ASCO dark horse Nanjing Legend Biotech shines with promising CAR-T data

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Nanjing Legend Biotech's anti-BCMA CAR-T cell therapy showed quick and durable remission of relapsed or refractory multiple myeloma.

Chinese firm Nanjing Legend Biotech grabbed attention at the American Society of Clinical Oncology (ASCO) annual meeting, showing that its CAR-T candidate could be a safe and effective way to treat relapsed or refractory multiple myeloma.

Researchers report that in an ongoing early-phase clinical trial in China, 33 out of 35 (94%) patients whose multiple myeloma had relapsed on previous treatments had clinical remission within two months of receiving Legend’s experimental anti-BCMA CAR-T cell product, dubbed LCAR-B38M, and the objective response rate was 100%.

These patients received three split doses (20%, 30% and 50% respectively) of cells over a week, and first signs of efficacy appeared as early as 10 days after the initial injection.

Among the 19 patients researchers have followed for more than four months—a criterion for full efficacy assessment set by the International Myeloma Working Group—14 reached stringent complete response (sCR), meaning there’s no detectable plasma cells in the patient’s bone marrow or myeloma proteins in the serum or urine. For the other five patients, one reached partial response, and the rest four very good partial response—even though one progressed three months after extramedullary lesion disappeared. All five patients who have been followed for over a year remain in sCR status.

In terms of safety, 85% patients experienced cytokine release syndrome (CRS), a common and potentially dangerous complication of anti-T cell injections. Researchers said the majority of those cases were mild and manageable, with only two grade 3 (severe) CRS having been observed, and the patients recovered after receiving tocilizumab. Besides, no neurologic side effects occurred so far.

“It appears that with this novel immunotherapy, there may be a chance for cure in multiple myeloma,” said Wanhong Zhao, main organizer of the current study on LCAR-B38M and an associate director of hematology at the Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China.

In the relatively new CAR-T realm, all eyes were on the race between Novartis and Kite, plus Juno and Bluebird, until Legend Biotech, a wholly owned subsidiary of GenScript, sneaked in its report almost last minute to the conference.

Juno was once forging ahead until patient deaths of cerebral edemas forced the biotech to ditch its lead therapy JCAR015 and refocus on JCAR017, which is constructed using a controlled number of CD4 and CD8 cells and is now initially meant for relapsed or refractory non-Hodgkin lymphoma. After that, the industry has been very sensitive to CAR-T therapies’ safety profiles.

Currently leading the pack are Novartis’ CTL019 and Kite’s KTE-C19, both targeting CD19, both with FDA priority review in hand, with Novartis slightly ahead by about two months in terms of FDA’s scheduled decision date. Although they’re pursuing different initial indications—Novartis for acute lymphoblastic leukemia and Kite for non-Hodgkin lymphoma—the similarity in their approaches could invite direct competitions in the future.

However, the rivalry between Bluebird Bio’s bb2121 and Legend Biotech’s LCAR-B38M is already showing at an early stage—both are targeting BCMA and both are working toward the same indication.

Bluebird Bio and partner Celgene this morning in fact posted updated results from the ongoing CRB-401 phase 1 trial of bb2121, its investigational anti-BCMA CAR T cell therapy, in 18 heavily pre-treated and very sick patients with relapsed/refractory multiple myeloma at ASCO.

This dose-escalation study is looking at the safety and efficacy of bb2121 and determine a recommended phase 2 dose. The pair said in a statement that 15 patients in the so-called “active dosing regimens” section for bb2121 saw an objective response, with a dozen hitting a “very good partial response” (VGPR) to complete response. This was seen as a positive update, though Legend appears to be grabbing the headlines. 

The difference between the two meds however is that Bluebird’s product consists of an extracellular single-chain variable fragment (scFv), but LCAR-B38M “is a single CAR with antigen binding domain of a non-scFv structure,” Frank Fan, Legend Biotech’s CSO and interim CEO, told FierceBiotech. “Our binding domain composed of two different heavy-chain variable domains (single-domain antibodies or VHH) and both VHH domains target the same antigen BCMA but target different epitope.” Fan said he believes their candidate could pose better efficacy because of that construct.

Fan said they started clinical study on their anti-BCMA therapy in late 2015 based on a 2004 study—which indicates the possibility of targeting BCMA in multiple myeloma—without knowing that Bluebird was actually also starting trials in the same field.

Perhaps because the population base in China is larger, Legend Biotech’s study has more participants so far than its rival. Fan said they plan to enroll 100 patients to this trial at four participating hospitals in China, while Bluebird’s trial plans to have half that many participants.

The primary outcome data completion date is currently set in December 2017. Numbers look promising right now, but Fan said they’ll need to follow patients much longer in what he called a “life-long follow-up” to confirm their med could have a potential curative effect. 

Fan said they plan to launch a similar clinical trial in the U.S., and they’d also explore the method in patients with newly diagnosed multiple myeloma. The company is looking for multiple financial and scientific partners to see the projects through. He also didn’t rule out the possibility of licensing out the out-of-China right to the med to another biopharma partner.