Doug Miehm, I cover the company for RBC. So Matt, maybe you could give a quick overview of the company, which stage of development you're at, and, you know, a couple of the successes that you've had this year.
Yeah, we've had a big year. Thanks for the question, and thanks to you and RBC for the invitation. We very much appreciate it. It's nice to be here on the podium, and it's.
Sure.
I do love these fireside chats because I feel like there's somebody else standing up here with me. No, we've had a fantastic year. And today we announced, we've been able to partner our program with a group called the Global Coalition for Adaptive Research, GCAR, which is a very august group that runs adaptive studies. So adaptive is basically a way of being more efficient in your study design, so it allows you to look in real time with paying a small alpha penalty, so that you can see if the study's working or not working. They partnered with us on a Phase 3 program for pancreatic cancer, which is something that's become a very big focus of the company in the last year and a half.
We previously announced that a combination of our product, with TECENTRIQ, which is an immune checkpoint inhibitor, specifically an anti-PD-L1 made by Roche, we were able to see a 62% objective response rate in pancreatic cancer, including complete response. Anyone that knows pancreatic cancer, it's a horrible disease. Outcomes are very, very poor. One-year survival is typically 25%, so it's a horrible disease. To be able to work with a group that will run the phase III on our behalf, who runs it so efficiently, was tremendous. What I think people need to appreciate is to be able to be selected. GCAR has just moved into the space. They announced earlier this year that they had acquired the Precision Promise program, which is an adaptive phase III for pancreatic cancer, from a group called PanCAN, or the Pancreatic Cancer Initiative.
It allows us to very expeditiously run this, but to be selected, we had 25 people on the selection committee that were the world's best KOLs. So the vetting process was tremendous. So to be able to be selected and to be able to be the first group that will be evaluated in this clinical program is just a tremendous opportunity for us. We couldn't be more pleased.
Okay, so you switched things around on me. I was going to start with metastatic breast cancer, but you know what?
Of course, we announced a phase III on you today. My apologies for being so rude about this.
That's okay. So why don't we continue on with that and maybe expand on GCAR a little bit? How did that, ultimately come about? What's the genesis of that relationship that you have with them now?
Well, it's interesting. It was a bit of a process, actually. We last August announced that we had been selected by PanCAN, which is the Pancreatic Cancer Initiative, for inclusion in their phase III adaptive design. And what's really attractive about this is they run the two major control arms. So in pancreatic cancer, the two big interventions for first-line therapy are either modified FOLFIRINOX, which is a very, very heavy drug regimen. FOLFIRINOX, each one of those is chemotherapy. So you're getting the cocktail of chemotherapy. And it's thought to be the best option for patients, but it requires the patient to receive a very, very heavy load of chemotherapy. The other option is Gem/nab-paclitaxel, which is two drugs. So it's much more—I don't want to say gentle, but gentle—for the patients.
We had run a study with a group called AIO in Germany, looking at our product. And I should say our product, Pela, stimulates immunological response. And I think this is very important for pancreatic cancer because if you talk with the KOLs, chemotherapy isn't sufficient for these patients. It's a very dense disease. It's protected by, basically, mesenchymal cells and stromal tissue that basically shields this disease from actually being treated appropriately. So if the immune system doesn't see it, outcomes for patients are very poor. And pancreatic cancer has been a challenge. Outcomes haven't really improved very much in the last 10 years. The thinking is you really need to be able to stimulate an immunological response. So Pela is something that we introduce into the bloodstream. We get replication in the tumor, and this causes a massive immunological response.
What we get is an influx of T cells rushing into the tumor, and we're able to see this with biopsies. We're able to see this with imaging. So it's a really nice way of basically labeling the tumor as foreign. Once you've started that process, it remodels the tumor microenvironment so it is less dense, so you can get more drugs in there. And then if we can create more T cells, we have essentially vaccinated the patient. So we were working with Roche, through an IST to look at areas where checkpoint inhibitors have failed. And so we could use the virus as a means of basically culturing the tumor in a way that checkpoint blockade would work. Now, we've historically worked in pancreatic cancer with just chemotherapy and saw some very nice results in terms of overall survival.
Typically, these patients live, well, one-year survival's 20%-25%, so very poor outcomes. Two-year survival's 4%. So, like, once you're diagnosed, it's a horrible diagnosis for you. What we're seeing is survival's approaching 50%, so a doubling of one-year survival. And our two-year survival has historically floated between 25% and 22%, so, like, about a fivefold increase. We were working with AIO and Roche, and what we reported was a 62% objective response rate. So what that means is, out of all the patients we treated, we saw at least a 30% reduction in their tumor volume, measured over two scans, which is tremendous for these patients because you can imagine if the tumor's getting smaller, the belief is that you will live longer because the tumor burden is being restricted.
We reported this, and we started working with PanCAN, and PanCAN reached out to us, and they said, "Well, this is phenomenal. Like, no one has seen, it's a tripling of the objective response rate from what people have ever seen," and including complete response, which means people had no detectable disease after treatment with the intervention of this checkpoint inhibitor and virus with this sort of less chemotherapeutic regimen. PanCAN accepted us. In August, we announced that we were going to move forward with them, and what we found out later is PanCAN was going to sell that program to GCAR. So we were going to transfer it, and GCAR and PanCAN are basically sister companies, so it's all, they're independent entities, but they've actually worked on each other's protocols. Employees go back and forth between the two.
They're both not-for-profit charities that are trying to find solutions to these horrible diseases. So they are of a similar mindset. They're both excellent entities. And we were indifferent. It's like, "Okay, well, GCAR will do it," but what they decided to, when they transferred over the Precision Promise adaptive study, they wanted to raise a severance so they could start from new, clean up some of the protocols, and go. So we had to announce that we were no longer selected. And then because they had made this severance between the two programs, everything started from zero. We had to go through the selection committee again. So it was—it was a process, but we're delighted to be able to work with them. It was just sort of a long six months where we were in limbo because the selection committees were very similar.
We knew a lot of the people involved. PanCAN, though, gave us a $5 million grant, and PanCAN and GCAR are working in these initiatives. PanCAN takes the not-for-profit money and invests in an accelerator program to look at promising treatments for pancreatic cancer. Typically what they'll do is run a phase II. If it looks promising, then it goes into the phase III adaptive program. It allows them to basically use it as a feeder. We're very fortunate in the sense that we did receive a $5 million grant from PanCAN to look at modified FOLFIR INOX in pancreatic cancer, which is the more aggressive treatment option with and without atezolizumab. We have another option to move into another phase III program.
So GCAR is looking after our phase III interests, and we're collaborating with PanCAN to develop novel ideas for other treatment options in pancreatic cancer.
Was there any reason why GCAR decided on pancreatic cancer to begin with? Is it?
GCAR, actually, their mission is to look at very hard-to-treat malignancies with these adaptive programs. They've worked in ovarian cancer. They worked in GBM. They worked in coronavirus during the worst of the pandemic. Pancreatic is something that was near and dear to their heart because it is such a difficult-to-treat malignancy. We need more rapid ways of exploring whether or not we can get new treatment options. And what GCAR and PanCAN have done, for people not familiar, they run a control arm, so standard control arm of gem/nab-paclitaxel versus modified FOLFIRINOX, and then you pay for your study arm. So you contribute to a control arm. But the goal is they want to have five, six, seven therapies currently running so that they can get answers very, very quickly.
For companies like ours, it's very attractive because it almost becomes a single-arm study that you're paying for because you make a small contribution to the control arm, as opposed to paying for all of it. Like, a lot of times people will see, you know, a 300-patient study. 150 of those patients are a control arm. They're receiving standard of care. You're only paying for, you know, 150 of your own patients. So you're making this massive expenditure, in a standard of care that's been run for in pancreatic cancer 25 years. Yeah. It's a very efficient way to do this. GCAR has really, I think, aligned themselves with a global coalition of academics, key opinion leaders, and academic sites, to more rapidly find solutions for these problems. I think it's, it's a tremendous opportunity for us.
You just mentioned that they want to do this rapidly. Perhaps you can talk about how the adaptive trial design is going to accelerate your—the program, here as well.
Well, I mean, typically when you think phase III programs, you're—you're thinking studies of, well, conservatively 400-600 patients, which is a tremendous outlay of cash because you're not paying for the control arm because it hasn't changed. Like, if—if Company A is running something in pancreatic, Company B something in pancreatic, they're all going to give half of their money to run a control arm. That's universally the same. So this is a way of allowing companies to more rapidly develop this. There's the cost-saving element, but there's also the—the time saving. So as opposed to a 600-patient study, we make a contribution to, I think it's 50 patients in a control arm and 100 patients on the test so that, we get to a go-no-go decision with a total of, you know, 150 patients.
You know, if we really do see this tripling of response rates again, you would just move into the second stage, which is an additional 75 patients. So you're looking at an approval or a BLA with 175 patients treated on a test arm, and, you know, roughly half of that on a control arm that is cost-shared across all the parties.
Okay. So why don't we talk then about when is this trial going to start, and what are going to be some key specific dates that you're going to be, and milestones?
This is very much in play, but what we've been told by GCAR, we were the first group selected for evaluation in this phase III program. Yeah. We signed an agreement with them to now move into running the simulations. We are working with them now on the clinical protocol. Now, I should say PanCAN had a clinical protocol that was approved by the agency, so they're just resubmitting it. Okay. We're not reinventing any wheels here. They've been able to look at things that worked and things that didn't work, but the overall structure of the study is the same. The statistical analysis plan is the same. They're working with Berry & Associates, who are some of the best statisticians on the planet. We're very excited to be able to work with them. So that aspect is basically a redo. It's a mulligan.
So we really don't anticipate there to be any issues with that. The hope is we get the protocols approved. They're thinking submission sort of August, September. FDA has 30-60 days to approve. We want to see site initiation this year with the first patient on early 2025. The goal is then to have the go-no-go decision made within 12-15 months. Okay. So early 2026, we'll know if we're a success in pancreatic cancer.
All right. So looking forward to that for sure. Okay. So why don't we switch over to MBC then? Perhaps, for those that don't know, you can just review the BRACELET-1 data, IND-213, what we're waiting for this year, and why it's so important. It's not very often that people are talking about overall survival data, and you are.
Well, especially in breast cancer. Right. What—so breast cancer, if you look at something like Ibrance, which is a $6 billion product, tremendously impressive in terms of results with PFS. It provides no overall survival advantage to the women receiving it. That should be caveated, though. It's hard to tell what your product does with overall survival when they go on to two or three or four rounds of therapy after the fact. There's a lot of things that can impact outcome. So, you know, there's some criticism leveled against it, but I don't think it's valid. We did a study with the National Cancer Institute of Canada called IND-213, which was a look at all-comers. It was 76 patients who had hormone receptor positive, triple negative, who had HER2 positive.
What we saw was really not much of an improvement in terms of objective response rate. There was a slight improvement. There was a 1-month improvement in PFS. But we saw a doubling of overall survival. And when you think about how this product works, it makes sense. What we're able to do is demonstrate that in patients who respond, we get a very active T cell response, but it takes about 4 or 5 months for those T cells to be sufficiently activated.
Right. You can imagine if your progression-free survival's only 3 months, if it takes us 4 or 5 months to get that T cell, we're probably not going to have a big impact on PFS. If anything, because we cause so much inflammation, it's often mistaken as progression of disease, where we've had patients who've come off, and then we find out they're living 5 or 6 years.
So OS is always the best endpoint because it's pretty easy to measure. Even I can do it. That one I can do. But IND-213 gave us this doubling of overall survival. We went to the agency, and they tore the data apart as they should. And I have to say, the FDA has been phenomenal in our interactions. Very professional, very engaged, very, very helpful. And I'll mention why that's so important because we could have made a major misstep, and I think the agency prevented us from doing so with enacting within the guardrails that they did. What they said to us is they said, "Where you're getting all this benefit is women with HR positive, HER2 negative disease.
Like, their outcomes are much, much better than the rest. So they said, "For your phase III or subsequent studies, really focus on that patient population," which was tremendous for us. And they said, "Your agent's not working the way you thought it was." We initially thought the virus was lysing the tumor cells so acting as chemotherapy. And it does that, but not as robustly as we think it did. What we're finding is the virus causes an inflammatory event within the tumor, which reactivates your immune system. So things like checkpoint inhibitors, which are, you know, a $5 billion, you know, segment of our industry, all they're doing is activating T cells. What we're doing is we're creating new T cells and expanding those populations. And this is why it works hand in hand with checkpoint blockade.
We create pre-existing T cell clones, or basically re-stimulate those anti-tumor responses. So the agency said, "Please develop biomarkers," which, through a collaboration with Roche, we are able to now definitively demonstrate that this is acting as basically a vaccine. With a co-development agreement with Pfizer, we were able to replicate the results. We actually looked at HR positive, HER2 negative patients, and we reported on BRACELET-1 last year at ASCO. And what we saw is a 50% improvement in median PFS with a hazard ratio of 0.29. Now, for people who aren't familiar, hazard ratio is a measure of the difference between two arms. So if the hazard ratio is 1, it means they behave exactly the same. There's like a near 100% chance that it didn't work. If your hazard ratio is 0.1, it means you have a 90% reduction in the number of events.
So the events here are progression to, again, a 30% increase in tumor. So a hazard ratio of 0.29 means that there's a 71% reduction in those PFS events over that period of time. So it's tremendously good. Most products are approved on a hazard ratio of 0.75. So this is outstanding. We have—well, to be honest, we reported at ASCO last year, we're still treating patients on the test arm who haven't progressed yet. So these women haven't progressed for more than 2 years. So the median was 9 months, but we get this benefit in some of these patients where they just seem to go on forever. This has caused a bit of a problem with our OS measurement because if you're not progressing, you're not dying. So this is really a first-world problem.
The study actually is officially completed at the end of May because the last patient has been on treatment for two years. We're still looking at overall survival. We know the control arm's reached maturity. We have not seen that event yet on the test arm. And God willing, we won't. I mean, the best outcome from these women is they live five or six or seven years. Makes it a little bit harder to report. We can show the survival occurs, but we can't give anyone a median number at this point. But it's, it's a good problem to have.
So with these types of data, and you will be reporting on these OS data later this year?
Well, at the end of the study, we'd like to report, "Study's finished. Here's what the data looks like as of X date." We would like to present it something like San Antonio, though, and hopefully by that point—and I say hopefully very much in air quotes—hopefully we've got to a median OS so that we can say, "Okay, the improvement is X number of months," or, or maybe there isn't an improvement, whatever the number is. But we would like to be able to definitively give that. But again, you know, if these women don't progress, then it's very hard to give that number. So it's very much a positive event for us. And we've been working with our collaborators and stakeholders to get this.
The other issue that's difficult to fathom, if you will, when someone's on active treatment, they're coming to the hospital every month to get treated. Once they progress, you track for survival, which means someone is phoning them to see whether or not they're answering the phone or if their loved ones are answering the phone on their behalf. So to not be invasive, you move from monthly checkups to about every four months so that you're not unduly harassing these people. So, that OS is subject to some variability because we only check in every four months.
Okay. So it looks like the data, well, will, will be positive, but, you know, we obviously can't say that.
Huge grain of salt, yeah.
Yeah. Okay. But you now are contemplating the registration study, and there's been some news around that even recently where you've sort of changed the way you were looking at what that study could look like. Maybe you could expand on that.
We—and again, this is the agency being wonderful, for lack of a better word. We approached the agency this time last year with a large phase III design. It was 400-600 patients, HR positive, HER2 negative, basically a redo of the BRACELET-1 study with PFS as a primary endpoint, OS as co-endpoint so we could capture it. Now, you can imagine we're still tracking PFS for some of these patients. So we do want to get to an endpoint quickly, but OS necessarily is going to be much longer because you have to follow that out. So PFS would get us a BLA much more quickly, and the agency said to us flat out—they said, "This is fine. Like, this all makes sense. It's logical. You're tracking what you did in BRACELET-1. You guys can start this study. It's not a problem.
But we very much want you to address ADCs, or so agents like Enhertu, which are a HER2-targeted, type of agent or antibody-conjugated, treatment, in the first-line setting, so after CDK4/6. And we said, "Well, they're not approved yet." And the agency said, "Yet." So they said, "You know, you can do this, but your informed consent has to say that you're forgoing agents like Enhertu, which could have an impact on both PFS and OS." So that sort of raised some flags with us because we thought, "Okay, well, the agency obviously knows way more than we do. They see all of these things. They see it confidentially.
They can't tell us anything, but they are giving us a very big red flag that we have to address this issue." So we sat down with KOLs and people at ASCO last year, and they said, "Well, we're targeting HR positive, HER2 negative. So Enhertu targets HER2. so you would think that if it was negative, Enhertu wouldn't work there. but what they're finding is patients with very little—ultra-low is what they refer to—so on the old pathology scales, they would be deemed to be negative. Now, with less than 1% and better testing techniques, they can say they are positive disease." Last week, Destiny 6 read out, and it demonstrated that Enhertu works in patients that are HER2 low and HER2 ultra-low. And what we're hearing from pathologists is they don't want to prevent women from getting access to these new agents.
So I think what we're going to find is they're going to bend over backwards to say that they're not truly negative, that they are indeed HER2 ultra-low. So because of the guidance given by the agency, what we've decided, or what we decided after ASCO last year, is, you know, we'd allow the OS to evolve to make sure that that's still a valid endpoint. We will move forward to PFS as a primary endpoint, but as opposed to targeting HER2 negative, we'll go in Enhertu-failed patients. I think if we had moved ahead, we would have failed because I just don't think those patients are going to exist anymore over the next year or two. So I don't think those patients, you will never find them again. I think everyone's going to be deemed to be an ultra-low.
So, Tom Heineman, our Chief Medical Officer, kudos to him and his panel of experts in their guidance and what they wanted to do with us moving forward. What we've also looked at is an approval path. We were looking at a 400-600 patient study. We're now looking at something much more like the PALOMA-1 study, which was where Ibrance had its approval. It was a 200-patient study, 2-to-1 randomized. What they were looking for was a hazard ratio less than—I think it was 0.65—which would give them a p-value of 0.05. They reached that with the 200 patients and filed for a BLA. So a much more efficient, now, you can imagine if the hazard ratio was 0.68 or 0.69, the p-value would have been 0.06, but you would be assured of a success in the subsequent study.
And in speaking with Pfizer, they said, "Well, what are you guys thinking in terms of a subsequent study?" And we said, "Well, basically, a 200-patient randomized study, 2-to-1, you know, looking at PFS as a primary endpoint." And they're like, "This is brilliant. Like, this is—it looks like our study." So, it's easy to look like a genius when you copy-paste. So, that is our thinking going forward. We are—we have submitted a request for a Type C meeting with the agency. We'll have that later in the month, and they have 35 days to give us their definitive meetings. But I think this is a much more efficient way to get us to a BLA and a lot less risky because we are going to be looking at Enhertu-failed patients who we've never treated before.
They're still taxane-naïve, so I'm not anticipating there to be an issue with the biochemistry, but it's a novel patient population for us, so we thought it's a more pertinent use of our time.
Well, we've got five seconds left, so I think we'll wrap it up here. But that was great. Thank you very much. It's going to be a very busy and exciting year for you.
I'm excited.
Okay then.
Thank you.