All righty, thank you. Well, good afternoon. Thank you for joining us on this next session here at the Jefferies Global London Healthcare Conference. Up here on the stage with me is the President, CEO, and Co-founder of Allogene, David Chang. David, thanks for joining us. You know, I'd love to say that you and I go many, many years back, from the early days when people were talking about phase I of CD19 CAR T for Yescarta, at that time, Kite.
Mm-hmm.
And there was lots of debate between Kite and Juno, and ultimately many years of execution, ultimately sold the company to Gilead, of which now was just in the morning session, and that's gonna do $2 billion and possibly greater now, and that was a huge success. You have embarked a team with Allogene to now take the next approach, which is trying to do this from an allogeneic standpoint to obviously improve patient convenience for this great medicine. Now, Wall Street seems to be a little bit skeptical. There's a whole variety of reasons for that, but maybe just tell us about why you are still excited about executing on this phase III, phase II pivotal program, why you think there's a huge opportunity, and why you think that this should be a great success.
You know, first of all, you know, when I think about, you know, the early days of Kite, now everybody thinks, you know, that was such a smooth ride developing CAR T, but that wasn't like that. For some of you who may have been there in 2014 AACR, when death related to cytokine release syndrome, essentially, you know, those events, you know, shut down the, you know, you know, the CAR T field momentarily. But I think there was conviction in certain individuals and, you know, moving towards the pivotal study, and even after that, you may remember cerebral edema that shut down one program that potentially jeopardized entire CD19 CAR T field. Which now, as you said, you know, from Gilead, I mean, that's getting to about $2 billion annual sales.
Mm-hmm, mm-hmm.
If you look at the entire field, including what BMS and Novartis is doing, this is a field that's continuing to grow. So, you know, from that perspective, I would say, you know, any innovation, there comes challenges. And also, you know, the loftier the goal is, you know, there are more challenges associated with it. What we are trying to do is really advance the, you know, cell therapy field to the next stage. What I mean by that is that currently cell therapy, as most of you may be familiar, is autologous. With autologous, there has been a lot of improvement in the manufacturing, as well as the capacity increase as the companies invest in the manufacturing.
However, it doesn't take away the fact that in the autologous, one, manufacturing has to be done, you know, on an individual patient level, and two, the process requires a lot of logistical and control. You know, you identify the patient, and then you have to schedule for leukapheresis. You know, the leukapheresis product gets shipped to a different location for manufacturing, and then there's a little bit of quiet period where you just have to wait for the product to come back to the clinic. Sometimes they do, sometimes they do, but takes a little bit of time. When you look at, you know, entire autologous field, I think, you know, there is a lot of growth potential, that's coming from the cell therapy, but that's still being quite slowed down because of the manufacturing challenges.
That's where we are coming, you know, with the allogeneic. Allogeneic cell therapy is fundamentally different. I mean, just think about the basic concept of using somebody else's cell as a universal product that can you can use across many different patient. The most critical thing is, you know, safety, and then also protecting the allogeneic CAR T cells from being rejected by the patient's immune system. And this is where we have spent a lot of time perfecting the lymphodepletion, and our approach is really enhancement of lymphodepletion by adding anti-CD52 antibody or ALLO-647 antibody to our lymphodepletion. In the phase I study, we have shown the depth of response as well as the durability. You know, what we are doing as we advance the program into the phase II is trying to reproduce, you know, what we have seen in the phase I study.
Yep.
Mm-hmm.
Now, what I would say, and I actually don't think there's a lot of debate about this, is that your data.
Mm-hmm.
G enerally looks very comparable to autologous, with similar CR rates, similar durability to the extent that you have followed them for X amount of time.
Uh-huh.
And that the products look very good, except yours is significantly more convenient. Fair?
Correct.
Now, as you... That, that sounds compelling, so you are now seeking to enroll a pivotal study to replicate those results.
Mm-hmm.
I n a large pivotal study. Now, there's two pivotal programs, two, two pivotal studies.
Yeah.
Tell us about those two studies. What is the timing of that? How do you feel about the progress of that?
Mm-hmm.
I would say it's two things. One is people feel like, can this company execute to actually enroll these studies? You are competing out there in the market with other therapies, particularly Yescarta, which is available to patients, so, you know, you would have to get into this study in.
Mm-hmm.
I nstead of taking an approved drug.
Yes.
There is a second pivotal study, which is trying to prove that the CD52 is a viable part of that.
Mm-hmm.
There's some skepticism around that. Tell us about your confidence to execute on this.
Yeah.
I n this environment.
Yeah, so the two study that you're mentioning is ALPHA2 and EXPAND study. ALPHA2 is a single-arm study where we're trying to demonstrate the clinical benefit of ALLO-501A. That's our CD19 allogeneic CAR T. We are targeting enrollment of approximately 100 patients, and, you know, using the primary endpoint, response rate, and also duration of response, which will require us to follow the patients for at least six months, before we can generate what we believe would be a BLA-enabling data. The points that you're making, you know, you know, one major difference, from the time that we were developing Yescarta back in 2014, 2015, there are a lot more, you know, options. There are three approved products, and also the manufacturing constraint that prevented the patients to access CAR T.
You know, that has relaxed a little bit as Gilead ramped up their manufacturing. We knew that this would be an issue. You know, also, not only these products are approved in the third-line setting, which is the indication that we are going after, they're also approved in the second-line setting. That also affects the patient flow as well as patient availability. So knowing that this would be a factor, you know, from the beginning, we had planned that this study has to be done globally, not just in the U.S., but also in Europe. And much of our effort has been focusing on bringing up the investigator sites outside the United States. We have all the regulatory approval to conduct a study in Europe, Canada, and Australia, and we have ramped up the site activation.
Now we're really monitoring, you know, how these sites where the, you know, access to approved cell therapy is not as readily available as in the United States will contribute to the enrollment. You know, so far, early indications are good, and we are maintaining that ex- from the execution perspective, the enrollment completion projection that we have guided, you know, which is first half of 2024, that we are maintaining it. Obviously, this is an ongoing activity, and we are continuing to monitor the progress and enrollment from the European sites.
Right. Generally, you need to complete enrollment of the 100 patients during the first half of 2024 in order to have six-month follow-up data on the primary endpoint by the end of the year, which is your guidance.
Mm-hmm.
By math, that would imply the next six or seven months. You think that there's a very good line of sight based on the sites you enrolled in U.S.?
Mm-hmm.
If you could tell us, you know, how that looks versus sites outside the U.S. and where you think that a lot of that could come, or it's just the totality of both of that?
I mean, in terms of, you know, distribution of patients, you know, we are not, you know, trying to target certain number of patients coming from the U.S. versus ex-U.S.
Okay.
This is a competitive enrollment, and, you know, for the indication that we are going after, there isn't any geographic, you know, distribution requirement that we see. So it's number of patients. So that's what we're doing.
Both, both U.S. and ex-U.S., is your point?
Both US and ex-US.
There are definitely sites you've identified, you're there on the ground, you're getting them ramped up. They have patients available because they either don't have great access to Yescarta.
Yeah.
They're not the, I don't want to say, top-tier, number one sites which are using Yescarta, but there's plenty of those other.
Yeah.
S ites out there.
Yeah, I mean, you know, our clinical team has really good interactions with the investigative sites, and obviously, we have chosen based on the investigator's input about how many patients that they can contribute reasonably in a month, in a period. That's how we sort of, you know, project out the enrollment.
Okay.
That's where, you know, we, you know, continue to guide, you know, about the, study, you know, the pace of the study enrollment.
Okay. So for executing on the pivotal study, which you just talked about for 100 patients, there's also this second study, EXPAND.
Mm-hmm.
W hich is to validate your anti-CD52 antibody for the lymphodepletion. Now, naturally, I mean, I think you could understand that people are reluctant to believe you can execute on that, which is a key part of the filing package.
Mm-hmm.
Just because you're asking people to be in a randomized study of getting one powerful regimen, but one regimen which may not have the lymphodepletion part. So who would enroll in that type of study? And you would say, "No, don't worry," what?
Yeah. I mean, you know, I'll be very frank. I mean, you know, we try to not have to do that study, you know, in discussions with FDA. But FDA, following the, you know, the guidance, felt that we have to demonstrate the contribution of ALLO-647 in a very discrete way. So that's why the randomized study is done. This study is targeting about 70 patients, much smaller than the, you know, the, the ALPHA2.
Okay.
It also uses a different, you know, endpoint because it's a randomized study. The randomization.
Endpoint?
Progression-free survival.
Okay.
So the randomization is patients—half the patients get standard FC, that's fludarabine and cyclophosphamide chemotherapy, and then the other half gets the lymphodepletion regimen that we are using. And then after that, everybody gets ALLO-501A. So here, we have gone after, you know, sites that are willing to do this study, because investigators who have been following us and, you know, review the data, you know, they feel, "No, you can't really treat the patients with FC. Your data doesn't really—your data says, you know, indicates that ALLO-647 or anti-CD52 antibody is needed." It's not just our data. If you look across other people who have advanced allogeneic CAR T, it is very clear that the standard lymphodepletion will not be sufficient. However, it is a regulatory, you know, requirement study, and we are proceeding.
We're really trying to coordinate the data readout from that study to the six-month data time point that will enable the BLA study. So we get asked questions about: Can you do the study? It is a challenging study, but we believe that we can do it, and also, this is a study that will be closely monitored by the data monitoring committee, and if there is any kind of clear indication that FC is futile, then we have an answer.
What is the data, so that I can go look at it?
Mm-hmm
T hat says that that is so obvious?
In terms of, yeah.
That FC plus 501A is going to not be very adequate because you're going to get rejection of the cells, people are going to progress. It's just not going to work. What is that data that I can look at?
I think, you know, the data that's coming is number of patients in the earlier program, that is a UCART19 program.
Okay
W here the patient, because of the availability of CD52 antibody, simply did not get it, so they just got standard fludarabine cyclophosphamide chemotherapy, and none of those patients, and the number, over the years has reached more than 10. Basically, they don't get cell expansion, and they don't really get the.
This is the old Cellectis data.
This is Cellectis, yeah.
In the original phase I Cellectis data of CD19, they treated 10 patients.
Mm-hmm.
You can go look at that data. They, they either did not have CRs or their CRs were not durable.
Yeah. So that will be number one.
Okay.
And then, in our study, throughout the course, we have used different doses of ALLO-647. So we can sort of look at the dose-response relationship that we can generate within the patients that we have treated. The range of doses that we have used is from 30-90 milligrams. So, you know, that gives the, you know, population-based dose-response relationship related to the ALLO-647 exposure.
Yeah.
And then, you know, second one, the third one, you know, which is somewhat indirect, is, you know, others who were using standard chemotherapy or even enhanced chemotherapy, where the chemotherapy dose went up quite high.
Uh-huh
T hey were not able to get the durability of the response.
Okay, the second data point, though, was that, was that related to cell expansion or just your own data showing that different doses of the anti-CD52, you got better results?
Yeah, the more exposure we got, the better response.
Okay. Mm-hmm. Now,
We published all that data. I forget when, but probably a year ago. I can definitely send you to the reference.
Okay. So getting back to it, to complete this journey by the end of the year of 2024, you believe you will... "Don't worry, we're going to execute on those 70 patients, randomize 1 to 1. There are sites that are available to do that. Don't worry, we're watching it. If it's futile, it could even stop early." I don't know, what sense do you think that confidence of, or probability of that would happen? Our sense is, presumably, you need to complete the enrollment of the study, and you will just see that PFS will not be as good as the.
Yeah.
A ctive arm. I don't even know if there's statistics around that. But your point is that by the end of the year, we'll give you an update on that. We'll either have one of those scenarios would have followed, or we'll just have it, and don't worry, we'll take it to the end.
Well, you know, I don't worry about, "Don't worry, don't worry.
Uh-huh.
I mean, you know, in my position, I should never say, "Don't worry, don't worry." But, you know, what I can guarantee is that we have a, you know, outstanding outstanding clinical team that's very experienced in the CAR T field, and we have deployed them to the fullest extent to enroll this study on the timeline that we have talked about.
So then the study reads out the results are positive. You filed with the FDA in 2025, you could be on the market. And people would say, "Okay, Mike, that's great. You have existing drugs out there, so Yescarta had a great launch, but there wasn't really any competition. You have competition because there's an existing product," or even longer term.
Mm-hmm.
T hat, Yescarta is moving to second line, so over a one, three, five -year period, a lot of the patients will have seen that, or they would, they could get Yescarta. So how do you fit in? What is your projections and numbers to say, "Look, even in a third-line DLBCL setting, we are going to do X. It is, we, we can still be a blockbuster drug, even with Yescarta there in third line, or even if Yescarta moves to second line, we can still be a great drug, even if they, if many patients go to that-
Yeah.
B ecause there's other patients available.
Yeah, you know, you know, obviously, we have, you know, the forecast about the potential, you know, you know, the.
Commercial opportunity.
C ommercial opportunities.
Third line.
I mean, you know, you know.
DLBCL
R ight now, while we are doing the, you know, the pivotal study, I mean, I think it's a little bit too early for us to detail it. It's a changing space, but you know, where, you know, what we are also doing is, you know, following the ongoing pivotal study with a second study.
Okay.
T hat will capture the patients in the earlier line setting.
Tell us about that.
Yeah. So, you know, patients, you know, we haven't really, you know, detailed about, you know, exactly what the study design and what patient population that we will go after, but we are factoring in the fact that available CAR T therapy, Breyanzi and Yescarta, have been approved in the second-line setting, you know, transplant eligible, as well as any patients.
Mm-hmm.
I mean, the label is a little bit different, you know, both in the U.S. and Europe. That's factoring in and trying to capture patients at that level or earlier. So, you know, in terms of... You know, this is a study that our study team has, you know, come up with, and it's getting a tremendous support from the KOL, and we're just, fine-tuning the last bits.... before we talk about exactly what the study is.
I wasn't clear on that. Would the population you go after be similar to that population label? Or you're saying you've looked at that, and you've carved out a population that would be different from that? The latter.
That's what I said, and.
Latter.
T hat's what I, yeah.
I think the latter.
Yeah, and unfortunately, I cannot go any more details about, you know, the—just stay tuned for another few months, where we will delineate the exact nature of the study as well as the patient population.
You have plans that, I don't know, this must be a phase II.
I mean, yeah, the idea is, you try to do it as seamless and, you know, try to get to the registrational stage as quickly as possible.
Okay. So some form of phase II slash.
Mm-hmm.
P hase III, or phase II that can expand to a pivotal in second line or earlier lines, that somehow reflects and takes into account the fact that there is already a second-line therapy out there, but there's opportunities to run a study.
Yes.
T hat can still compete.
Mm-hmm.
I n that space. Okay. And, so sorry, just in the next few months, is that something like, you're gonna disclose that at this other San Francisco Healthcare Conference, or what, what are we talking about here?
Okay, look, don't let me get into saying more than what I should be saying, but stay tuned.
Okay. Now, tell us then about the fact that many people, I'd say, that capacity.
Mm-hmm.
O f, 'cause I wanna go into this whole market opportunity.
Yeah.
I, I feel like people think that even if you execute on this, even if you run this study, that the sales opportunity.
Yeah.
C ause we kind of got back into second line, and you told me you didn't want to tell me projections, but people feel like this market opportunity post Yescarta is a shrinking market and/or that there's these other therapies. So do you still believe that there's hundreds and hundreds and hundreds of millions of dollars of opportunity in third line, even if people get Yescarta in second line, or.
Yeah.
E ven with competitors of Yescarta being in third line?
Yeah.
Do you feel that, and why would that be?
I mean, I think, you know, probably the best way to respond to that question is, we can estimate amongst the patient who are treated with drugs.
Right.
You know, how many patients would be, you know, in the U.S. and Europe, based on the approved indication? And then, you know, we've sort of tracked how many patients are being treated, you know, every year.
Mm-hmm.
When we do the calculation, we come to the conclusion that still only a fraction of patients are receiving the CAR T.
Right.
There may be some patients who are not eligible for CAR T, but as the treatment improves, more patients will be eligible. And in the third-line setting, I mean, the current estimate is, you know, still after, what, almost seven years after the approval, it's still about one third of third-line patients are getting the CAR T.
Yeah.
And then, when it comes to the second line, I think despite it being about a year after the launch-
Yeah
Y ou know, the penetration is still, you know, way below, you know, you know, you know, 20%.
Even if you fast-forwarded, say, five, egiht, five years down the road, a proportion of people will get Yescarta in second line.
Yeah.
A large proportion of people, I don't want to use the word majority, but I could say 50%, but at least 50% of people, and I could use Jefferies estimates, consensus estimates, half the second-line might get an autologous product. The other half of the population may not. If they don't.
Yeah.
T hey would still be eligible for your product. In third line, that would be, I think, the case to be made.
Yeah. I think the, you know, the available patient who can benefit from the CAR T.
Mm.
S till is being underserved by the autologous CAR T. And yes, manufacturing capacity will go up, but the logistics will not improve because that is very intrinsic to the autologous. So in that setting, I do believe that if you introduce a product that has a comparable efficacy.
Mm-hmm.
M aybe a little bit better safety, you know, 'cause that's what our data is showing.
Mm-hmm.
A nd the convenience of the off-the-shelf.
Mm-hmm.
I do believe that that will get a lot of traction.
Is that partially because you believe that this could be more amenable to, I don't want to say tier two centers, but centers that are not equipped and doing.
Yeah.
A ll of this autologous, which is, quite frankly, let's be honest, it ain't a community center, right? It's not, probably not a community center.
Well, right now, CAR T cannot be used in.
Right.
The community center.
Let alone in patients.
Yeah.
These are at the big centers.
Mm-hmm.
Then there's big centers that don't currently use Yescarta, and then there are.
Yeah.
C enters below that, and there's opportunities.
I mean, the current estimate is in the United States, you know, there is about, you know, you know, 160-170, in that range, I don't have the exact number, that are certified to use commercial CAR T products.
Okay.
I mean.
That still leaves a significant amount.
You know, there's a lot of sites that will have to refer the patient to those sites, you know, to make the patient receive the CAR T.
Yep.
We are definitely targeting, you know, I don't want to call it as a second tier, but the centers that do not have access to the CAR T.
Right.
B ut still doing transplant and other very intense treatment.
Okay.
T o manage any kind of emerging side, you know, side effects.
Last question to wrap up in the one minute that I have. So you are embarking and looking to execute on this, on the two pivotal studies?
Yes.
You even hinted that you are seeking to go earlier, which I think is a clear positive in second line.
Mm-hmm.
A nd you'll be in a few months, you'll give us some more updates. Wall Street has said you've got current cash now of, remind me?
About 500 is how we.
500, yep.
ended the last quarter.
Consensus or Jefferies estimates thinks that that could be $hundreds of millions of burn in 2024. You still have money, and the formal guidance is in 2025.
Second half.
Second half of 2025. So that brings us to the one-year mark of where biotech or bankers would tell you: "Okay, you know, Wall Street gets worried about that." So at what point between now and end of 2024 with data, which is right about the one-year time point, how do you think about capital and opportunities for that?
Can you ask an easier question once in a while?
It's over the next 12 months.
Yeah.
Y ou're gonna come up on data, but you're also gonna come upon the one-year cash mark.
Yeah, I mean, you know, nowadays, you know, the cash conservation for any company, I mean, you know, whether you're private or public company, I mean, you know, that's always the case.
Yeah.
We are doing everything possible, and at this point, cash conservation is coming in terms of prioritization.
Okay.
This is really being very selective of which programs do you invest in.
Okay.
I mean, that was part of the reason that we decided not to move ahead with the BCMA program and putting all the focus on CD19.
Yeah.
So, you know, combination of, you know, cash conservation and taking any opportunities that we can raise money, and that also include, you know, traditional financing or any kind of partnering.
Where would pharmaceutical partnering or other sort of strategic partnering weigh into that? Is that up there? 'Cause I would think that that would be an easy way to do it, because a pharmaceutical company could help you enroll, invest-
Yeah, I mean.
Long term and do that. Uh-huh.
You know, a few years ago, we were not too interested in partnering.
Yeah.
But, at this point, you know, given the current market situation, and also the fact that when we look across the you know pipeline, not only we have CD19 program, we have solid tumor programs.
Yeah.
CD70 already has generated a clinical proof of concept as, allogeneic CAR T.
Yeah.
And we have candidates that are ready to go, targeting DLL3 and Claudin 18.2.
Yeah.
Very exciting targets in solid tumor. So it's really... You know, in this case, you know.
The.
The fact that we are not being able to invest in all of them.
Yeah.
A lso makes it more critical that, you know what? You know, let's be more.
Open-minded about those opportunities.
Precisely.
Good. Thank you very much, David. Look forward to the execution, the updates, over the next six-12 months.