SHANGHAI – Nanjing-based Legend Biotechnology Corp. has partnered with Janssen Biotech Inc., a subsidiary of Johnson & Johnson, to develop in CAR-B38M, a promising chimeric antigen receptor T-cell (CAR T) therapy for multiple myeloma that targets B-cell maturation antigen (BCMA).

Little-known Legend began to live up to its name when it made its mark at the 2017 American Society of Clinical Oncology (ASCO) meeting, demonstrating that CAR-B38M had a 100 percent objective response rate in 35 Chinese patients with relapsed and/or refractory multiple myeloma. After four months, 14 of 19 (74 percent) patients achieved a stringent complete response.

Janssen clearly took notice.

The pharma firm agreed to provide Legend with $350 million in cash with future undisclosed milestones for a piece of CAR-B38M's potential upside. Worldwide profits and costs will be shared 50-50. Legend will keep a greater chunk of the cost and profit-sharing for the Greater China region, its home market, making the split 70-30.

Legend will use the funds for further development of CAR-B38M as well as for other CAR T assets for solid tumors and blood cancer that are in preclinical development. Plans are underway to study CAR-B38M in the U.S. next.

Legend takes a unique approach to CAR T, using a patented bispecific antibody platform which allows for one antibody to target and bind cooperatively to two different epitopes on the BCMA domain, locking firmly onto the target.

BCMA is highly expressed in patients with multiple myeloma, an incurable blood cancer. Multiple myeloma occurs when malignant plasma cells grow unchecked in the bone marrow. Many patients relapse after initial or secondary treatment and become resistant to treatment. In 2015, it is estimated that 124,225 people were diagnosed and 87,084 died globally.

According to data compiled by Globaldata, China will have the highest number of diagnosed multiple myeloma cases in the world by 2023 with 30,073 cases (up from 13,698 cases in 2013).

More than three months after making a splash at ASCO, on Sept. 18, Legend's parent company, the Hong Kong-listed Genscript, gave a study update. The study had been extended to 71 patients with relapsed or refractory multiple myeloma across four hospitals in China.

The announcement was prompted by the death of one patient two days prior.

At that time, 40 of the treated patients were followed up for at least three months, among which 24 patients achieved complete response, 12 achieved very good partial response, three achieved a partial response with one unreported response due to a patient dropping out of the study.

Among all the treated patients, 66 patients experienced different levels of cytokine release syndrome (CRS), a potentially fatal condition when the immune reaction consisting of a feedback loop between cytokines and white blood cells.

The company did not disclose the severity of the cytokine storm however, in the more positive presentation at ASCO (of 35 patients), six patients were free of CRS, 17 patients had grade 1, 10 patients had grade 2. At the more severe grades of CRS, two patients experienced grade 3 with no grade 4 or 5.

The beginning of a legend

Legend is the brainchild of Frank (Xiaohu) Fan who, in 2014, as the newly hired director of antibody services at Genscript, pitched his boss a CAR T project.

Fan, a China-trained surgeon who did his doctorate in transplant immunology at Hiroshima University, was excited about the potential in bispecific antibody CAR T treatments. He set up Legend Biotech as a subsidiary in April 2016. Legend now has 140 staff globally and GMP capability to manufacture CAR T therapies.

Legend has grown under the auspices of Genscript Biotech Corp., a CRO that provides early stage biological research services encompassing gene synthesis and molecular biology, peptide synthesis, custom antibodies, protein expression, antibody and protein engineering, and in vitro and in vivo pharmacology.

Genscript is Legend's majority shareholder with 85 percent ownership; Fan retains 10 percent with 5 percent held by management.

According to Steven Ma, vice president of public and investor relationships, Genscript has no further plans to get into the business of discovering and developing assets and will remain focused on services.

China has emerged as a hotbed for CAR T studies. It attracts researchers and biotechs in part because studies can be greenlighted by hospital ethics committees as a surgical procedure sidestepping the more rigorous and time consuming CFDA review process for drugs. CAR T therapies require extracting a patient's T cells and genetically engineering them to specifically identify and kill cancer cells. In the case of CAR-B38M, it takes Legend two weeks to reengineer the cells to attack multiple myeloma cancer cells before inserting them back into the patient. 2017 saw the CFDA announce many new rules for drug review and approval and, on Dec. 22, the agency also announced trial rules for treating cellular therapies as drugs, offering a path to commercialization. Getting a head start, on Dec. 11, Legend's clinical application was formally accepted as the first CAR T clinical trial application accepted nationally by the Center for Drug Evaluation (CDE) (CXSL1700201).

The new rules are expected to better regulate the safety and standards of trials conducted in China.

According to a December paper in the Journal of Hematology & Oncology, there are 121 CAR T trials in China as listed on as of July 2017. The majority of those are in the major cities of Beijing (30) and Shanghai (22) and of the 121 studies almost half (57) have CD-19 as a target as a treatment for B cell malignancies, including leukemia, lymphoma and myeloma.

There are dozens of other CAR T contenders in China such JW Biotechnology (Shanghai) Co. Ltd. (a joint venture between Juno Therapeutics Inc. and Wuxi Apptec), Fosun Pharmaceutical Group Co. Ltd., Kite Biotechnology Co. (a JV between Fosun and Kite) and local players like Innovative Cellular Therapeutics Inc., which is looking to tackle the challenge of affordability and manufacturing to scale cell therapies which are largely bespoke.

But Legend's main competitor in the anti-BCMA CAR T space for multiple myeloma is Bluebird Bio Inc.'s BB-2121. (See BioWorld, Dec. 12, 2017.)