Azelaprag

近日，BioAge公司决定停止一项azelaprag+tirzepatide联用的Ⅱ期临床试验STRIDES，原因是，在接受azeraprag +tirzepatide的受试者中观察到转氨酶升高现象，而在tirzepatide单药组中未观察到。 受此消息影响，BioAge当日股价盘后大跌67%。 STRIDES是一项随机、双盲、安慰剂对照Ⅱ期临床试验，该试验旨在评估 azelaprag单药/联合tirzepatide的安全性和耐受性。结果显示，azelaprag+tirzepatide组中的有11名受试者出现转氨酶升高。 目前，STRIDES已经停止新受试者招募，已入组受试者也停止给药。公司打算进一步分析已入组受试者的临床数据。 从公司CEO的发言来看，对azelaprag的未来并不乐观。 抗衰老的失利 azelaprag是BioAge的首选管线，也是公司能再次获得资本青睐的主要原因。 BioAge最早是一家致力于开发抗衰新疗法的Biotech公司，成立于2015年。 当时，BioAge重点推进两条抗衰老管线BGE-117和BGE-175，前者是一种缺氧诱导因子-脯氨酰羟化酶（HIF-PH）抑制剂，针对肌肉衰老。BGE-175是一种PGD抑制剂，针对免疫力衰老，当时已进入临床Ⅱ期阶段，BGE-175也是当时投资人最关注的一条管线。 不过，这两条核心管线仅让资本支持公司走到了C轮（2020年），在2021年，BioAge便先后BGE-175和BGE-117将两条管线放弃。 如果没有其他的管线支撑市场的期待，那么BioAge可能就此陨落。 减肥药给的机会 而azelaprag让资本给予了公司又一次机会。 2021年4月，BioAge从Amgen引进了azelaprag，2个月后（2021年6月），司美格鲁肽便获FDA批准减重适应症，凭借在减肥这一适应症拓展，诺和诺德获得巨大的商业机会。 随着应用人群的不断扩大，司美格鲁肽的痛点——肌肉流失逐渐暴露出来，据统计，司美格鲁肽减掉的体重中有25%—40%是肌肉，肌肉流失除了导致运动能力下降，还会增加患心血管疾病、骨质疏松症等风险。 而azelaprag则显示出有望改善GLP-1肌肉流失相关的副作用。 azelaprag是一款口服小分子apelin受体激动剂。Apelin是一种在身体运动后释放的运动因子多肽，可调节新陈代谢并促进肌肉再生。Azelaprag旨在模拟apelin，来提高减重者的基础代谢率和胰岛素敏感性，同时抑制炎症和肌肉萎缩。 在小鼠模型中，azelaprag与tirzepatide联用时能将减重率增加一倍以上，同时恢复健康身体成分以及改善肌肉功能。在将azelaprag与semaglutide联用时，也观察到了类似的结果。 2022年12月，在BioAge公布的Ⅰb期临床试验中，azelaprag显示可减少≥65岁健康老年人的肌肉萎缩，并维持肌肉蛋白合成。 azelaprag的这一价值也吸引了GLP-1龙头礼来的青睐。2023年10月，BioAge与礼来达成合作，开展azelaprag+tirzepatide联用的临床试验。此外，礼来还参与了BioAge的最新一轮融资，即2024年2月BioAge宣布在超额认购的D轮融资中筹集1.7亿美元。 趁着风头，BioAge也进行了IPO，2024年9月，BioAge成功在纳斯达克成功上市，筹集1.98亿美元资金，超出最初1亿美元的目标。 可以说，azelaprag支撑了市场对公司的全部预期。 目前BioAge还有两条管线在研，一款口服小分子脑穿透性NLRP3抑制剂处于临床前阶段，用于治疗神经炎症驱动疾病，公司预计在2025年下半年提交IND。另外一款还处于更早的发现阶段，未披露靶点。 参考出处 https://ir.bioagelabs.com/news-releases/news-release-details/bioage-labs-announces-discontinuation-strides-phase-2-clinical

The combination of an experimental BioAge Labs drug with the approved Eli Lilly obesity medication Zepbound has hit a major setback: a safety signal observed in some clinical trial participants that has led the biotech to stop the closely watched mid-stage study. The worrisome signal is elevated liver enzymes, BioAge disclosed after Friday’s market close. For BioAge’s drug, azelaprag, or for any medication, higher levels of such enzymes are a potential sign of drug toxicity. The company said it will stop dosing all participants with the experimental drug and no additional subjects will be enrolled in the Phase 2 study. BioAge added that it has notified all clinical trial investigators as well as regulatory authorities. The disappointing clinical trial development comes less than three months after BioAge raised more than $200 million in an IPO buoyed by azelaprag’s potential to improve weight loss while also preserving muscle mass. One of the known issues with Zepbound and other obesity medications in its drug class is that the weight patients lose includes muscle as well as fat. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech Preserving muscle mass is a key goal for companies developing the next wave of obesity drugs. Companies developing such drugs, either as part of combination treatments or as monotherapies, include Scholar Rock, Rivus Pharmaceuticals, and Skye Bioscience. Strong investor interest in BioAge’s approach enabled the biotech to upsize its IPO with shares priced at $18 apiece. After closing Friday at $20.09, BioAge’s stock price crashed to about $6.60 per share in after-hours trading. Azelaprag is a small molecule designed to bind and activate the apelin receptor, which regulates muscle metabolism, growth, and repair. BioAge initially tested the drug for preserving muscle mass in elderly patients, posting results showing the prevention of muscle atrophy. The small Phase 1b test also showed no safety signals. BioAge shifted the drug’s focus to obesity after encouraging preclinical tests of the molecule dosed in combination with Lilly’s Zepbound showed greater weight loss than Zepbound alone. Furthermore, the study showed improvement in body composition and muscle function. Those results led to a collaboration with Lilly. The Phase 2 clinical trial, named STRIDES, had a targeted enrollment of 220 participants age 55 and older. It was designed with four patient groups. Two cohorts were testing daily oral doses of azelaprag and weekly dosing of Zepbound, each as a monotherapy. Two additional groups are testing the drugs in combination, one arm testing azelaprag once daily and the other testing azelaprag twice daily. BioAge said the elevated liver enzymes levels were observed in 11 of the 204 patients enrolled so far. The participants who had these higher liver enzymes received azelaprag, but the company did not specify the cohorts in which these signals occurred. BioAge did note that no such signals were observed in the Zepbound-only group. In those who showed higher levels of liver enzymes, BioAge said there were no clinically significant symptoms. Follow up of the already enrolled participants will continue off of the study drug, and the company plans to analyze clinical data from all subjects. BioAge expects to have an update for azelaprag in the first quarter of 2025. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News “We made the difficult decision to discontinue the STRIDES Phase 2 study of azelaprag because it became clear that the emerging safety profile of the current doses tested is not consistent with our goal of a best-in-class oral obesity therapy,” BioAge CEO Kristen Fortney said in a prepared statement. “While this outcome is a significant disappointment, we remain encouraged by azelaprag’s promising preclinical and Ph1b efficacy profile.” If the safety signal leads BioAge to abandon azelaprag, company and investor focus will turn to a brain-penetrating small molecule inhibitor of NLRP3, a protein complex associated with neuroinflammation. Unlike azelaprag, which was licensed from Amgen, BioAge discovered its NLRP3-blocking molecule internally using its platform technology for analyzing human longevity data. Fortney said that as BioAge assesses next steps for azelaprag, the company will continue to advance the NLRP3 program as well as additional programs stemming from its technology platform. In its financial reports, BioAge has said it expects to submit an investigational new drug application for the NLRP3 drug in the second half of 2025, potentially laying the groundwork to begin clinical testing in 2026.