All right, let's go ahead and get started. This is the Fireside Chat with HOOKIPA Pharma. My name is Vikram Purohit. I'm one of the bio-tech analysts with the research team. Before we get started, just need to read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, very happy to have Jörn and Katia here with me from HOOKIPA Pharma. Appreciate it. Thank you so much for your time.
Thank you.
Before we get in any pipeline specifics, Jörn, maybe you could just provide a brief overview of Hookipa's platform, the technology, and kind of where the pipeline sits right now.
Yeah. HOOKIPA has a very elegant technology, and that's based off of the idea that, for cancer cell killing, what is essential is T cells, antigen-specific T cells that come to the tumor and, and start the killing process. Our technology is able to drive unprecedented levels of T cells, incomparable, we don't see anybody else who does this, in a systemic in-vivo manner and, and with a, with an off-the-shelf product. The way we're doing this is we're engineering an antigen into a virus that has natural propensity to infect dendritic cells and kick off, supercharge, we say, the activation and expansion of antigen-specific T cells that then go and, and find the tumor.
It's interesting because that's a natural process that gets kicked off, and the T cells will go and find tumor cells no matter whether that's a primary tumor or metastasis. So this technology is proven to work. We can show in animals that against oncoviral targets and also against self-antigens, we drive these high levels of T cells, up to 50% or every second T cells from the body is turned antigen-specific. And we have proven that this technology also translates to human.
Mm-hmm.
So in HPV-16 positive cancer patients, we've shown safety in 130 patients. We've shown that the T cell mechanism drives the same levels of T cells that we've seen in animals. We've seen monotherapy biological activity that translates into better and longer median overall survival compared to pembrolizumab or nivolumab. And lastly, we've doubled in combination of our drug HB-200 in HPV positive head and neck cancers. We've doubled the objective response rates that pembro would have alone when we combine HB-200 with pembro. So a strong technology platform, and, and a, a program which at this point in time has proven in the totality of data that it's worth taking to pivotal trial.
Got it.
We have two more clinical programs. We have Gilead and Roche as partners, and we have $166 million committed dollars for developing our pipeline.
Great. That's a great in, introduction, so thank you. Thank you for that. Maybe from there, let's just go into straight, straight into a discussion on the pipeline then. HB-200, just give us a quick summary of where does that development program stand right now, and also recap for us some data you presented recently, that seems to have given you a lot of conviction in the next steps for this program.
Yeah. So we went through a phase I/II study, dose finding and dose escalation, and then the phase 2 portion of the trial. At this point in time, we have shown and released data on a subset of patients. We're expanding, maturing this and are at the point where we're deciding how to progress it into the next stage, which is a pivotal trial. I'll let Katia comment on this more-
Yeah.
also on the data.
Yes. So during the first part of the study, during the phase I, we did dose escalation and establish HB-200 as monotherapy activity by itself, basically. We are following this initial cohort of patients who received HB-200 in monotherapy and looking at additional endpoints for efficacy. So now we're looking mainly at median overall survival. We already observed objective responses and stable disease for more than six months in some of the patients. So it was very encouraging to see monotherapy activity just for our product on its own. Now we are in the second part of the study, as Jörn said, and we decided in that second part to go earlier in the line of treatment and to really focus on patients with head and neck squamous cell carcinoma, and look at the combination with pembrolizumab in the first-line setting.
Pembrolizumab is the standard of care, and as Jörn said, what we started to see in the initial cohorts that we discussed in June is that an objective response rate, looking at confirmed response in those patients, of 43%. And that compares well with the data from the pivotal trial from pembrolizumab, where the objective response rate is between 19% and 23%. We're continuing to follow those patients as well, looking at median progression-free survival and median OS, and as we said in June, those endpoints are not reached. And that the reason why we're turning back to the phase one data in monotherapy is to look at endpoints like median OS that are starting to pop out.
What we saw is that in monotherapy with HB-200, there is a clinical benefit provided, not necessarily at the level of objective response rate of stable disease or, or more likely in addition, with a median OS that is extended compared to the second-line plus standard of care pembrolizumab. You know, in checkpoint inhibitor naive patients, so in checkpoint inhibitor-experienced patients, we see a median overall survival of 14.2 months, which compares very well to the eight to nine months found with pembrolizumab. And, you know, this is important because those patients are heavily pretreated, received 3-11 prior treatment. So this is really encouraging. There's no standard of care in second-line plus for those patients, so the standard of care in first-line and no standard of care afterwards.
The ability to see this clinical benefit in monotherapy permits us to think that this clinical benefit will translate in the first-line setting in combination with pembrolizumab.
Understood.
We're starting the pivotal trial sometime in Q2 2024.
Okay.
We're preparing for it and looking forward and think that this is a very good decision based on the totality of evidence. As just said, the combination monotherapy, survival benefit, T cell, robust T cell technology platform and safety.
Great. I think one question some people have had is: how to think about response rates versus durability, for the data set that you just recently had presented. How would you guide people on how to think about the importance of durability, and at what point might you have a data set that speaks to the durability response as well?
Yes. So, it's really important because objective response rate, coupled with duration of response, could be endpoint for accelerated approval.
Mm-hmm.
So a lot of people look at that, obviously. For those patients with head and neck squamous cell carcinoma, pembrolizumab, and the reason why it's used compared to chemotherapy, is that there is a long duration of response of 22-24 months, so almost two years. So as you can imagine with our cohort, we're very excited about that, but we still need to continue to follow our patients for many additional months for that. But that's the reason why those patients, you know, when they are at the metastatic and recurrent stage, are treated with pembrolizumab monotherapy. And this is the reason why we want to combine with pembro monotherapy rather than pembro chemo or chemo, where the duration of response is much less.
So what oncologists do, who treat patients with head and neck, they put first the patient on pembrolizumab, and for those who respond, there is a potential large benefit. So same for the combination. The idea is that if we can show with the combination, that we can extend much beyond chemotherapy, basically, pembro plus HB-200 will become the standard of care, and, and there will be no chemotherapy for those patients.
I see. I see. Okay, that's interesting. In terms of commercial opportunity, just based on the pivotal program you plan to start second quarter of next year, you know, roughly how many patients do you think that maps to?
Yes.
From, like, a label perspective.
So, first of all, head and neck cancer, high unmet need, about 950,000 patients around the world, new cases per year. And of those, 470,000 will die every year across the world. When you narrow it to our findings, it's about 98,000 patients per year, and of those, about 60,000 patients are HPV-16 positive. So, a really important market potential for blockbuster. Also no treatment for those patients that is HPV-16 specific. So really important to distinguish ourselves from more general treatment like checkpoint inhibitor and have a targeted therapy that can really help those patients in a very specific way. Yes, go ahead.
So Katia now talked about oropharyngeal-
Mm-hmm.
- but HPV-16 positive infections also cause other cancers.
Mm-hmm.
The opportunity obviously expands if you look at vaginal, anal, penile, cervical cancer, that could also be HPV-16 positive. Our trial currently is for metastatic, recurrent metastatic patients.
Mm-hmm.
You could see a vaccine approach like ours to be used, prior to patients becoming metastatic when they have ctDNA measurable in the blood. Or you could even think of neoadjuvant treatments before surgery to debulk or similar things. So I think the potential for HPV-16 positive cancers in total, beyond what we're doing directly, could have several billion-dollar revenues.
Got it. And then on that point, how do you think about indication expansion potentially for additional HPV-16 positive tumor types? Is that something that you're actively considering internally or not?
Oh, yes. I mean, considering, yes, because the rationale is very clear, that the antigens are clear. E6/E7 are linked, and only tumor cells have them, so it's a very specific treatment. And with these incredible T cell responses that we can generate, we could potentially be used in a platform approach, if you want, in all these different organs. At this point in time, HOOKIPA as a company, and given the state of capital markets, despite $166 million committed cash, we will be focusing on a trial that gets us an approval, potentially with an accelerated approval on the way for metastatic recurrent patients, HPV-16 positive oropharyngeal. Yeah, and once we see capital markets give us more money, we can expand that.
We could also think of partnering opportunities, because for a big pharma company, it would be less difficult to have the capital available to follow all the opportunities that you have with this drug.
Sure. If you were to look into potentially partnering HB-200, I mean, in addition to capital, what capabilities or what sort of know-how would be interesting to bring in from a partner? And what else would you be looking for besides capital in when you're evaluating partnerships?
Yeah, I think it is capital, and it would be the ability to really go broad. Have a broad development program with multiple programs running at the same time. I think we have evidence enough today that we can take this forward, and not just in recurrent oropharyngeal, but also other areas, but it would require that support.
Got it. Okay. Maybe then we can pivot on to additional parts of the pipeline beyond HB-200. Maybe first we can discuss the prostate program. Just, kind of recap for us what you've seen there pre-clinically, what gives you conviction in this program, and, you know, what success here could, could open up for the arenavirus platform?
Yeah. I'd cut to talk about data and what we've done in terms of experiments, but it's important to note that there is a drug, Provenge, produced by originally Dendreon, and that was a dendritic ex vivo dendritic cell vaccine.
Mm-hmm.
So they took dendritic cells out, manipulated them, put them back in, and drove T cell responses with an antigen load. This drug still sells and provides a benefit to patients. The responses in terms of T cell responses they saw are a magnitude smaller than what we can produce in-vivo. So we have the more elegant technology in-vivo, not extraction and manipulation outside-
Mm-hmm.
But just driving the system. And we have some degree of biological activity here. So that's point number one. The second point that's critically important in this program, and this is why it's something that will come, become available to investors relatively soon, it's the question of can we repeat what we've seen in animals, which is similar T cell responses to self-antigens.
Mm-hmm.
Yeah, so we have a preclinical, we've seen up to 50% of T cells in oncovirus targets become antigen specific. We've seen the same with self-antigens, and if we could repeat that in the clinic, would be fantastic, 'cause it would open up for lots of different self-antigens.
Right.
We are currently running that trial. It's a phase I, dose escalation, trial, and by Q1 of next year, we will have the first group of patients that will show safety and immunogenicity. If we're seeing immunogenicity, that would be proof that we are breaking central tolerance, which would be fantastic.
Great. Great.
So, to elaborate a little bit about what we saw in the preclinical model-
Mm-hmm.
is that we saw the same level of T cells induced towards murine self-antigen than the model that we use for HPV-16. In addition to that, we know that in human we see the same level of T cells in the murine model, so by transitivity, we assume that we will be able to see that level of T cells also in prostate cancer. This is super important, and coming back to exactly what John was saying about the specificity, we are different because we induce tumor-specific CD8 T cells. We're not just relieving the brake. And we know that checkpoint inhibitor have recently failed, you know, in monotherapy or in combination in that setting. So we believe that really inducing this very high level of CD8 T cells will permit to attack better issue like the tumor.
Got it. Okay, great. So 1Q24 is the initial data set for that, for that program?
Yes.
Safety, immunogenicity. Have you guided to how many patients worth of data this might be?
Two handful.
Okay. Got it. Great. Maybe let's just keep digging through the pipeline then. You also have a KRAS program-
Mm-hmm.
partnered with Roche.
Yeah.
Just, kind of give us a recap on how that program came to be, how your partnership is structured with Roche?
Yeah.
and what some next steps there are.
Yeah. So, two reasons we understand why Roche liked this program. One is, again, the high levels of T cells that we can drive, and they were interested in that in the first place. The second is in designing our vector system, we chose to pick the five most prevalent mutations of KRAS that are implicated in three indications: lung, colon, and pancreas. So it's a pan-KRAS approach with the five most prevalent mutations packaged into our viral vector. Commercially, the advantage of this is you have one product, systemic, in-vivo, off the shelf, for three different indications whenever those indications are combined or linked to KRAS mutations. So they like this approach. We closed the deal with them, which has a totality of bio dollars of up to roughly $1 billion, and it started off at target.
There is an option for a second program. It's undisclosed what antigen that is. So the first one is KRAS, and in 2024, they should be in a position to decide on the second program.
Okay.
At this point in time, we're working preclinically. We have initiated the program at proof of concept in animals, and we're currently translating into clinical trial. In the second half of 2024, we will have the start of the clinical trial, phase I, with Roche, and we're responsible to take it to the end of phase I-B.
Got it. Okay, so you're starting the phase one study-
In twenty-four.
Second half of next year. Yeah. Got it. And then in terms of economics and what this could all mean from a top-line perspective for HOOKIPA?
Yeah. So we have not guided and cannot guide to any-
Got it
revenues. The proceeds from milestones are more than covering the costs that we have to take the program forward. The phase I is a cost share between Roche and us.
Mm-hmm.
And again, for us, it's cash positive. And, and there is a significant payment to be expected, at IND, so next year, a, a material payment. And the next, sort of very big payment is going to be at handover after phase Ib, when Roche exercises the option to take it into phase 2.
Okay. Got it. That's helpful. Let's talk about your partnership with Gilead, both HBV and HIV. So maybe a couple of questions there. First, what are the current terms of the Gilead partnership? How are the economics split, and then where does each of these programs currently stand? Let's start there.
Yeah. So first of all, it's an important question, because why Gilead?
Mm-hmm.
It's because we decided some time back that we did not want to invest our own dollars into infectious diseases, but the technology works just the same. Now, in HIV, you need to kill HIV-infected cells, and it's the T cells that do it. Gilead saw our technology and the incredible amount of T cells that we can drive and decided that they wanted to go into two programs for functional cure. One is functional cure for HBV, the other one is HIV. And we have started working with them and have basically had them cover the entire cost of development from the first moment on. We didn't have to spend a single dollar. They gave us the money we needed to take things forward.
Now, we will have, on the HBV program, $190 million in pre-commercial, commercial milestones and double-digit royalties, up to, and we have $240 million in the HIV program in milestones.
Mm-hmm.
Plus, mid-single to low double-digit royalties on the HIV program. The first one, HBV, went in the clinic this year in Q2. It will most likely have sufficient data to decide to go into phase two in 2024. Again, 2024-
Mm-hmm.
is a big milestone-rich year for us. And so far, the collaboration has worked well, and things have progressed well, and we know that recruitment works, so things are on track. The HIV program is a little different. They paid for it. They gave us an equity drawdown facility to support payments for it. We're taking it to the end of phase I-B.
Mm-hmm.
At this point in time, we're working hard on getting the IND ready at the end of Q3, beginning of Q4, to be able to start a clinical trial for the HIV program in 2024, in the first half.
Okay.
So now looking at the totality of our pipeline, HBV, HB-200 will get pivotal. HB-300 will have a big readout, phase I.
Mm-hmm.
HBV will have a good readout in phase I. The HIV program will start in the clinic, and the HB-700 KRAS program will also start the clinic. So go to 2024, and we will have five programs in clinical trials.
The HBV data, just kind of, any guidance you have on how to interpret that data set, what you're looking to establish from the initial data there?
It will be safety and immunogenicity data.
Okay.
And what they're trying to do is they went through an extensive program of testing in non-human primates, and they would like to show that these levels of T cells are important. Now, both HBV and HIV are cocktail drugs, so it's not just the vaccine. The vaccine is a key component because it does the killing of infected cells. But in HIV, for example, you have to wake the cells up. There's a dormant reservoir that... And that's a different drug. And there's one that could increase still the activity of T cells. So it's going to be, in totality, probably-
Mm-hmm
... the three different agents that they're putting together. So what they need to see at this point in time is immunogenicity. Can we provide the T cells that then actually do the killing? And we will see that initially from the HBV program in 2024.
Got it.
For HIV, it's going to be 25.
Got it. So definitely early days for the HIV program, but just based on what you know so far about the science, about the mechanism, what do you think the future use could be, and kind of where do you think, theoretically, this kind of treatment could fall within the HIV kind of treatment options that are currently out there?
It's a functional cure.
Yes, exactly. So the idea here is for patients who have completely the virus completely eradicated just using the natural defenses, et cetera. But I think a combination also will be important, and this is what Gilead is working on, is finding the different components of a combination.
Mm-hmm.
that could achieve HIV cure for patients, for individuals living with HIV.
Got it. Okay, great. If more broadly, when we look at your pipeline over the next kind of 6-12 months, as you pointed out, quite a few catalysts from a data flow perspective, from just moving trials forward, blocking and tackling with your current programs. But is there scope, you think, to fuel more R&D productivity and nominate more programs within your pipeline? Or do you think you're currently kind of more in execution phase with what you currently have?
We have gotten permission by the FDA to use what's called a Drug Master File. That's the ability to basically piggyback on previous data that you have had in the context of other programs earlier.
Mm-hmm.
And not have to go back into bio-distribution and tox studies in animals, and you can accelerate the process to a new drug. The reason why you can do this is because we're using the same vector, and the testing around the vector has been done with one antigen. We're exchanging the antigen, but the virus remains the same, and the safety properties are the same as well, and that could help us reduce the time. So, at this point in time, I think that's a very interesting indicator for us to be able to increase efficiency in using this novel arenavirus technology to drive more programs.
Obviously, given capital markets and the current state, we do some preclinical work, but we won't be able to expand massively at this point in time. We could do partnerships.
Mm-hmm. Okay, got it. Maybe that's a good segue into my final question for you. To summarize for us, kind of your current cash balance, you've alluded to it already, but where does it currently stand? How far of a run rate does that provide? And what are all the things that are contemplated in that guidance? And is there any flex in that guidance? Could it change based on how certain programs progress throughout the course of the next year?
Yeah. So the first message is, we've been able to fund the company even in the worst of capital market times. One was in March this year and last year, and in June this year and March of last year. So we have very strong backing from some important investors that we're very happy about, that they are supporting us. That has given us a cash position committed to $166 million by the end of June. This, in principle, depending on management decision and success, will take us through 2025.
Okay.
Being, quote, "overly," successful, would mean we would spend more, which is a decision that would have to be prudently taking, taken. Reducing the pace at which we're driving into the phase 2, phase 3 of our HB-300 program could reduce the spend and allow us to go longer. So yes, could we be flexible about spending? Mm-hmm. Our business plan currently looks at us driving the 24 milestones-
Mm-hmm.
getting some initial data from 204, we call it, the pivotal study, and with this in the business plan, run until sort of second half of 2025.
Got it. And to clarify, are there any sort of partnership milestones contemplated in the guidance or?
There are milestones that we're receiving, like the IND in the KRAS program.
Mm-hmm.
We have incorporated into that cash runway.
Got it. Great. Great. And with that, we're actually right at about time, so let's go ahead and close out there. Jörn , Katia, thank you so much. Really appreciate it. Thanks for doing this, and yeah, let's go ahead and close out. Thanks.
Thank you, Vikram.
Thank you.
Thank you so much.