Okay, well, I guess we can get started. So hi, everyone. My name is Emily Shutman. I am an associate here at Leerink on Andrew Berens's targeted oncology team, and I'm happy to have with me Reinhard Kandera, the CFO of HOOKIPA. So thank you for being here today. Maybe just to start, can you just maybe provide a brief overview of the company and the HOOKIPA Arenavirus platform?
Absolutely, and thanks for having us here. So HOOKIPA's pipeline is based on our proprietary Arenavirus vector platform, which has proven to be a very potent instrument to generate high levels of CD8+ T cells. Actually, we think there is no other technology that is capable to generate similar levels of CD8+ T cells with an off-the-shelf, very tolerable technology. So that's the key takeaway. It's applicable in many cancer indications. It's also applicable in infectious diseases. And based on this technology, we've built the pipeline with a lead product currently in a phase II testing, with preparations ongoing to go into a pivotal study. The indication is HPV-positive head and neck cancers. And we've shown in preliminary data that we were able to double the overall response rates that is shown with the current standard of care, which is pembrolizumab.
We also have a great partnership with Gilead in infectious diseases, developing hepatitis B and HIV therapies, both programs going into the clinic. HPV actually is already in the clinic, led by Gilead. And for HIV, we've recently cleared the IND and will dose the first patient shortly. We have a strong cash position disclosed of $117 million by the end of the year. And we have a very catalyst-rich year 2024 ahead of us.
Great. Yeah, I'd like to dive into that in a little more detail. So yeah, maybe just to start with the HB-200 program. So you're obviously targeting HPV-16 patients, as you mentioned. I guess I'm wondering if you could just describe the characteristics of these patients and how they're different than the HPV-negative head and neck segment.
Yeah. So obviously, we are targeting the HPV subgroup, mostly oropharyngeal cancers, where it's, I think, well known that the E6, E7 antigen is an oncogenic driver, and therefore it makes a very good target. We're not focusing on HPV-negative. It's exclusively HPV-positive cancers.
Great. And is the treatment paradigm for these patients any different than the HPV-negative segment? And I'm also wondering about the prognosis of those patients relative to their negative counterparts.
The current standard of care is the same. Pembrol for CPS-positive patients, that's the current treatment paradigm. However, I would say you see a couple of emerging therapies where I think we do have differences between HPV-negative and HPV-positive targeting modalities. With the current standard of care, I think we've seen slight differences looking at the Keytruda data between HPV-negative and HPV-positive. But it's fair to say that the prognosis in both groups for metastatic recurrent cancer is still quite poor, with 20%-25% response rates.
Got it. OK, that's helpful. You touched on this a little bit, but I was wondering if you could just summarize the phase II pembro combo data. I believe you toplined it in June and then presented it at ESMO. Just, yeah, summarize that.
Yeah. So we first reported 15 patients of single-arm combo data, HB-200 and pembro, where we could show more than 40% overall response rate compared to 19%-23% for pembro alone. We reported five more patients, bringing the total to 20 at ESMO. And we could see the signal still being the same, still being strong. And we are adding more patients. We'll soon be able to report data on a bigger patient cohort. And we'll also update the market on those patients that we reported initially, because the duration, obviously, is an important question that investors are interested in.
Yeah, definitely. I actually want to talk about the update we're expecting in the first half on the first-line combo cohort. Can you maybe just provide a little bit more color on what we could expect in terms of duration and that update?
Yeah. So as I said, we'll not have definitive duration data. But obviously, we will report spider graphs. We will show how those patients that initially responded are doing. And as you may recall from the data at the last cut, many of them were still on study. And we'll be able to update that data with definitive duration data probably towards the end of this year. And importantly, we'll also be able to add patients. So 15 patients, 20 patients, still a relatively small patient cohort. Our goal is to update to 35%-40% patients. And seeing the same result in that bigger patient group would certainly confirm a very solid basis for a pivotal trial. That's the key arm. And I would also add, we are currently in discussions with the FDA on a route to licensure.
We'll also guide the market on a very precise plan to get this drug to market in an expedited way.
Got it. OK, yeah, that makes sense. Maybe going back to sort of duration, I guess, how might the durations you're seeing in your study compare to some of the durations we've seen in maybe some of the pembro studies, like KEYNOTE-048, for example? And I guess, do you sort of view that as the bar for duration in an HPV-positive setting?
Yeah. I think we look at our drug as something that could bring the pembro benefit to a bigger proportion of the patients. So the pembro duration of response in that indication is nice. The problem is, it's just happening in 20%-25% of the population. If you can do this in 40%-60%, we've actually, in the CPS high group, we've got 60% response rate. If you can bring this benefit to a bigger proportion of the patients, that would already be a big, big success. So physicians like pembro. They like IO versus IO and chemo. There have been questions on duration. Actually, we know from various settings that pembro combinations, be it with chemo, be it with cetuximab, actually doesn't result in a survival benefit. Obviously, we are an IO/IO combination.
Our hypothesis is that with such a combination, you can overcome that deficiency that other combinations have shown, and it did not get approved by bringing the pembrolizumab benefit to more patients.
Makes sense. Can you speak a little bit about why pembro, or maybe pembro in combination with HB-200, might provide longer durations than something like cetuximab with chemo or pembro with chemo?
It's hard to say why. I would say the hypothesis is that it's really an IO/IO combination versus other modalities that have proven to not be beneficial for survival.
Got it. OK, that is helpful. And then, yeah, you touched on the randomized pivotal trial you are preparing for. So I was just wondering if you could provide some color on how these preparations are going and any color on the design, the trial design that you guys are thinking about.
Yeah. So we are preparing intensively. We've selected the CRO, we've manufactured the study drug, we've submitted our protocol to the FDA. And we are currently in a very active dialogue with the FDA about a route to licensure. I would say these discussions are going very well. And we'll soon be able to update the market on the exact strategy. The one thing I would like to point out is, if you look at the response I've already mentioned it if you look at CPS-positive patients with a CPS score between one to 19 and the patient group with CPS score 20 and above, you see quite a difference in our study. So we do extraordinarily well in the high CPS group, with response rates in the 60% range. And obviously, that could be a very interesting setting for an accelerated path to licensure.
So that is part of our current discussions.
Got it. So you might see an accelerated path in the CPS over 20 segment specifically, or in both the CPS over 20?
Specifically in the over 20 population.
OK, got it. And that's been part of your FDA dialogue, I assume?
That is part of our dialogue.
Great. OK, that makes sense. And so will the phase III trial, I guess, be powered for these different CPS subgroups? And I'm wondering what other sort of powering assumptions you're thinking about and subgroup analyses you guys have been weighing.
I think that that is the main one, with a very pronounced overall response rate. I think the patient population, to statistically prove that, is quite moderate and doable in a reasonable time frame. I would also want to mention that response in pembro, monotherapy response in HPV-positive subgroup has also been a question. It may be a bit higher than in the entirety. So when we do our powering assumptions, we are on the conservative side. So we've assumed a somewhat higher monotherapy efficacy for pembro for the comparator arm than in the head and neck cancer setting overall.
Great. Yeah, what, I guess, response rate have you assumed? Because that's something we've sort of observed in the literature, too.
Yeah. So we've seen 19% overall that goes to 23% in the high CPS score. There have been subgroups reported of HPV-negative versus HPV-positive, I would say, trending towards 25% response rate for HPV-positive versus more 20%-ish in overall. I think this is directionally what we are thinking about.
Right. OK. And is that from the KEYNOTE randomized trials, or is that from other sort of analyses?
It's mostly from sub-analyses of the various KEYNOTE studies.
Got it. OK. What's the reason why HPV-positive patients maybe have a slightly higher response, too?
To pembrolizumab, I think we can only hypothesize here. The composition is the general health situation may play a role. So you have smoke, alcohol abuse patients that are stronger represented in the HPV-negative segment that may have to do with that. But it could also be the mortality. I think it's not well enough known.
Got it. And how do these patients typically respond to EGFR therapy? And what does that maybe say about the unmet need for this particular segment?
I think that's also a big question at the moment, how do HPV-positive patients respond to EGFR? I think, and I cannot speak about other therapies, I would say, for the specific subgroups of patients where the E6/E7 mutation is an oncogenic driver, I think we see a very strong case for a targeted HPV therapy. I think within the HPV group, you may have subgroups where HPV is actually present but maybe not the driver. And EGFR may be a modality that could be of benefit for those patients as well. But I think we've clearly seen with EGFR modalities that their efficacy is mainly driven by the HPV-negative patient group.
Got it. OK, yeah, that's helpful color. And then for the control arm in the trial, what are you thinking of randomizing against?
Pembrol monotherapy, yeah, plus placebo, of course.
Right. OK, that makes sense. And I guess, it's early, obviously, but maybe you could lay out some of the timing of the trial, when you think you might be able to see preliminary data, when you might be able to file?
It's a bit too early to elaborate on that. All I can say at this point is, given the data, given the strong response rates that we see, it will be a reasonably small patient population so that the trial can be enrolled within a very reasonable time frame.
Got it. By reasonably small, we're thinking like.
Rather, two years rather than four years or something like that.
Got it. OK, that makes sense. And then, yeah, we spoke about the bar, the pembro monotherapy bar in these patients. Something we were looking at was the LEAP-10 study that was presented a week or so ago at the ASTRO Conference. And I think they demonstrated pembro monotherapy efficacy higher than what has been previously demonstrated in an HPV-agnostic population, around 28% overall response rate. I'm just wondering what your sort of thoughts are on that data set, if you think that raises the bar at all for randomizing against pembro or just how you guys are thinking about that.
Yeah. I think with our very pronounced increase in response rates, I would say that 1% or 2% or 3% up or down, still, I think, in a relatively small patient cohort, shouldn't swing the needle too much. But overall, this data is another confirmation of a somewhat increased pembro standalone response rate in HPV. But it's not that in the 30s, not that our 40%+ response rate could be driven by the fact that the patients are only HPV-positive.
Yeah, especially because your response rates are so much higher than that anyway. I understand, yeah. I guess, also based on sort of the LEAP-10 data, we've been thinking a little bit about the correlation between ORR and overall survival. I guess, what do you sort of think about that topic and how overall response rate may or may not be predictive of a survival benefit in this HPV-positive population?
Yeah. I think it's been shown in various instances that adding chemo or EGFR inhibition was not beneficial for survival. I think that is exactly the reason why we think that another modality, another IO modality, helping mechanistically the pembrolizumab mode of action is actually what is needed to translate higher response rates into survival benefit. And that's exactly what we are doing. We know from various instances that one reason why pembrolizumab doesn't work in some patient populations is there is simply not enough T cells around. So that's exactly what we can do. That is a great synergy. And I think, if you have that synergy, we see nothing that would explain why such a combination should not have a strong survival benefit if you see response rates going up.
Sure. Yeah, I think that makes a lot of sense. It's helpful color. And then maybe could you just provide some additional color on your path forward in the second line setting? Because you have some combo data there. There's some monotherapy data there. Just kind of wondering how you're thinking about that opportunity.
So we view the monotherapy data as an important element that gives us confidence in our modality and in the independent contribution of HB-200s. Since we have very strong data in the pembro combination in first line, we do not think that it would make sense to develop a pembro combination also in the second line. We should directly at the first line. For monotherapy, we've shown some nice activity. But we do not think that this could be a monotherapy product. So second line may be interesting in other combinations. We've shown great preclinical data in combining our T cell technology with other immunomodulators. So for those patients that would not respond to the HB-200 pembro combination in first line, I think combining HB-200 with another novel modality immunomodulator could make sense, but not in the pembro combination.
Sure. Yeah, that's interesting. I guess, what are there specific immunomodulators you guys are considering?
We've looked at a variety of things. We've identified a couple of immunomodulators that actually worked great and have a couple of publications out about that.
OK, great. That's helpful. Are you thinking about any indications for HB-200 beyond head and neck?
Absolutely. So there are other HPV-driven cancers. I would say anal cancer is the most attractive one, cervical cancer, penile, vaginal cancer. So there is potential above and beyond head and neck. I would also say that earlier lines of treatment represent a great opportunity, especially for our mode of action, very well tolerated, activating the immune system. So we could prevent recurrence. And that would be a great indication as well. So we view the specific patient population as just the beginning. And from there, we could work to extend the label.
Definitely, yeah. Yeah, so would you be thinking about it in the adjuvant or neoadjuvant setting, or?
Exactly. Exactly. We'll soon do some investigator-led work in that area that gives us some initial data.
How much bigger is that pool of patients relatively to the first line?
Obviously, given that in a huge proportion of patients, surgical removal is quite successful. Those who end up with recurrent or metastatic disease are only like 20%-30% of the totality of diagnosed patients. So this would add the other 70% as a potential patient cohort.
Great. OK, that's interesting, yeah. Definitely sizable. Maybe, yeah, we could turn to some of the other programs. So I know you're expecting an IND for HB-700 and KRAS mutant cancer soon. I guess, yeah, could you provide an update on the status of that and maybe some more color on the program in general?
Yeah, yeah. So we think this is a very attractive program, including five different KRAS mutations targeting a huge proportion of mutations that drive important cancers like lung, colorectal cancer, pancreatic cancer, an attractive product design. The IND filing is imminent. We've announced that. And yeah, you will soon see an update from us on that topic.
OK, great. We'll be looking forward to it. And yeah, maybe could you provide color on how the search for a new partner has been going for HB-700?
So HB-700 has originally been with Roche. The design of the product was done in close collaboration with Roche. Unfortunately, like some other early clinical collaborations, Roche decided for strategic reasons to not continue the program with us. So we gained back the rights. Given that we are focusing our spending at the moment at getting HB-200 to approval, we'll certainly take a slower pace in moving forward with HB-700. And we've also said that we are looking for a new partner. The Roche termination process is still ongoing. Actually, until the end of April, we are still partnered with Roche on that program. But we are ramping up for new partnering discussions.
OK, got it. That makes sense. I think there's also a few other sort of multi-KRAS drugs in development. A private company called Quanta has one. RevMed, obviously, has the pan-RAS. Your program's early. But I'm just kind of wondering if you have any thoughts on how HB700 might be differentiated from these other multi-KRAS drugs.
Yeah. The differentiator is clearly the CD8 T cell responses, the specific CD8 T cells that we are generating that would work nicely in such a modality. We'll provide some preclinical data that we have generated in the Roche collaboration in the second quarter of this year that we think will speak for itself and to the potency of the technology.
Got it. Yeah, in what sort of format might that preclinical data be made public?
Scientific conference, most likely.
OK, makes sense. And then, yeah, moving to the HB-500 program, maybe could you just sort of provide an overview of that asset?
Yeah. So HB-500 in HIV, we are using our replicating vector technology for that. We actually entered into this partnership early on in 2018 with Gilead. We developed our vectors from scratch, including the vast know-how of Gilead on the target antigens in this indication. The program ran through extensive preclinical testing, including non-human primate models that Gilead has available. And it ticked all boxes within Gilead for clinical development. So we have filed the IND. We've cleared the IND. And we will dose the first patient soon in the phase one trial. We are responsible for that phase one trial. And Gilead has the option to take over after phase I.
Got it.
Gilead is funding the entire program.
OK. Are they weighing in on the trial design? Or is that sort of more in your hands?
Of course. Of course, the trial design has been agreed with them.
Got it. And maybe could you provide a little color on what that phase 1 trial design is?
It's a classical phase I in HIV-infected patients. We'll have a control group in the study. Again, we'll provide a bit more update and color on the study design when we announce the first patient dose.
Got it. Which is in the first half, correct?
Which is in the first half.
OK, great. And then the prostate program, the HB-300 program, I believe that was put on pause a few months ago. I guess, could you provide an update on how that's going? And if there's a chance, you might.
Yeah. We've conducted a small phase 1 dose escalation study that has been fully enrolled. But we decided to not enroll more patients and to focus on 200. If more funding would become available or a partnership, we would rank 700, HB-700, as the next program to be progressed. So most likely, HB-300 will continue to be in pausing mode for the foreseeable future.
Got it. OK. That makes sense. I guess, maybe in our last minute or so, returning to the HB-200 program, I think you also provided some immunogenicity data last year in second line. Can you sort of, I guess, summarize that and discuss how that impacted?
Yeah. We can just say our immunogenicity in second line, in first line, it's similar. So you don't see huge differences on how patients react. And I would say it's outstanding. Everyone who's seen the T cell responses is simply impressed by the level of T cells. It's kind of in the 100-fold increase of CD8+ T cells with a very high proportion of patients actually showing a response. So that's the core strength of our technology. And once again, not only in the preclinics, but also in this clinical setting, we've been able to prove this impressive immunogenicity.
Great. OK. Sounds great. Maybe just could you remind us of your cash position and what your runway looks like?
Yeah. We had $117 million in cash at the end of 2023. That corresponds to roughly two years of cash burn when you look back.
OK, great. I think that about takes us to the end. So thank you so much for chatting with me today. It's a great experience. Thank you.
Thank you for the good questions.