Obecabatagene autoleucel

iStock/ Jian Fan Having established success in cancer, biopharma is now looking to leverage CAR T therapies against a new target, autoimmune disorders, with several early- to mid-stage readouts expected this year. In September 2022, an intriguing report went up on Nature Medicine. Though the study was small, its impact on biopharma has been huge. The study enrolled five patients with systemic lupus erythematosus (SLE), a chronic autoimmune condition where the immune system targets the patient’s own body. SLE triggers inflammation in organs across the body and can manifest as a wide variety of symptoms, including fevers, blood clots, swollen extremities, fatigue and mouth sores. There is currently no cure for SLE, but the Nature Medicine paper sparked hope that one might be near. The study tested a relatively new technology called CAR T cell therapy, which often uses a patient’s own immune T cells, modifying them outside of the body to make them more potent against certain target cells and then injecting them back into the patient. This approach has already seen success in cancer, with several therapies having earned the FDA’s approval: Gilead’s Yescarta, Johnson & Johnson’s Carvykti and Novartis’ Kymriah, to name a few. The Nature Medicine study hinted at similar promise in autoimmune diseases—all five treated patients hit and maintained remission for an average of eight months and no longer needed other treatments to keep SLE at bay. Two years later, the New England Journal of Medicine published a slightly larger study —including 15 patients—that confirmed these findings and pointed to even broader benefits. CAR T therapy not only elicited remission in SLE patients but also resulted in encouraging response rates in those with idiopathic inflammatory myositis or systemic sclerosis. “Cell therapies are the only modality that appear to provide a prolonged period of drug-free remission, which can be transformative for [a] patient’s quality of life,” Sami Corwin, an analyst at William Blair, told BioSpace in an email. The CAR T approach, in particular, offers a one-time treatment option and is “not associated with chronic side-effects,” as compared with other modalities, Corwin added. Though T cell engagers and NK cells are also being eyed as autoimmune treatments, CAR T therapies are leading the charge—for good reason. “CAR T therapies have already demonstrated remarkable success in conditions like lupus and systemic sclerosis by selectively depleting autoreactive B cells, resulting in sustained immune reset,” Katy Rezvani, head of the Institute for Cell Therapy Discovery & Innovation at MD Anderson, told BioSpace in an email. The biopharma industry is now seeking to expand on this early success, with Bristol Myers Squibb, Kyverna, CRISPR Therapeutics and more progressing CAR T therapies in a wide range of indications, including SLE, multiple sclerosis and stiff person syndrome. Here, BioSpace reviews five of the most advanced players in this space and how they’re harnessing—and innovating on—CAR T technology to address autoimmune diseases. BMS Brings CAR T Cancer Expertise to SLE A leader in CAR T therapies for cancer, Bristol Myers Squibb is now leveraging its cell therapy expertise to address autoimmune diseases. The pharma is working on CD19 NEX-T , an investigational CAR T therapy designed to seek out the cell surface protein CD19, which is highly expressed in B cells. Once it binds to CD19, the CAR T construct activates, releasing a cocktail of inflammatory cytokines and other chemicals that destroy the target B cell. This approach is similar to how BMS’ CAR T therapy Breyanzi works—only this time, the pharma is using this mode of action not to kill cancerous B cells in lymphomas but to deplete defective immune cells that mistakenly attack healthy cells. In an email interview with BioSpace , Rosanna Ricafort, vice president and head of late development, hematology and cell therapy at BMS, called CD19 NEX-T a “top priority” for the pharma, with which it plans to “push the boundaries in immune-mediated diseases.” In service of this goal, the pharma is running the Phase I Breakfree-1 and Breakfree-2 studies of CD19 NEX-T in SLE. At the 66th Annual Meeting of the American Society of Hematology in December 2024, BMS presented early data from both trials showing that three patients followed for at least six months were able to stop all other therapies without showing new signs of disease activity. One patient hit the definition of disease remission at six months. Aside from SLE, BMS is also advancing CD19 NEX-T for multiple sclerosis (MS), for which it unveiled early data last month, pointing to encouraging safety and tolerability. The pharma expects to provide additional early-stage data from the Phase I CD19 NEX-T program this year, building up to pivotal trials as soon as the data allow. “Our ultimate goal is to target the root cause of disease and drive long-term, treatment-free disease control for patients with severe forms of these autoimmune diseases,” Ricafort said. Kyverna Targets First CAR T Therapy for Stiff Person Syndrome This year, Kyverna Therapeutics is anticipating several key milestones for its investigational CAR T therapy KYV-101. Like BMS, Kyverna’s approach targets CD19 to eliminate dysfunctional immune cells, leading to what the biotech calls an “ immune reset ” in patients with autoimmune diseases. KYV-101 is unique in that it is designed specifically to avoid cytokine release syndrome and improve tolerability. Kyverna is testing KYV-101 for three target conditions : Stiff person syndrome (SPS), myasthenia gravis and lupus nephritis. Of these, the most mature indication is SPS, for which Kyverna expects to complete enrollment of a Phase II trial by mid-2025, building up to a topline readout in early 2026, CEO Warner Biddle told BioSpace in an email. Typically afflicting women more than men—and more frequently diagnosed in people 20 to 60 years of age—SPS is a rare disorder that arises when the body makes antibodies that attack the enzyme glutamic acid decarboxylase, which plays a role in the production of a neurotransmitter involved in muscle control. Common symptoms include muscle stiffness and painful spasms. If all goes well for Kyverna this year, the biotech expects to file a Biologics License Application for KYV-101 for SPS next year. “We believe this focused approach in SPS will enable us to deliver the first CAR T cell therapy in autoimmune disease to the market,” Biddle said. Beyond SPS, Kyverna is also looking forward to several catalysts in myasthenia gravis this year, including aligning with the FDA on a registrational path for the CAR T therapy in the first half of 2025, followed by a topline mid-stage readout in the latter half of the year. Kyverna’s autoimmune CAR T program is comprehensive, with the company having treated the most patients with a CAR T cell therapy so far, according to Biddle. CRISPR Homes in on Off-the-Shelf CAR T Market Seeking to build on the momentum from its Vertex Pharmaceuticals–partnered gene therapy Casgevy, CRISPR Therapeutics is now moving its allogeneic next-generation CAR T therapy CTX112 through clinical trials in various autoimmune diseases. The key advantage for CTX112 is its off-the-shelf availability, CRISPR Therapeutics Chief Medical Officer Naimish Patel told BioSpace in an email. “The drawbacks of autologous CAR T cell therapies”—those that draw cells from the patients themselves—“are that they are very expensive, require patients to stop their immunomodulatory therapy to get T cells harvested, are not widely available … and are associated with potentially severe side effects.” CRISPR Therapeutics is evaluating the potential of CTX112 in various autoimmune diseases, supported by safety, pharmacokinetic and pharmacodynamic data from cancer studies. The asset is currently in Phase I development for SLE, but at the 43rd J.P. Morgan Healthcare Conference in January, CEO Samarth Kulkarni bared the company’s plans to expand testing to other autoimmune indications. In its fourth-quarter and full-year 2024 business report last month, CRISPR Therapeutics revealed it had expanded its basket trial for CTX112 to include systemic sclerosis and inflammatory myositis. Updates for study are expected mid-2025, as per the biotech. “We see incredible potential for our allogeneic CAR T program, and we are looking forward to sharing a broad program update on CTX112 mid-year 2025,” Patel said. Autolus Awaits Q1 SLE Readout for Obe-Cel The only therapy on this list with an FDA approval under its belt is Autolus Therapeutics’ obecabtagene autoleucel, also called obe-cel, which was cleared by the regulator in November 2024 for relapsed/refractory B cell acute lymphoblastic leukemia. In this indication, obe-cel is marketed as Aucatzyl. Like most of the other assets in this class, obe-cel targets the CD19 epitope. Autolus is seeking to set its candidate apart from the rest of the space through a unique CAR construct that has what it calls a “ fast-off ” kinetic mechanism, which, unlike the traditional approach, enables the controlled binding of the CAR molecule to its target, in turn activating T cells in a similarly controlled manner. According to Autolus, this fast-off scheme closely mirrors the physiological interactions of T cells with their corresponding receptors. Results from a Phase Ib/II study of obe-cel in B-cell acute lymphoblastic leukemia, published in the New England Journal of Medicine in November 2024, suggest that Autolus’ fast-off approach improves T cell persistence and lowers exhaustion, leading to better clinical outcomes. More than half of patients achieved complete remission after obe-cel treatment, with an estimated 12-month overall survival rate of 61.1% Autolus still doesn’t have such detailed data for obe-cel in autoimmune diseases. The biotech is currently running the Phase I CARLYSLE study in advanced SLE, for which initial data are expected in the first quarter of this year, as per a November 2024 company presentation . Cabaletta Anticipates Multiple Catalysts for Rese-Cel in 2025 Cabaletta Bio—which launched in November 2018 with a stated focus on autoimmune disease—was ahead of the curve in this space. It is also the only company on this list that is developing its investigational cell therapy exclusively for autoimmune diseases. CABA-201 , also called resecabtagene autoleucel or rese-cel, is an investigational CAR T therapy that also targets CD19. What makes rese-cel unique is that it contains a 4-1BB domain, which is a protein commonly expressed on activated T cells that helps enhance their activity . Recent preclinical evidence has pointed to the potential of targeting 4-1BB to address autoimmune diseases. Cabaletta is testing this approach in the clinic with its Phase I/II RESET program, which is assessing rese-cel in a wide variety of autoimmune disorders, including myositis, SLE, systemic sclerosis, myasthenia gravis, MS and pemphigus vulgaris. Of these indications, the biotech named as primary focuses myositis, SLE and systemic sclerosis, for which rese-cel’s mechanism has the potential to “achieve robust improvement in clinical disease activity within 3 months of treatment,” according to its website . In a corporate presentation last month, Cabaletta unveiled initial clinical data from the RESET program, touting “consistent and deep” depletion of B cells 22 days after infusion. Additionally, treatment with rese-cel resulted in strong treatment response, pointing to the potential to achieve drug-free remission in patients with refractory disease. Similarly, rese-cel showed the potential of a “drug-free clinical response” in systemic sclerosis, while early data for SLE pointed to promising rates of remission. Cabaletta has several other rese-cel milestones lined up for 2025 , including more clinical and translational readouts throughout the year and a meeting with the FDA to align on a registrational path for the asset.

截止至2024年12月31日，美国FDA共批准了7款CAR-T细胞治疗产品。随着几大厂商发布2024年财报，CAR-T治疗产品在2024年的销售成绩也都出炉了。（注：国内CAR-T销售未纳入统计） 从第一款CAR-T上市至今，已经有8年，CAR-T治疗产品的销售趋势也从早期的快速爬升，到逐渐平缓，到2024年部分产品有下跌趋势，但更多的还是呈上升趋势，尤其是BMS的Breyanzi，同比上涨105%。 总体来说，CAR-T治疗产品的销售距离预期还存在一定的差距。 诺华 Kymriah 2023年是Kymriah上市的第8年，也是销售持续下跌的第3年。 Kymriah在2021年达到了5.87亿美元的年销售峰值后，开始持续下跌；2022年的年销售为5.36亿美元，2023年为5.08亿美元（同比下降5.2%），2024年为4.43亿美元（同比下降13%）。 根据诺华2024年财报，Kymriah第四季度的销售额在美国以外地区销售额下降，部分被儿科业务和25岁以下B细胞急性淋巴细胞白血病（pALL）的年轻成人患者的强劲表现所抵消，以及被滤泡性淋巴瘤（FL）适应症在美国以外市场的销售增长所抵消。 延伸阅读：首款CAR-T卖不动了？未来将更加残酷 吉利德 Yescarta Yescarta于2017年10月18日首次获得美国FDA批准，用于三线及三线以上治疗LBCL成年患者。2022年4月1日，Yescarta获得FDA批准用于二线治疗LBCL成年患者。 与2023年相比，Yescarta在2024年全年的销售额增长了5%，达到15.7亿美元。主要是由于美国以外地区的需求增加和平均实现价格上涨，部分被美国需求下降所抵消。 吉利德 Tecartus 2020年7月24日， 吉利德/Kite公司的CD19 CAR-T细胞疗法Tecartus获得FDA批准，用于治疗复发或难治性套细胞淋巴瘤（r/r MCL），成为第三款上市的CD19 CAR-T细胞治疗产品。2022年9月6日，Tecartus获得欧盟批准用于R/R ALL。 与2023年相比，Tecartus的2024年全年销售额增长9%，达到4.03亿美元，主要受美国以外地区需求增长的推动，部分被美国需求下降所抵消。 BMS Breyanzi Breyanzi是第四款获得FDA批准的CD19 CAR-T产品，于2021年2月首次获得批准用于治疗三线治疗LBCL。 2024年，Breyanzi实现了7.47亿美元的销售额，同比上涨105%。根据BMS所发布的2024年财报，Breyanzi是BMS投资组合收入增长的主要驱动之一。 BMS Abecma Abecma是BMS第二款CAR-T细胞产品，也是首款获得FDA批准的BCMA CAR-T细胞治疗。Abecma于2021年3月26日获得美国FDA批准，用于治疗四线治疗多发性骨髓瘤。 Abecma的2024年的总销售额为4.06亿美元，同比下降约14%。Abecma的销售延续了2023年的下降趋势。 尽管Abecma作为首款上市的BCMA CAR-T细胞产品，具有市场首发优势；但可惜在前线MM治疗上，FDA延迟了决定，与其竞争对手（Carvykti）同日获批，来到同一起跑线上，随着Carvykti的市场竞争，Abecma销售压力越来越大。 强生/传奇 Carvykti BCMA CAR-T明星产品Carvykti于2022年2月28日首次获得FDA批准上市，用于四线治疗R/R MM。 Carvykti的2024年销售额为9.63亿美元，同比增长92.7%。 另外，值得注意的是，中国药监局（NMP）于2024年8月批准了西达基奥仑赛（Carvykti）上市。 延伸阅读：传奇CAR-T国内上市！ Autolus Aucatzyl 2024年11月，美国FDA批准Autolus Therapeutics的CD19 CAR-T细胞产品Aucatzyl，用于治疗复发性/难治性成人B细胞急性淋巴细胞白血病（r/r B-ALL）的成人患者。 但是由于上市较晚，Aucatzyl在2025年未有销售数据披露。但是根据Autolus公司报告，预计将在2025年1月底之前完成30个治疗中心的授权，覆盖约60%已经确定的目标患者群体；预计到2025年年底完成对60个治疗中心的授权，覆盖约90%的目标患者群体。 参考资料： 1.诺华2024年财报：https://www.novartis.com/sites/novartis_com/files/2025-01-interim-financial-report-en.pdf 2.吉利德2024年财报：https://www.gilead.com/news/news-details/2025/gilead-sciences-announces-fourth-quarter-and-full-year-2024-financial-results 3.BMS2024年财报：https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Reports-Fourth-Quarter-and-Full-Year-Financial-Results-for-2024/default.aspx 4.Autolus Therapeutics业务更新：https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-provides-business-updates-and-2025-overview 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·