BioPharma, Pharma

Janssen sees a potential myeloma CAR-T edge, exec says at BIO

The company plans to open its upcoming trial of a Chinese-developed CAR-T at four initial sites later this year.

Although bluebird bio’s CAR-T cell therapy for multiple myeloma is already in a registration-directed clinical trial, Janssen sees plenty of room to muscle in as well.

Janssen – a division of Johnson & Johnson – said May 30 that it would start a Phase Ib/II trial of the therapy in the second half of this year. Michael Kalos – Janssen’s vice president for immunooncology and oncology cellular therapeutics, was on hand at the ongoing BIO meeting in Boston to talk about the program.

Janssen spent $350 million to acquire global rights to the CAR-T from a hitherto obscure Chinese firm, Nanjing-based Legend Biotech, which announced data at last year’s ASCO meeting to much fanfare showing all 19 patients responded, including 14 who had a complete remission.

For the Phase Ib/II study, the investigational new drug application is open, and the trial will start with four US sites before expanding to additional sites in the US and eventually in Europe, Kalos said. Janssen gave the therapy the internal development name JNJ-68284528, while Legend had dubbed it LCAR-B38M.

Both LCAR-B38M and bluebird’s bb2121, it’s nearest competitor, target a myeloma cell-surface protein, or antigen, known as BCMA. While acknowledging that bb2121 is much further along in development than the LCAR-B38M – bluebird plans to file for Food and Drug Administration approval next year – Kalos said Janssen and Legend’s product has attributes the company views as advantageous. In particular, he said, it binds to two sites, or epitopes, of BCMA, whereas bb2121 binds to one. The hypothesis is that LCAR-B38M may be able to overcome a problem that has long plagued CAR-Ts, whereby patients respond to therapy, only to relapse with disease that continues to express the antigen but resists therapies that target it because of epitope loss.

However, bluebird Chief Financial and Strategy Officer Jeff Walsh said in a subsequent interview that it would be necessary to wait for the data to bear that out, and Kalos also said the dual-epitope binding is a “perceived advantage.” Still, targeting two epitopes allows tighter binding and hence mitigates the effects of epitope loss, Kalos said.

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Another criticism of the LCAR-B38M data was that while impressive, it was in Chinese patients, who undergo a multiple myeloma treatment paradigm that differs markedly from that of American patients, meaning they start with different baseline characteristics. In particular, even patients in the fourth or fifth line of treatment in China likely have not received myeloma therapies common in the US like Revlimid, Pomalyst and Darzalex, said Wim Souverijns, Celgene’s head of global hematology and oncology marketing, at the 2018 ASCO meeting. Celgene is partnering with bluebird to develop bb2121 and manufactures Revlimid and Pomalyst, which are immunomodulating drugs. Janssen markets Darzalex, which is a CD38-targeting monoclonal antibody.

Still, even though the treatment paradigm in China is different, Kalos said that is not necessarily a criticism of the LCAR-B38M program because those patients nevertheless have difficult-to-treat disease.

For the time being, Janssen plans to develop its manufacturing capabilities around the CAR-T internally, with plans to build plants around the world, Kalos said, with Novartis and Kite Pharma serving as models. Novartis markets the CAR-T Kymriah for pediatric leukemia and adult lymphoma, while Gilead Sciences – which bought Kite for $11.9 billion last year – markets Yescarta for lymphoma. Both CAR-Ts target the CD19 antigen. Both companies have developed manufacturing plants themselves. Meanwhile, bluebird has partnered with Swiss contract manufacturer Lonza to make the viral vector it uses for bb2121, and Celgene manufactures the product, Walsh noted.

Photo: Alaric DeArment, MedCity News