Adopt Summit – Celgene has a plan for Juno’s new lead

When you’re forced to scrap your lead asset and switch to a back-up, presenting a clear and firm new plan can help calm the market. No such luck for Juno, which after the long-overdue scrapping of JCAR015 could only manage a vague steer on a pivotal trial of JCAR017 at some point later this year.

Fortunately, Juno has a CAR-T partner, Celgene, that is far more forthcoming with a strategy. Speaking at yesterday’s Adopt Summit in London Jens Hasskarl, Celgene’s senior medical director of clinical R&D, revealed the design of Transcend World, a registrational trial, even going as far as suggesting a JCAR017 dose.

None of this makes up for the fact that Juno is now up to two years behind Kite Pharma and Novartis in the race to bring the world’s first CAR-T therapy to the market. But Celgene’s guidance could help steady the volatility in Juno’s stock in the wake of JCAR015’s discontinuation and the relative lack of clarity on the path forward.

“Later this year”

At last week’s fourth-quarter call Juno’s chief executive, Hans Bishop, said that while JCAR017 in lymphoma was the group’s priority “our goal is to select the dose, and start a potential registration trial ... later this year”, without revealing further details.

Dose selection depends on ongoing data from an earlier lymphoma trial, Transcend, which is testing 50 and 100 million cell doses (a 150 million dose was abandoned). At last year’s Ash meeting 60% of 20 evaluable patients on the lowest dose were reported to have had complete remission at any point within three months, and serious neurotoxicity and cytokine storm rates in 22 patients were an impressive 14% and 0% respectively.

But yesterday Mr Hasskarl outlined Transcend World, a multicentre single-arm trial of JCAR017 provisionally dosed at 100 million cells. This would include lymphodepletion with fludarabine and cyclophosphamide, he told the Adopt Summit, and measure safety and efficacy over 2-24 months after a three-week manufacturing process.

Celgene being Juno’s ex-US partner for CD19-directed CAR-T therapies, Transcend World will focus on Europe and Japan. But it will, along with Transcend, form Celgene’s ex-US registrational package, confirmed Mr Hasskarl.

CD19 CAR-T timeline in diffuse large B-cell lymphoma
Project  Company  Study  Registrational? Trial ID  Detail Timing
KTE-C19  Kite  Zuma-1 Yes NCT02348216  Positive 3mth data Sep 2016; positive 6mth data Feb 2017 Rolling BLA to be completed Q1 2017
CTL019  Novartis  Juliet Yes NCT02445248 3mth data (50 pts) due Q1 2017; 3mth data (80 pts) due Q2 2017 US & EU filings due Q4 2017
JCAR017  Juno  Transcend No NCT02631044 5x10^7 cell dose data at Ash 2016 10^8 cell dose data possible at Asco 2017
JCAR017  Celgene/Juno  Transcend World Yes, ex-US JCAR017-BCM-001 Celgene suggests 10^8 cells as tentative dose  Subject to confirmation of dose
JCAR017  Juno  Yes, US Dose yet to be determined Beginning "later in 2017", filing in 2018/19

“Before we start we have to agree on the final dosing, but that doesn’t influence the registrational study,” he stated. He also insisted that Juno had a US registrational strategy – logical even if this has not been communicated fully to the market.

Juno hopes to report data from the 100 million cell dose in Transcend at Asco, and its decision on the pivotal dose will depend on the CAR-T cells’ expansion kinetics, tolerability, response rates and durability.

Juno investors will surely already be making comparisons against Kite’s Zuma-1 trial of KTE-C19, which at three months had a best complete response rate of 47%. However, Transcend recruited relapsed as well as refractory patients, while Zuma-1 had only chemo-refractories, and Juno also included sicker patients with an ECOG score of 2.

A separate threat for JCAR017 will come from Novartis’s CTL019, whose registrational lymphoma study, Juliet, is due an interim three-month readout imminently. Juno is putting a brave face on matters, saying the leading therapies still leave 60-70% of patients not achieving durable complete remissions within six months.

Out of Orbit

Celgene had separately been planning to start Orbit, its own trial of the now discontinued JCAR015, and recently told EP Vantage it was evaluating plans in light of the deaths that caused Juno to halt the US Rocket study; clearly Orbit is now a non-starter.

In the meantime, no one is any the wiser as to why JCAR015 – and not, for instance, Kite’s very similar construct, KTE-C19 – was associated with cerebral oedema. Indeed, the mechanisms behind neurotoxicity are not fully understood, and the ability of CAR-T cells to cross the blood-brain barrier might just hint at a theory.

For now Juno is hoping that the defined-cell composition of JCAR017 will allow it to maintain efficacy at a relatively low dose of cells. On the other hand, perhaps some CAR-T players will go back to basics on design: a major theme of the Adopt Summit was tonic signalling – signalling in the absence of antigen – to which some attribute adverse events.

Another Celgene partner, Bluebird Bio, stressed how it had picked bb2121 as a lead anti-BCMA CAR partly thanks to its low propensity for tonic signalling. Early data in multiple myeloma have been highly promising, with a surprising lack of serious neurotoxicity or cytokine storm; an update is due at Asco.

A novel theory has emerged, with a paper in Nature last month suggesting that eliminating endogenous T-cell receptors from CAR-T cells might avert tonic signalling. Still, there is a “dirty secret”, Bluebird’s director of cell immunotherapy, Kevin Freeman, said at the summit: “All CAR-Ts tonically signal.”

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