partners with Formycon to Advance Commercialization of FYB203/AHZANTIVE® in the Asia-Pacific Region On February 5, 2025, Klinge Biopharma GmbH, the exclusive global commercialization rights holder of FYB203/AHZANTIVE® (Aflibercept), announced an exclusive licensing agreement with multinational pharmaceutical company Lotus Pharmaceutical. Under the terms of the agreement, Lotus will be responsible for the commercialization of FYB203/AHZANTIVE® in the Asia-Pacific region, including Indonesia, Malaysia, the Philippines, Singapore, Taiwan, Thailand, Vietnam, and the Hong Kong Special Administrative Region. Concurrently, Formycon also signed a finished product supply agreement with Lotus. According to the agreement, Klinge will receive an upfront payment from Lotus and is eligible for additional milestone payments tied to product launch and sales achievements. Furthermore, Klinge will receive royalties based on Lotus’ net sales, with Formycon sharing in Klinge’s revenues at a rate ranging from mid-single to low-double-digit percentages. This payment structure not only provides Klinge with initial financial support but also incentivizes all parties to collaborate closely toward the successful commercialization of the product. FYB203/AHZANTIVE® is a biosimilar to Eylea® (Aflibercept), used for the treatment of neovascular age-related macular degeneration (nAMD) and other severe retinal diseases. The drug works by inhibiting vascular endothelial growth factor (VEGF), thereby reducing the formation of abnormal blood vessels in the retina. VEGF is a protein that promotes the formation of new blood vessels, but its overexpression in certain eye diseases can lead to vision loss or even blindness. By blocking the action of VEGF, FYB203/AHZANTIVE® helps stabilize or improve patients’ vision. FYB203/AHZANTIVE® has achieved significant progress in development, receiving approval from the U.S. Food and Drug Administration (FDA) in June 2024, followed by European Commission approval in January 2025. Currently, Formycon and Lotus are working closely together to prepare submissions to regulatory authorities in the Asia-Pacific region, in accordance with local regulations, to facilitate the timely launch of FYB203/AHZANTIVE® in these markets. This process includes the consolidation of clinical data and adaptations to meet local market requirements. 14. Daewon Pharmaceutical Partners with AstraZeneca Korea to Promote Asthma Treatment Products In early February 2025, Daewon Pharmaceutical announced a collaboration agreement with AstraZeneca Korea to take on the distribution responsibilities for AstraZeneca’s asthma treatment products in the South Korean market. This partnership aims to leverage Daewon’s robust sales network and market expertise to broaden the reach of these essential medications, ensuring that more patients have access to effective treatment options. The agreement includes an upfront payment, sales-based milestone payments, and royalties calculated based on net sales. This structure ensures mutual benefit: AstraZeneca Korea can rapidly expand market share for its products through Daewon’s extensive distribution channels, while Daewon Pharmaceutical gains financial returns from successful product promotion and strengthens its presence in the respiratory disease market. Budesonide/Formoterol (Symbicort) is one such combination product included in this partnership. It consists of a long-acting β2-agonist (LABA) and an inhaled corticosteroid (ICS), designed for long-term control of asthma symptoms. Budesonide helps reduce airway inflammation, while Formoterol relaxes the airway smooth muscles, making breathing easier. This combination therapy effectively alleviates asthma symptoms and reduces the risk of acute exacerbations. These asthma treatment products have been approved globally and have been marketed in numerous countries for years, backed by extensive clinical experience and safety data. For certain products within this collaboration, additional registration steps or labeling adjustments may be required to comply with Korean regulatory standards. However, given their proven efficacy and safety profiles in other markets, it is expected that they will quickly gain recognition and be widely adopted in South Korea. 15. MITEM Pharma Acquires FLISINT® from Sanofi, Committed to Safeguarding the Interests of Patients with Rare and Life-Threatening Diseases In February 2025, MITEM Pharma announced the successful acquisition of the specialty drug FLISINT® from Sanofi. This acquisition underscores MITEM Pharma’s ongoing mission to improve the quality of life for patients suffering from rare and life-threatening diseases. Through this collaboration with Sanofi, MITEM Pharma not only expands its product portfolio but also strengthens its expertise in targeted therapeutic areas. FLISINT® is a specialty medication designed for the treatment of specific rare diseases. Although its exact indication was not disclosed, the name suggests that it may be intended for the treatment of a genetic disorder or metabolic condition requiring specialized attention. The mechanism of action of FLISINT® likely involves addressing enzyme deficiencies or abnormal protein expression caused by genetic mutations, thereby alleviating symptoms and slowing disease progression. For example, it may function through enzyme replacement therapy or by modulating intracellular signaling pathways to restore normal physiological functions. FLISINT® has successfully completed multiple phases of clinical trials and has been approved by regulatory authorities in several countries and regions. This confirms the drug's safety and efficacy, offering an effective treatment option for patients with specific rare conditions. However, with ongoing scientific advancements and the accumulation of new data, further studies may be necessary to explore broader applications or to optimize the formulation for enhanced efficacy and reduced side effects. Conclusion The series of partnership agreements and acquisitions in February 2025 reveals an overarching trend: globalization, specialization, and technological advancement are reshaping the pharmaceutical industry. Whether it's deepening market penetration through local collaboration (such as the partnership between Daewon Pharmaceutical and AstraZeneca Korea) or entering emerging markets (such as X4 Pharmaceuticals' agreement with Taiba Rare for the Middle East), these partnerships demonstrate how pharmaceutical companies are leveraging each other's strengths for mutual benefit. More importantly, they share a common goal—to enhance healthcare access and outcomes for patients worldwide. It is noteworthy that these collaborations go beyond traditional sales and distribution agreements and extend into R&D partnerships. For instance, MITEM Pharma’s acquisition of FLISINT® from Sanofi, as well as Daré Bioscience’s co-development of the biodegradable long-acting contraceptive implant Casea S with Theramex, highlight the growing importance of long-term strategic alliances in driving innovation and accelerating product development in today's rapidly evolving healthcare environment. In summary, the pharmaceutical collaborations of February 2025 mark the dawn of a new era—one characterized by cooperation, resource sharing, and a focus on addressing complex health challenges. As technology continues to evolve and societal awareness of health deepens, we can expect to see more such partnerships emerge, further advancing the frontier of medicine and delivering new therapeutic possibilities to patients around the globe. How to get the latest progress on drug deals? If you would like to access the latest transaction event information, you can click on the 'Deal' module from the homepage of the Synapse database. Within the Deal module, you can search for global pharmaceutical transaction information using labels such as Drugs, Organization, Target, Drug Type, Deal Date.  Furthermore, you can obtain the original link to the transaction coverage by clicking on the "Deal Name." In the analysis view, you can see the most active assignors, assignees, popular targets, and other dimensions of analysis, as well as the distribution of research and development statuses at the time of the transaction, to help you better understand the search results. The Synapse database also supports the ability to view current transactions from the dimension of "drugs" (by selecting "drugs" from the "Adjust Dimension" dropdown menu above). Targeting transactions involving renowned pharmaceutical companies that are of interest to the industry, such as Merck, Roche, etc., Synapse has identified a group of "leading companies" through drugs that have achieved global sales exceeding 1 billion US dollars in 2022. Transactions involving drugs from these leading companies can be filtered by clicking on the "Leading Company" tag on the left-hand side. In addition to the drug transaction module, you can also view related transaction history on the drug detail page and the institution detail page. Click on the image below to explore new pharmaceutical funding transactions!