Ash 2017 – Bluebird’s CAR-T holds up as BCMA competition grows

An eagerly awaited update from Bluebird on its Celgene-partnered multiple myeloma CAR-T asset bb2121 did not disappoint, with the Ash meeting over the weekend hearing of remissions deepening over time and a reasonably safe profile relative to other projects.

BCMA, the antigen target of bb2121, is a major theme of Ash, and multiple presentations showed how quickly this space has become crowded. Still, Bluebird is determined to proceed fast, and alongside the phase I study just updated it recently began Karmma, a pivotal trial to run alongside in a bid for first-mover advantage.

As such, the phase I data served largely to confirm the promise of bb2121; no findings were available from an expansion cohort that has now recruited 12 patients, and Karmma as well as Bluebird’s follow-up asset bb21217 will now increasingly seize the limelight. Bluebird gained 18% Monday, while Celgene was up 2%, on the strength of this and other studies presented at Ash.

Remissions develop

The bb2121 trial’s previous update, at Asco, showed four complete and 12 partial remissions across 18 patients at various dose levels. Yesterday, the NCI’s Dr James Kochenderfer reported results from 21 heavily pretreated multiple myeloma patients, whose best responses had advanced to 10 complete and six partial remissions.

Of most interest are the data for 18 subjects dosed at 150 million cells or above, where the complete and partial response rates stand at 56% and 33% respectively. The chosen dose for Karmma is 150-300 million cells, and this pivotal study will aim to enrol 94 subjects and measure overall remission as primary endpoint.

Interestingly, unlike in dose escalation, neither Karmma nor the expansion cohort stipulates BCMA expression as an enrolment criterion. David Davidson, Bluebird’s chief medical officer, told EP Vantage: “The CAR is so exquisitely sensitive that it can pick up levels of the antigen way below the levels that assays can detect.”

The relative safety of bb2121 came as a surprise when the first phase I data were revealed a year ago (Asco – Mystery Chinese group gives Bluebird a run for its money, June 5, 2017).

And safety continues to be good, with cytokine release syndrome of grade 3 or above seen in only 10% of subjects. There was one, reversible, grade 4 neurotoxicity in the expansion phase in a woman with the highest tumour burden of any of the patients seen so far.

The same subject had only 1% BCMA expression, and yet is now in a very good partial response. “This answers the question, do you need a high level of BCMA expression to get an important response and expansion? The answer is no,” said Mr Davidson.

On the negative side of the equation, three initially responding patients have now relapsed while retaining the BCMA antigen, said Dr Kochenderfer, adding: “In one patient BCMA expression went down somewhat.”

There were two patient deaths not due to disease progression – one of cardiac arrest and the other of myelodysplastic syndromes after discontinuation.

Comparing anti-BCMA CAR-T therapies
Developer Bluebird NCI Novartis Nanjing Legend MSKCC
Project bb2121 Anti-BCMA CAR CART-BCMA LCAR-B38 MCARH171*
Co-stim domain 4-1BB CD28 4-1BB 4-1BB 4-1BB
Gene transfer Lentivirus Gamma-retrovirus Lentivirus Lentivirus Gamma-retrovirus
Conditioning Cy/flu Cy/flu Cy (none in first cohort) Cy Cy/flu
BCMA expression required? >50% (none in pivotal trial) >50% None Clear expression >1%
Median prior therapies 7 7 9 3 7
Efficacy 9 CRs & 8 PRs (3 relapses) in 18 pts at high doses 2 CRs (1 relapse) & 11 PRs (5 relapses) in 18 pts at highest dose 1 CR & 5 PRs in 10 pts at highest dose 15 CRs & 13 PRs (1 relapse) in 35 pts 2 PRs in 2 pts at highest dose
Relevant dose (million cells) 150-800 9 500 3 split doses, 1.2-7.1 137
Note: Juno's commercial construct JCARH125 (4-1BB, lentivirus) should enter the clinic in Q1 2018; Fred Hutchinson Cancer Center's FCARH143 (lentivirus) is in phase I.

Bluebird will be acutely aware of growing competition here, though it still has the advantage of safety and development speed on its side.

Dr Kochenderfer is separately involved with work at the NCI on a different CAR construct against BCMA. An Ash update yesterday revealed that 26 subjects were now evaluable: overall response rates amount to 81% in 16 high-dose subjects but only 20% in those given lower amounts of cells.

Another BCMA-targeting CAR, CART-BCMA, is in development by the University of Pennsylvania and Novartis. After seeing some remissions in non-lymphodepleted subjects a study of this has now started in two cohorts using chemo conditioning, and has seen responses ramp up with the higher of two doses, though cytokine release and neurotoxicities remain problematic.

Poseida Therapeutics, partnered with Johnson & Johnson, told Ash on Sunday that its first CAR-T asset, P-BCMA-101, which uses a transposon rather than a virus for transduction, had entered phase I/II. There was no significant Ash update from Nanjing Legend, the Chinese company that surprised Asco with a near-100% response rate with the LCAR-B38M CAR in a far less refractory patient population.

And another BCMA asset that could see increasing interest is Juno’s JCARH125, which could enter the clinic in early 2018. Ash data from Memorial Sloan Kettering’s related but non-commercial construct, MCARH171, showed a 60% remission rate, all partial, in five subjects across two doses.

Juno recently struck a deal with Lilly to combine JCARH125, which like CART-BCMA uses a fully human binding domain, with gamma-secretase inhibitors, which it argues can increase cell surface BCMA expression.

Parallel work

If this is all indicative of looming competition, Bluebird is refusing to rest on its laurels. As well as running Karmma in parallel with the phase I programme, the company is already talking about moving anti-BCMA CAR-T into earlier lines of multiple myeloma therapy.

“It’s going to be an iterative process ... including potentially [going] head to head in newly diagnosed multiple myeloma,” said Mr Davidson. “There’s a large population of frail newly diagnosed patients who aren’t eligible for autologous transplant – maybe they will be eligible for CAR-T if we can figure out how to optimise safety and efficacy.”

And Bluebird does not accept the argument that later-line patients might be too frail to tolerate CAR-T therapy, expecting Karmma to enrol quickly. “Let’s just say [Bluebird’s partner] Celgene is pretty engaged,” said Bluebird’s chief executive, Nick Leschly.

And already a trial has begun of bb21217, a Bluebird anti-BCMA asset that Celgene recently opted into that aims to employ phenotypically younger cells. Mr Leschly calls this a solution to “something we’re not even sure is a problem. But by the time you figure out it’s a problem you’re two years away from the clinic.”

In the current BCMA frenzy two years is a long time.

This story has been updated to reflect the status of JCARH125 and Monday's share price close, and to correct the status of bb21217.

To contact the writer of this story email Jacob Plieth in Atlanta at [email protected] or follow @JacobPlieth on Twitter

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