CAR-T will have to negotiate several stumbling blocks on its way to becoming a market success, but a little-appreciated threat – at least for the first wave of CD19-directed cell therapies – is Amgen’s (NASDAQ:AMGN) already available biological Blincyto.
And on Friday, at the EHA meeting, the group posted the first overall survival figures for Blincyto, which strongly backed its place in the market. Initial response data are still much better for CAR-T than for Blincyto, but the question is whether treatment with the Amgen drug could put a serious squeeze on later-line CAR-T therapy.
It all comes down to the way patients respond to Blincyto. If they relapse by antigen escape – loss of part of the CD19 antigen, which has been documented both with CAR-T and with Blincyto – it would make them ineligible for subsequent treatment with an anti-CD19 CAR project, such as those being developed by Kite, Juno and Novartis.
Hold on the market
This might never become a problem if Blincyto fails to establish a market niche, but for now the signs are in its favor.
At the EHA’s presidential session on Friday Amgen said the drug’s Tower study resulted in adult ALL patients living for 7.7 months on average, versus 4.0 months for standard of care chemotherapy (p=0.012). Blincyto was given accelerated approval in December 2014 on the basis of Tower, but survival data have not been available until now.
There are no comparable survival numbers with CAR-T, but response rates provide a clue. In adult ALL Blincyto can put around 40% of patients into complete remission (CR), while Juno’s lead CAR-T project, JCAR015, has most recently shown a CR rate of 87%.
However, the issue is how many post-Blincyto patients could go on to receive a CAR-T therapy. With 60% not responding to Blincyto the pool is considerable, but the fact that some will have lost the CD19 antigen – known to occur in around a third of relapsers/non-responders – will narrow the potential significantly.
Blincyto works similarly to anti-CD19 CAR-T therapy, but in a simpler way. It is a bispecific molecule comprising two antibody-derived binding regions, one of which binds the CD19 antigen on tumor cells, and the one CD3 on effector T cells.
The idea is to bring T cells into close proximity with the target, to form an immunological synapse and bring about cell-mediated lysis. Anti-CD19 CAR-T targets the same tumor antigen, and the tumor-killing function is performed by the T cell on which the CAR is expressed, with intracellular signalling domains being triggered once the target is engaged.
While CAR-T therapies seem more efficacious, perhaps because CARs form larger synapses with target cells than do bispecific T-cell engagers like Blincyto, they will not hit the market for another year or so.
Price is also a consideration; this is around $178,000 per patient per year for Blincyto versus perhaps $500,000, including hospital stay, for CAR-T. The lower cost of Blincyto will help maintain the Amgen drug’s place in settings before CAR-T, and how big a market will exist in post-Blincyto patients is not clear.
One way for CAR-T companies to overcome the difficulty could be to look at different indications or focus on targets other than CD19. The Amgen drug is also filed for padiatric ALL, and in trials for lymphoma – both are near-term CAR-T uses.
An antigen whose importance could now grow is CD22, and it has been suggested that targeting this protein could treat CD19-negative relapsers as well as CAR-T-naive patients – without a similar risk of CD22 antigen escape (The next CAR-T target generates promise and caution, April 25, 2016). Juno’s JCAR018 is the most advanced anti-CD22 CAR, with Novartis a little further behind.
Ultimately Blincyto underlines how crowded and uncertain a target CD19 is. The real winners in CAR-T will emerge from novel constructs targeting solid tumors, but there is a long way to go before that goal can be achieved.