Interview with Christopher Heery, Arcellx
Arcellx’s CART-ddBCMA has recently presented positive results, with analysts saying it is matching J&J-Legend’s revolutionary Carvykti. What did it take to get here & what are your next steps?
We are extremely pleased to see the patients who have enrolled in our clinical trial doing so well, these results have given us the confidence to move the program into pivotal stage studies by YE. We believe the clinical results we have seen so far are enabled by the unique properties of the D-Domain, the novel, synthetic binding domain at the core of the Arcellx story. The BCMA-directed D-Domain in this product, is small, has a simple protein structure, and is highly stable. We believe these properties enable the high transduction efficiency in our cell population and high surface density of CAR expression on a per cell basis.
Having a very high percentage of cells CAR positive and a high quantity of CARs per cell provides potential advantages around efficacy, safety, and manufacturability. Importantly, though, we have not seen tonic signalling even with high CAR density, which we believe is also related to the D-Domain properties. Because of its size and simplicity, the D-Domain binding sites do not appear to cross link and cause self-activation, even at this high surface density. The lack of tonic signalling has been associated with decreased cell exhaustion (i.e., better serial killing potential) and decreased toxicity (i.e., less cytokine production in the absence of cancer cell killing). The result is a unique combination. We have a final product comprising approximately 70% CAR+ T cells, with high CAR expression per cell, and no detectable tonic signalling. We believe this combination is what enables exceptional clinical efficacy without any cases of Grade 3 or higher CRS reported to date in the RP2D. It is also possible this combination may account for efficacy in patients with difficult to treat cases, like those with extramedullary disease and high tumor burden.
Chief Medical Officer
Christopher will be speaking at the BCMA Targeted Therapies Summit on 12-14 July.
Can you give us any insight on the work you doing at Arcellx and why you decided to focus on targeting BCMA?
BCMA was initially selected as an ideal candidate to demonstrate the potential for D-Domains to be effective binders in CAR T cell therapy because it was known to be an excellent target that could result in meaningful clinical benefit. Given the results of this phase 1 trial, we decided to pursue approval and commercialization for CART-ddBCMA to help address the overwhelming need for more great therapies for the thousands of patients with multiple myeloma who could benefit from its availability.
What do you believe to be the biggest challenge within the BCMA Targeted Therapies space at the moment?
My opinion is that the biggest challenge presently with BCMA targeted therapies is making CAR T therapy widely available. Even with two approved CAR T products there is still an overwhelming need for the availability of CAR T cells targeting BCMA. I believe continued research is important as it leads to product candidates like CART-ddBCMA which demonstrates that different products may have different advantages even compared with other BCMA targeted therapies.
The second biggest challenge, though, is understanding the mechanisms of resistance to BCMA-targeting. We need to better understand why some patients achieve deep, durable responses of >2 year and why some relapse around 1 year. If we could understand why this happens, we might be better able to address that cause with complimentary therapeutics or timing of therapy in the disease course that would result in better overall outcomes. One key driver of differences in outcomes is the presence of negative prognostic factors like extramedullary disease (EMD). This kind of analysis can help with both patient selection, development of combination therapies, and expectations for therapeutic outcomes.
What needs to be done to overcome this challenge?
To overcome the challenge of incomplete access to BCMA-targeted therapies, the answer is fairly simple: we need more approved products being produced at larger scale. We believe CART-ddBCMA could contribute positively to this shortfall of available BCMA-targeted therapies.
To overcome the challenge of BCMA-therapy resistance, we have to understand why it happens and target that mechanism of resistance.
What would you say has been the most exciting breakthrough recently in the BCMA space?
Well, I am biased, but I believe the finding that a single dose of CAR T therapy can result in responses that last more than 2 years without any other complimentary therapy is truly incredible. I think many did not believe that was possible 5-6 years ago. Perhaps more impressive than that is the fact that this may be the outcome for more than half of all patients, even in the relapsed or refractory setting. And to be in a position to deliver a therapy with this type of longevity coupled with a safety and manufacturability profile that could make it broadly adopted is very exciting for us.
Why is it important for everyone to come together at the BCMA Targeted Therapies Summit?
A summit on the topic of BCMA targeted therapy allows those working in the field to share important ideas about what has been learned with different agents targeting BCMA and perhaps better understand how we can improve a given agent or the optimal selection of a given agent for a given patient. The ultimate goal is to match the best therapy to each individual patient.
What are your highlights on the agenda and what are you most looking forward to?
I look forward to hearing more about novel approaches to patient selection of therapeutic modalities. I hope to hear new ideas about how patient management will evolve across therapeutic options over the next 4-5 years.
Can you give us a sneak peek into your presentation?
Of course, I will talk in more depth about some of the unique aspects of our binding domain and some of the advantages we think it may afford in CART-ddBCMA. I will also talk about our preclinical data and clinical plans for our dosable, controllable ARC (T cell) – sparX (infusible protein binding domains) platform, starting with our first agent in this platform, ACLX001, which targets BCMA.
The BCMA Targeted Therapies Summit returns on July 12-14. With the summit just around the corner, make sure to save your place now to hear from Christopher Heery alongside a range of other anti-BCMA experts.