MRT-2359

iStock, lerbank Molecular glue degraders are gaining traction in the clinic as well as funding from Big Pharma, with their potential to treat previously “undruggable” cancers and immunological diseases. Here are five clinical programs worth keeping an eye on. Molecular glue degraders, known for their ability to break down disease-causing proteins, are gaining traction in the clinic and driving sizable Big Pharma deals that reflect the modality’s market potential. Pharma giants like Bristol Myers Squibb, Novartis, Eli Lilly and Roche have poured millions into acquiring assets and partnering with smaller biotechs to develop molecular glues into treatments in areas such as cancer and immunology. The promise of molecular glues comes down to selectivity and an ability to hit novel targets, said Robert Driscoll, senior vice president of equities research at Wedbush Securities. For drugmakers seeking pipeline prospects to make up for ongoing patent losses, these glues could pave the way to novel targets with limited market competition, he said. “When we look at the market potential of these molecular glues, the ability to potentially tackle undruggable targets unlocks some doors,” Driscoll told BioSpace . “If you have a novel target, you have a real advantage versus other folks out there who will be fast followers. The market potential there is huge.” Molecular glues were discovered essentially by accident in the 1950s when the morning sickness drug thalidomide—infamous for causing birth defects—was found, along with related molecules, to spur immuno-modulating interactions by degrading disease-causing proteins. One of those related molecules—lenalidomide—went on to become the blockbuster cancer drug Revlimid from Celgene, a company that was acquired by Bristol Myers Squibb in 2019 in one of the largest pharma deals in history. Thalidomide and its analogs are the only molecular glues currently approved by the FDA, all of them manufactured by Bristol Myers Squibb as the multiple myeloma treatments Revlimid, Thalomid and Pomalyst. Now, the molecular glue pipeline is brimming with potential, with Big Pharmas and smaller biotechs alike betting on the promise that these molecules can offer new approaches to difficult disease targets. Here, BioSpace takes a deep dive into five standout programs leading the way in molecular glue R&D. BMS’ multiple myeloma relapse renegade As the only drugmaker to have successfully developed and marketed a molecular glue protein degrader for multiple myeloma, BMS is ahead of the curve with its CELMoD program of oral therapies for blood cancers. Among the key molecules in the company’s pipeline is CC-92480, or mezigdomide. In a Phase 3 trial , the asset, when combined with Amgen’s Kyprolis and a corticosteroid, showed improvement in progression-free survival (PFS) in patients with multiple myeloma that has returned following previous treatment. The combination, nicknamed MeziKd, is “a follow-on from approved early-generation molecular glues” that offers an oral option for patients with multiple myeloma with potential to be best in class, according to Driscoll. Paul Richardson, director of clinical research and clinical program leader at Dana-Farber’s Jerome Lipper Multiple Myeloma Center, in a March press release touted the drug combination as an important new regimen for patients whose cancer doesn’t respond to treatments like Darzalex or BMS’s own Revlimid. “While treatment advances have been meaningful, far too many patients with multiple myeloma still relapse or stop responding—making the need for new options urgent,” Richardson said in a prepared statement. MeziKd “could address a key unmet need” for relapsing patients, he added. Monte Rosa’s AI-propelled assets caught Novartis’ notice Monte Rosa Therapeutics is among the smaller companies making a splash in this space, securing two deals with Novartis to develop molecular glues derived from the biotech’s AI discovery engine. Novartis paid $150 million up front with the potential for $2.1 billion in milestones in a licensing agreemen t with Monte Rosa in 2024 to advance the latter’s molecular glues targeting the VAV1 protein. The Swiss behemoth followed that up last year with another $120 million in upfront payments and milestones that could bring deal’s total to $5.7 billion. In clinical trials for immune-mediated and autoimmune conditions, MRT-6160 in a first-in-human trial showed VAV1 degradation greater than 90%, as well as T cell, B cell and cytokine inhibition. Monte Rosa has also demonstrated clinical effectiveness with another molecule called MRT-2359 in patients with metastatic castration-resistant prostate cancer via a Phase 1/2 study with interim results released in December 2025. MRT-2359 is being combined in this trial with the anti-androgen medicine enzalutamide. Monte Rosa’s AI discovery platform has allowed the company to work more quickly than basic screening approaches normally allow, Driscoll said. “The discovery of novel targets is expanding the target space here and allowing Monte Rosa to come up with new targets and apply that to selectivity challenges, adding efficiency to the process,” he continued. Collaboration Novartis Sticks With Monte Rosa in Second Molecular Glue Deal Worth up to $5.7B Novartis and Monte Rosa first partnered in October 2024 for a molecular glue asset for immune-mediated and autoimmune diseases. This time, the pharma is putting $120 million down upfront for more of the biotech’s AI-discovered degraders. September 15, 2025 · 2 min read · Tristan Manalac Read more C4 touts ‘best in class’ potential for DACs C4 Therapeutics has also caught Big Pharma’s attention with its molecular glue-based degrader-antibody conjugates (DACs) C4 pulled in a $73 million series A financing round almost a decade ago along with a strategic collaboration with Roche. The partners followed that up in April with another licensing deal worth $20 million upfront and up to $1 billion in milestones down the road. Together, the companies are developing cemsidomide, formerly known as CFT-7455, a molecular glue degrader that targets the proteins IKZF1 and IKZF3 to treat multiple myeloma. The drug candidate is in a Phase 2 trial following a successful early-stage study in which C4 touted high overall response rates. “C4 is claiming best-in-class potential, and that’s very exciting for the multiple myeloma space, which doesn’t have too many oral drugs,” Driscoll said. Neomorph and numerous partners target HIF Another biotech with deep Big Pharma connections, Neomorph is currently running a Phase 1/2 trial of its molecular glue degrader NEO-811 in patients with locally advanced or metastatic non-resectable clear cell renal cell carcinoma. The San Diego–based company calls the HIF signaling pathway inhibited by NEO-811 the “ Achilles heel ” of clear cell renal cell carcinoma, and the program has attracted collaborations with industry giants AbbVie , Biogen and Novo Nordisk , each with more than $1 billion in potential milestone payments. Similar to Monte Rosa, Neomorph has “gone all-in on molecular glues” and a platform that allows the company to discover novel signals in proteins that make them an ideal target for degradation, Driscoll said. Neomorph’s library of molecular glues is based on “rational design rather than random chance,” according to the company, which allows for more intentional targeting of disease as early as the discovery stage. Deals AbbVie Teams Up With Neomorph for Molecular Glue Collab Worth up to $1.64B Protein degradation–focused Neomorph nabs its third Big Pharma deal of around $1.5 billion in less than a year. January 23, 2025 · 1 min read · Annalee Armstrong Read more Degron, Takeda aim to stick it to solid tumors Degron Therapeutics’ lead molecular glue degrader DEG6498 entered the clinic late last year to treat advanced solid tumors using an RNA-binding protein that was considered “previously undruggable,” according to a May press release announcing the company’s $40 million series A extension. And the company, like many of its molecular glue peers, has picked up critical Big Pharma funding, this time from Takeda, which in 2024 signed a deal with Degron worth up to $1.2 billion. Most importantly, Takeda gained access to Degron’s discovery platform, called GlueXplorer, which uses AI to predict novel targets. Takeda CSO Chris Arendt at the time lauded the ability of molecular glues to aim at targets that had previously been undruggable and inaccessible by other treatments. AI’s application in finding new targets for molecular glues allows the field to advance at a faster clip than would otherwise be possible, Driscoll said. This strategy, he said, “is where the magic is happening.” Business Takeda Joins Hot Molecular Glue Market With $1.2B Deal Riding the growing wave of interest in molecular glue degraders, Takeda has partnered with Chinese biotech Degron Therapeutics to develop novel therapies for oncology, neuroscience and inflammation. May 23, 2024 · 2 min read · Tristan Manalac Read more

mCRPC作为近年来肿瘤的两大显学之一（另一个无疑是PDAC），在Pluvicto获批并迅速形成规模销售额之后，各路力量纷至沓来，ADC、TCE、降解剂、以及各种小分子都在各显神通，而近一两年正是密集读出早期临床结果的时间段。 借ASCO机会，系统整理了一遍各个modality在mCRPC各线的最新临床结果，当然也是在claude code协助下，故也将CC版本数据对比底稿和相关技能.md文件放在知识星球，欢迎看官大佬们斧正。 1 试验设计和基线 除了已获批的核药Pluvicto，多数mCRPC新药都还只读出了早期临床探索的结果，其中绝大多数临床试验是针对3-4L经治的患者（通常包括ARPI和紫杉醇等），有以下几个临床的设计和基线比较值得一提：1）Novartis使用了新核素Ac225的靶向PSMA核药，在一期分别探索了化疗和核药都未经治、化疗经治但核药未经治、化疗和核药都经治等几层，果然是家大业大，也给我们给患者分层提供了很好的视角；2）宜联的B7H3 ADC入组了明显转移灶更重的患者，特别是肝转和肺转比例全场最高；3）映恩的B7H3 ADC则入组了基线经治线数更多的患者，最多居然高达14线，而且有超1/3是核药经治，也专门区分做了核药经治亚组的研究；4）Abbvie的双抗ADC和Monte Rosa的GSPT1分子胶，都入组了超过1/2核药经治患者；5）Amgen和J&J的两款TCE，都同步推进了单药和联用的探索，只不过区别在于分别与阿比特龙和多西他赛联用。 从整体开发策略来看，由于Pluvicto的带头示范效应，大家都试图毕其功于一役，将前线taxane naive直到后线RLT treated一网打尽，Ph1/2开始就做大几十甚至上百例（像DB-1311在二期一口气做了将近20个cohorts），覆盖不同setting患者，有的还单药和各路联用方案齐头并进，也客观反映出竞争激烈程度。 2 有效性 由于各个试验的设计和基线差异较大，我们首先按照化疗和核药经治的情况分成三层，每层内做到尽量可比，且各试验都尽可能选取比较有指示性意义的剂量组（例如RP2D）。 1）紫杉醇未经治患者 在Pluvicto率先挺进taxane naive患者、且目前已经在这一层取得不错渗透率的情况下，这也就成为后续mCRPC新药的兵家必争之地。 从PSA50响应率来看，Pluvicto树立的标杆是50%左右，新一代α核素看起来大幅领先，B7H3 ADC中宜联也能达到50%+，双抗ADC品种更胜一筹，TCE们普遍表现优异，而小分子AR PROTAC和EZH2抑制剂则相对弱势。不过，我们必须认识到，PSA作为PD marker的指示性意义并不算好，后文会看到诸多肿瘤响应和生存期获益与PSA降幅不一致的情况，像此处Ac225-RLT亮眼的PSA50比例很大概率就与基线PSA奇高有关（见前文）。 从ORR来看，Pluvicto水平在50%左右，刚才在PSA50表现突出的Ac225-RLT和ABBV-969都哑火了，B7H3 ADC中的宜联和翰森略逊于Pluvicto，AMG-509联用阿比特龙则是唯一明显胜出的新药。 从数量尚少可评估rPFS的试验来看，Pluvicto的标杆在11.6个月，YL-201或因观察期太短而大幅落后，AMG-509联用阿比特龙的ORR优势也并未转化成rPFS获益，反倒之前不声不响的XNW-5004联用恩杂鲁胺弯道超车。 总而言之，在taxane naive pts中Pluvicto已经建立起相当坚实的有效性壁垒，目前尚无能构成显著威胁的挑战者，AMG-509+阿比特龙和XNW-5004+恩杂鲁胺这两个毕竟是联用方案，虽分别在ORR和rPFS上展现出优势，但多少都有些小样本称雄的意思，且在这两个终点上又各自都有些不匹配，尚待未来观察。 2）紫杉醇经治但核药未经治患者 taxane treated患者是mCRPC的主战场，目前Pluvicto的$2b销售额主要来自这一层，也是绝大部分新药的首选切入点。这一层的竞争明显激烈得多，不同临床试验的患者基线也参差不齐，因而我们需要尽量详细审视不同试验之间数据差异的可能来源。 从PSA50响应率来看，Pluvicto联用标准化疗的水平在46%，Ac225-RLT和ABBV-969同样响应率相当高，B7H3 ADC中也就YL-201和HS-20093与之基本持平，TCE里边尤以带遮蔽的JANX-007和VIR-5500大幅超出，小分子的CYP11A1抑制剂也可圈可点。 从ORR来看，Pluvicto水平同样在50%左右，一众B7H3 ADC们基本都达到40%左右、当然其中基线病情轻重不一会带来一定偏倚，TCE则略有点令人失望只有VIR-5500勉强跟上核药和ADC的步伐，JNJ-343以及几乎所有小分子的响应率都让人大跌眼镜。 针对taxane-treated患者的rPFS数据就丰富很多了，Pluvicto的8.7个月很明显并不令人满意，ADC们是目前生存期获益最明显的类别、特别是ABBV-969，在B7H3 ADC里边翰森意外地在轻基线且PSA50和ORR都占优势的情况下rPFS偏短，TCE的生存期还是不理想，恒瑞的AR PROTAC在响应率不足的情况下反而生存期尚可，EZH2抑制剂则携联用恩杂鲁胺之威表现不俗。 总而言之，在taxane treated pts中已经有相当多新药有能力向Pluvicto发起挑战，PSMA/STEAP1双靶ADC最为突出（两张瀑布图是真的赏心悦目），B7H3 ADC群体也都很有希望，而寄予厚望的TCE则尚缺少ORR和rPFS的有力数据。 3）核药经治患者 随着Pluvicto渗透率提升，核药经治的末线患者群体也逐步扩大，又考虑到CRPC生存期较长，即使末线市场也不容有失，所以不少研发者都专门在早期临床中挖掘了核药经治亚组。 目前可评估的数据并不算多，ABBV-969再次全场表现最佳PSA50达到70%、ORR达到50%，Ac225-PSMA这种“换核素”思路也还算有效（顺便也证实了PSMA表达的稳定），DB-1311作为入组核药经治患者最多的ADC至少在ORR表现尚可。 3 安全性 从整体的不良反应发生率来看：核药确实足够安全，≥G3 TRAE基本在15%上下；ADC们毒性普遍较大，≥G3 TRAE都在50%上下，仅有映恩的DB-1311干净很多；TCE分化较大，老一派的AMG-509毒性太大、甚至需要非常复杂的滴定，带mask之后会好很多（但如前所述药效似乎差了些），而强生的KLK2则显得过于安全、以至于会怀疑是不是还有向上探索剂量的空间；AR PROTAC安全性还可以，但毕竟有效性表现一般；EZH2里XNW-5004很值得一看，前线有效性颇有亮点的前提下，安全性也尚佳；CYP11A1抑制剂则整体都不温不火。 再看因TRAE而导致停药的比例：核药在5%左右；ADC里面，YL-201虽然总体TRAE偏高、但停药比例控制很低，DB-1311反而停药比例不低；TCE里面，AMG-509高得完全没法看，而JNJ-343都完全没有停药的、再次提示可能有继续爬剂量的余地；剩下的除了ARV-766以外，停药比例都非常低。 最后看具体的不良反应类型，值得关注的包括：核药的口干发生率60-90%，虽然≥G3很少；除DB-1311以外ADC们的血液毒性依然居高不下，特别是ABBV-969的≥G3血液毒性还是挺吓人；TCE的CRS是老生常谈，AMG-509尤其严重、附带很高的肌肉疼痛和皮疹，JANX-007带上mask之后依然偏高、还额外多了由于linker不稳定导致的肝毒性；MRT-2359和ODM-208血液毒性也不低，而QLH-12016还撞上了小分子的QT延长问题。 综合有效性和安全性来看，核药相对均衡，ADC药效有冲击力、但毒性也偏大，TCE在优化后能控制毒性、但药效目前尚不占优势，EZH2也有一战之力，其他尚不太容易挑战核药地位。