Vibostolimab

iStock/ Bulat Silvia More than a decade after Merck’s Keytruda and BMS’ Yervoy ushered in the immuno-oncology revolution, the space is at a crossroads, with experts highlighting novel targets, combinations and pre-emptive immunization as the next wave for IO. Last year marked 10 years since Keytruda’s seminal approval . That FDA greenlight signaled a new day in immuno-oncology and set the stage for the subsequent approvals of several more checkpoint inhibitors. Now, the field is looking for its next breakthrough—but it’s been a bumpy road. Overall, the immuno-oncology (IO) space “continues to be quite disappointing,” Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace . “Industry is in search of that next great IO target, and they just haven’t been able to identify one that works.” In the last 15 years, the FDA has approved 11 checkpoint inhibitors — therapies targeting immune checkpoint proteins, including PD-1 and its partner protein PD-L1, plus CTLA-4 and LAG-3—to help the immune system locate and attack cancer cells. While Keytruda, an anti-PD-1, gets the most credit for having kickstarted the IO revolution, it was preceded by a CTLA-4 inhibitor called Yervoy, which BMS picked up in its $2.4 billion acquisition of Medarex in 2009. Two years later, the FDA approved Yervoy as the first anti-CTLA-4 drug. “That, really, along with the anti-PD-1s, kind of ushered in this whole immuno-oncology revolution,” Suvannavejh said. Jeremy Levin, now CEO of Ovid Therapeutics who was instrumental in BMS’ transformation to an immuno-oncology company in the aughts, agreed: “It became increasingly clear that there was science that said that this whole concept of immune modulation was beginning to evolve, and that CTLA-4 was breaking open the first concepts behind it.” Lately, however, the industry appears to have hit the proverbial therapeutic wall. But it’s not for a lack of trying, according to Christiana “Chris” Bardon, co-managing partner of MPM BioImpact. “When PD-1 was first released, we spent a lot of energy as an industry looking for the next PD-1 and we must have had tens of thousands of combinations of drugs in the clinic, testing everything with PD-1,” she told BioSpace . “Basically, we were looking for the next-generation IO checkpoint inhibitor.” But despite the emergence of more therapeutic options targeting the immune system, IO treatment response rates have plateaued at around 30%, Caroline Loew, CEO of Mural Oncology, wrote in a November 2024 opinion piece for BioSpace , meaning that 70% of patients do not respond to these therapies. “Despite the incredible efficacy of PD-1,” Bardon said, there is still a huge unmet need. “We still have many cancers that don’t respond to PD-1, things that are immunologically cold.” Striking Out With TIGITs Branching out has proven difficult, however. In the IO space, Suvannavejh said anti-TIGIT checkpoint therapies have been “probably the biggest disappointment” in the past two years. In December 2021, Roche ignited the field with promising results from the Phase II CITYSCAPE study of its anti-TIGIT drug tiragolumabin in metastatic non-small cell lung cancer (NSCLC). When combined with the company’s anti-PD-L1 blocker Tecentriq, tiragolumabin reduced the risk of disease worsening or death by 38% compared to Tecentriq alone. “I think the IO space was in kind of a low place about five years ago until Roche announced positive Phase II data for their TIGIT antibody,” he said. “All of a sudden, people were like, ‘oh my god, IO is back.” But in the Phase II/III data reported last year, the tiragolumab/Tecentriq combo failed to significantly improve progression-free and overall survival versus Keytruda and chemotherapy in patients with NSCLC and Roche elected to terminate that study. The excitement fizzled after that, Suvannavejh said. It was almost the nail in the coffin for TIGITs, or at least the buzz around the drug class. Seven months earlier, in December 2023, Merck had struck out in NSCLC with its experimental anti-TIGIT antibody vibostolimab when the candidate, in combination with Keytruda, failed to hit the endpoints in a mid-stage study. Recent results have breathed new life into the space, however. In September 2024, iTeos and GSK sparked excitement with Phase II results from patients with NSCLC taking a combination of iTeos’ anti-TIGIT candidate belrestotug and GSK’s anti-PD-1 therapy Jemperli. The combo elicited a 30% better confirmed objective response rate versus Jemperli alone. The partners are now studying the regimen as a first-line therapy for NSCLC in a Phase III trial . While it remains to be seen if TIGIT-targeting checkpoint inhibitors will reach the market, Bardon noted that the industry has seen some progress with drugs that hit CTLA-4 and LAG-3. In October 2022, the FDA greenlit AstraZeneca’s anti-CTLA-4 drug Imjudo, in combination with its first-generation PD-L1 inhibitor Imfinzi, for hepatocellular carcinoma, while the LAG-3 space saw its first approval in March of that year in BMS’ relatlimab (in combination with Opdivo and marketed as Opdualag) in unresectable or metastatic melanoma. Looking ahead, Bardon said ivonescimab—a PD-1/VEGF bispecific antibody in development by Summit Therapeutics, “is really the new . . . wave of checkpoint inhibitors.” “Ivonescimab has shown superiority to PD-1 alone, which is incredible,” she said. In September, Summit presented Phase III data at the International Association for the Study of Lung Cancer’s 2024 World Conference on Lung Cancer, showing that ivonescimab outperformed Keytruda in first-line advanced NSCLC. In the HARMONi-2 trial, Summit’s candidate cut the risk of disease progression or death by nearly 50% compared with Keytruda. While the results sent Summit’s stock skyrocketing by as much as 140%, some analysts urged caution , particularly noting that the data were from a trial run only in China. “Results may or may not be generalizable beyond the China-focused patient population initially assessed,” BMO Capital Markets wrote in an investor note at the time. Summit is currently studying ivonescimab in a multi-regional Phase III NSCLC study in the U.S. Bardon added that ivonescimab has the potential to work in multiple tumor types outside of lung cancer and predicted that it would be “a huge blockbuster in the future.” Pfizer appears to agree. Last week, the New York–based pharma struck a deal with Summit to combine its vedotin-based antibody-drug conjugates with ivonescimab. Part of the reason the industry has not been successful in developing checkpoint inhibitors “is that the development path is very, very hard,” Bardon said. One key challenge, she explained, is that most checkpoint therapies do not have monotherapy efficacy and therefore need to be developed in combination with PD-1 drugs. Definitive combination therapy can only be demonstrated in a comparator trial. “It’s just a very difficult and long path to de-risk the drug.” In this way, ivonescimab benefited from being created and developed in China, where there are faster enrollment times, limited treatment options and clinical trials are less expensive, Bardon said. Other IO targets of particular interest, Suvannavejh said, are PRAME (preferentially expressed antigen of melanoma) and the “very complicated RAS pathway, which includes the commonly mutated KRAS.” “This is a pathway that people have been trying to target for decades,” Suvannavejh said. “[It is] very difficult to do, trying to get that mix of efficacy and safety.” Amgen and BMS already have KRAS drugs — Lumakras and Krazati —on the market for NSCLC. The developmental “darling” of this space, Suvannavejh said, is Revolution Medicines, whose daraxonrasib is currently in a registrational trial to treat cancers with a wide range of common RAS mutations. Other players include Eli Lilly, Immuneering Corporation and Erasca. IO Developments On the Horizon Levin indicated that the IO space is at a crossroads. “The first wave of immuno-oncology has passed us by,” he said. “We know what we know about it.” Biopharma’s appetite for IO is certainly understandable. For Merck, Keytruda brought in a cool $29.5 billion in global sales in 2024 and ranks among the best selling drugs of all time. With that drug going off patent in just a few years’ time, many companies are eager to grab more of a market that is projected to be worth more than $17 billion by 2032. So, how does biopharma catch the next wave? For Suvannavejh, the answer lies in identifying novel targets—potentially through artificial intelligence and machine learning. As an example, he offered Compugen , a Tel Aviv–based biotech that uncovered a previously unidentified checkpoint called PVRIG using its proprietary computational discovery platform. Compugen is currently studying the resulting asset, COM701 , in trials of ovarian, gastric and other cancers. “That’s what companies can do if they want to go down this path of like, hey, maybe there’s another checkpoint inhibitor that we just haven’t identified yet,” Suvannavejh said. Meanwhile, Levin said the current focus is on combination therapies. “The world teaches you this repeatedly for complex diseases,” he continued, citing childhood leukemia, hypertension and congestive heart failure as examples of where combinations have ultimately been the answer. However it’s done, Levin continued, the holy grail for IO is pre-emptively engaging the human body to defeat a cancer cell before it has even proliferated. “Immuno-oncology is the clue that you can do this,” he told BioSpace . “It says that you can absolutely galvanize the human tissue to reawaken attack on a cancer cell. The big question is, can you actually pre-emptively immunize us such that we can be ready for this?”

在2024年，全球制药行业经历了诸多挫折，许多备受期待的药物在临床试验中“夭折”。这些失败不仅给药企带来了巨大的经济损失，也凸显了药物研发的复杂性和不确定性。下面，让我们一起来看看去年一整年较为突出的十起失败案例： （1）Emraclidine 适应症：精神分裂症 研发公司：艾伯维 形式/靶点：M4选择性正向变构调节剂 艾伯维（AbbVie）在2023年12月宣布以87亿美元收购Cerevel Therapeutics，看中的正是其精神分裂症药物Emraclidine。Emraclidine是一种M4选择性正向变构调节剂，艾伯维希望通过这一收购复制其他成功药物的路径。然而，事情并未如预期发展。 在2024年，艾伯维报告了Emraclidine在两项II期临床试验中的失败，表明该药物未能达到预期的疗效。这一结果不仅让艾伯维的收购计划蒙上阴影，还导致公司在2025年初计入了35亿美元的减值支出。 尽管如此，艾伯维并未完全放弃Emraclidine，其首席科学官Roopal Thakkar在J.P. Morgan医疗保健会议上表示，公司计划将该药物作为现有疗法的辅助药物进行测试，并考虑未来重新尝试单一疗法。 图片：千库网 （2）Losmapimod（洛批莫德） 适应症：面肩胛肱型肌营养不良症 研发公司：Fulcrum Therapeutics/赛诺菲 形式/靶点：p38α/β丝裂原活化蛋白激酶抑制剂 Losmapimod是一种p38α/β丝裂原活化蛋白激酶（MAPK）抑制剂，由Fulcrum Therapeutics开发，用于治疗面肩肱型肌营养不良症（Facioscapulohumeral Muscular Dystrophy，FSHD）。这种罕见病是一种遗传性肌肉疾病，主要影响面部、肩部和上肢的肌肉，导致患者逐渐失去肌肉力量和功能。 2024年，赛诺菲（Sanofi）与Fulcrum Therapeutics达成合作，赛诺菲支付了8000万美元，获得了Losmapimod在美国以外地区的开发和商业化权利。这一合作基于对Losmapimod在早期临床试验中显示出的潜力的期待，尤其是在抑制炎症和改善肌肉功能方面的潜在效果。 然而，Losmapimod的研发之路并非一帆风顺。早在2021年，该药物在2b期临床试验中就未能达到主要终点，显示出对患者生物标志物的显著影响不足。尽管如此，Fulcrum仍然对Losmapimod的潜力保持信心，并决定推进其进入III期临床试验，希望通过更广泛的患者群体验证其疗效。 2024年，Losmapimod的III期临床试验结果令人失望。试验结果显示，该药物未能显著改善患者的肌肉功能或减缓疾病进展。这一失败不仅让赛诺菲的8000万美元投资面临风险，也使Fulcrum不得不重新评估其研发战略。 Losmapimod的失败对Fulcrum Therapeutics产生了深远影响。公司不得不裁员40%，并将研发重点转向其他项目。这一事件也凸显了罕见病治疗领域的高风险性，尤其是在临床试验阶段，药物的疗效和安全性仍存在诸多不确定性。 图片来源：千库网 （3）Dalzanemdor 适应症：阿尔兹海默病、亨廷顿氏症和帕金森疾病 研发公司：Sage Therapeutics 形式/靶点：NMDA受体正向变构调节剂 2024年，Sage Therapeutics在神经退行性疾病治疗领域遭遇了重大挫折，其核心药物Dalzanemdor在针对帕金森病、阿尔茨海默病和亨廷顿病的II期临床试验中连续三次失败。这一系列失败不仅对Sage的股价造成了沉重打击，也严重动摇了市场对其研发能力的信心。 首先，4月公布的帕金森病II期PRECEDENT研究结果显示，Dalzanemdor未能在轻度认知障碍患者中显示出与安慰剂相比的统计学显著差异。随后，10月公布的阿尔茨海默病II期LIGHTWAVE研究也未能达到主要终点，药物在改善患者智力方面未显示出显著效果。11月，亨廷顿病的II期DIMENSION试验再次失败，进一步证实了Dalzanemdor在神经退行性疾病治疗中的局限性。 这些连续的失败反映出神经退行性疾病治疗领域的复杂性和高风险性。尽管Sage在药物设计上采用了NMDA受体正向变构调节剂这一创新靶点，但临床试验结果表明，该药物在改善患者认知功能和延缓疾病进展方面未能达到预期效果。此外，这些失败也凸显了在神经退行性疾病领域，药物研发需要更精准的患者选择和更严格的临床试验设计。 尽管Sage在Dalzanemdor项目上遭遇了挫折，但公司仍在努力推进其他研发管线，例如产后抑郁症药物Zurzuvae，这表明Sage并未完全放弃在神经科学领域的布局。然而，未来Sage能否在其他项目上取得突破，仍充满不确定性。 （4）Ocedurenone 适应症：慢性肾病 研发公司：诺和诺德 形式/靶点：新型非甾体类盐皮质激素受体拮抗剂 2024年，诺和诺德（Novo Nordisk）在慢性肾病（CKD）治疗领域的希望因Ocedurenone的III期临床试验失败而破灭。这款新型非甾体类盐皮质激素受体拮抗剂曾被寄予厚望，诺和诺德在2023年10月以13亿美元的高价从KBP Biosciences引进该药物，旨在挑战拜耳的同类药物Kerendia。然而，Ocedurenone在2024年6月公布的III期CLARION-CKD试验中未能达到主要终点——降低慢性肾病患者的蛋白尿和稳定肾功能。 这一失败对诺和诺德造成了重大打击。公司在2024年上半年财报中披露，因Ocedurenone项目失败导致了57亿丹麦克朗（约合8.02亿美元）的减值损失。此外，诺和诺德还因认为KBP在合作中隐瞒了关键信息，包括II期临床试验中期分析显示药物无效的结果以及合规性问题，而对其提起诉讼。尽管如此，诺和诺德并未放弃其他适应症的探索，但最终在2024年11月彻底放弃了Ocedurenone项目。 Ocedurenone的失败也凸显了创新药研发领域的高风险性，尤其是在临床试验阶段。尽管诺和诺德对Ocedurenone的潜力充满信心，认为其具有显著的疗效和安全性优势，但最终未能在关键的III期试验中证明其价值。 图片来源：千库网 （5）GSK3943104 适应症：单纯疱疹病毒感染 研发公司：GSK 形式/靶点：重组蛋白疫苗 2024年，葛兰素史克（GSK）在生殖器疱疹疫苗的研发上再次遭遇挫折。其候选疫苗GSK3943104在II期临床试验中未能减少复发性生殖器疱疹的发作次数，导致GSK放弃了这一关键研究计划。 单纯疱疹病毒（HSV）感染是一个全球性重大医疗需求，全球约有5亿人受到这种终身无法治愈的感染影响。尽管GSK在2010年曾放弃过一款预防女性生殖器疱疹的疫苗研发，但公司对HSV感染的研究兴趣并未减退。 此次失败后，GSK表示将继续跟踪参与者，以获取复发性生殖器疱疹的数据，并为未来HSV相关研究提供参考。这一挫折也使得HSV疫苗研发领域的公司数量减少，BioNTech和Moderna的早期疫苗项目可能成为此次挫折的潜在受益者。 （6）Vibostolimab (维博利单抗) 适应症：高风险切除黑色素瘤 研发公司：默沙东 形式/靶点：抗TIGIT抗体 默沙东（Merck & Co.）的抗TIGIT抗体药物Vibostolimab在2024年的临床试验中遭遇了重大挫折。该药物原本被设计用于高风险黑色素瘤术后的辅助治疗，但在III期试验中因“免疫介导的不良事件”导致停药率过高，最终不得不提前终止试验。 此外，Vibostolimab联合派姆单抗（pembrolizumab）用于肺癌治疗的III期研究也因不良事件发生率高于预期且未能提高患者生存率而受阻。尽管罗氏（Roche）的同类药物tiragolumab在食管癌试验中取得了一定进展，但在肺癌试验中也遭遇了连续失败。这些连续的失败不仅凸显了TIGIT靶点在免疫肿瘤学领域的开发难度，也反映了免疫检查点抑制剂在不同癌症类型中的疗效可能存在显著差异。公司最终决定停止进一步的研究与开发。 （7）Simufilam 适应症：轻度至中度阿尔兹海默病 研发公司：Cassava Sciences 形式/靶点：细丝蛋白A（Filamin A protein） Cassava Sciences开发的Simufilam曾被视为阿尔茨海默病治疗的希望，但其III期临床试验未能达到主要终点，导致公司股价暴跌85%。不仅如此，该公司还因2b期数据误导性陈述面临美国证券交易委员会的调查。在III期试验中，Simufilam未能显著改善患者的认知功能，这一结果让市场对其前景失去信心。尽管Simufilam的失败早有预兆，但其股价的暴跌和随后的裁员仍凸显了阿尔茨海默病治疗领域的高风险性。Cassava Sciences不得不重新审视其研发策略，以应对这一挑战。 图片来源：千库网 （8）Fordadistrogene movaparvovec（莫哌达基） 适应症：杜氏肌营养不良症（DMD） 研发公司：默克 形式/靶点：基因疗法 辉瑞的基因疗法Fordadistrogene Movaparvovec用于治疗杜氏肌营养不良症（DMD），但在III期临床试验中未能改善患者的运动功能。该药物在研发过程中一直存在安全性问题，导致试验进度受阻。 最终，辉瑞在2024年6月宣布放弃该项目，导致公司财务损失2.3亿美元，并在北卡罗来纳州的制造业务中裁员150人。这一失败凸显了基因治疗在罕见病领域的挑战，尤其是在确保疗效和安全性方面的双重压力。 （9）Xevinapant 适应症：头颈部鳞状细胞癌 研发公司：默克 形式/靶点：细胞凋亡蛋白抑制剂 默克集团（Merck KGaA）的细胞凋亡蛋白抑制剂Xevinapant在III期临床试验中未能延长头颈部鳞状细胞癌患者的无事件生存期。尽管公司高管曾对Xevinapant的成功充满信心，但最终试验结果未能达到预期目标。 这一失败不仅抵消了默克每1.5年推出一款新药的目标，也凸显了肿瘤学领域的研发风险。尽管如此，默克在其他肿瘤学项目中仍取得了一些进展，例如CSF-1R抑制剂匹米替尼（pimicotinib）在罕见癌症中的成功。 （10）Suzetrigine 适应症：疼痛性腰骶神经根病 研发公司：Vertex Pharmaceuticals 形式/靶点：NaV1.8疼痛信号抑制剂 Vertex Pharmaceuticals的NaV1.8疼痛信号抑制剂Suzetrigine在2024年经历了一段跌宕起伏的旅程。尽管Suzetrigine的II期临床试验并未达到预期效果，导致Vertex公司股价下跌，但该药物最终在2025年1月获得FDA批准，用于治疗中度至重度急性疼痛。这一批准标志着几十年来人类在疼痛缓解方面取得的第一项重大研究进展。 Suzetrigine的II期临床试验主要针对的是腰骶神经根病（lumbosacral radiculopathy），一种疼痛性的脊柱疾病。临床试验结果显示，与基线相比，患者的疼痛指数平均下降了2.02点，达到了临床试验的主要目标。然而，安慰剂组中的100名参与者的疼痛指数也下降了1.98点，这一结果引发了投资者的恐慌，导致Vertex的股价在数据公布后不久下跌了15%。不过，自从去年12月中旬达到低点以来，受到FDA批准的Journavx上市的推动，公司股价已经上涨了20%以上。 图片来源：千库网 Vertex随后进行了事件分析来了解临床试验中发生了什么，并揭示了不同研究低点中安慰机组参与者的可变性。据公司介绍，在大约40%的安慰剂组参与者反应较低的地点，两个试验组的结果之间存在着“更大的分离”。尽管这些试验并未表明Suzetrigine比广泛使用的止痛药维柯丁（Vicodin）更有效，但该公司对这种药物的信心最终在2025年1月得到了回报。FDA批准该药物用于治疗中度至重度急性疼痛，这一成功为疼痛管理领域带来了新的希望。（生物谷Bioon.com） 参考资料： 2024's top 10 clinical trial flops