Ristoglogene Autogetemcel

近日，Beam Therapeutics宣布，与FDA就其核心管线BEAM-302在α-1抗胰蛋白酶缺乏症（AATD）中的监管路径达成了一致。FDA已经同意，公司可以使用“12个月的AAT生物标志物”数据作为替代终点，用于支持BEAM-302的加速批准申请。 BEAM-302这一加速批准路径的确定，也将其原先市场预期的上市时间从2030年提前到2027年左右。 受此消息鼓舞，Beam的股价上涨了约22%。 生物标志物替代终点 BEAM-302是一种治疗α-1抗胰蛋白酶缺乏症的体内基因编辑疗法，AATD通常由SERPINA1基因的G-to-A点突变（PiZ突变）引起，一方面，这种突变会导致循环M（功能）-AAT蛋白水平不足，从而引发肺部疾病，同时，错误折叠的Z-AAT蛋白会在肝细胞中聚集，进而导致肝脏疾病。 BEAM-302则能通过CRISPR碱基编辑技术直接修复致病突变，减少致病Z-AAT蛋白的产生。 此前，BEAM-302已获得FDA授予治疗AATD的孤儿药资格以及再生医学认定。 根据2025年8月，Beam公布的 I/II期试验最新数据显示，60mg剂量组中，第28天时，BEAM-302组患者体内的平均总AAT蛋白水平达到12.4µM，已超过公认保护阈值（11μM），其中校正M-AAT蛋白占总循环M-AAT的91%，致病Z-AAT蛋白较基线下降了79%。 安全性方面，BEAM-302的耐受性良好，无剂量限制性毒性（DLT）或严重AE。所有不良事件（AE）均为轻度至中度，ALT/AST升高≤1级且可自行恢复，输注相关反应轻–中度。 公司表示，将在2026年一季度前公布BEAM-302的更新临床数据，并披露关键开发计划。 这里也要浇下冷水，虽然现在，FDA似乎表现出对基因编辑疗法审批态度的放宽，但鉴于此前发生的几起FDA突然变脸案列，BEAM-302最终能否凭借“生物标志物”这一替代终点获得批准上市，还是存在一定的不确定性。 FDA态度突然转变，悲催Biotech又吃CRL FDA突然翻脸，公司股价大跌49% 今年提交首个BLA Beam Therapeutics是张锋联合创办的一家基因编辑公司，开发碱基编辑疗法。Beam2020年在纳斯达克上市。 碱基编辑是基于CRISPR系统开发的一种新型基因编辑技术，可以在不依赖DNA双链断裂的情况下，精准定位且直接编辑基因组中的单个碱基，实现对单个位点更精确的定向修改。这一优点使得其受到广泛关注。 基于碱基编辑技术，Beam曾建立了十余条管线。不过先前为了预防寒冬，Beam进行过裁员重组，停止了一些管线（如BEAM-201：同种异体CD7-CAR-T疗法）的开发。 目前，还有7条管线在研，这些管线主要分为两大类—体内（LNP和AAV疗法）和体外（造血干细胞与T细胞疗法）碱基编辑疗法。 体外碱基编辑疗法BEAM-101是公司目前开发进度最快的项目，被开发用于治疗镰状细胞病（SCD）和β地中海贫血（TDT），已经推进到I/II期临床阶段。根据公司在新闻稿披露的计划，其预计最早在2026年底前提交BEAM-101的上市申请(BLA)。 除了BEAM-101和BEAM-302外，Beam还有两款管线进入临床阶段。 BEAM-301是一种体内碱基编辑疗法，被开发用于治疗糖原贮积病(GSD1a)，目前正在进行Ⅰ/Ⅱ期剂量探索试验，Beam预计在2026年报告初步临床数据。 另外，管线方面，Beam还布局了一些抗体药，BEAM-103便是一种抗CD117单抗，目前正在健康人群中进行I期临床试验，公司预计2026年上半年完成所有剂量组给药。 比较值得一说的是，Beam一直以来都保持较为安全的现金流。截止2025年12月31日，公司预计账上现金、现金等价物以及有价证券约有12.5亿美元，预计至少可以维持公司运营至2029年，短期内无融资方面的压力 。 参考出处： https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-sets-strategic-priorities-its-genetic-disease https://beamtx.com/wp-content/uploads/2025/04/BEAM-302-A-potential-base-editing-therapeutic-for-alpha-1-antitrypsin-deficiency-Alpha-1.pdf https://www.fiercebiotech.com/biotech/touching-base-beam-ceo-gene-editing-biotech-big-push-vivo-delivery

In what CEO John Evans called Beam Therapeutics’ “big push,” the company will now prioritize in vivo delivery for its next-generation sickle cell disease therapies.\n Few companies stand better poised than Beam Therapeutics to reap the first fruits of the FDA’s promised flexibility toward cell and gene therapies. The biotech is pioneering treatments based on base editing, the very technology used to treat baby KJ last year. The infant’s case, underpinned by a custom gene editing therapy that was rapidly cleared by the FDA for experimental use, is now frequently invoked by U.S. health officials as proof of their dedication to fostering the next generation of genetic medicines.One sign that the FDA intends to keep its promise around regulatory flexibility came recently for Beam’s lead genetic disease program, BEAM-302. The company and the agency have agreed that Beam may use biomarkers evaluated over a year to support a potential application for an accelerated approval of the gene editing candidate as a treatment for alpha-1 antitrypsin deficiency (AATD), Beam said in a Jan. 11 release—the eve of the annual J.P. Morgan Healthcare Conference.“That’s classic accelerated approval,” Beam’s CEO John Evans said in an interview with Fierce on the sidelines of JPM. “We have biomarkers […] and they all predict clinical benefit, which is what the FDA wants to see. We would do accelerated approval, get to market, and then do a confirmatory trial.”AATD is caused by changes in the SERPINA1 gene, which instructs the production of the lung-protecting AAT protein. A lack of functional AAT leaves patients\' lungs vulnerable, and an accumulation of misfolded AAT can lead to liver damage.BEAM-302 is designed to correct the PiZ mutation that’s common in most patients with severe AATD by introducing a one-time adenine-to-guanine (A-to-G) correction of their DNA. The therapy involves a liver-targeting lipid nanoparticle (LNP) carrying Beam’s base editor. The biomarker-based path to potential approval marks a win for Beam, and investors celebrated the news by lifting the company’s share price by 22% on Jan. 12. Back in November, Evercore ISI analysts projected that regulators may require functional endpoint data to hand out an endorsement, which would push back a potential launch into 2030.Initial phase 1/2 clinical data reported last year showed that BEAM-302 at the 60-mg dose level helped three AATD patients with lung disease achieve an average AAT level of 12.4 μM at Day 28. By then, the corrected M-AAT protein made up an average 91% of total AAT in circulation, as the amount of the mutant Z-AAT had decreased by 79% versus baseline. On the safety side, BEAM-302 was said to be well tolerated in altogether nine patients across three doses explored. M-AAT is the most common form of AAT that protects the lungs and liver.A successful AATD therapy would need to reach AAT production of at least 11 μM, with the vast majority being functional protein, accompanied by a dramatic reduction in mutant protein, Evans said. With the trial results generated so far, BEAM-302 has ticked those boxes.“Now it’s just a matter of, do we continue to see that robustly? How does the data evolve? Is it durable? And then, as we treat more and more patients—adding another 50—is the safety consistent?” Evans said.Beam is testing two additional doses—up to 75 mg of the drug or two 60-mg doses administered a few weeks apart. It’s also treating AATD patients with liver disease in part B of the phase 1/2 trial. The company plans to report updated data from both parts and its pivotal development plan by the end of March.In AATD, Beam is racing against several RNA programs, including Wave Life Sciences’ RNA editing candidate, plus Takeda and Arrowhead Pharmaceuticals\' RNA interference program fazirsiran.Evans said he was surprised by how many patients favor one-time treatment. Existing AATD treatment options include lifelong augmentation therapy.Meanwhile, Wave’s early data recently underwhelmed expectations. But there’s an ongoing safety concern around permanently editing a patient’s DNA versus RNA.Safety-wise, Beam is treading carefully on two fronts: minimizing off-target editing and managing short-term acute toxicities from delivery.“It turns out that these are actually quite specific tools, and we have amazing assays,” Evans said. “You literally can go super-deep resolution sequencing on every single base in the entire genome—there are 3 billion of them.”The LNPs so far appear to be well tolerated, especially compared to viral vectors used in other gene therapies. But Evans noted that to ensure liver tolerability, their doses can’t go too high. Another SCD cell therapy? While Beam investors are highly focused on BEAM-302’s blockbuster opportunity in AATD, the company has another potentially closer-to-market program, ristoglogene autogetemcel (risto-cel), a base-edited cell therapy for treating sickle cell disease (SCD). There, the company is wrapping up a phase 1/2 trial and is guiding to an FDA filing as early as the end of 2026.With risto-cel, Beam plans to go up against Vertex and CRISPR Therapeutics’ Casgevy and Genetix Biotherapeutics’ Lyfgenia. All three agents involve modifying a patient’s own blood stem cells. Ristol-cel and Casgevy are more similar as they both use CRISPR gene editing to increase fetal hemoglobin (HbF), but Beam hopes that base editing could give its program an edge.Evans called the double-strand break induced by traditional CRISPR a “genotoxic event” that impacts the viability and robustness of the cell. Through chemical conversion of a base without cutting both DNA strands, risto-cel could lead to a more efficient manufacturing process that requires fewer cycles of cell collection, which means patients can get the final product faster and health facilities can save resources. Once infused, the modified cells could get to work faster, with more rapid engraftment.SCD patients who received BEAM-101 in a phase 1/2 trial underwent at the median just one cycle of mobilization for cell collection, and the neutrophil and platelet engraftments—which suggest that the new, healthy stem cells have successfully traveled to the bone marrow to start producing healthy blood cells—happened in less than 20 days. The early results, published last year, compared favorably to Casgevy’s data in a phase 3 trial in a larger group of patients.“Everyone has asked, ‘Why hasn’t the market grown more quickly as these launches have gone off?’ And from everything that we hear, it is really the struggle with the collection and manufacturing steps that is slowing it down,” Evans said.However, doctors and investors seem less convinced that BEAM-101 boasts enough differentiation.“[O]ur KOL feedback suggests that the incremental benefits do not yet significantly move the clinical needle, and more data (larger [number of patients] and longer follow-up) are needed to determine which therapy would be preferred choice,” Evercore analysts said in their November note.Evans acknowledged that some industry watchers view BEAM-101 as more of a wait-and-see story as they continue to hold a cautious view of the SCD market. For the longer term, Evans believes that deeper resolution of the disease, with increasing HbF levels and decreasing sickle hemoglobin and hence less anemia, would help an SCD treatment gain more traction.While improving these clinical markers is key for patient outcomes, the broader commercial success of SCD therapies may ultimately hinge on more than just efficacy. A major inflection point could come for SCD if a treatment can get rid of the need for toxic chemotherapy conditioning, currently a necessary step to clear out existing stem cells in a patient’s bone marrow to make room for new therapeutic cells.About 90% of SCD patients are not getting a transplant cell therapy because of the chemo component, Evans said.Toward that goal, Beam has developed BEAM-103, an antibody that’s designed to suppress hematopoietic stem and progenitor cells that express CD117, and BEAM-104, a next-generation HbF-boosting cell therapy that includes an additional edit to CD117 that spares it from BEAM-103. Essentially, the combination offers a potential nongenotoxic alternative.But moving into JPM, in what Evans called Beam’s “big push,” the company said it will now prioritize in vivo delivery for its next-generation SCD therapies. That pivot mirrors a broader surge in in vivo cell therapies, highlighted by major investments from heavyweights like AstraZeneca, Gilead Sciences and Bristol Myers Squibb, as well as federal support from the Advanced Research Projects Agency for Health (ARPA-H).The ability to go in vivo is enabled by advancements in targeted LNP delivery that allows the therapy to bypass the liver and get directly to hematopoietic stem cells (HSCs). Beam is ironing out the specifics in the coming weeks, and it may or may not use the BEAM-103 antibody, according to Evans. But one thing is clear.“We’re putting all of our eggs now in that basket,” Evans said. Edit, regulate, fundCasgevy and Lyfgenia were approved by the FDA in late 2023. But Beam’s in vivo program is still in the lead optimization stage without a candidate to move to the clinic, putting its most optimistic commercialization timeline well into the 2030s.“We’re never moving fast enough for my satisfaction,” Evans said. “But ultimately, it’s all limited by science.“I think in vivo to HSC has been a dream for a long time, but it needed some of these technical breakthroughs before I would even have said it was ready for prime time,” Evans continued. “I think we have those now […] There’s nothing fundamental that we need to discover in order to make this real. Once you get to that point, now it’s just a foot race to go as fast as you possibly can. I think you’ll start to see it accelerate.”The advancement of cell and gene therapies is also highly dependent on support from regulators. Hoping to replicate the one-off success for baby KJ, the FDA recently introduced the “plausible mechanism pathway” to expedite the development and approval of personalized gene editing therapies. Under this approach, rather than approving each individual therapy, the agency would essentially approve a treatment mechanism to be adopted in similar bespoke therapies.“We’re quite eager to do that ourselves,” Evans said. “Of course, we’re doing [AATD] where we’re going to treat tens of thousands of patients potentially with one single kind of editor. But we can equally manufacture bespoke editors for smaller populations and take advantage of that plausible mechanism pathway.”Beam is hoping to talk to the FDA about potential regulatory flexibility on BEAM-301, a candidate in glycogen storage disease Type Ia (GSDIa), which affects “hundreds of patients at most in the U.S.,” Evans said.The agency “has done a lot of listening” and has come up with new approaches to regulating cell and gene therapy, Evans said.Beam has at least found some initial support from Big Pharma. The Massachusetts biotech reached a potential blockbuster research collaboration with Pfizer in late 2021. The initial four-year term of the deal expired at the end of 2025. For now, the two companies are tight-lipped on whether Pfizer has extended the term or opted into any program.“Big Pharma is watching this space very closely,” Evans said. “What they’re generally doing, like with any long-term disruptive new technology, is they want to have a seat at the table.”As gene editing is still growing up, Big Pharma now prefers partnering or licensing over full-on platform acquisitions, Evans observed.Beam has generated more than $900 million of funding through business development and had an estimated $1.25 billion in cash as of the end of 2025, which will be able to cover its transition into a commercial firm, Evans said. With a clear regulatory path forward for BEAM-302 and enough funding to sustain operations into 2029, Evans said right now is the first time that he’s felt the company has the capital on hand to execute fully on the pipeline’s potential.  “This is a business that’s still quite labor-intensive and people-intensive,” the chief executive said. “The more streamlining the FDA does, the better it gets. But it’s still going to be expensive to do this.”