Ash 2018 – The balancing act behind Bluebird’s Goldilocks CAR

Amid a frenzy of BCMA-targeting multiple myeloma therapies Bluebird Bio’s bb21217 falls neatly into the Goldilocks zone.

Bluebird was the first group to report striking remission data with an anti-BCMA CAR-T therapy, bb2121. As its partner Celgene pushes this towards commercialisation, the follow-on asset bb21217 thus has to be neither so bad that its development becomes pointless nor so good that it makes bb2121 instantly obsolete.

Today at Ash Bluebird revealed the first clinical results backing bb21217, showing this Goldilocks thesis remaining largely intact. “Our two principles were: don’t break bb2121, and see if you can get it to be more persistent,” its chief executive, Nick Leschly, told Vantage. “That thesis is still alive.”

In the broader sense, however, an even more delicate balancing act will be going on at Celgene. In addition to owning rights to bb2121 and bb21217 the big biotech group also has in its portfolio no fewer than three other anti-BCMA CARs, acquired through its takeover of Juno.

At some point the day of reckoning will come at which Celgene will decide to focus on one of these CAR-T therapies and ditch the rest. Early data with the Juno-derived JCARH125, MCARH171 and FCARH143 are being presented at Ash tomorrow.

Lowest dose

The bb21217 presentation concerned the first 12 subjects treated, all at the lowest dose of 150 million cells. Three of these reported stringent complete remissions, with a further seven PRs yielding an overall response rate of 83%; there was one grade 3 cytokine release and one grade 4 neurotoxicity, both in the same subject.

One of the partial responders relapsed after some four months. University of California San Francisco’s Dr Nina Shah, presenting the data, said three further dose levels were planned, up to 800 million cells.

Of course patients will need to be followed longer to establish how deep the responses are, but the relevant comparison in the ongoing bb2121 study is a 57% overall response specifically at the same relatively low cell dose. Bluebird’s chief medical officer, David Davidson, said “it does not appear that we have broken” bb2121.

bb21217 swimmers plot. Source: Ash presentation.

Still, anyone nervously eyeing Bluebird’s $6.7bn valuation might well wonder how much success is already priced into the stock. The latest cut of the bb2121 study, at Asco, prompted a selloff despite yielding an impressive 80.6% ORR in the 36 patients who received 150 million cells or above (Asco 2018 – Good might not be good enough for Bluebird, June 2, 2018).

bb2121’s biggest problem might be patients relapsing. Waning durability of the responses was a main concern at Asco, and the lack of an Ash update for bb2121 might make some investors nervous. Celgene and Bluebird recently completed enrolment into bb2121’s pivotal KarMMa trial, and have set 2020 as the filing target.

The thinking behind bb21217, meanwhile, is to improve cell persistence by modifying the manufacturing process to include a PI3K inhibitor, which is thought to drive the T cells towards a memory-like phenotype. Clearly higher dosing and longer follow-up is needed to determine whether persistence can be improved.

The decision to develop bb21217 was taken early on, likely on account of the speed with which competition in BCMA targeting is building up. There is no better sign of the extent of this competition than the frenzy of anti-BCMA assets being profiled at Ash, comprising CARs, bispecifics and antibodies alike.

Being first to market is important, but in such a fierce race even a two-year headstart might ultimately not count for much.

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