Gilead ups its bet on Arcellx and BCMA

Arcellx, one of the big winners from this month’s ASH abstract drop, today got another boost with further buy-in from its partner Gilead. The big biotech, which shelled out $325m in up-front cash and equity last December to co-develop CART-ddBCMA, is handing another $85m to Arcellx, alongside a $200m investment.

Under the new deal the companies will expand development of CART-ddBCMA into lymphoma, while Gilead has also exercised an option on ACLX-001, a next-generation BCMA-targeting Car. Gilead must believe that it can take on the leader here, Johnson & Johnson/Legend’s Carvykti, just as others are admitting defeat. Still, with Carvykti’s manufacturing problems, maybe there is room for other BCMA contenders.

Only yesterday, 2seventy bio said it wouldn’t meet 2023 revenue guidance of $470-570m for its Bristol Myers Squibb-partnered BCMA-directed Car-T therapy Abecma. The group blamed “competitive dynamics”, seemingly a reference to Carvykti, which has shown better efficacy in fourth-line multiple myeloma, where both products are currently approved.

Best in class?

However, Arcellx has argued that CART-ddBCMA has best-in-class potential thanks to its use of an artificial, rather than antibody-derived, binding domain. The group reckons this results in more transduced cells being Car-positive than with Carvykti, allowing lower effective cell dosing and less toxicity. 

The available data reinforce the view that CART-ddBCMA should be competitive. The latest cut from a phase 1 study in late-line multiple myeloma (MM), detailed in a 2023 ASH abstract, showed a 100% ORR in 38 patients – including 29 complete responses – and a landmark 12-month PFS of 74%.

This puts the Arcellx/Gilead project in line with Carvykti, which produced a 98% ORR and a 75% 12-month PFS in the registrational Cartitude-1 trial.

Of course, CART-ddBCMA will have to replicate this result in more patients. Arcellx and Gilead are already running the Immagine-1 pivotal phase 2 trial in fourth-line MM, with first data due in the second half of 2024. This study had previously been on clinical hold after a patient death, but that was lifted in August after less than two months.

A study in earlier lines of therapy, Immagine-2, is also in the works. And now lymphoma is on the agenda, although today’s press release did not give details on plans. Lymphoma is an unusual target for a BCMA-directed Car, but there is some evidence that this antigen is expressed on B cells, and not just on plasma cells.

Manufacturing

With Car-T, manufacturing is another important part of the puzzle, and J&J and Legend are scrambling to meet patient demand. In addition, Legend said at yesterday’s Jefferies meeting in London that out-of-spec rates with commercial Carvykti had been higher than expected.

Here Arcellx is also claiming an edge, with its most recent corporate presentation pointing to a 100% manufacturing success rate with CART-ddBCMA. 

Under today’s deal, Gilead is also licensing ACLX-001, said to be a dosable and controllable Car-T therapy. The theory behind the technology is that separating the antigen-recognition and killing functions of the therapy could lead to improved safety. 

The project comprises two components: soluble protein antigen-receptor X-linkers (SparX), proteins that target BCMA, and antigen receptor complex-T (ARC-T) cells. The cells are designed to activate only when engaged with a SparX protein bound to a myeloma cell. 

ACLX-001 is in a phase 1 trial in fourth-line MM, with data possible this year.