Competition is heating up in the race to develop CAR-T therapies for multiple myeloma as abstracts from numerous companies in the US and abroad went online Thursday, featuring clinical trial data ahead of the 2018 American Society of Hematology meeting. But the CAR-Ts as a whole face competition as well from cheaper, easier-to-administer monoclonal antibodies with the same antigen target.
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A search on the ASH abstract page turned up numerous investigational cell therapies for myeloma, particularly CAR-Ts targeting the BCMA antigen, a cell-surface protein highly expressed in the disease. The ASH meeting will take place Dec. 1-4 in San Diego.
The most advanced CAR-T for myeloma in development is bb2121, a construct that targets the BCMA antigen, from Cambridge, Massachusetts-based bluebird bio and Celgene Corp., currently in a registration-directed Phase II clinical trial and expected to go before the Food and Drug Administration next year. In an oral presentation at the meeting, the companies will showcase preliminary Phase I data on what they tout as the next-generation version of bb2121. Dubbed bb21217, the new construct is similar to its predecessor, but includes a phosphoinositide 3-kinase inhibitor, whose addition is designed to make the cells more potent and enable them to persist longer. Although data on seven patients evaluable for a response showed six of them responding to treatment, the abstract noted that longer follow-up would establish whether the modification makes the therapy more powerful than bb2121.
Last year’s American Society of Clinical Oncology meeting in Chicago saw the introduction of a BCMA-targeting dark horse competitor to bb2121, LCAR-B38M, developed by Nanjing, China-based Legend Biotech, with strong response rates and low toxicity. But a global licensing deal with Johnson & Johnson subsidiary Janssen Biotech announced in December 2017 brings the new therapy to the global stage. The ASH abstract of Phase I data shows an 88 percent overall response rate among 50 patients, including a 74 percent complete response rate, while most patients experienced adverse events, including 90 percent who had cytokine release syndrome.
But both products could face competition from monoclonal antibodies – particularly bispecific antibodies – targeting the same antigen, such as Amgen’s AMG 420. Whereas the CAR-Ts must be administered in a hospital inpatient setting and will likely the high price tags that the two FDA-approved CAR-Ts do, bispecific antibodies like AMG 420 can be given in a doctor’s office and will likely cost far less. The two approved CAR-Ts – Novartis’ Kymriah (tisagenlecleucel) and Gilead Sciences’ Yescarta (axicabtagene ciloleucel) – each carry a $373,000 list price for lymphoma and, in Kymriah’s case, $475,000 for leukemia, not including supportive care costs that can equal or exceed the list prices.
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According to Phase I dose-escalation data on AMG 420 that will be in an oral presentation, among 35 patients treated, six had complete responses – including three at the 400-microgram dose and one each at the 200-microgram and 100-microgram doses. Among the patients receiving 400 micrograms, responses were ongoing at 4.6 months or more, and all three responses were minimal residual disease-negative. Serious adverse events included infections and cytokine release syndrome, as well as peripheral polyneuropaty, cardiac failure, edema, pyrexia, biliary obstruction and renal failure.
AMG 420 was developed under Amgen’s Bispecific T-Cell Engager, or BiTE platform, the same one it used to develop Blincyto (blinatumomab), which is used for acute lymphoblastic leukemia and targets CD19, the same antigen as Kymriah and Yescarta. GlaxoSmithKline and Celgene are also developing BCMA-targeting bispecific antibodies, while Celgene additionally has an antibody-drug conjugate targeting the antigen. As such, the antibodies could present competition for BCMA-targeting CAR-T therapies given their likely cost and logistical advantages.
Still, an earlier study indicated the potential to use the two different therapeutic modalities sequentially. In data presented at this year’s ASCO meeting, Gilead showed that adults with acute lymphoblastic leukemia were able to respond to Yescarta regardless of whether they had previously received Blincyto.
Clinical data from several other cell-based therapies for myeloma are also being presented. These include new BCMA-targeting CAR-T constructs from several Chinese firms, particularly Shanghai-based firms CARSgen Therapeutics and HRAIN Biotechnology. Seattle-based Juno Therapeutics – which Celgene acquired in January for $9 billion – will feature its own BCMA-targeting CAR-T, JCARH125, in an oral presentation.
Photo: CGToolbox, Getty Images
