Moderna, Inc. (NASDAQ:MRNA) Moderna Oncology Investor Event June 3, 2024 7:15 PM ET
Company Participants
Stephen Hoge – President
Kyle Holen – Head of Development, Therapeutics and Oncology
Michelle Brown – Vice President, INT Oncology
Rose Loughlin – VP, R&D Strategy
Lavina Talukdar – SVP & Head of IR
Conference Call Participants
Luca Issi – RBC Capital Markets
Gena Wang – Barclays
Dina Elmonshed – Jefferies
Terence Flynn – Morgan Stanley
Jess Fye – JPMorgan
Myles Minter – William Blair
Mani Foroohar – Leerink Partners
Stephen Hoge
We’re going to get started. Thank you, everybody, for taking some time out of ASCO and your time here to spend with us. I’m Stephen Hoge, I’m the President of Moderna. And I’m going to be providing a little bit of context upfront for the data we’re going to be viewing today, which will cover our full oncology pipeline. We’re incredibly excited to do that.
Before I dive in, we will be making forward-looking statements during this presentation. Those are covered by the Safe Harbor Act. You can find these slides and our reference to it on our website.
Okay. So over the last number of years, we have been building a pretty extensive pipeline. Now we’re going to spend almost all of our time today in oncology, focused on INT because we have some exciting data, clinical data, and obviously the presentations from today. And we’re looking forward to questions on that. But we did want to take the opportunity today to give a sense of all of the other efforts that we’ve got advancing in clinical development, including cancer antigen-specific therapies, some novel therapeutics that have been working on actually even before INT and then some new and exciting technology partnerships that we think will translate into clinical studies very quickly here.
So our agenda for the day, we’re going to try and get through relatively quickly and then get to Q&A. But we’ll start off with Dr. Kyle Holen, who will walk through our overall frame for INT and how we’re thinking about how it might transform cancer. We’ll hand it off to Michelle Brown, who — Dr. Michelle Brown, who leads our I&T program, and we’ll run through the data that was presented by Dr. Weber at ASCO this week.
Kyle will come back and provide a little bit of voiceover on some of the other programs that we have in early clinical stage and then Dr. Rose Loughlin, who leads all of research for us in the therapeutic space, including oncology, will come and share some of our work in the external partnerships and why we’re so excited about those.
So without further ado, I’ll turn it over to Kyle.
Kyle Holen
Thank you, Stephen. So really excited to be here and particularly excited about talking about our oncology portfolio. The oncology portfolio has advanced in really exciting ways not just our INT program, but I’ll share with you some of the advancements in the checkpoint program as well, the Triplet program.
I’ll start off by sharing with you a little bit about why we think INT is going to be so impactful. So you all are familiar with the amazing impact that immune therapies have had across many different types of cancers. Checkpoint inhibitors have really had a dramatic impact in the cancer field. But unfortunately, despite this success, there’s a clear unmet need. And I share here some of the response rates amongst these tumor types. And I’ll also share with you, although there are some response rates, complete responses are very, very uncommon. And so we know that there’s an unmet need, and we’re excited to see how INT can help address that unmet need.
So one of the things that we’re doing at Moderna is first, having a focus on resectable cancers, we think that’s the highest likelihood of success for INT. And so we’re looking at all kinds of different adjuvant therapy treatments with INT, but there’s a ton of opportunity outside the adjuvant setting. We’re looking into early cancer management, treatment during patients who may have positive screening tests, and we’re looking later on into metastatic settings and other lines of therapy. So we think INT potentially has the ability to play across the entire spectrum of cancer treatment. And one of the examples of where we think this is evident is in the AACR abstract that we presented recently, where we saw really remarkable responses in metastatic and advanced head and neck cancer.
Okay. With that, I’ll have Michelle, Dr. Brown, come up and talk a little bit more about INT. And then I’ll come back and tell you a little bit more about the rest of our portfolio.
Michelle Brown
Okay. So it’s nice to see everyone, and welcome to ASCO. We’re very excited today to be talking about the data that was presented this morning, with our 3-year follow-up of our randomized Phase II study. And as we were reflecting about this ASCO experience, we really realized that we’ve been on a journey with everyone over the past year as we’ve been teaching and learning about what it means to have an individualized therapy and what that actually means for patients and then also the broader development strategy.
So without further ado, I’m sure a lot of you saw the press release this morning. And then this is the presentation that Jeff presented on the podium today. I’ll walk you through some of the data sets and why we’re so excited about it.
So this slide, when we first introduced it starting last year, we did have a substantial learning curve to teach everyone about what INT was, which is essentially an individualized neoantigen therapy that encompasses up to 34 patient-specific neoantigens, concatamerized on a single mRNA strand that’s administered intramuscularly to a patient. And when that happens, that mRNA strand enters into the natural antigen processing system, where those neoantigens are expressed on antigen-presenting cells, activate T cells and allow them to target specifically to an individual patient cancer cells. So we’ve seen this slide, and this is really where we think INT is unique in the sense that it is: one, administered intramuscularly; second, it’s the first of its kind to design a specific therapy for each individual patient looking at their tumor mutation profile, but also their HLA type.
And obviously, this is a follow-up to our Phase II study, which I’ll get into in just a second that reported out last year where we showcased our primary analysis that showed a clinically meaningful improvement in recurrence-free survival and distant metastasis-free survival. So after we passed that substantial endpoint last year, we had a planned follow-up for an additional year because we heard from the data set that it was early. We really needed to understand what this new class of immunotherapy would do and if it would provide long-term benefit. So we planned on watching patients for an additional year to look specifically at that durability of effect.
So you should be familiar with this Phase II randomized study. It enrolled high-risk Stage III/IV adjuvant melanoma patients. We randomized them to our INT plus pembro arm versus pembrolizumab. And mind you, pembrolizumab is standard of care. This is what it is used. It has set the standard, and no combination therapy in this space has ever shown a benefit above pembrolizumab. We designed the study with a very powerful and sort of aggressive hazard ratio because we wanted to see something that could be potentially transformative to patients. And we use the standard recurrence-free survival endpoint in addition to distant metastasis-free survival. And then we also really wanted to look at safety because in this population where you’re talking about potential cure, we really want to make sure that there’s a good risk benefit. And then as we hear today, there was a couple of other exploratory endpoints looking at biomarker populations and then also overall survival.
So this is the data set that we saw from Jeff this morning. What we reported for our primary analysis essentially ran to the first hatch mark at the 18-month follow-up, where we had a separation of our combination treatment arm versus the pembrolizumab standard of therapy arm with a delta of 17%. Importantly to know what we see over time is that, that treatment effect for the combination only gets better. So we have this durable, clinically meaningful treatment effect for INT plus pembrolizumab. And importantly, we may see with the pembrolizumab control arm in yellow there, that this essentially performed as we would expect it to. So it looks very similar to the KEYNOTE-054 study. It looks very similar to nivolumab’s CheckMate 38 study. So what we see with this treatment effect for IND is really the powerful potential of the combination, not necessarily anything as a limitation of that control arm.
And importantly, what we see is the spreading of the curve over time to again emphasize that durability. And with this extra time, what we see also is a couple of really important things. The first is that the primary analysis had 44 events. This one with an extra year of follow-up only had 47 events, meaning in an entire year, we only had 3 extra patients have some kind of event, really showcasing again that potential treatment effect for INT. We also see that the hazard ratio has gone to 0.51, so 49% protection in recurrence-free survival, and we see a shrinking of the confidence interval below 1, really emphasizing that statistically significant p-value, which is 2-sided at 0.019. So we’re excited with the 3-year follow-up data because it confirmed essentially what we saw with our primary analysis, but it also shows really what the potential and durable potential of this treatment could be.
And this is true not only for recurrence-free survival, but it’s also true for distant metastasis-free survival. And for those that play in the adjuvant space, distant metastasis-free survival is really important because these are the patients that have the higher risk of death in metastatic disease. Their surgeries are bigger, their outcomes are worse. So really making a profound impact on this endpoint is very meaningful for patients. And what we see again is that from the time we had our primary analysis at that 18-month mark all the way to where we are today, we see this expansion of the INT treatment effect with an 89.3% of patients not experiencing this type of distant recurrence or death. We also see that the hazard ratio is quite profound at the 0.384 and that the p-value here is also very significant at 0.015. So again, both of these primary and secondary efficacy endpoints really showcase what INT can do, and this is the first time any combination has been able to show this above standard of care pembro in this setting.
The other big piece that we showcased today was our overall survival. Now the thing to remember about overall survival is it takes a long time so it is very early on in our days for monitoring these patients for overall survival. And most patients and most studies don’t see a separation until many years later. So this is an early trend, it’s a preliminary trend, but what we see is it’s very positive. And what I want you to focus on is the fact that 96% of patients in the combination arm are alive at the 3-year mark. And we have a hazard ratio of 0.425. So the first data set of its kind. We anticipate following these patients even longer, and we hope to see the same trend we saw with RFS and DFS, but we have a lot more work to do with the overall survival, but it’s very encouraging especially for patients today.
The other piece that we showcased here that’s a little bit different than what we’ve done before is that we looked at the different biomarker populations. And what we’ve reported previously is that those patients that receive the INT combination do well irrespective of the type of biomarker we look at. So those with high TMB, low TMB, PD-L1 high, PD-L1 low ctDNA-positive, ctDNA-negative, the combination works for all of those patients better than pembrolizumab standard of therapy.
While we also have heard, though, as one of the top questions is, well, what happens with INT in relation to HLA? Because we know HLA can be population-specific, patient-specific and it’s a mechanism of resistance for a lot of IO therapies. And just to remind everyone, INT is individualized. The algorithm that’s used looks at that patient’s specific tumors, but it also looks at their HLA type. So we’re designing a therapy that is truly specific for them, and it should work irrespective of HLA status.
In addition, because of the breadth of neoantigens that we’re selecting, we should have an intrinsic mechanism to get away from loss of HLA or heterozygosity. So what we wanted to test with this or show is essentially that: one, the algorithm is working, to each specific patient; and two, even if the tumor is trying to come up with a resistance mechanism, the INT combination arm does well irrespective. And as Jeff said today, the red line is higher than the orange line and the blue line is higher than the green line, which essentially means that irrespective of HLA status by INT combination does well, similar to everything else from the biomarker populations we’ve seen.
The last piece I wanted to highlight at least from the data set that was shown today was that we really think about risk benefit in this patient population, right? These are early-stage patients. They’re looking for cure. They don’t want these long-term adverse events that might be compounded with IO-IO combinations that have been tested or treatments that are in the metastatic setting that are marching their way down. And so one of the things that’s really important is that INT, when we look at it in combination with pembrolizumab, we see a very manageable safety profile, where we don’t see an increase in serious adverse events. We don’t see an increase in Grade 3 adverse events. We don’t see an increase in immune-mediated adverse events. And these are all really important for patients on their long-term outcomes. So overall, what we’ve seen not only in the primary analysis, but with additional long-term follow-up is the safety profile for INT is stable and it’s what we would have expected. And it’s really based off a little bit of fatigue, some fever, some malaise, everything that we would sort of expect from this type of therapy, but we’re not seeing anything as far as increased serious adverse events go.
So as Jeff concluded today, our 3-year median follow-up data showed a clinically significant and durable improvement in RFS and DMFS, with the 49% reduction in the risk of death and a 62% reduction in the distant metastasis. We see a very positive trend in overall survival. We’ll continue to watch these patients and really see how that evolves over time. We believe in this manageable safety profile and really the positive benefit risk we have for these patients. And so far, any way we look at different populations, different susceptibilities, essentially the INT plus pembrolizumab arm does better than standard of care pembro, irrespective of what we look.
Now obviously, we need to thank all of the folks at Moderna, all our folks with their collaborators at Merck and then the clinical trial sites and the patients that make this possible, and we’re very excited to showcase that data set today, and we look forward to future data sets.
Now while we are thinking forward, we don’t have anything yet. We did want to reflect backwards a little bit for some of the data that we’ve presented at previous conferences because we think it showcases and encompasses what we’re really trying to achieve with INT.
And one of the things that I’ve said about this technology overall for INT is that it really sits at this precipice and interface of technological advancement with next-generation sequencing and our understanding of cancer biology. And not only is that showcased in what we’re achieving for INT, but it’s also showcased with how we’re designing our studies to learn about what INT can do and how we’re sitting sort of at that peak of technological advancement. So everyone has been listening to ASCO and sort of paying attention to the early oncology space has most likely heard about ctDNA. And ctDNA is being used in a multitude of ways. First is to identify patients that are at higher risk for their disease coming back, but it’s also being used to understand treatment effect.
And so we were really excited to actually monitor ctDNA longitudinally in our studies to see what INT would do and then also how we can use ctDNA in the future to help us identify patients or understand INT even further.
So this data set was presented at ESMO. And this one is basically our RFS curve on the left, your left, and the DMFS curve on the right. And essentially, this is ctDNA patients that are either negative at baseline or those that had positive status. And most patients are — most thought leaders at this point think that having ctDNA after your surgery is a negative prognostic factor, those patients don’t tend to do well. And that is indeed what we see. Those patients that are ctDNA-positive don’t do as well irrespective as those that are ctDNA-negative. But what’s important here is what we see irrespective of the ctDNA status is that the INT combination with pembrolizumab does better, irrespective of those high-risk patients or those low-risk ctDNA patients compared to pembrolizumab.
And then what’s also really exciting about this data is that we see an early split because we hear with INT that it takes time to manufacture. It’s only going to maybe work for these lower-risk patient populations. And what you see in these curves is that INT can make an impact early and it can make an impact for those that are at highest risk in this setting. So obviously, this is a small data set. We’re going to continue looking at this technology, but it is very encouraging results for, again, the potential of what INT can do.
The other piece we were looking at in addition to those patients that are higher risk or lower risk is we were looking at what INT will do for their ctDNA dynamics as a whole. And NRP201 study, we essentially found that there’s 3 patterns for ctDNA. So the first is those that basically are — have positive status, get treated and then drop to negative. So showcasing that their disease is essentially was present even after surgery and got cleared with treatment. So those are the molecular responders, and that’s in this #1 bucket.
What we have is the #2 bucket, which is the polar opposite. It’s these patients that were positive to start after surgery, they’re high risk, they got treated, they stayed high risk, meaning that they most likely weren’t responding to treatment the best way.
And then we have an interesting bucket with the ctDNA-negative pattern, which is essentially those that were negative the entire time. And one of the things with the ctDNA negative is that this is very dependent on the tumor type, and we know that melanoma doesn’t tend to have a lot of positive status. So even seeing these patterns was quite profound in this setting.
The last piece I’ll call is that in the molecular responder category, you’ve got obviously different patterns of response, where someone could start negative, and then maybe their disease starts coming back like what you see in the red dots, and then essentially treatment ends up taking care of that disease coming back. So it really showcases sort of the dynamics on a molecular level of what’s happening in a patient.
And then if you want to translate that to clinical outcome, we essentially showed that those that had the ctDNA-negative pattern, meaning they probably had very little disease left, did better. They had less recurrence. Not surprising. Those that had ctDNA positivity that stayed positive didn’t do so well, which again is not very surprising because obviously it means that they’re not responding to what we’re giving them. And then the ctDNA-positive were right in the middle of the road.
And what’s important there is if you actually look on the bottom of the graph, what we see is that the combination essentially doubled the amount of molecular responders compared to pembrolizumab, meaning that the combination is doing something not only on the clinical side, but also on the molecular side. So this data is very encouraging. It’s a highlight we’re trying to do to understand INT as a whole. And then this will actually guide some of our development strategies as we move further along.
So I’m going to take us a step back out of the clinical data for a minute and showcase what Stephen has already showed, which is our INT portfolio, if you will. So we have announced over the course of the year, the launch of 5 new studies, so our Phase III in adjuvant melanoma in partnership with Merck started enrolling back in July of last year. Our Phase III in adjuvant non-small cell lung cancer started towards the back end of last year as well. And then in February and March time frame, we released the cutaneous squamous cell carcinoma, which is a Phase II/III, we started enrolling; followed by our renal cell carcinoma Phase II study in the adjuvant setting; and our Phase II bladder cancer study in the adjuvant setting. So you can really see that based off of the data set we have showed you for the P201 that we’re very excited about the potential for INT in the adjuvant space. We’re varied about the potential for patients. And in partnership with Merck, we’ve launched a multitude of studies to impact not only melanoma but a broad range of tumor types.
And then basically, what I’m going to show you in a series of slides is what the schema is. But essentially, the theme is the same. They’re adjuvant studies. They’re randomized. We have the appropriate control with the standard of care. And importantly, these are all powered to show a statistically meaningful improvement for INT versus that standard of care. And that’s true for our Phase III study, which is currently enrolling. That’s true for our non-small cell study, which is currently enrolling. That’s true for the CSCC study, which is currently enrolling. I’m sounding like a broken record, and for bladder and then for RCC. So really, this is a thank you to the entire sort of Moderna-Merck team for the litany of studies that we’ve launched. And then I see Kyle is coming up, so I’m going to wrap this up quickly.
As Kyle showcased, we’ve done and as you saw in the previous slides, we’ve done a substantial amount of work in understanding the potential for INT in the resectable space. We have could potentially ctDNA to start moving us towards the continuum on the right and potentially use it for high-risk patients on the left. And then as Kyle alluded to, we were very encouraged by our AACR data in advanced squamous cell carcinoma, the head and neck, which potentially shows the potential for INT in the metastatic setting. I’m not going to go over all of that data. This was showcased at AACR. It essentially was part of the P101 study, which was our Phase I study and will showcase an expansion cohort.
The thing I will say is that this population was truly representative of advanced metastatic population. They didn’t have the best performance status. They had burned through a number of treatment options. Overall, their prognosis was relatively poor. What we saw in this sort of later-stage population is that INT safety was the same as what we would expect across the board. And importantly, what we saw from the spider plot at the AACR presentation and is showcased by the very nice flat lines on the bottom of the screen is that we had patients that when INT was on board in this metastatic setting, we got a deepening of their clinical response. We got increased disease control, and we had patients that were very advanced have complete responses. So that shows that we’re doing something right in the adjuvant settings for doing all of these clinical studies, but there is potential and promise to potentially make an impact in these later lines. So obviously, we’re very excited about the P201 data today. We’re using it as fuel for the litany of studies we’re doing for tomorrow and then we’ve got a lot of work to we would want to go beyond now.
All right. With that, I will hand this back to Kyle.
Kyle Holen
Thank you. Yes. Thank you, Michelle. We’re really excited about INT, but equally excited about the rest of the oncology portfolio, which we haven’t spent a lot of time talking to you about. So I’d like to share a little bit of those thoughts right now. I’ll start with our checkpoint antigen-specific therapy 4359. So 4359 works a little bit differently than what you think of as a checkpoint antibody. So whereas a checkpoint antibody takes off the brakes, if you will, for a T cell activation, what 4359 does is it directs those T cells, directs them specifically to IDO or PD-L1. And the reason why that’s important is because it has a direct tumor effect and it allows the T cells to have a specific activation against the tumor.
We are excited about the possibility of the Checkpoint vaccine. And therefore we’ve included on here this slide, the schema for the Phase I trial, which includes expansion cohorts. So we’re currently enrolling in combination therapy with a Checkpoint inhibitor in the metastatic setting. And these, there’s 2 cohorts here in this expansion. There’s a cohort in non-small cell lung cancer and first-line non-small cell lung cancer that are PD-L1 positive, over 50%. And then we also have a frontline metastatic melanoma study that’s enrolling. So both of these studies should give us a really good idea of what additional benefit checkpoint vaccine will have over pembrolizumab alone.
The other asset in our portfolio is our triplet therapy, also known as 2752. So 2752 is a combination of OX40, IL-23 and IL-36. These mRNAs are injected directly into the tumor and elicit a very robust immune response. That immune response is really exciting because part of the mechanism of action for this combination is it induces tumor cell killing that unleashes antigens, which train the T cells then to go out and attack those specific antigens. And so because of that, we’ve seen abscopal effects, meaning that we’ve injected the tumor and we’ve seen lesions distant to the injected tumor have tumor responses.
This is a schematic of our Phase I trial. So we’ve had multiple different types of tumors enrolled into the study including some lymphomas, and we’re expanding into a melanoma CPI refractory setting.
And then the other study that’s been pretty exciting to see is an investigator-sponsored study in DCIS, where we’ve seen really robust immune responses in injecting these DCIS tumors. And this is ongoing work that’s being done by Dr. Laura Esserman. She presented some of these data at the San Antonio Breast Cancer Conference, and we hope to have updated data coming up at this year’s San Antonio Breast Conference.
That was a real quick overview of some of our other pipeline assets. Now I’m going to pass things over to Dr. Rose Loughlin is going to talk to you about some of our external engagements. Thank you.
Rose Loughlin
Thank you. All right. So in addition to the clinical pipeline that we walked you through today, we wanted to share just a little bit about some of our early efforts, which are really looking to diversify the oncology pipeline that we have with our platform. So we recognize that our platform is well suited for multiple therapeutic approaches in immuno-oncology. And we also recognize that there is a depth of expertise in each of these types of approaches that can really be critical to success, so we have identified partners in different areas who can really bring that design and biology expertise to our platform through collaboration. So we’ll give you a preview of each of these different product concepts.
Starting with TCR bispecifics. So these are a form of T cell engager. And like many T cell engagers out there, they do have a CD3 binding domain, that identifies the T cell and helps it. What’s unique about this format is the other binder. Instead of recognizing cell service proteins like your CD19 or your BCMA, it’s actually a TCR mimetic, so what it recognizes is a specific peptide presented on an MHC by the cancer cell.
Now this really opens up a new target space for a T cell engager. You can look for intracellular proteins as cancer antigens. So not only can you look at a bigger target space, but you can also pick targets that are more specific to cancer cells. And so this can let you open up that therapeutic index as you’re developing your T cell engager.
Now what’s important to also recognize about this format is that it is HLA-restricted. So that bispecific is specific to a certain HLA type. So much like you think about INT being individualized and being able to help any patient with any HLA, we look at our platform the advantages we have in manufacturing, speed and costs and know that we can pursue additional HLA types once we understand that a cancer antigen is a good target therapeutic index and it’s starting to show that clinical signal.
Our platform also has the ability to combine different bispecifics. So we call it multiplexing. You might think as a combination, but they’re actually just one therapeutic in our eyes. You can actually pursue multiple cancer antigens in one therapeutic. So through our collaboration with Immatics, we’re bringing these forward. They also have 2 bispecifics that are already in the clinic in recombinant protein forms. We’re very much looking forward to those data and want it teaches us about this field.
So the second concept is actually an enhancer for T cell therapies. So engineered T cell therapies have been transformative in certain spaces, particularly, the hematological malignancies. But in other spaces, you can see limited persistence of the engineered T cells once they’re infused. You can see partial responses or exciting responses but limited durability.
And so what we’re looking to do is after you have infused an engineered T cell therapy, then we provide an mRNA enhancer. And what that does is within that patient’s body, it’s presenting the same antigens that those engineered T cells are designed to recognize. And outside of that suppressive tumor microenvironment, it’s actually looking to present that antigen to those T cells to help them activate to help them proliferate.
Now we have 2 collaborations right now in this space. These are clinical combinations. So we’re looking to combine with Immatics’ IMA-203, which already has Phase I data out there in metastatic melanoma, and so we have designed an enhancer that presents the specific epitope on PRAME that, that TCR-T cell therapy is designed to identify.
We also have a collaboration with CARsgen on CT041, which has Phase I data in gastric and pancreatic cancers. And similarly, our enhancer in codes for CLDN18.2, which is what the CAR in their CAR-T is designed to recognize.
Now this type of combination is a relatively new application and a new field. And so we’re really looking forward to getting data and looking and seeing if we think this application could work across different types of cell therapies regardless of target, regardless of format and really enhance the performance of those cell therapies and settings where it’s been a little bit challenged, particularly solid tumors.
And then finally, we’re working on our own cell therapies, but with an in vivo approach. So this is in the CAR-M space. So with our mRNA and an LNP, we can infuse those into patients and actually transfect a patient’s myeloid cells in vivo with a CAR-M. so we’re transfecting monocytes. They might be trafficking around. We can transfect macrophages, which might already be in the target organ. And with that CAR, you can help those monetizing macrophages if they are circulating.
Once they reach the tumor stay there and actually change their state, and this is where our collaboration with Christmas really comes in because the design of that CAR is very specific to myeloid cell biology, and they’ve been working on this for quite a while. So once it’s in that environment recognizes that antigen, it moves into a pro-inflammatory in one state. It stays present there. It starts releasing cytokines and other proteins that help make that suppressive environment a little bit more inflammatory. And it also starts to phagocytose cancer cells.
Now the myeloid cells do not have to eat the entire tumor. But by eating cancer cells, they actually turn into an antigen-presenting cell themselves. And so they are showing those antigens for the cancer cells to all of the other T cells in that microenvironment. And so what we’re really excited to see is in Carisma’s clinical programs, which are ex vivo, whereas ours are in vivo, but they follow the same principles. Their translational data is showing this multifaceted MOA. So we hope this gives you a sense of the diversity of different approaches we’re looking at in the early oncology pipeline.
And I think I’m handing it over to Lavina or Stephen for Q&A.
Stephen Hoge
A little bit of both. Thank you very much, Rose. And I’ll ask maybe Kyle, Michelle and Rose. They can stand near Lavina, and we’ll try and answer we can in about the 20 minutes we have. So please, and Lavina has the wand, and we’ll approach people. Lavina?
Question-and-Answer Session
A – Lavina Talukdar
So if I can please ask that you identify yourself and your affiliation before your question. Thank you.
Luca Issi
Luca Issi, RBC Capital Markets. I have 3 quick questions. So first, maybe how you’re thinking about impacting the NADINA trial that we’ve seen at ASCO. Implication for your study feels to me that new standard of care is PD-1 plus CTLA-4 and the new adjuvant settings now. So do you still have space to potentially amend the protocol and maybe explore your INT as add-on in death settings? Any thoughts there, much appreciated, too.
How should we think about potential for an interim look for the Phase III? Is the Phase III designed to have an interim look? And if so, after how many events and how much alpha you’re spending there for the interim look?
And then quickly on the accelerated approval and potential for accelerated approval. In your mind, is that less or more than 5% chance?
Stephen Hoge
I’ll take that question first, and then maybe hand it off to Kyle and Michelle to handle NADINA in the Phase III.
So on the accelerated approval, as we’ve said before, we think this is pretty compelling. When the hazard ratios are getting to the numbers we’re talking about here and when there’s a trend on overall survival, it’s an appropriate question to ask. We have not yet because we wanted to show diligence in enrolling the Phase III and completing the manufacturing site, activities that we are well underway on this year.
We wouldn’t be asking if we didn’t think it was a reasonable public success, but I wouldn’t dare to assign a number to it. And at the end of the day, it’s not our call. It will fall for regulators both in U.S. and Europe to make that decision.
Kyle Holen
Maybe I’ll respond to the NADINA question. So any treatment that’s going to help patients, we’re all for. And so it’s exciting to see that hazard ratio of 0.32. I mean it was incredible. But I had some concerns about NADINA. First, it was an investigator-initiated study. We don’t know if it would meet any type of regulatory bar. Secondly, they only have 9 months of follow-up. I think they really do need to do a further follow-up on that study. Third, 47% of those patients after 2 cycles of ipi/nivo had Grade 3 or worse side effects. So it can be challenging to try and administer that therapy. And lastly, as Dr. Weber said today during the session, a small percentage of patients would be eligible for that type of treatment based on the eligibility criteria for NADINA. He said in his practice, he likely only sees about 15% of his patients that be eligible for that therapy.
So despite the fact that Christian mentioned that all studies should stop and amend immediately to change their control arm, that’s not part of our plan. The current standard of care, we believe is pembrolizumab adjuvantly, and so we’re continuing with that plan.
And then for the Phase III, maybe I’ll just quickly mention, yes, we do have interim analysis planned. We have not disclosed how much alpha we’re spending or the timing of those interim analyses. And is there anything else you want to add on the Phase III?
Michelle Brown
Yes. No, we’re very excited about the Phase III Dr. Weber said. It’s enrolling, and we’re very excited about the support for the patients, the support from the sites and then obviously, the sort of continued data sets like we’re showing with the 3-year only uplift the momentum we see for the Phase III.
Stephen Hoge
It’s amazing that we’re seeing for the Phase III, and it’s just really heartwarming to know that people are so invested in that study.
Gena Wang
Gena Wang from Barclays. So maybe follow two questions. One also maybe ask about the market opportunities. A few doctors we talked talk about that could be a niche market opportunity for melanoma. Maybe you can help us understand why the comments is wrong?
And then second question is also for accelerated approval pass, why manufacturing readiness is important. We haven’t seen any other therapy like they have to have a manufacturing-ready even cell therapy before they were able to submit for accelerated approval.
Stephen Hoge
Okay. Thank you for that, Gena. So I’ll take the second part of that first because it is really important. This, as an individualized treatment, is unlike anything we’ve ever done in our platform before. It is sort of like cell therapy, but we’re going to be trying to do it at a much larger scale, particularly as you move into histologies like lung. And so for that reason, in order for us to be able to license a facility, at the end of the day, it will be a facility not just the concept of an INT that will be the subject of review and a license from a regulator like the FDA. We have to establish that facility so it can be inspected. And so we certainly could, in our clinical trial right now, rely. We’re manufacturing INTs, about 1,000 this year for the ongoing Phase IIIs if you just do the math. And you could rely upon those facilities, which are Norwood, for the manufacturer of commercial scale INT. But we really think that wouldn’t be the optimal overall long-term plan.
From a commercial perspective, it’s not the right economics, as you know, from Norwood, yours and others who’ve been there. It’s got a phenomenal number of programs that are running through it. It’s our R&D site. We also do our large-scale commercial manufacturing for other vaccines. And so for a whole host of reasons, we don’t actually think it makes sense to establish INT personalized manufacturing there, and we’d rather dedicate a separate facility.
That’s a facility that we’ve been building in Marlborough, Massachusetts, for almost a year now. And we’re well down the path to establishing that. And that would be the facility that we would expect to be a part of our submission and that ultimately would be inspected as a part of that submission and license to manufacture INTs. It is because it is such a unique manufacturing challenge, we’re not scaling out to billions of doses. We’re scaling down to 9 or 10 doses for an individual but scaling out to thousands of different medicines every year that we’re making in that facility. And because of that engineering, it is unlike anything else we’re doing. We really do you think it’s going to be best served long term by that purpose-built facility.
Kyle Holen
And in terms of the niche market. We don’t believe this is a niche market. Look, there’s thousands of patients that are out in the U.S. alone for INT and then you think globally, there’s clearly a high unmet need. As you saw from the curves that Michelle had presented, almost half of the patients recur with pembrolizumab. So there’s a huge unmet need in this space, and we think that INT can fit it. But the other important component of this is that we don’t believe that INT is relegated to just melanoma. It should be histology agnostic. And so that’s why you see such a broad range of different tumor types that we’re expanding into bladder, renal, lung, melanoma. There’s head and neck cancer data. So I — so far, we don’t believe that there’s any reason why any tumor type should not respond to INT. So that doesn’t sound very niche-y to me. But of course, our first step out of the gate is going to be in melanoma.
Anything you want to add to that, Michelle?
Michelle Brown
No, I think you said it nicely.
Dina Elmonshed
This is Dina from Jefferies on behalf of Mike Yee. In terms of the metastatic setting in INT, you had really good results for the head and neck, but you’ve started with a lot of adjuvant studies. I’m just thinking about your strategy there given these positive results. Do you plan moving into the metastatic settings? And then if so, which specific tumor types would you be able to do that first?
Michelle Brown
Yes. So I think that you can see based of all the studies that we’ve had that we’re definitely invested in the adjuvant space, but we’re also making biologically rational prudent decisions, right? So we’re still learning about INT. We’re still making sure that the manufacturing is up in time. We’re still making sure that those patients are getting their treatment in an up-front manner as quickly as possible. So we really believe and are following the data from the P201 study and what it’s set forward is that litany of studies.
Now we know that the metastatic setting is just a larger hurdle as a whole, right? We know those patients are sicker. They move faster. They have bulkier tumors, so the hurdle for a mechanism of action like INT and an individualized therapy where you need their sample to sequence and then generate their individual medicine to get delivered to them, it has a whole litany of different questions than the adjuvant space. But as Kyle showed that we really are thinking about making rational decisions today to make those learnings and then open the door to find out where those boundaries are for INT. We believe in the head and neck data from the P101 study. So we really are thinking about exploring that. We also really believe in the safety profile for INT and the risk benefit that could be for earlier-stage patients. So we’re really thinking about that.
What you also see in our adjuvant space is very warm tumors, very high TMB tumors, right? But we also know that we have a pancreatic cohort in our P101 study. And so we’re starting to sort of expand not only that warm tumor environment but also out into those colder TMEs. So what you’re seeing is a solid foundation for learning and then an expansion out for the opportunities for INT.
Kyle Holen
The other thing I’ll just add real quickly is the other thing that gives us confidence in potentially moving into the metastatic space is what Michelle had showed previously with the ctDNA-positive patients. Those essentially are behaving just metastatic patients, the ctDNA-positive melanoma patients. And if they’re responding as well as they are to INT, I think we’ve got a pretty good shot at metastatic, but only studies will tell us whether or not we’ll have efficacy. But those studies are currently being planned, and we will let you know what those studies are in due time.
Terence Flynn
Terence Flynn, Morgan Stanley. I know you guys had made an effort to rename the vaccine from PCV to INT, and you’ve done a lot of initial dose ranging work. Can you just talk to us about that decision and also some of the decisions on doses for some of these subsequent trials, how you’re kind of choosing dose and confidence there? When you think about frequency of dosing, obviously, with the durable data you’re seeing here, how does that factor into longer-term decisions?
Stephen Hoge
Sure. You want to take the dose side?
Kyle Holen
I’m going to take the PCV to INT, but maybe I’ll let you take the dose question or — but anyway, let me start with PCV to INT. So one of the reasons why we decided that INT made more sense in this setting is because we’re not really using INT as a preventative therapy. And most people think vaccine as a preventative therapy to make sure that they don’t get COVID or RSV as some 2 prime examples of other products in our pipeline.
And so we’re not using this as a preventative therapy. We’re using it as a treatment, and that comes with a very different profile and consideration of perhaps toxicities that you might not expect from a very aggressive chemotherapy or IO agent. So that led us to change the nomenclature to INT and individualized neoantigen therapy as opposed to having a vaccine as a part of nomenclature.
Stephen Hoge
The only thing I’d add to that is there was at least one major regulator outside the U.S. where the use of the word vaccine was actually a problem for them in terms of classification of how they would regulate their product. And so there were even regulators who said, look, you’re really doing therapeutic intent, the word vaccine will create more problems than it is. So it wasn’t just that interpretation. We’re actually advised externally as well.
Kyle Holen
And you’re correct. We’ve done some dose exploration. We think we have a very good dose as clarified by P201 data. So we don’t really want to fix what isn’t broke, so we’re moving forward with the same dose and schedule with our future studies, with some minor modifications based on how the chemotherapy is administered and how the IO agents are administered. But we strongly believe in the dose that we’ve been using for the 201 study and that we’re currently in for 001.
Anything else you want to add about dosing schedule?
Michelle Brown
Yes. So with dosing schedule, I think the key is that we want to manage that risk benefit and then also patient convenience, right? We know the IO agents when we’re paired with pembro or every Q3 weeks or Q6 weeks, we think from a biological perspective, from a priming and reexposure perspective that we think the Q3 week makes the most sense to allow for the T cell mobilization as you saw with both the P101 and P201 study. We’re very encouraged by the data we’re seeing. And we also believe that with the 9 doses, what we’re doing is appropriately mobilizing T cells and training and activating them, but we’re not exhausting them. And so we’re standing by the dosing schedule that we see, and you see it throughout all of the future studies that we have.
Kyle Holen
We have looked at immunogenicity to understand if that’s the case. And yes, we’re seeing activated T cells long after the last dose of INTs. So we feel pretty confident that they’re not getting exhausted from the current schedule.
Jess Fye
Great. Jess Fye, JPMorgan. I had three. Coming back to NADINA and its relevance and the comment that less than 20% of patients would meet those criteria. Can you talk conceptually about why or why not neoadjuvant treatment like wouldn’t benefit other subgroups who are otherwise candidates for adjuvant melanoma treatment? And I’m just thinking about even if it were like the SWOG 1801 regimen that might dovetail a little bit more with kind of what you’re already working on versus ipi/nivo?
Second, regarding the Phase III in adjuvant lung. I know you said there’s a lot of enthusiasm to enroll the Phase III for melanoma, presumably because you have this Phase II data. So how is enrollment going for adjuvant lung?
And then lastly, following up on Terence’s question, I guess, if you’re seeing those activated T cells and good kind of durability, is there any consideration to maybe like spacing up dosing frequency, at least a little bit further into treatment?
Kyle Holen
Great questions. So let me first tackle the NADINA question. So I think that based on SWOG1801 data, neoadjuvant approach does make sense, but there hasn’t been any efforts to change any labels globally or really significantly change the standard of care. And so when we go out and talk to melanoma doctors, there hasn’t been a big shift to a neoadjuvant approach. And so we believe that it’s still relevant for us to continue on with our current plan, which is giving INT in the adjuvant setting.
Now sometime in the future down the road maybe that will continue to shift at some point. But right now, we think we have the best strategy to continue with INT in the adjuvant setting with pembro adjuvantly.
The next question was about the lung enrollment early days. Very early days, and we can’t really comment too much about enrollment. We’re still getting countries open. We’re still getting sites up and running, and we might be able to give an update sometime in the future. But right now, we don’t really have a good sense of what that enrollment is going to look like.
And then the last question was about spacing out the administrations. It’s a really interesting question. I think that might be something that we could explore in other studies. The challenge right now is that we believe that the schedule that we have is effective, and I wouldn’t want to compromise that efficacy by exploring that in another indication. So we’re sticking with the current schedule, but it may be something that down the road we could exploring in a translational study.
Michelle Brown
And I think the only thing I’ll add is with — even the neoadjuvant space, everything we hear about is what is the risk benefit? How do you identify those truly high-risk patients? And so even with SWOG1801, they still had a very narrow population where you could have the palpable tumors, right. So you’re really trying to identify the appropriate patient population. And I think the data is still early days, as Kyle alluded to.
I think we’re all excited about this like treatment effect for metastatic to adjuvant to neoadjuvant. We see more and more of that creep, but we’re also still hearing is, where is your risk benefit? Who are the patients that really need this, who are the ones that can watch and wait? And I think we’re still early on in those days. So for what we see, we really believe in where INT is sitting in the adjuvant space, but that’s not to say that we wouldn’t explore it earlier on. We’re seeing that with our cutaneous squamous cell study. It’s in the perioperative space. And even in P101, we have a perioperative gastric cohort in perioperative non-small cell lung cohorts. So we are definitely exploring it, but we’re just not there yet for melanoma because it’s just so novel at this point in time in understanding those patients.
The one thing I will add is that we see enthusiasm across the board for INT across the tumor types that we have. We really aren’t hearing, oh, you have metastatic or you have melanoma data, we’re only really excited about melanoma. That’s just not the case because INT is so individualized to the patient that we see that level of engagement and enthusiasm really across all of the studies we’re seeing.
Kyle Holen
The other shift that has to happen to make 1801 a reality is the practice patterns have to change. That means a medical oncologist has to see these patients before the surgery happens, and that’s not happening yet. That hasn’t been that shift in practice patterns, and it’s hard to do. We’ve seen that in breast cancer, where it took a long time for that neoadjuvant approach to really take hold because, and they had many, many multidiscipline clinics, and they had a very, very aggressive patient advocacy organization to try to push that to happen. I’m not seeing that shift happening yet, and it may take a long time to get there.
Myles Minter
Myles Minter from William Blair. I think going back to AACR when we looked at the head and neck cancer data, there was about 23% of patients that actually had detectable T cells that are activated against your vaccine. So I’m just wondering whether you’ve learned anything across your trials that can help boost that response. And in ctDNA-positive patients that have responded in the melanoma study, like what did their T cells look like in terms of percentage of responses? Just coming back to the comment that, that ctDNA positivity might be a surrogate for more metastatic indications.
Michelle Brown
Yes. So first things first, in the P201 study because it was so focused on establishing INT as far as the clinical efficacy goes, we did not sample a lot of patients in for apheresis for T cell responses. That was not the priority. And we are launching what it’s called Part B of that study, where we are enrolling additional patients for additional translational analyses to really understand that lens of the neoantigen presentation, more of the immunogenicity work, more about recurrences and all of those pieces. So there is a translational arm that is now enrolled in that study. So we’ll know more with that.
With the P101 across the board, any time we’ve looked at the translational data, we showcase that we are mounting T cell responses to approximately about 1/3 of the neoantigens that we’re including. But these are pretty high T cell responses. And currently, on the literature, we don’t know how many neoantigens need to mount a T cell response to be able to drive a clinical benefit, right? And that is a magical number. It could be just one.
Kyle Holen
It could be one. That’s all you need.
Michelle Brown
But what we believe in is that what we’re doing with our algorithm is that we are selecting the ones that we think are going to be more robust. They’re having multiple shots on goal, allows us to minimize tumor escape, increase neoantigen cross-linking, elicit more T cells into that milieu, which then will help with like clonal escape and those pieces. So it’s a synergistic mechanism. And I don’t think it’s just going to be this one for one, like you get one T cell, one neoantigen, and that’s going to do it nor do I think having a magical number up to 34 is going to be. It’s somewhere in there and what happens in that individual patient.
But we are, in all the studies that you see, collecting a lot of samples for these patients to really understand what INT can do. And the beauty of it is that it is based on a computer-based algorithm, so that gives us the latitude to take those learnings from clinic, put it back on to the algorithm and then move that forward to iterate on itself.
Now the novelty is that we don’t want to break it, we believe it. And so there’s always this balance of learning and application that we’re also going to be thinking through with the development.
Kyle Holen
I’m also really excited about some novel techniques that we’re using, including T-cell receptor sequencing. And looking at that T-cell repertoire, I think, we’ll be really informative. So more to come in that space, but we’re learning a lot about how INT works.
Mani Foroohar
Mani Foroohar from Leerink Partners. I struggled to add on to some of the excellent questions that have already been asked. But I do want to follow up on Luca’s question. I don’t think it could be quite as quantitative as set a 5% line. But let’s talk about timing, which I think you can talk about. Let us presume that we get to all the various manufacturing questions and discussions that you’re having with the FDA and other regulators, which we’re not entirely privy to, but you certainly are. Those are resolved in a satisfactory fashion. You have regulatory feedback letting you know those results in a satisfactory fashion at some point this year, I would guess.
What is the process from that point? Presuming the Phase III is fully enrolled, which I would guess it is, should we expect a press release? Should we expect commentary at ASH, SITC, JPMorgan next year? What would be your philosophy and timing on when you tell us, “Oh, we’ve decided to file. We’ve made a decision based on these phenomenon, these analyses.”? When might you tell us? And what metrics will you use to decide we should file we shouldn’t file?
Stephen Hoge
It’s a fair new approach. I won’t say 5% or not or anything. But let me do the best to characterize how we’re thinking about it. Obviously, I won’t break any new ground and giving a date or specific time. We’re — we’ve said particularly the 3 things that we think are necessary: durability, manufacturing facility and enrollment in the Phase III. We feel like with the data we have right now, we’ve got the first in terms of durability, and it’s pretty compelling hazard ratios, and we’re pretty set on that.
The manufacturing facility, we’re well down the path, we hope to give tours in the future. But we would assume that our ability to establish the right operational cadence in that manufacturing facility will happen soon. We are obviously in the Phase III, already manufacturing at a scale that’s almost commercial for an individualized treatment, 1,000-plus patients this year. So we have some line of sight to that some confidence to it.
When it comes to the Phase III enrollment, we’re well down that path as well. I think one of our investigators may have made some news on that recently. So I won’t confirm or deny, but we’re really happy with the brisk pace of enrollment in that study. In many ways, we feel ahead of schedule. The next announcement we would make will be with our partner Merck when we’ve completed that enrollment. At that point, we would know, we would all know that we’ve kind of satisfied at least those 3 criteria.
Now the question of how we would approach regulators. Obviously, there’s, we’re breakthrough designation, prime designation, we have the opportunity to engage in those conversations. We’ll keep those confidential while we’re having them because there will be some back and forth. It’s likely not a one and done. If we did get to the point where we were going to proceed with submission because we got an indication that, that was an appropriate thing to do at this point, we would talk to our partner, Merck, and it would be a joint decision on public disclosure. Obviously, it’s a significant one for us. And so we would lean into wanting to make sure people were aware of that because it would start to become a big part of our activities and work for the short term.
So I can’t give you a date when that will happen. We’re getting real close to all the pieces being there. But the next step for us is to finish this enrollment in the Phase III.
Lavina Talukdar
Great. It looks like we’ve exhausted all questions. I’ll hand it back over to Stephen just for — and the team for concluding remarks.
Stephen Hoge
Yes. I just want to, first of all, thank my colleagues for the excellent presentation and Q&A, and obviously thank all of you for taking the time. It’s an exciting moment for us. It’s our second chance to do this at ASCO. We hope, to many and others who asked questions, we answered those questions that maybe next year we’re talking about even more specifics on the progress of the INT program and some of these milestones being behind us. But we also hope to be able to share some of the progress and the clinical data on some of those other programs because we really do believe that we’re just at the beginning of showing the potential of our platform to impact cancer and help cancer patients across the world.
So thank you for being here. Thank you for your time, and hopefully we’ll see you again next year.