Good morning, and thank you for joining the HOOKIPA Pharma Conference Call, announcing the preliminary data from its HB-200 clinical trial. The slide deck that accompanies today's webcast is also available in the Events section of the HOOKIPA website. During today's call, management will be making certain forward-looking statements. These statements may include statements regarding, among other things, the efficacy, safety, and intended utilization of investigational agents, our clinical and non-clinical plans, our plan to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development, and possible intended use of cash and investments. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause the actual events to differ materially from those contained in the forward-looking statements.
These and other risks are described in our periodic filings made with the SEC, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date. The company disclaims any obligation to update such statements. I'd now like to pass the presentation over to Jörn Aldag, Chief Executive Officer of HOOKIPA Pharma.
Data on HB-200 for HPV positive head and neck squamous cell carcinoma. I'm Jörn Aldag, the Chief Executive Officer of HOOKIPA, participating in this webinar are my colleagues, Dr. Katia Schlienger, Chief Medical Officer. Am I on mute?
You are not. Please go ahead.
With me, participating in this webinar are Katia Schlienger, Chief Medical Officer, Klaus Orlinger, Chief Scientific Officer, and Reinhard Kandera, Chief Financial Officer. We're delighted that after our presentation, Dr. Alan Ho, an associate attending physician at Memorial Sloan Kettering Cancer Center and a study investigator, will share his views on the HPV head and neck cancer landscape. After this session, you will have an opportunity to ask questions that the team will then answer. We're really excited to present our clinical results today and our development plans for our lead program, HB-200, for recurrent metastatic HPV 16-positive head and neck squamous cell carcinoma. HPV-positive cancers are difficult to treat disease and remain a significant unmet medical need with poor survival.
This is why we're super pleased that the totality of the data we generated positions us well to prepare for a potentially registrational trial in the first line in combination with pembrolizumab. These HB-200 data are the core of our presentation today. They are an endorsement for our lead program in head and neck cancers, and they are a validation for our novel arenavirus technology platform, based on which we are building a rich, owned and partnered pipeline. Just to remind you on that before we go into the HB-200 data, our second oncology program, HP-300 , to treat prostate cancer, started a phase I trial in Q1 2023. We expect to release data from the trial in H1 2024.
HB-700 is an oncology program targeting several of the most prevalent KRAS mutations and could become a single injectable, off-the-shelf product for lung, pancreatic, and colon cancer. It is partnered with Roche in a deal worth almost $1 billion and is expected to move to the clinic in 2024. Our infectious disease programs, partnered with Gilead, are also progressing well. A clinical trial for a functional cure for HPV-infected patients is underway since Q1 2023, and we expect data from this phase I trial in 2024. We expect to file an IND for our HIV functional cure program in HIV this year and expect to start the phase I trial in 2024.
In summary, there will be 5 HOOKIPA programs based on arenavirus in the clinic in 2024, 3 of which are partnered with top pharmaceutical companies in their field and 2 of which are wholly owned by HOOKIPA. All our pipeline programs will lead to a significant number of value catalysts over the next 18 months. Let's go to the HB-200 data. With our HB-200 development program, we addressed several fundamental questions that are important to be answered before starting a pivotal trial. Safety. Does the drug actually deliver the expected T-cell biology? Is HB-200 active as a monotherapy, which is critical for, from our perspective, to show the contribution of goods? Is the combination of HB-200 with pembrolizumab in combination stronger than pembrolizumab alone? The answer is very clear, and the totality of this data is important.
HP-two hundred and pembrolizumab combined double the objective response rates published in the KEYNOTE-048 study. Objective response rate is 43% versus pembrolizumab of 19%. This is what we prior to delivering this data, called the case of success. We're also very proud that our agent delivers clinical responses in monotherapy. Second, third generation immunotherapies, in most cases, don't do this in CPI-resistant patients, and we're showing monotherapy with a duration median overall survival of 14.2 months in the intent to treat population. The T-cell biology shows unprecedented tumor-specific CD8 T-cells, which infiltrate the tumors, and we will see later in the presentation that this is associated with clinical benefit.
Lastly, and importantly, we have a very favorable safety profile that we've built over 130 patients who've been treated with HB-200 in monotherapy and in combination. All of this bodes well for preparations for pivotal first-line head and neck squamous cell carcinoma trial. There are, in addition to this, other opportunities that we're exploring that Katya will talk about in her presentation later on. With this, I will pass over to the discussion of the clinical trials. In this presentation here, you will see data from 3 cohorts. The first that Katya will be talking about is the first line in combination with pembrolizumab, our phase II portion of the trial. The second cohort is the second to seventh line patients, in also phase II pembrolizumab. This is second line and beyond.
The third cohort is an update on monotherapy data, from previous data that we've shown, where we're focusing on median overall survival. I will pass over to Katia at this point for a more detailed discussion of our data.
Yes. We will first present the cohort of patients who received HB-200 plus pembrolizumab in the first-line setting. Next slide. For the first time, we're presenting here the objective response rate for the cohort of patients with HPV 16 PD-L1 positive head and neck squamous cell carcinoma, who received HB-200 plus pembrolizumab in the first-line setting. We had 15 patients with at least 3 months of follow-up, and 14 patients were evaluable with at least 2 imaging assessments. All patients were CPI naive. The response was evaluated by RECIST 1.1 by investigator assessment as a primary objective of the phase II part of our study. 6 patients developed a confirmed response, 5 patients developed a confirmed PR, and 1 patient developed a confirmed complete response.
The disease control rate is 71%, including now patients with stable disease. This compares well with the data obtained in KEYNOTE-048 for the current standard of care of pembrolizumab in monotherapy. The star depicts the patients who are still on treatment in our study, and you can see on the x-axis, the PD-L1 CPS scores for each of those patients. In blue are the patients who responded, who had stable disease, best response of stable disease, and in red are the patients who progressed. Next slide. We now looked at the response in 2 dimensions. Not only the change in the sum of diameter, but also the response over time. The black arrows indicate patients who are still on treatment.
With almost 6 months of follow-up, currently, the median OS and median PFS is unreached or are unreached in this cohort. We can see that some patients are continuing with a confirmed partial response over time, some at 9 months, 10 months. We can see also two type of kinetic of response. Some patients are responding at the first imaging assessment, and some patients stay on stable disease and then start a shrinkage of the of that tumor, who eventually can convert in a partial response. On the next 2 slides, we will show 2 study cases with these different kinetics. Next slide. This patient was a patient with a low CPS score, HPV 16 positive oropharynx cancer with a CPS of 1.
This patient was refractory to platinum-based chemo radiation for his local disease treatment, a particularly bad prognosis for that patient. The patient developed a partial response in his 2 lung mets at 5 months into treatment. This response was confirmed, and you can see that even one of the lesions completely disappeared. This patient is continuing treatment in our study at 10 months. The next patient number 2, is a patient also with HPV 16 oropharynx cancer with a CPS of 86, treated in the first-line setting. This patient developed a rapid response at 6 weeks into treatment, and that response was confirmed at the next scan and is ongoing treatment at 4.5 months. Next slide....
Now we will focus on the cohort of patients who received pembrolizumab plus HB-200 in the 2nd-line plus study. Next slide. In the 2nd-line plus study, we enrolled 15 patients heavily pretreated, and it was their 2nd to 7th line of treatment in our study. 5 patients were evaluable by RECIST 1.1, with at least 2 imaging assessments. 1 patient developed a confirmed PR, and 3 patients had the best response of stable disease. In this small initial cohort, the median PFS was 5.3 months, which is encouraging comparing to the 2nd-line plus median PFS for checkpoint inhibitor at 2.1 months. Next slide. Now we will focus on the 3rd cohort, which is the initial cohort of patients who received HB-200 monotherapy during dose escalation.
On the swimmer plot, you can see in dark blue the times those patients were on our study, and in light blue, the follow-up for this patient for median overall survival. In these 11 patients treated with HB-200 in monotherapy, the preliminary median OS is 14.2 months in the intent to treat population, means in all patients who received at least one dose. In patients who were evaluable, the median OS was not reached. This compares well with the median OS observed in the 2nd-line plus setting with checkpoint inhibitor of 8-9 months. Next slide. Here we present 2 cases of a patient treated with HB-200 in monotherapy. The first patient on the top had a lung metastasis who progressed on pembrolizumab plus lenvatinib, which was his first-line treatment.
After 5 months into our study, the patient developed a partial response of -33%, which was confirmed twice. Of note, the patient progressed on 3 scans before starting treatment on our study. The patient discontinued treatment at 8 months, had surgical resection of the remnant of his lesion, had no residual tumor, and is ongoing long-term follow-up with still no residual tumor and no subsequent treatment. The second patient is a patient who had received 4 prior line of treatment, including chemotherapy and checkpoint inhibitor. He developed a near PR in his 3 lung mets, and one of them is represented here, and the nodule he had in the spleen.
Pretty quickly, after 2.6 months, the patient stayed on treatment and he developed a near PR, -29%, never reached the PR status and stayed on our study for 11 months, after which he progressed. As per protocol and upon signing an additional consent, patient could have pembrolizumab added to our HB-200 vector, and that is what happened for that patient. This patient is continuing on treatment at 20 months in our study with a combination of HB-200 plus pembrolizumab. Next slide. Now I will pass on the floor to Klaus Orlinger to describe the functional T-cell response associated with clinical benefits in a patient who received HB-200 in monotherapy.
Thank you, Katia. The goal of the biomarker work is to link the clinical benefit presented before, to the mode of action of our therapy. As a reminder, the mode of action of HB-200 is induction of tumor-specific T-cells, migration and infiltration thereof in the tumor, followed by killing of tumor cells by infiltrated CD8 T-cells. This slide shows induction of systemic T-cells induced by HB-200 as a monotherapy without confounding factors of a combination drug. Importantly, similar results were observed in the combination with pembrolizumab. The left graph indicates a more than 170-fold median increase of tumor-specific T-cells in patients treated with HB-200, and that is ranging up to more than 1,200-fold.
On the right side of the slide, you see the percentage of tumor-specific CD8 T-cells in the blood of these patients. At baseline, when patients come on trial, we can hardly measure any tumor-specific CD8 T-cells, but those get elevated massively and can reach up to 48% of all CD8 T-cells, which means that in this specific patient, almost every second CD8 T-cell is specific for the tumor. It is, however, important that these responses are not only transient, but durable and functional, and that is shown on the next slide. Shown here on the top graph is the durability of tumor-specific T-cells throughout the therapy. The blue line indicates the median tumor-specific T-cell level of patients in the HB-200 monotherapy, measured by ELISpot methods.
Responses come up early as the treatment start and remain at high levels throughout the therapy for many months. Below, in the pie charts, an analysis of the functionality of these tumor-specific T-cells at various time points throughout this treatment is shown. While the functionality of T-cells is a critical determinant for immunological control of tumors. We did observe the tumor-specific T-cells increase in polyfunctionality throughout the treatment, which is indicated by the blue areas in the pie charts. In short, we observed rapid induction of high levels of tumor-specific T-cells that are durable and not exhausted, but increase in their functionality during the treatment. This analysis shows tumor-specific T-cells in blood, and it is, of course, important that we can drive these T-cells into the tumors of our patients, and that's shown on the next slide.
Shown here is an analysis of all paired tumor biopsies from patients treated in the HB-200, in the monotherapy cohorts, indicating the perecentage of T-cell levels in tumors of patients upon therapy. The analysis showed that we could elevate T-cell levels in tumors of multiple patients, as shown on the right side of this graph. For those, where T-cells were elevated, a clinical benefit in terms of disease control or stable disease is typically observed. This indicates an association of the induction of tumor-specific T-cells by HB-200, in the clinical benefit, of our patients. Next slide, please. With that, I would hand back to Katia to walk you through the safety database of the HB-200 therapy.
Yes. We will now go over the safety profile of HB-200, now assessed in more than 130 patients. This table presents a favorable safety and tolerability of HB-200, administered either in monotherapy or in combination with pembrolizumab in more than 130 patients. The serious adverse event related to study treatment were reported in 7% of patients in our study. Most importantly, the discontinuation of dose reduction due to treatment-related adverse event occurred in only 2% of the patients, which is important because it means that most of the patients will stay on treatment to be able to benefit from treatment as long as possible.
Another point is that this favorable safety and tolerability profile of HB-200 in monotherapy or in combination with pembrolizumab, permits us to think that it will allow combination with other immunotherapy or other treatment that would benefit from the induction, specifically of tumor-specific CD8 T-cells. Next slide. You know, we've went over the combination data in first line for HB-200 plus pembrolizumab, with a doubling of the objective response rate, the activity in second-line plus in combination with pembro or in monotherapy, and also we saw functional T-cells associated with clinical benefit. We have a favorable safety and tolerability profile in more than 130 patients, and now we are preparing a randomized trial in the first line setting with registration in that.
As you can see here, in green, this is our plan for 2024. We will prepare a randomized trial in the first-line setting of HB-200 plus pembrolizumab versus pembrolizumab. We have received Fast Track designation by the FDA, and we have a Merck collaboration with a supply agreement for pembrolizumab. The FDA has reviewed already the study design for this study. That's, you know, based on the data for the first-line cohort. For the second-line setting, alone or in combination, we would like to have the data mature a bit more, with more patients enrolled in second-line plus in combination with pembrolizumab and continuing to accrue data in terms of duration of response for those patients and for the patients that have received HB-200 monotherapy.
In 2024, we will decide, based on the maturation of this data, if we would like to pursue a registrational path for the 2nd-line plus setting, either in monotherapy or in combination with pembrolizumab. We also are looking at other combination, such as cytokines based treatment. We have also some small signal searching study ongoing in the local disease setting. We have phase 0 and a neoadjuvant study, which we intend to report later this year. We have also a planned adjuvant study in patients with high risk of developing recurrent or metastatic disease. Next slide.
We're coming to the conclusion here. We're very proud of the data that we've generated, and it's in essence, the totality of the data that support progression into pivotal study. Doubling the response rate is what is widely known in the industry as something that you would call success. We don't think that doubling the objective response rate comes as a surprise, if you consider that HB-200 is clinically active alone as a monotherapy with a long duration of effect.
Also HB-200, proof and validation of our T-cell biology, of being able to drive incomparable T-cell levels of antigen-specific T-cells, is helping us to get these terrific responses that we've seen in patients with head and neck squamous cell carcinoma. The safety profile, obviously, is important, and with this, as Katia said, we are now moving forward into the pivotal first-line treatment of head and neck squamous cell carcinoma in a clinical trial. We're continuing to recruit patients in our current study, and we're starting in parallel, we're preparing the pivotal trials for going forward. This concludes the presentation. With that, I am very pleased and delighted that Katia is joined by Dr. Ho. Dr. Ho is a study investigator with whom we're working closely. He is the associate attending physician at Memorial Sloan Kettering Cancer Center, and he will discuss with Katia his views on the HPV positive head and neck cancer landscape. Katia.
Yes. Dr. Alan Ho is a medical oncologist who specializes in the treatment of head and neck malignancy at Memorial in New York. Welcome, Dr. Ho. We just heard the results of our phase I/II study of HB-200 plus pembrolizumab in patients with HPV 16 head and neck cancer. To put this data into context, I have prepared four questions that I would like to discuss with you. First, can you tell us more about the current standard of care for patients with head and neck squamous cell carcinoma, specifically in the first line setting, and is there an opportunity for improvement?
Yeah. You know, thank you so much for having me and for the invitation to be with you here today. KEYNOTE-048 was the phase III trial that established the new first-line standard for head neck cancer patients to be either, you know, pembrolizumab alone or with chemotherapy, regardless of HPV status. This integration of immunotherapy into head neck cancer management has certainly been a paradigm-shifting development for our patients because of the opportunity to have unprecedented depth and duration of responses with these agents. The most recent report really showing that the median duration of pembrolizumab response for patients with PD-L1 positive disease can be about 2 years. The continuing challenge is really that these immune-based responses are just not being achieved in enough of our head neck cancer patients.
The response rate with pembrolizumab alone in KEYNOTE-048 was only about 20%, and even lower for patients who had low PD-L1 immunohistochemistry scores. In fact, over a third of patients on the trial with pembrolizumab alone had progression of disease as best response. Because of this, in many clinical scenarios, many of our practitioners are still giving pembrolizumab with chemotherapy, which was associated with a higher response rate and a survival benefit over the prior standards, as a way to hedge against the higher rates of progression that can also be seen with pembrolizumab alone, despite exposing patients to the toxicities of chemotherapy. The other thing to point out is that the median duration response with chemotherapy plus pembrolizumab is also quite short.
It was only about 7 months, raising questions about how much the chemo was actually adding or contributing to immune-based responses with pembrolizumab, while certainly associated with more toxicity. The unmet need here is really developing novel combinations with pembrolizumab that expand the benefit of immune-based responses for our patients, to a higher percentage of our head neck cancer patients, while preserving a favorable adverse event profile that's all commonly associated with immunotherapy combinations. In this context, the data just shared in the first-line setting with HB-200 and pembrolizumab is very encouraging, you know, albeit in a small cohort of patients.
Thank you. Do you think also that showing monotherapy activity for immunotherapy is important in the context of those patients?
Yeah, you know, I think what KEYNOTE-048 demonstrates is that for immunotherapy to be more effective for head neck cancer patients, this will have to be done with combinations. In that context, observing monotherapy activity is important so that we know how each of the components in future combinations are really contributing to efficacy observed. Yeah, you know, I was very encouraged by the data generated with HB-200 along both the biologic observation, that you can really induce strong tumor-directed T-cell responses, and now the preliminary efficacy data showing that HB-200 alone can induce regressions in some patients, and maybe even in that small cohort, have a long duration, a long survival benefit as well. So yes, very, very helpful to see that and very encouraging to see that.
A third question is that why do you think that a combination of immunotherapy may be important for patients? How does the combination data presented today fit into that setting? You are touching a little bit on that, in your last response, but moving, if you like, in the field from combination with chemo to combination with immunotherapies.
I think in terms of immune checkpoint blockade, you know, pembrolizumab and PD-1 targeting has been the most successful. As I mentioned in response to the first question, the response rates to pembrolizumab alone are simply not good enough. It doesn't make those immune-based responses more accessible enough for our head neck cancer patients. We really need the combinations to enhance that benefit. The significant focus and interest in the field, and certainly the preference of our patients, is to develop these combinations to make immune-based responses more accessible to patients, but also avoiding the toxicities of chemotherapy, which are still integral parts of standard of care right now.
Observing that HB-200 plus pembrolizumab is highly tolerable in the patients that we've treated, I'm extremely encouraged by, you know, the response rate, the response data shared, and the early suggestion that these responses may be quite durable, albeit in a small sample size and needing more follow-up. I think at minimum, what this shows is that HB-200 plus pembrolizumab should be further evaluated in larger cohort patients in a first-line setting, and I think it certainly warrants moving forward with it.
Thank you. Data presented today are in patient with HPV 16 oropharyngeal, head and neck cancer. Given the targeted nature of HP-200, specifically in an HPV 16 driven disease, what are your expectations for applicability in other HPV 16-driven cancers?
Yeah. I think the HB-200 head and neck cancer data, first and foremost, you know, is a very important proof of principle that these agents can induce strong T-cell responses against the E6 and E7, the HPV antigens that are expressed in HPV 16 positive tumors, and that those, that biologic outcome can really contribute to immunotherapy-based responses. You know, given that other HPV 16 driven cancers likely still have persistent expression of E6, E7, I think it's reasonable to extrapolate and say that these agents should be tested and may have efficacy against those malignancies, like, you know, cervical cancers or anal cancers, penile malignancies, and others.
You know, and within head neck cancer itself, as was kind of mentioned with the 2024 plans, I think there are also other opportunities beyond the first-line setting to develop HB-200 to help improve the outcome of head neck cancer patients, and we are also excited about those opportunities, whether in the, in the adjuvant setting or high-risk patients.
Thank you very much, Dr. Ho. That was really great. I'm going to take the opportunity to thank, our patients, their families, their caregivers, our investigator on our study, all the study personnel, the study coordinators, the nurses, the PAs who participated in our trial. We will now open the session on the question and answer. Thank you.
Katya, Dr. Ho, thank you very much indeed. As you say, we now turn to the Q&A, and the HOOKIPA team will be happy to take any questions you may have. If you'd like to ask a question, then please click the Raise Hand icon on Zoom, and we'll then come to each of you in turn to ask a question in person. If you're listening on the phone, then please key star nine to indicate that you'd like to ask a question. If you'd prefer to submit a written question, then please type it into the Q&A box at the bottom of your screen, and we'll read it out on your behalf. The first question is from Brian Abrahams. Brian, if you would like to unmute your microphone, and please go ahead.
Hi there. Can you hear me?
Yes.
Great. Well, thanks so much for taking my questions. Just a few. I guess first off, are you looking at T-cell responses in the combo arms as well, and are you observing similar patterns of expansion and correlation to responses? Can you give us a sense of when we might see the next data cut from this from both the front line and second line? Then I'm not sure if Dr. Ho is still on the line as well. Well, maybe you could maybe further expand upon just the relationship between both PD-L1 expression and HPV positivity to with response to checkpoints and what you might expect with this to see in this particular population. Thanks.
You're on mute,Jörn .
You're back, Jörn. Thank you.
Yeah. Klaus, will you take the T-cell question?
Yeah, I can, of course, take the T-cell question. Yes, as indicated earlier, we also do measure the systemic T-cell responses of patients in the pembrolizumab combination. We have analyzed already the T-cell responses from the patients that Katia showed in the waterfall plot. What we did observe is similar T-cell induction in the pembrolizumab combination as compared to monotherapy. All of the patients have more than 1% of tumor-specific T-cells that are induced by the therapy and does range up to more than 30%. It's perfectly comparable to what you have seen before for the monotherapy trial.
Yeah. The next data cut will be towards, year-end, early in 2024, Brian. Katia, on the HPV positivity and CPS?
Yes. Certainly there have been suggestions that the prognosis is better for patients who are HPV positive versus HPV negative. In the 2nd-line plus setting, you know, CheckMate 141 reported median overall survival for patient p16 positive, a surrogate of HPV 16 positive, and that was 9.1 months for the overall survival, compared to 7.5 months in all over in patient with all comer head and neck squamous cell carcinoma. There could be, you know, small benefit in terms of prognosis for those patients. Yes, we agree, and we are counting for that when designing our randomized phase II trial.
Got it. That's really helpful. If I could maybe just squeeze one more in.
Sure.
Just curious, what you'll be looking for from the second line group to make a go, no-go decision. I mean, I'm sort of wondering whether overall response rate will be sort of the primary focus or the extent to which in this more refractory population, other aspects, including, you know, T-cell response, PFS, and overall survival will be the main drivers for that go, no-go decision. I'll hop back in the queue. Thanks.
Yes. No, certainly an important question. In the 2nd-line plus setting, you know, we believe that the benefit of the combination or HB-200 monotherapy extend beyond the objective response rate or even the PFS, and can be directly impacting the overall survival for those patients. That provides a bit of guidance for how we would shape up, you know, a registration strategy for those patients.
Great. Thanks again.
Thank you.
Brian, thank you very much indeed for your question. The next question comes from Andrew Berens. Andrew, if you'd like to unmute your microphone and go ahead with your question, please.
Great. Thanks, and congrats on the data. I know it's been a long time coming, guys. Based on Dr. Ho's comments, just wondering if you had the PD-L1 status of the patients in the first-line trial? Also, I know in the spider plots, it looks like you're seeing pretty durable responses, but any idea what the median duration of response will be in this setting?
Yes.
For that, please.
Yes. In regards to the PD-L1 status for those patients, as you saw, it was indicated on the x-axis for the waterfall plot for the patient in first line. We do see activity certainly in the patient with high CPS. Indeed, the objective response rate for the CPS more equal to 20 is actually 71%, and the disease control rate is 100%. You know, that makes a lot of sense, considering that for patients who the resistance to activity by CD8 T-cells is driven by PD-L1 expressions. The more PD-L1 expressions, the more effects you see with the combination. We are certainly, that makes a lot of sense, and that validate actually our mechanism of action.
You, can you clarify your second question? Sorry.
Yeah, I'm just wondering what you're seeing in terms of the median duration of response in the first-line setting, relative to what we would expect with KEYTRUDA alone?
Yes.
You know?
Yes. So we don't have enough for follow-up right now for that cohort with six months of follow-up. We will continue to collect the data and report them early 2024, you know, for an update. Thank you, Dr. Berens, for your question.
Okay. I know you're obviously in the planning stages for next steps, but can you just give us some general idea what the regulatory pathway could look like if things continue to be favorable and progress as they have so far?
The regulatory path, in terms of, first line, you mean, or second?
Yes. Yes.
First line. Yes, we have planned this randomized phase II trial of HB-200 plus versus pembrolizumab with registrational intent. We are planning to have objective response rate as a primary endpoint. At the time of the final data for ORR, we'll have an interim analysis for us. We believe that it's really important to obtain, to have any chance of getting any registrational status at this point.
Okay. In the mono cohort that you showed, it looked like the HB-200 doses varied. Can you just remind us what you're using to determine the dosing frequency that was administered?
Yes. We reported last year at ASCO, all our cohort during those escalation with 1 vector or 2 vector, we decided that on the recommended phase II dose with alternating 2 vector, based on safety tolerability, immunogenicity data, also, you know, the response that we see and the quality of the response in visceral mets. Based on that, you know, this is the dose that we're bringing forward in monotherapy.
Okay. Thank you very much, and congrats again, guys.
Thank you.
Thanks, Andy.
Andrew, thank you very much for your question. The next question comes from Asthika Goonewardene. If you would like to unmute your microphone and go ahead with your question, please.
Hi, guys. Good morning. Can you hear me okay?
Yes.
Yes.
Awesome. Excellent. I'd also like to offer my congratulations on very encouraging early data here and combination. It's good to see that that pan out. I just wanted to maybe I know it's still early days here. We need to see the durability mature and looking forward to that. Maybe if you can dig into maybe the first-line cohort data that you had here. Can you give us some color on the tumor burden in the patients who had a response? Katia, I'm wondering if you could maybe tell us a little bit about what the target lesion diameters were prior to therapy?
Yes, I can give you. That was variable for patients. I can tell you, for example, that the patient with a confirmed complete response had two metastasis of almost 4 cm total. We had some patients with diameter of 2, 3 cm. We have some patient with a diameter of 6, 7 cm, total sum of diameters. That patient, for example, with a confirmed complete response went from 3.9 cm to non-detectable or within normal measurement for lymph node of 0.8 cm. Substantial disappearance of your like, of those metastasis.
Got it. Okay. In the presentation that you hope to make at a medical meeting, will you be also showing in tumor, sorry, tumor biopsy data with maybe a look at your T-cell infiltration in the tumor as well? I understand you're kind of disappearing the tumors here, but are you going to be able to biopsy some of these patients and show what the T-cell response is in the tumor?
I'm going to take the first part of that question and then pass it on to Klaus. In the first-line setting, it's very difficult to obtain biopsies because first of all, the patient are in good shape, and you don't want to change that. Also, they have the option to receive pembrolizumab, just treatment, you know, by the oncologist with no biopsy, nothing. To be able to enroll in your trial, you know, it's better to not obtain biopsy in that setting. However, we have other settings, especially in the earlier, local disease, so prior to any treatment where we're collecting data. Klaus, if you can elaborate on that.
Yeah, I mean, we discussed it. Taking biopsies in the first one will definitely hurt recruitment, which is one of our priorities, of course. A very good setting for doing this in-depth biopsy analysis is the neoadjuvant setting that Katja mentioned, where we actually treat patients with a single dose of our vector after diagnosis, and we obtain pre-dose biopsies and then the surgically removed tumors. With these tumors, we are doing in-depth biomarker analysis to show, on the one hand, infiltration of T-cells in the tumor, but also we intend to analyze the modulation of the tumor microenvironment mediated by the HB-200 oncotherapy. This data is currently developing, and as soon as mature enough, we plan to present it at a scientific conference.
Got it, guys. Final question is, you know, we were talking about recruitment and getting patients on to study, but in the view when we think about the pivotal study, what do you think is the right number of patients that you're going to need for a pivotal study? How long do you think, Katia, that you'll need to recruit that? Obviously, I don't want to use the recruitment for the phase I/II study as a go-forward rate. How should we be thinking about the recruitment rate you should be able to get once you have more sites activated and the pivotal study going?
Yes. for recruitment, you know, obviously it's a larger study, to be powered for OS, and therefore we're planning to have 100 to 150 centers enrolling for this study.
The number of patients?
Yes. The number of patients would be 250 to 300 patients.
if I can push you on, how long do you think you'll take to do that, recruit that patient number?
Yes. We're still evaluating that, but we think it's going to take us less than two years to recruit. We'll have also an interim analysis and then the final objective response rate data concomitant with an interim OS analysis.
Got it.
The final OS.
Got it. Thanks so much for taking my questions, guys, and congrats again on the data.
Thank you.
Thank you.
Asthika, thank you very much. The next question comes from Alec Stranahan. Alec, if you'd like to unmute your microphone and go ahead with your question, please. I think you're on, Alec.
We cannot hear you, Alec.
I tell you what we're going to do, Alec. We're going to move to the next one. If you want to have a look at your microphone, and we'll try and come back to you in just one second. The next question comes from Gospel Asonye. I hope I got that right. Gospel, if you'd like to go ahead with your question.
Congratulations, guys. This is Gospel on for Vikram. We have two questions. The first one is, could you at least discuss the intended first-line trial design for the study that you expect to begin in 2024?
Yes. The design is a randomized trial with a ratio of 1:1. Assessing HB-200 plus pembrolizumab versus pembrolizumab. Patients are HPV 16 and PD-L1 positive, are screened prospectively, with oropharynx, metastatic or recurrent disease.
Okay, thank you very much. Second question is, how does this decision to move into a first line pivot to, program impact your capital allocation priorities, if at all, across your pipeline for 2023 and 2024?
That's a, it's a good question. We, you've seen the pipeline earlier on, and you see that our internal programs are actually HB-200 and HB-300. The other ones are funded by Roche and Gilead. We have very strong partnerships and basically a significant portion of the cost of that is actually covered. We did actually execute on a $50 million raise to have sufficient capital to make the movements and preparations necessary to move into the HB-200 first line pivotal trial. I let Reinhard comment a little bit more on cash at hand and cash run rate and so on.
Thank you, Jörn. We thought as a company, it is important to go into this next step with a strong balance sheet. We were able to add $50 million through the financing that we announced last night. With that, we will be funded certainly through the end of 2025, and we will have substantial catalysts from the pipeline that Juran has mentioned. Foremost, additional data from the HB-200 program, which will remain our key area of spending, but also from a developing pipeline with the prostate cancer programs and with other programs progressing.
Awesome. Thank you very much. Appreciate it.
Gospel, thank you very much for your question, and let's go again to Alec Stranahan. Alec, hopefully we can hear you now.
Great. Can you hear me, guys?
Yep.
Awesome. Well, thanks for taking the questions. Appreciate the update. I just wanted to circle back on the pivotal study. I think, Katia, you mentioned that you have met with the FDA regarding the path to registration. You've mentioned ORR as being a registration intent. Would that be sufficient in the first line setting, or is OS, or I guess PFS as a surrogate, maybe allowable? Were those patient numbers based on FDA feedback and your expected powering, or any other color around what's sort of going into that thought process would be helpful, and I've got a follow-up. Thanks.
Yes. Certainly, you know, besides the obvious response rate, the totality of the data as a secondary endpoint, and most importantly, the key secondary endpoint of OS, powered appropriately, would be key to obtain any kind of approval. This is what we're looking at, you know, OR and OS as key endpoints, alpha powered for assessing the clinical benefit of our combination versus pembrolizumab.
Okay. Maybe we could talk about the second line, the second line arm. U hmm. Could you give a little bit more color around the patient profiles? I know it's small n, but specifically the one patient with the PR. Just trying to reconcile the two data sets in terms of, you know, understanding the synergy between HB-200 and pembro.
Yes. That patient, you know, like, patient in that cohort had. That was their 2nd to 7th line of treatment. All the patient had received a checkpoint inhibitor and platinum before. Only one of the patient had received the cetuximab. This is a very small cohort, and we would like to continue to enroll patient and follow those who are presented here. They all had low CPS. You know, recent data seems to show us that a patient with PD-L1 CPS score higher, even in the 2nd-line setting. In the 2nd-line setting, checkpoint inhibitor do not require in the U.S. minimum, we should like.
I think it's important to enlarge a little bit our cohort here, which had very low CPS, like that patient had a CPS of 5. Most importantly, all those patients were previously treated by checkpoint inhibitor and chemotherapy. They have progressed at a different time of treatment. They had different size of tumor. And received, you know, 1 to 6 line of treatment for the cohort.
Yeah, Katia, we're encouraged by the medium progression-free survival as well, right?
Yes, exactly. You know, understandingly, you know, we would like to confirm this data, in terms of duration for those patients, with a larger cohort and more follow-up, for that cohort.
Okay. That's helpful. Thanks. One last quick one, if I may. It sounds like you're all systems go for the frontline pivotal. What would be the gating around running a registration study in the second line setting? I guess, what would you want to see from the ongoing study to give you confidence to start that study, given the path to registration may be a little bit shorter? Thanks.
Yes. In the second line setting, you know, I think a randomized study will be necessary compared to the best choice of therapy by physicians, so that would be the control. You know, to choose an endpoint here, I think durability will be key. Again, I don't believe that in the 2nd-line plus setting, objective response rate will be enough. I think durability and ultimately OS will be important to collect in those patients, and probably in an intent to treat population.
Great. Thank you.
Alec, thank you very much indeed. The next call, we think comes from Arthur He on the mobile. Arthur, you may need to dial star six to unmute on your mobile, please.
Hi, and the team.
Hi.
Can you guys hear me?
Yeah.
Yes.
Yeah, first, congratulations on the strong data. It's really encouraging, we see this non-chemo combo in the head and neck patient. Most of my question has been asked. Just want to follow up on the first line setting. Did you see a difference of the HPV 16 expression between the responder and the non-responder patient? Also regarding the total dose received of the HB-200, is there also a difference between the responder and non-responder?
Klaus, you want to take the first part about HPV 16 expression?
I mean, we characterized the HPV 16 expression, so not the E76 proteins, but the mRNA in the monotherapy. We did not see any association then with the therapy effect, so to say. In the pembro combination, we did an analysis of the baseline biopsies. As mentioned before, we don't have any on-treatment biopsies, and we could not observe any differentiating factors so far from responders and patients that did not respond. No, no association with HPV 16 expression was identified.
For the duration and the number of dose, our cohort is too small, I don't know the answer to that question. We're continuing to enroll, we're going to pass, you know, the 20 patient, and we continue to enroll to 30 or 40 patients in that single-arm cohort. Perhaps as the data mature, we will be able to report those data next year.
Okay, great. Seem like the patient with CPS score higher show a better benefit or to from the HB-200. For the pivotal study, you're gonna initiate in 2024, are you gonna apply a cutoff for this PD-L1 score for the patient inclusion? If so, what the cutoff gonna be?
We will use a CPS, a PD-L1 CPS score of 1 and above. The reason why is that even some of the response are more in the high CPS score, the durability, stability, overall survival could be very beneficial in patient with a CPS lower score, like we see in the second-line plus setting in combination with therapy. It makes a lot of sense to include this patient because we do see trend for benefits, for benefit in terms of durability of response.
Gotcha. Thanks. My last question is, based on the HB-200 data you guys gathered so far, what the, in how could this inform your study for the next program, the HB-300, which we could expect the initial data in the next or next year? Just to want to pick your brain to regarding that part. Yeah, thanks.
Yes. We already have used, the data from HB-200. We have a Drug Master File for, that was submitted with the IND, collecting all the information on CMC and preclinical data. HB-200 program had defined, the 2 vector, therapy, the frequency of administration, mode of administration, and also the dose. By the way, we have a poster at ASCO on the design of the HB-300 study Saturday morning in the prostate cancer session.
Okay, thanks. Thanks for taking my question, and congrats again. I'll talk to you soon.
Thank you.
Thank you.
Thank you very much indeed. We've come to the end of the in-person questions. We've had a number of people have submitted written questions. There are quite a few, and we are running out of time, so I'm going to take one from each person, which seems reasonable, and I'm sure the panel will come back to each person with the others, if they are able. The first one submitted was from Aloysius Wolf, and the question here: Beyond T-cell numbers, are gamma delta T-cells increasing? Is the NK cell compartment increasing? Is there a broadening of an in-patient antibody response?
We, in our analysis, did not look at these types of T-cell responses. It's classic CD8 T-cell responses that we were looking at. Antibody responses, we have antibody responses against E6 and E7. We have characterized, what we have seen is that already at baseline levels, these antibody responses are very high, and there was not a significant elevation of these antibodies on treatment. I think this is more due to the fact that already at baseline, these antibody responses are very high. Also, on the NK responses, we have not characterized it yet in our clinical trials.
Thank you very much indeed. The next one comes from Jennifer Kim. How actively are you considering further exploration of HB-200 in other HPV 16 plus tumors?
Katja?
Yes. so, yes, we considering, you know, the similarity of the mechanism for oncogenicity across all HPV 16 tumor, we are certainly considering other indications, such as gynecological, cervical, and in probably in combination and also probably looking at earlier setting. We don't have the plans that has been disclosed yet. We would like to go there. We think it's very important and interesting.
Katja, thank you very much. Then 1 question from Roy Buchanan. I know you won't guide to 2024 expenses, can you give us a sense of expense trajectory and major capital expenditures planned through 2024?
Yeah. I can take that. You've seen a very consistent cash outflow, call it, from operations of around $20 million. As our pipeline progresses, as we move towards a pivotal study, expect that to increase moderately. There will not be jumps that we expect in 2024. We haven't given specific guidance with respect to that timeframe, but expect a moderate increase in expenses compared to what you see on average in the past couple of quarters.
Thank you, Reinhard. Conscious that we're now over the top of the hour, and many people are at the start of their day, we're going to call it there, and I'm just going to hand back to Jörn for a final word, please.
Yeah. I'd like to thank Alan first for his great contributions. It's very clear that there is a significant unmet medical need for patients with HPV positive head and neck squamous cell carcinoma, in addition to what to the great results that we're seeing with pembro. That bodes well for potential innovative treatments such as HB-200. This is why we are extremely pleased about our data and the additional option that it may offer for these patients. With this, I'd like to conclude the session, and thank you all very much for participating. Bye-bye.