Daraxonrasib

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?”

在一个行业资本寒冬阶段，融资和BD是小型biotech创始人的第一能力，企业现在不需要一个高高在上的纯科学家创业者。我们要获得一些东西的时候，必然也要放弃一些东西。以我的资历，来说这些，显然不太合适。但毕竟这是在互联网，能教姚明打篮球的都大有人在。更何况我现在转做投资，似乎也能说那么几句。刚做投资半年，一个已投，一个准备投，比有些行业合伙人，我觉得是强不少，开个玩笑。投资这块的水货，多如牛毛，一脚踩下去，水汪汪的。这是不争的事实，但这种情况，短时间内也很难改变。所以，创业者不要冀求中国短时间内投资市场从业者的专业能力的迅速提升。 大多数成功者，大都是顺应时代的人，逆时代逆潮流行事不是一个明智的选择。 狂热阶段，没有几个人是理性的。所以，有了现在众多的困难的biotech创业者。 当下的biotech，在今年肯定还会继续死去一批，能够投资的基金，现在也已经在快速收缩，未来也不需要那么多投资机构，很多时候内卷，就是因为投资机构散落，各自为营导致的，不能合力，最后只能都死。 有些创始人，如果短时间内不能找到好工作，其实还是要想方设法的赚钱，不说养团队，更重要的还要养活自己。 管线有竞争优势及未来广阔的市场前景，仍然有议价能力。当下阶段，便宜肯定还是投资人很看重的一点。这个便宜，是投资机构认为的便宜才可以。降估值是现在能融到钱的很重要的策略。续命比什么都强。 从药物形式来看，全球销售前二十的药物仍然以抗体（融合蛋白），小分子，多肽为主，这些仍然是国内投资的主要重点。基因治疗，细胞治疗，窘境突出，国内市场无法支撑，国外也在逐渐遇冷，BD交易数量远不及抗体（融合蛋白），小分子，多肽，所以整体国内机构虽然布局，但是数量可能也相对少一点。 世界形势云诡波谲，更多的是走一步看一步。但仍然需要做事的人。生物药，无论是二级市场还是一级市场，大家手里的钱，都不再那么宽裕。如果还有子弹，如果相信未来会更好，那现在肯定是做事的时候。如果未来更差，那现在更得做事，不然来不及做事了，做错了，也没人会在乎。 现在能做的方向有很多。 ADC 经历了国内这几年的ADC的发展，国内的biotech的局势分布已经接近明朗，DXD微改的企业，如恒瑞，百利天恒等，豪森也基本贯彻了这条道路，目前已经有了不错的对外BD，百利天恒也取得了不错的进展。其它如exatecan的应用，如普方，百奥泰，信达，普方已经被成功收购。 当下的follow式 ADC，已经来到了末尾，如果一味布局跟随微改式的ADC，可能会面临尴尬的局面，因为已经有临床试验证明在经喜树碱治疗后，后续相应机制的ADC效果会削弱。 我们从目前的数据来看，ADC除了在DS8201在HER2阳性乳腺癌等适应症有较为亮眼的数据外，其它适应症以及其它ADC，惊艳度一般，甚至出现PFS获益，OS并不获益的情况。而通常PFS在5-8个月之间。 惊艳度不够，价格高昂，英国国家卫生与临床优化研究所(NICE)与阿斯利康/第一三共为未能就其HER2-ADC药物Enhertu的价格协商达成一致，NICE最终拒绝推荐其在英国用于治疗her2低表达乳腺癌患者。在国内可能也会面临这种局面。 所以，未来降价，联用PD1抑制剂走一线是其必经选择。当然新兴靶点及适应症还有一些机会。 也开始有新的尝试，吉利德在ESMO上公布了双ADC I期联用临床试验初步数据，即Sacituzumab govitecan（SG）与enfortumab vedotin（EV）联用作为二线治疗转移性尿路上皮癌（mUC）的方案，客观缓解率高达71%，具有良好的耐受性，进一步证明不同靶点不同机制的毒素双ADC联用开发，或许也是未来可以选择的一种开发路径。在一定程度上，也增强了双毒素单ADC开发的可能性。默沙东在clinical trials网站上，登记了一项靶向TROP-2 ADC药物（MK-2870/SKB264）+Nectin-4 ADC药物(Enfortumab Vedotin)+PD-1抗体Pembrolizumab，在晚期尿路上皮癌瘤患者中启动1/2期临床MK-3475-04C/KEYMAKER-U04，编号为NCT06483334，预计将于2024年8月启动，计划入组人数为98例。这都为不同机制ADC联用或者双payloadADC的开发，提供一定的理论基础。 如果双payload ADC能够成功挑战DS8201，那将为ADC开启下一个里程碑，所有的靶点又可以摆到台面，重新被开发，这在未来具有巨大的价值和潜力。也是ADC新的起点。 在我开发ADC的经历中，是发现过不同机制的ADC有协同作用，但要考虑活性的匹配，及未来临床毒性和安全性的问题。linker的改造也可能会在这其中起到很大的作用，解决本身疏水性payload载荷过多导致ADC理化成药性问题。 旧有的跟随式ADC，除了新靶点，新适应症的突破外，如果一味模仿，未来必定尴尬。国内几乎每家都在做，这在未来将是巨大的隐患。所以，探索新的联用方式，以及下一代ADC，可能未来取得突破的关键。 同时，双表位ADC，在我的研发经历中，并没有发现更优的特质。近日，zymeworks也选择终止旗下双表位HER2 ADC，ZW49（zanidatamab zovodotin）的临床开发。对于双抗ADC，也无需过多赞誉和期待，它需要一定的应用背景。如果患者不适合，它可能所获得效果更差。 一定找到合适的定位，才能发挥双抗ADC的优势。 白介素的改造 信达的IBI363 (PD-1/IL-2α-bias)，着实亮眼，数据目前呈现也比较扎实，如果成功，将会引领下一代重磅药物的浪潮。而信达IBI363的成功不一定代表其它细胞因子改造的成功。其设计与其它公司的设计采取了相反的策略。但其理论对IBI363改造提供一定理论依据，在肿瘤细胞内有一群肿瘤特异性T细胞（tumor-specific T cells，TSTs）表达CD8，PD1，CD25，α-biased IL-2突变体可以更有效地激活肿瘤特异性T细胞。TSTs高表达CD25，从而可以更好地接收到α-biased IL-2的信号。同时在外周，'not-α'IL-2能够显著扩增外周T细胞，而α-biased IL-2突变体则更偏向于扩增外周Treg细胞，从而减少IL-2带来的毒性作用。使得α-biased IL-2具有更优的抗肿瘤活性，且安全性更高。这使得IBI363爬坡很高，能够满足PD1抑制剂起效剂量。 CD3/41BB多抗 第一代CAR-T，因缺少共刺激信号，如41BB，CD28等，效果极差，后来加上共刺激信号，才成就了如今的CAR-T。这也为CD3，41BB双抗和多抗，提供一定的理论基础。CD28，目前临床数据来看，有很多风险存在，41BB具有更多的可能。 如今对于CD3双抗和41BB双抗的设计均为依赖TAA的T细胞激活，以实现对肿瘤细胞的精准杀伤。所以CD3双抗，并不跟41BB冲突，且存在联用优势。 Englumafusp alfa是罗氏一种双特异性抗体样融合蛋白，可同时靶向B细胞上的CD19，以及T细胞等免疫细胞上的4-1BB，从而引发强烈的共刺激信号，增强和延长细胞活性，增强抗肿瘤活性。Englumafusp alfa在T细胞受体信号存在且严格依赖CD19交联的情况下，通过4-1BB激动作用对T细胞提供强烈的共刺激，与CD20/CD3 T细胞衔接双特异性抗体联用，可以进一步增强后者的抗肿瘤活性。 罗氏正在开展1期临床试验中评估englumafusp alfa与CD20×CD3双特异性抗体格菲妥单抗（glofitamab）联用，治疗复发/难治性非霍奇金淋巴瘤（r/r NHL）患者。 初步研究数据表明，该联合疗法在侵袭性r/r NHL（r/r aNHL）患者中显示出良好的抗肿瘤活性，最佳客观缓解率（BoR）为67.0%，完全缓解（CR）率为57.0%；二线治疗r/r侵袭性NHL患者的BOR为77.0%，CR率为77.0%。此外，联合治疗具有与格菲妥单抗单药相当的安全性和细胞因子释放综合征（CRS）情况。 这将是未来新一代T cell engager改造的机会。 自免 长效皮下多抗注射将成为下一代自免抗体药物的主流。2024年3月5日，Apogee Therapeutics公布长效IL-13抗体APG777的一期临床数据，半衰期长达75天，非灵长类研究数据表明：APG777和Lebrikizumab相比，可以更长久抑制pSTAT6水平。 2024年6月13日，明济生物制药（北京）有限公司和艾伯维（纽约证券交易所股票代码：ABBV）共同宣布一项开发FG-M701的许可协议。FG-M701是一种用于治疗炎症性肠病的下一代TL1A抗体，FG-M701通过独特的工程化改造，旨在为炎症性肠病治疗提供更高的疗效并减少给药频率，目前正处于临床前开发阶段。根据协议条款，艾伯维将获得FG-M701在全球进行开发、生产和商业化的独家许可权。明济生物将获得1.5亿美元的首付款和近期里程碑付款，并有资格获得后续高达15.6亿美元的临床开发、监管注册和商业化里程碑付款，以及高达净销售额低两位数比例的分级特许权使用费。 目前在自免适应症中不同靶点如TNFa，IL23，TLIA等也展现出协同作用，所以未来多抗皮下长半衰期药物，可能会成为设计的主流，同时拥有着巨大的商业前景。 小分子及联用ADC/双抗 2025年1月7日，强生宣布了3期MARIPOSA研究的癌症治疗金标准终点总生存期 (OS) 的积极顶线结果，该研究评估了 RYBREVANT ® (amivantamab-vmjw) 加 LAZCLUZE™ (lazertinib) 作为表皮生长因子受体 (EGFR) 外显子 19 缺失 (ex19del) 或 L858R 替代突变的局部晚期或转移性非小细胞肺癌 (NSCLC) 患者的一线治疗。无化疗联合方案达到了最终预先指定的 OS 次要终点，并且与目前的标准治疗药物奥希替尼相比，OS 具有临床意义和统计学意义的改善。预计中位 OS 改善将超过一年。 2024年，Revolution pharmaceuticals公布旗下RAS(ON)多选择抑制剂RMC-6236早期胰腺癌临床数据，在KRAS G12X亚型患者中位PFS达8.1个月，任意类型RAS突变达7.6个月，而benchmark仅为2.0-3.5个月。对于KRAS G12X亚型患者，2线治疗RMC-6236中位PFS达8.1个月，3线治疗中位PFS达4.2个月，benchmark相应基线下mPFS仅为2.0-3.5个月和1.9个月。 对于KRAS G12X亚型患者，中位OS，RMC-6236未达到，benchmark为6.1-6.9个月。RMC-6236耐受性良好，安全性可控。目前胰腺癌主要以化疗为主，PFS仅有3个月左右。RMC-6236无疑展现了巨大的市场潜力。 2024年4月5日，阿斯利康在Clinicaltrials.gov网站上注册了三期临床试验TROPION-Lung14，奥希替尼联合或不联合Trop2 ADC新药Dato-DXd一线治疗EGFR突变阳性非小细胞肺癌。 与此同时，阿斯利康也在开展奥希替尼与EGFRxcMET ADC（AZD9592）联用临床，为未来小分子靶向治疗+ADC提供了一定的思路。 未来RAS(ON)多选择抑制剂也或成为未来一线联用ADC重要基石药物。 同时，CD3/CLDN18.2双抗也在胰腺癌中展现了初步的疗效，或许也是RAS(ON)多选择抑制剂联用的一种可能。 除此之外，2025年1月16日，FDA还有批准了sotorasib联合帕尼单抗（EGFR抗体）治疗KRAS G12C突变的结直肠癌。 而在几个月之前，刚批准了adagrasib联合西妥昔单抗治疗KRAS G12C突变的结直肠癌。 都说世界是一个草台班子，其实这话是也不是，多好的公司，多好的机构，都有一些看似高大上，实则一地鸡毛的事情。没有十全十美的公司，正如没有十全十美的人。但总需要真正的做事的人。