Last December, striking initial data from Bluebird Biotech marked BCMA as a promising multiple myeloma antigen that could be targeted by CAR-T therapy. At Asco, however, Bluebird was upstaged by a virtually unknown Chinese group, Nanjing Legend Biotech, whose own anti-BCMA CAR was granted a coveted late-breaker.
That said, Bluebird’s own Asco update was impressive, showing efficacy extended to more patients given bb2121, though not without a logical uptick in toxicity. It will be vital for investors to tease out the differences between Bluebird’s and Nanjing’s studies, especially as Nanjing’s interim chief executive, Frank Fan, told EP Vantage he wanted his data to stimulate partnerships and financing.
So far Nanjing has been funded by its parent company, Genscript, a Hong Kong-listed contract manufacturer of biologicals. It had no cell therapy expertise until three years ago, when Mr Fan joined and formed Nanjing as a subsidiary focused entirely on development of CAR-T therapies.
The BCMA-directed CAR, which it designates LCAR-B38M, is its lead and currently only clinical-stage asset, and so the data unveiled today at Asco from a phase I Chinese trial could endorse its technology.
These show 33 of 35 multiple myeloma patients going into initial remission, comprising 15 complete and 13 partial remissions. Legend highlighted the fact that five patients followed for over a year were in CR, and that overall there had only been one relapse, from a patient who had initially gone into PR.
This is surprising mainly because Mr Fan admits that the LCAR-B38M cells do not persist for more than a few months. It is a generally accepted fact that long-lasting remissions require good persistence of CAR-T cells, and there have been relapses in other BCMA-targeting trials.
“Maybe once the product is potent enough it can kill all the myeloma cells, and then – game over, right? It doesn’t matter whether there is persistence or rejection,” said Mr Fan. “Maybe the patients get cured.”
Though Nanjing’s trial required BCMA expression as an enrolment criterion, LCAR-B38M is actually a bispecific, targeting CD38 as well as BCMA. Mr Fan said his group had also designed a bispecific hitting two different BCMA epitopes, while in preclinical development it has a CD22/CD19 bispecific, and an anti-CD123 CAR.
This is one difference versus Bluebird’s bb2121, which is an anti-BCMA monospecific CAR. Another is the multiple myeloma subjects’ baseline characteristics: Bluebird’s had failed on three to 14 lines of therapy, with a mean of seven, versus just three for Nanjing.
|Available clinical data with anti-BCMA CAR-T therapies|
|Group||NCI||Bluebird/Celgene/NCI||Nanjing Legend Biotech||Novartis/Penn|
|Binder/co-stim signalling||Murine/CD3ζ & CD28||Murine/CD3ζ & 4-1BB||Murine/CD3ζ & 4-1BB||Fully human/CD3ζ & 4-1BB|
|BCMA expression required?||Yes||Yes||Yes||No|
|Median prior treatments||7||7||3||9|
|Latest efficacy data||1 CR (relapsed) & 7 PRs in 16 pts||4 CRs & 12 PRs (1 relapse) in 18 pts||15 CRs & 13 PRs (1 relapse) in 35 pts||1 CR & 3 PR in 9 pts|
|Safety summary||Toxicity substantial but reversible||1 death – cardio-pulmonary arrest (unrelated)||Transient CRS||1 death – candidaemia/progressive disease|
|PR: partial response, CR: complete response, CRS: cytokine release syndrome|
At Asco Bluebird reported that its bb2121 trial had now 18 evaluable patients, up from the nine it detailed last year (Triple meeting – Bluebird upstages its Ash rivals, December 1, 2016).
It reported an 89% overall remission rate, though this comprised only four CRs; still, the only two patients not responding were in the lowest-dose cohort. While in December Bluebird boasted of no cytokine release or neurotoxicity above grade 2, it has now seen two cytokine release syndrome cases that quickly resolved, and still no serious neurotox.
Nick Leschly, Bluebird’s chief executive, stressed that responses (all but one of which is ongoing) could theoretically deepen and develop into CRs. Strong CAR-T cell expansion was seen, with the cells persisting in some patients for six months; the trial aims to enrol 50 subjects, and the next cohort will look at patients with lower BCMA expression.
For Bluebird and Nanjing alike it will be important to show durability of response, given the numerous relapse pathways that are emerging. A follow-on construct from Bluebird, bb21217, will enter the clinic in the second half, and the aim is to show improved durability, though that seems like “solving a problem we’re not sure we have yet”, Mr Leschly told EP Vantage.
Mr Fan does not seem focused on making improvements to LCAR-B38M, saying this second-generation construct with a murine binding region works well enough. He said Nanjing had also filed a patent for CAR-T technologies incorporating immune checkpoint inhibitors, and was working on a non-viral, allogeneic platform.
A major question for Western investors, however, is whether the data Nanjing has generated in China are replicable. “The reason we are disclosing our data at Asco is to recruit investigators in the US, because we are now planning to file [to begin trials] in the US to reproduce our China success,” he said.
Several other players beyond Novartis are on Bluebird and Nanjing’s tail with BCMA-targeting approaches: Juno’s fully human construct is in phase I, while Kite’s KTE-585 and Autolus’s bispecific against BCMA and TACI should enter clinical trials this year.
The Asco data underline BCMA’s promise, though this target is fast becoming a field as crowded as CD19.