Investigative CAR-Modified T-Cell Therapy Shows Strong Efficacy in Multiple Myeloma

In an interview with Pharmacy Times, Rami Elghandour, chairman and CEO of Arcellx, discussed the company’s investigative CAR-modified T-cell therapy. In addition to showing significant efficacy in patients with relapsed/refractory multiple myeloma, Elghandour said the company is hoping to address the scalability issues that continue to be a challenge in CAR T therapies.

Q: What does the current treatment landscape look like for relapsed/refractory multiple myeloma?

Rami Elghandour: So, myeloma is the third most common blood cancer and unfortunately, it is an incurable condition. In terms of the treatment landscape, it's quite variable, partly because of the variability of the disease as well as physician preference. Generally, after diagnosis, the first 2 treatment options are chemotherapy and transplant if the patient is eligible. After that there are a range of combination therapies that are utilized, including immune-modulators, proteasome inhibitors, steroids, and monoclonal antibodies. And they're used in combination over time and those comprise the first 4 lines of therapy. And then CAR T therapies are currently utilized in fifth line or last line as an intervention. However, due to the advantages of CAR T therapy, which I'm sure we'll get into, there is a push from both the physician community as well as the patient community to see CAR Ts utilized in earlier lines.

Q: What are the limitations of these treatments?

Rami Elghandour: So, in terms of the non-CAR T options, the limitations are really durability, safety, and quality of life. As I mentioned, there's a range of these different therapies that are used in combination. Some of them could be more efficacious if it weren't for a toxicity profile that limits greater doses or more potent doses. The durability of response varies greatly in some of these therapies. And then [there’s] quality of life. The majority of those therapies require ongoing maintenance and so while they extend life, they certainly also take away from some quality of life.

From the CAR T perspective, the limitations are really safety and scalability. So, some of these CAR Ts, while they provide wonderful benefit, come with some serious and ongoing side effects which have to be managed. And then scalability has really been the name of the game in the CAR T world. Even large companies such as J&J and Novartis have really struggled to provide CAR T therapy to meet the demand even in later lines. And so, one of the biggest challenges, as wonderful as CAR T therapies can be, is manufacturing in enough large enough capacity to really meet the patient demand.

Q: Can you discuss the investigational treatment from Arcellx?

Rami Elghandour: Our lead clinical program is CART-ddBCMA and it is a treatment, a CAR T autologous CAR T treatment option for relapsed and refractory multiple myeloma. And really what makes our CAR T different is our binding domain. In autologous CAR T, the cells are the cells irrespective of the treatment option you are going with. So, what really differentiates one therapy from the other is the binding domain. And what we utilize is something called the D domain and it is a novel synthetic binder that does not exist in nature and is proprietary and unique to ourselves. And what makes a difference are a couple of really key attributes. So, we tend to see a high transduction efficiency with our D domain, meaning that when we transduce cells with our viral vector to make our CAR T therapy, more of them are CAR-positive or pull in from tumor killing, relative to scFv-based binders, which are most broadly utilized, as well as the bivalent tandem approach, which is utilized by one organization. And that high transduction efficiency effectively allows us to have a lower overall total cell dose while still delivering a potent therapy, which may be one of the reasons we're seeing a really remarkably positive safety profile with this therapy.

In our phase 1 study so far, we also tend to see a unique combination of having high surface expression while having really effectively low-to-no tonic signaling with our therapy. And that really allows us to utilize our therapy in environments with very low antigen expression and effectively go after clearing that very last tumor cell without exhausting our CAR T. So, one of the challenges with CAR T therapies is you get something called T-cell exhaustion. The binders interact with each other in the absence of tumor activity, and essentially exhaust these T cells before they're able to clear the tumor activity. So, being able to have a therapy with high surface expression, meaning a lot of binder on the surface of the cell so they can get every last tumor, but at the same time not seeing that interactivity where they can activate in the absence of tumor activity and get exhausted. This is a really unique combination and very much unique to our binding domain and what differentiates our technology.

Q: What did the phase 1 trial find with regard to efficacy?

Rami Elghandour: So, at ASCO in June of this year, we reported our latest results with a median overall follow-up of a little over 12 months, 12.1 months. We had 100% overall response rate and 71% of our 31 patients who were evaluable at that time point achieved a complete response or a stringent complete response. And notably, 39% of those patients had what's called extramedullary disease, meaning that while myeloma is a cancer of the bone marrow in the blood, these particular patients fully formed solid tumor masses outside of their bone marrow in their soft tissue, like, for example, their liver. And those are notoriously difficult patients to treat. And to have the kind of response that we had there with that high of a proportion of those patients was pretty remarkable.

In terms of our patients with the most follow up, we had 16 patients with 12 months or more follow-up [and] 81% of those patients achieved a complete response or a stringent complete response. And in that patient population, 8 out of the 16, or 50%, had extramedullary disease. So again, that is pretty remarkable, at least in our view, given the efficacy combined with the challenging patient population that we are able to help.

Q: What did the safety data find and how to these adverse events compare with those of current immunotherapy drugs?

Rami Elghandour: So, that's a great question. Notably, we've had zero grade 3 [cytokine release syndrome] in our recommended phase 2 dose, which again, when viewed in concert with the challenging patient population that we're treating is also a very notable finding, because generally speaking, the higher the tumor burden, the worse the toxicities that you might see. So, the fact that we have these very sick patients and zero grade 3 CRS is very notable. We've also had one case of grade 3 ICANS in our recommended phase 2 dose to date. And the combination of that safety profile, we believe could lead to a best-in-class therapeutic pending further studies.

Q: Where does the phase 2 study stand?

Rami Elghandour: So, we are planning to initiate our phase 2 study by the end of the year this year. We're very excited about that. One of the things that I mentioned earlier, about how important scalability is in CAR T therapy. So, having been one of the companies that have had the opportunity to see some of the other advances and other therapies launch ahead of us, we really had the opportunity to step back and learn from some of those scaling exercises and make long-term decisions that we believe will help us scale once we hit the commercial market. So, that made us take a little bit of time upfront here to line things up properly, so that when we hit the ground running in our clinical study, and ultimately, for commercialization, we believe we'll have a scalable therapy.

Q: The therapy has also been granted Fast Track, Orphan Drug, and Regenerative Medicine Advanced Therapy Designations by the FDA. What does all of this mean for its development?

Rami Elghandour: That's a great question. You know, the FDA recognizes the importance of these therapies and what an impact they can have for patients. And so, they have put together these various programs to really help companies that are working on impactful therapies get those therapies to market as quickly as possible. And specifically, it allows us to have more interactions with the FDA to get more timely feedback. So, we can advance the program as quickly as possible, but also limit the number of questions that tend to come later in the process and at the time of approval. So that's been remarkably helpful for us and something that we've certainly taken advantage of. In terms of orphan drug designation, that tends to be a commercial benefit, it effectively gives you exclusivity for a 7-year period post-commercialization. So, that certainly can be a value as well. But we have really benefited greatly from the support and the interactions with the FDA. And again, I can't stress enough how much they recognize the importance of these therapies and have been very constructive in that dialogue and helping us progress forward.

Q: You mentioned scalability—how are you approaching that issue?

Rami Elghandour: Yeah, so one of the unique attributes of the D domain, as I mentioned earlier, is that high transduction efficiency. And that really is a window into the consistent manufacturability over our cell product. Thus far, we've had 100% success rate manufacturing cells for our patients, and we see very consistent metrics and all the key attributes that you would want to see from a manufacturer ability perspective with our drug product. As I mentioned, also, we've made some decisions in our operational planning that really attuned to scalability. For example, changing to a viral vector manufacturing method that is much more scalable, and making sure that our process is as automated as possible, and requiring the least sort of amount of manual intervention. So, that combination of the unique attributes of the binder, as well as long-term decision making around the commercial process, will hopefully allow us to really scale this therapy in a way that can benefit the most patients possible over time.

Q: Is there anything you’d like to add?

Rami Elghandour: So, this has been an incredibly tough year in biotech, as I'm sure you know. But we've been able to find success and I would say that's a combination of a couple of different things. We were able to go public in February and we had a successful follow-on in June following ASCO, which I think obviously helped us a lot and have the resources and the capital required to grow our company.

But I always like to go to the why. So, we have been able to do that, and I think it always starts with people. We have incredible people in this organization. We lean heavily into diversity, not just as something we talk about, but a real foundation of what we do. And I think you can see that reflected in our management team and our board of directors, and across our entire company. So, I'd say our incredible people and the diversity of those people is really powering us forward. Certainly, having great data and biotech is really helpful. And we've had really strong data so far and hope to continue that.

And then lastly, we're going after a meaningful opportunity with a platform technology, meaningful again, in that there are unfortunately a lot of patients suffering from myeloma and ones that we can help. So, there's a huge opportunity to make a really big impact there. But also, our platform really hits some of the core challenges in oncology more broadly, and it's already in the clinic. So, one way I like to describe ourselves is that we're a company with a high floor and a high ceiling, meaning that we have something very tangible that could really help a lot of patients today, but we also have a shot on goal that can be really transformative and one that we're actively pursuing.