Hello and thank you for joining this Hookeeper webinar, Advancing Novel Immunotherapies. In a moment, you will hear a presentation from Hookeeper CEO, Jorgen Aldag and Translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center and Co Investigator in Hukipa study, Dmitry Zemarin and CMO and Global Head of R and D, Igor Matyashansky. Following the presentation, there will be an opportunity for you to ask questions and we'll provide details on how you can do that at the end of the prepared remarks. And now to the presentation. Jorgen?
Welcome, everyone. We are excited to update you on our great progress in our efforts to advance novel immunavirus based immunotherapies in cancer. We show early proof of concept of our HPV cancer program based on which we believe to have opened the door for many more cancer therapies to come. I'm incredibly proud to be here today to report on our first immune oncology trial of HB-two hundred Huquipa's patients with HPV-sixteen positive cancers with a focus on data from head and neck patients. This is a moment to say thank you to all those patients who pinned hope to our therapy, clinical investigators who helped advance the trial and all my collaborators at Hukipa who have been working with much enthusiasm to reach this point.
Pertz. This is also a moment to remember that just 5 years ago in 2016, we set a bold vision to develop our novel renovirus technology to create a new approach to cancer immunotherapy. Cancer researchers have established that a significant quantity of potent non exhausted cvat cells in and around tumors were paramount control or shrink tumors. Many cancers cannot be cured due to a lack of tumor antigen specific killer T cells. Huquipa.
Many therapies do not work effectively in patients who lack such T cells. This is the area of our strength. Hukipa's. Part of the potent target specific T cells seems to be the ideal tool to overcome the challenge of too few potent and specific T cells. Hence, we committed our company to address this urgent need for people fighting cancer.
Only 5 years ago, data from our ongoing Phase 1 study was selected only 5 years later, data from our ongoing Phase 1 study was selected for an oral presentation at ASCO. This is great recognition Hookeepa's unique platform to redefine success in effective cancer treatments. Next slide, please. Today Doctor. Ho from the Memorial Sloan Kettering Cancer Center delivered at ASCO the first report of the safety, tolerability and preliminary antitumor study of HB-two zero one and two zero two, an areinovirus based cancer immunotherapy in patients with HBV-sixteen positive cancers.
In this talk, I will use HB-two hundred to refer to 201 or 202 separately altogether. Next slide. The ASCO oral presentation is based on data from our ongoing Phase 1 trial. We're in early stages and we see great potential given the results reported to date and that we'll review further today. We were bold in our design of this trial.
While many new compounds are investigated in combination, We intentionally started the HB-two hundred program evaluating our therapy as a single agent monotherapy, So no combination with another immune therapy or a costimulatory agent. And we did this in heavily pretreated patients who have progressed on standard of care, including checkpoint inhibitors, the most difficult of all situations to tackle here. HP200 is a Phase 1 trial still in dose escalation. We expect to define our recommended Phase 2 dose at year end 2021. We'll start several Phase 2 studies with and without checkpoint inhibitor in Q1 of 2022 and intend to file for BLA on the basis of Phase 2 data.
Next slide. The HP200 trials has shown great early results. Here is some perspective. HV-two hundred induces an unprecedented number of circulating T cells to become target specific to seek their NM cell, notably up to 40% of all these T cells become antibody specific. Historically objective response rates to single agent active immunization therapies in 3rd plus line head and neck cancer patients have been HP-two zero one shows an encouraging preliminary overall response rate of 18% as a single agent And still ongoing median progression free survival of 3.5 months is longer than progression free survival of CPIs, checkpoint inhibitors in second line adenocancer.
Next slide. Let me summarize our 3 most important takeaways. Hukipa's total T cell platform generates unprecedented T cell responses, at times converting almost half of the CD8 T cell pool to be specific for the desired cancer target. 2nd, HB-two hundred is the only systemic and intravenous active immunization treatment with clinical efficacy, adding monotherapy in cancer patients who progressed on standard of care, including checkpoint inhibitors. And thirdly, based on the translational safety and efficacy results seen to date, we believe our Versatile platform has the potential to address the major challenge of cancer immunotherapy, which is the lack of T cells at the tumor site inability to turn a cold to more hot.
There is a myriad of applications where this capability of generating these kinds of T cells to be really useful across a broad range of tumor types. Next slide. Now Doctor. Dmitry Zammerin, Translational Research Director in China Schologic Medical Oncology's Morris and Kettering Cancer Center and Co Investigator on our ongoing Phase 1 study. Will talk to you about why T cells matter and how they should be seen in historical and comparative context.
Danny Ivan Atushansky, Hukipa's Chief Medical Officer in Golovout of R and D, will offer additional insights into the data presented at the ASCO oral, will provide new important translational data, including early biopsy results. Finally, I will briefly discuss the path forward. Sildimitri, please take over here. Next Slide 8.
Thank you, Yaron, for the kind introduction. As Yaron has mentioned, my name is Dimitri Zamaren. I'm a translational Research Director in Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center. And my clinical and preclinical research actually focused on cancer vaccines and viruses. A multi core investigator on this ongoing Phase 1 HB200 study.
So over the next several minutes, I'm going to provide a framework in which to evaluate the T cell immunogenicity data as well as the clinical data that were presented earlier today at ASCO presentation by my colleague, Doctor. Alan Hogue. Next slide, please. So recognition of cancer by the immune system is dependent on activation of a specialized immune cell call the T cell, the TDA T cells also known as killer T cells playing a central role. And these T cells normally recognize for an antigens that are associated with viral and bacterial infections or abnormal and mutated proteins that can be associated with cancer cells.
These proteins are collectively known as antigens and relevant to today's talk, it is actually a viral protein that are associated with cancer cells that serve as antigens that we're trying to target. So activation of CD8 T cells requires recognition of the specific tumor antigen that's presented on presented on another specialized immune cell called antigen presenting cells shown in blue here. These activated T cells then proliferate or stand and then migrate to the site of the tumor through the peripheral vasculature and it's at the site of tumor obviously where they mediate killing of the cancer cells. And also upon infiltration of the tumor, they become called tumor infiltrating lymphocytes for chills, which is a term that you commonly hear. Next slide, please.
So mechanisms of immune resistance can be present in multiple levels. Cancers are smart. They have found ways to evade the immune response, which allows them to grow. And this immune resistance can Hukipa's. I'm not sure to start with the lack of the ability of the immune system to recognize these tumor antigens, but downstream, it may also include multiple other mechanisms of resistance Hukipa's, even to the established immune response.
And this includes inactivation of T cells through a number of mechanisms that lead to T Hukipa's. And also through generation of a very immunosuppressive microenvironment, and it can decrease the effectiveness of the T cells that can actually penetrate the tumors. And clinically, once the cancers are able to evade the immune response, they grow and they metastasize and spread to other areas. Next slide, please. So the solution to this raising of the T cell control is really the basis of active immunization therapies, also known as cancer vaccines.
Active immunization therapies are designed to wake up the immune system by either dosing the pre existing responses to the cancer antigens that these patients Hukipa's or by development of new CD8 T cell responses to the cancer antigens. And these responses are then mediated through CD8 and then the killing mechanism that I have described several minutes ago. Next slide, please. So given that HPV associated cancers, such as cervical and TANF cancers as well as some others EXPARAZI's foreign viral antigens, there's a high rationale for targeting of these antigens using active immunization. And we have recently summarized the progress of immunotherapy for H2U related cancers in this review that was published in Cancer Discovery several weeks ago.
And in general, while the strategy has been shown to be effective in elimination or control of precancerous lesions, also known as pre neoplastic or pre invasive disease. The successes in the advanced or established cancer setting has unfortunately been relatively marginal, specifically for the single agent vaccines. However, there are some positive data that are emerging for these active immunization strategies against cancers Huquipa. These vaccines are used in combination with other agents, most frequently immune checkpoint inhibitors. Next slide, please.
So let us now consider the process of how this type of active immunization therapy can work to create a highly specialized keloid T cell army that can control cancer. So there are 3 key steps to generation of tumor specific T cells as I have highlighted before. First, the T cells need to recognize and become activated in response to the specific tumor antigen, which is expressed by the cancer. Next, these antigen specific T cells need to expand or proliferate, shown as multiply on this slide. And finally, these 2 mimetic and specific T cell need to travel or migrate to the site of the tumor where they need to infiltrate the tumor in order to mediate their killer.
So I want to cover how these three critical steps apply to the HB200 data that was seen at the ASCO presentation today and that that Ibo will go over later. So next slide please. So how do we know whether a vaccine is generating a cancer specific T cell response and whether these T cells are capable of killing. While there are a number of assays that have been developed to assess for T cell functionality, And most of these assays involve taking the T cells out of the patients, usually out of peripheral blood, and then assessing, first of all, the overall So the way that the T cell fitness for killing is measured is by assessing T cells for specific markers. And the most two common the 2 most common markers that are frequently used are cytokines called NKTR-one gamma and tumor necrosis alpha.
Those are proteins that are secreted by activated T So T cells, which become positive for these markers in response to the antigen, are very fit for killing. And the more markers they express in general, the better. This is called poly functionality. So on the right side of the slide, you see this pie chart that are summarizing the assessment of these markers in the patients who received a single dose of HB-two zero one or HB-two zero two vaccine. And they do show that these vaccines are capable in generating high quality CD8 positive T cells, which are fit for killing.
You can see that the number of these double or even triple positive T cells. So we know that they are good T cells, and they should be able to kill cancer cells. Next slide, please. But aside from the functionality of the T cells, the number is actually very important. So what is the overall number of quantity of these antigen specific T cells that could be generated by such an approach?
And this number, as I mentioned, is a key determinant of efficacy and is frequently used in vaccine studies as a measure of immunogenicity. We The quantity is a percentage of killer T cells, which are specific for the tumor antigen relative to the entire population of the killing T cells and the patient's blood. So how many is sufficient? We don't really know the number precisely. We know that the more, the better.
In most of the vaccine studies, if you can achieve a level of 3% to 5%, the vaccine is considered to be a good vaccine and capable of generating enough T cells to mediate the killing. Another important note to highlight is that when we measure these T cells, we need to measure them directly from peripheral blood rather than just taking them out of the patient, expanding them and then seeing whether we can identify them. Obviously, the latter strategy can identify the T cells that are specific for the antigen, but it tells us nothing about the relative predominance in peripheral blood. So the direct measurement directly from the peripheral blood is more important. So on the right side of the slide, these HB200 Phase 1 immunogen.
The immunogenicity data show that as a single vector HB-two zero one can indeed generate HPV specific CD8 T cell responses, and these T cells represent approximately 4% of the total CD8 positive T cell pool. So that's great. As I highlighted before, 4% is great, but not as exciting. What was more impressive is this T cell response generated when the 2 vector approach was used, using the HV-two zero two and HV-two zero one. And this resulted in antigen specific T cells representing 40% of the total CD8 positive T cell pool.
In other words, 40% of all peripheral blood CD8 positive T cells on now recognizing vaccine antigens. And this level of reactivity is really unprecedented and is larger than anything that has been previously reported for active immunization types of strategies. So this level of HPV reactivity does not generate tumor killing, There's probably no future for HPV targeting, but hopefully that's not the case. Next slide, please. So the generation of these HPV targeted T cells and blood is certainly a good thing, but the T cell is useless unless they actually can make it into the tumor where they mediate the killing.
This is a very important last step and it has been demonstrated that presence of the CD8 T cells in the tumor Can correlate directly with survival of multiple solid tumors, including HPV positive head and neck cancers. This has also been associated with response to immunotherapy. So to assess whether the T cells actually make it into the tumors, tumors are typically stained for the presence of CD3, which is a general T cell marker and also CD8, which is a marker of these cytotoxic T cells. And here, the AAV-two hundred biopsy data from a single patient Huquipa's for the biopsy obtained pretreatment and post treatment clearly demonstrate that in this patient that had a cold tumor, tumor that had absolutely no T cells, Hukipa's study with HB200 has led to tumor infiltration with T cells. Next slide, please.
So to sum up the Phase I data that has been generated so far, They do demonstrate that the HB200 and renal therapies are capable of 2 major things. First of all, the antigen specific T cells that can be achieved with this type of vaccination are historically unprecedented. And secondly, It's actually evidence of tumor shrinkage that has been observed by the vaccine as a single agent, something that has not really been seen by the prior vaccine studies. And although the data are early, I believe that there is probably a causal relationship between the T cell levels that we're observing with this vaccination strategy as well as the efficacy that we have seen today. And furthermore, given just my general involvement in the vaccine Slope.
If this level of systemic response to HPV active immunization therapy does not result in clinical efficacy, as I mentioned before, there's probably Hukipa. No HP reaction will result in clinical efficacy. So from a scientific perspective, this will be a very important answer for us to get. But although I do certainly hope that this strategy will be effective and will open up the doors for more studies and combinations and early data so far Hukipa. So I'm going to stop here.
I'm going to turn the presentation over to Igor now, but I will be happy to answer
Hukipa. Great. Well, thank you, Dimitry, for putting some of our data in a broader perspective. Allow me to further expand on the next slide with some additional detail on some of the themes that both Jorn and Yamitra introduced. I want to speak to you about the following three points.
1, does our clinical data firm the arenavirus mode of action of driving nonprocedent and antigen specific T cells, as the preclinical data suggests. 2, do we have evidence that HP-eight thousand two hundred is an immunotherapy agent effectively controlling cancer as a monotherapy without other agents in the post checkpoint inhibitor setting. And 3, what evidence do we see to date for relationship between the mode of action and the biological activity seen in the trial. Focusing first on driving unprecedented antigen specific T cells. Next slide.
Sohu. Thank you. First, let me quickly remind you, our arena viral vectors are nonlytic, Hukipa's function via systemic intravenous dosing, naturally target antigen presenting cells and allow for full antigen incorporation. And as a result, preclinically, as we have seen here, we have demonstrated significant induction of antigen specific CDAT cells in multiple tumor models, T cell tumor infiltration and an associated dose dependent efficacy. Based on this preclinical data and benchmarking ourselves To the field as a whole, we felt confident that if we could induce such potent and specific immune responses In people, we should see efficacy even as monotherapy and even in advanced cancer patients.
Albeit, we are well aware, as Dimitri has pointed out, that this has never been done before.
Next slide.
In April, at AACR, we showed immunogenicity from our patients demonstrating that HP200 was able to use mid single digit level antigen specific CD8 T cells following just one administration of our vectors. Just with one dose, the sneezing up to 8% of all of the CDAT cells in the body have been focused exclusively on cancer antigen of our interest. This is already, as you heard Dimitri say, an enormous accomplishment. Furthermore, these several hundredfold increases were measured via direct assay without any kind of artificial expansion. Next slide.
Now at ASCO, we have shown what happens when we follow-up with additional administrations. As can be seen, all patients undergo significant antigen specific CD8 T cell reduction. And in many of our patients, we are coming close to, if not exceeding the upper limit of quantification for these assays. Also supported at ASCO, the data here shows a direct Elispot measurement, corresponds to about an average of 6% and a range as high as 40%. This means that at this extreme range, almost half of all of these patients' CD8 T cells have been refocused on HPV 16 positive cancer.
Later in the presentation, I will review the impact of these T cells on tumor shrinkage. Finally to note, these CDEP cells in response occur very quickly, often just within 2 weeks. Huquipa. As we know, these patients have advanced cancers, and we, as treating physicians, know that speed is critical. The therapy must work fast within weeks.
Otherwise, the battle is already lost. Next slide.
And this is why all of this
is so exciting because everything we have seen preclinically from the magnitude of induction Next slide. Summarizing this part. Early clinical data confirmed the arena virus mode of action, specifically being able to drive unprecedented antigen specific CD8 T cell levels. All patients do indeed show increased CD8 T cell levels following our treatment, at times reaching a size up to 40% completely recapitulating the data that we have previously shown preclinically confirming it in the clinic. Hukipa extremely exciting and validating from a technology proof of mechanism point of view.
As Dimitri has said, I paraphrase that this level of immunogenicity does not result efficacy, which kind of needs to question her biology a little bit. However, the MD clinical oncologist in May asks, this is all nice. What about the patients? What about efficacy? Next slide, please.
I remind you that we began this strong exploring many facets of our technology. We explored not only 3 week, but every 2 week dosing schedules. We explored not only intravenous continuous administrations, but also one dose of intratumoral following the intravenous continuous administration. And we also explored 2,111 and202,201 alternating therapies. Just to remind you, 2,002 and 2,012 different iridoviral backbones, but having the same HPV cancer target in common.
As Alan Ho showed at ASCO, our BEST data has come from the every 3 week intravenous dosing schedules. During the talk, I will therefore focus on patients with head and neck cancers who receive HP200 every 3 weeks via intravenous administrations to explore in more detail the relationship between dose and efficacy seen to date. Next slide. So to remind you, as of March 31 data cutoff, we had 38 patients dosed, 14 received HB-two zero one intravenous every 3 weeks. 8 received HB-two zero two-two zero one intravenous every 3 weeks.
The remainder received either intra tumoral and or every 2 weeks dosing. The number of evaluable patients efficacy scans are shown below to be 14 and 4 11 and 4, respectively. Next slide. The demographics of the 22 patients who received intravenous therapy every 3 weeks, as seen here, were not different from the demographic profile of the therapeutic patients as a whole. Notably, patients had advanced disease and were heavily pretreated with an average of 3 prior treatments, 82% of all patients had prior checkpoint inhibitors and specifically excluding patients excluding patients with nasopharyngeal head and neck cancer for which checkpoint inhibitors are not standard of care or Hukipa's head and neck squamous cell carcinoma patients had prior checkpoint inhibitors.
Further, 90% had prior platinum and 80% at different metastatic disease. Next slide. Before restating our Hukipa's static solid tumors are not curable. As patients progress in treatment, their response to their next treatment becomes less and less. Wide, but it's multi pictorial.
However, more advanced patients are sicker, can tolerate less than the toxicity associated with most cancer therapies. And unfortunately, as Dimitry has said, cancer evolves, you're better at either fighting or evading the therapy itself. Now focusing on HPV positive head and neck squamous cell carcinoma, we see that in the first line advanced metastatic setting This is the first therapy patients who present with advanced and or metastatic disease. The response rate is, as a percentage, is at best in the mid-30s, as you can see in the gray pie chart. Our first is Lyme is our best therapy.
As oncologists, we are not saving our last for BEST. Our BEST must be our first so patients will die. And here, our BEST unfortunately means that 70% will not respond at all best therapy. And in this case, some combination of checkpoint inhibitor chemotherapy. Less patients progress in first line therapy options in the 2nd line treatment or for even less.
Response rates are usually less than 20%, as shown in the orange pie chart, which means that over 80% of patients are not even expected to respond. As Dimitry has already mentioned, response rate to active immunization of third line is, well, marginal at best. And you can see if you look at the overall survival or median progression free survival rates, a similar trend is observed with median progression free survival already in the second line dropping more than 50% from the first line. Although extrapolations are completely linear, it is obvious to include that third line survival rates are to be expected to be even less than those in second line. Next slide.
This is what makes our data for me as an MD clinical oncologist, so exciting. Except for the one nasal pharyngeal patient we've all of our head and neck squamous cell patients are 3rd line or more, have you seen chemotherapy and checkpoint inhibitors previously? And we are seeing both our responses and a prolonged progression free survival with further dose escalation ongoing. So putting our data on top of the data shown earlier in the first and second line setting, we see that despite the fact that the expectation for the 3rd line response rate was about 0%. We are actually seeing an 18% rate.
And progression free survival is effectively worse than second line, worse than 2 months, just like second line, seemingly worse than the first. And yet our data shows quite the opposite. This is what gets me so excited. Patients are living longer Seeing here in the tumor's slide, it comes obvious that many of these third line advanced patients are not only responding but staying on HP-two hundred therapy for a Hukipa's. Focusing on HP-two zero one and comparing dose level 1 life with a dose level 2 dark, we are clearly seeing that patients on dose level who are staying on therapy even longer than dose level 1.
Next slide. And for 201, while it's still too early to make comparisons to 201 alone from a time on therapy analysis after they've started related in 201, It is notable that nearly all the 202201 patients are still on therapy as of the beta cutoff. Next slide. Now looking at this data at a waterfall plot, it is easy to see that more than half of our patients show evidence of tumor regression. And while we could not compare 20 to201 to 201 alone on the SUMR plot shown before, On this wonderful plot, it appears that many more of the 202-two zero one patients, as seen by the red color, Hukipa's.
In other words, there are more reds to the right than to the left of the slide.
Next slide.
Looking at this data outside the curve plot, In fact, we see quite clearly only one patient who is truly rapidly progressing. All other patients either had prolonged stable disease or had rapid responses. We could see some patients that we presented back in December, and we have seen additional patients showing response in the lower part of the curve. Next slide. So putting it all together, I've shown you that for 2,01, we have an overall response rate of 18% for head and neck squamous cell carcinoma, disease with disease control rate of 73% and a median progression free survival of 3.5 months.
For our initial cohort of patients of 202-two zero one. Although we have not seen any form of PR to CRs, our disease control rate is 100%, with 3 of the 4 patients showing evidence of tumor shrinkage following just one cycle and a median progression free survival, There's already 3.5 months and ongoing, exceeding the progression for survival of checkpoint inhibitors even in earlier settings. Next slide. Furthermore, the clinical efficacy of monotherapy in the advanced setting HUKI PUTS. Specifically, no grade 3 or higher, no one has continued due to adverse events.
While tolerability of therapy is almost always an issue in late disease, it is not an issue here. Furthermore, combinations with other agents are clearly going to de risk at this point, not only by this very favorable tolerability profile, but also by the fact that we were already combined with pembrolizumab in 3 separate patients without any additional success that we observed. An example of this was shown back in December for combining with 2 0 1 and another example will be shown shortly for combining the 2,201. Next slide. Summarizing here, We see early signs that HP200 is defection in controlling cancer as a monotherapy in the post checkpoint inhibitor cell.
Specifically monotherapy with HP-two 1000000 like other monotherapy active immunization therapies, We have seen 2 objective responses and a disease control rate that goes high at 73% for 202 2 1 and SOPHOR 100 percent for 202-two zero one in advanced patients as monotherapy. As well, we have seen additional benefit when combined with checkpoint inhibitors. Finally, HP200 has a benign safety profile, supportive combinations with many different therapies. Next slide. So far, we have spoken quite a bit about immunogenicity and efficacy separately.
However, is there a relationship between the 2? I would say on a high level that our relationship is in its early stages of being defined. So But what we do know so far is indeed supportive of our relationship between the 2. Let me share you some data. Slide 39.
Regarding dose response, data on the various efficacy plots are shown here before, but it's have already suggested the emergence of dose response. Here, it is presented directly. On the left, comparing response rates, target lesion shrinkage as measured at the first scan for 201 dose level 1, 201 dose level 2 and 202201 dose level 1. Hukipa's. We see that as either dose increases or we switch from a single vector to a dual vector approach, both modifications geared to give us greater immunogenicity, We see an increase in response rates.
This is also seen when compared to progression free survival of dose level 1 to dose level 2. Remember, median progression free survival for the 2022-two zero one combination is still ongoing. Next slide. Additionally, to meet you already has shown you this, we have begun to examine whether our peripheral blood specific CD8 T cells penetrate the tumor. Here, we see an example prepared by showing the absence of CD8 T cells before and the obvious presence thereafter.
These data are very reminiscent of the blood immunogenicity shown earlier. Next slide. Finally, a picture is over a 1,000 words. This is our first patient, Sergio, to have received 202-two zero one, the alternating 2 vector therapy. This patient had an oral tarantula HPV16 positive head and neck cancer that was treated with radiation therapy in 2018.
The patient who developed metastases in the lymph nodes and the lungs have a subsidiary with cisplatinib with some improvement. However, the patient subsequently progressed and entered a clinical trial with an investigation with triple therapy of menolizumab, divalumab and cetuximab. There was some improvement with the triple therapy and then again progression, this time mainly in the soft tissue surrounding the thyroid gland. So in the top Huquipa's. You can see the baseline situation and enter into our clinical trial with a CAT scan here and more easily in the zoomed in picture showing the soft tissue mass kind of surrounding the trachea in the place of the thyroid.
The patient received is at one cycle of HB2201, HB2102 then 201 and has a rapid induction of antigen specific cVAT cells reaching 35% by direct measurement. The CT scan, this initial 6 week evaluation, shows a 20% reduction in the peristyloid soft tissue tardic lesion. Shortly after the scan, the patient complained to difficulty swallowing the investigator, who was at that time concerned about possible esophageal obstruction involved lymph nodes besides that pembrolizumab. No additional safety signals were noted. The repeated CT scan 6 weeks later, right around the time of the data cutoff, shows further reduction in the thyroid soft tissue mass to a 40% reduction and an increase in antigen specific CDT cells to similarly 40%.
Next slide. Summarizing. Early data does indeed suggest the relation between T cells Hukipa's. To come back to Dimitri's point that if we don't see clinical efficacy with these kinds of T cells, not sure what we do with clearly, we are seeing efficacy, which is a good sign. Efficacy measures do indeed improve with higher dose and with the auto immune signal vectors.
HP-two hundred therapy causes a similar increase in TDS T cells in blood and tissue biopsies. And in these tissue biases, there is further early evidence that HB200 decreases the immune suppression in the tumor microenvironment. At this point, I'm going to hand it over back to Johan, who can tell us what comes next.
Pertz. Our Phase 1 data on A321 monotherapy are exciting And we haven't yet reached optimal dosing. Furthermore, we're only starting to see the data on our alternating 2 record therapy, with its notable single agent activity, its compelling T cell based mechanism of action and its benign safety profile, HD200 is likely to be a strong match for combinations with checkpoint inhibitors. In Q1 of 2022, we will start randomized Phase 2 in combination with a PD-one inhibitor. In addition, provided our data continues to support it, we will start 2 second line trials in advanced metastatic HPV16 positive cancers.
The first will be a monotherapy in a late stage head and neck cancers, Hukipa's letter in combination with CPI checkpoint inhibitors for anal cancer where there is no current standard of care. Next
slide.
Our HB200 was the first study ever where we put an renovirus therapeutic into humans. While to date, this established proof of concept successfully, there was a lot of learning with this new model team, which took time. Now that we have designed and tested arena virus constructs in humans and have set up our manufacturing processes, other programs can build on this expertise and potentially move significantly more quickly towards the clinic. The urea virus approach is now becoming a platform. Our ability to drive the antigen specific T cells can be leveraged to produce best in class therapies in multiple indications, potentially as monotherapy and or in combination with other new modulatory agents whose potential is often limited due to a lack of T cells at the tumor site.
Pertz. We have demonstrated pre clinically that we're able to break tolerance in animal models. We believe we can translate this to humans just like we did in the HB-two hundred program. Our first program targeting cell pathogens will be in the prostate cancer space. Also mutated oncogene such as KRAS could be very interesting targets for our therapy.
In addition, Next slide. And to wrap up, here are our key milestones. The next comprehensive data update will be no later than 4Q 2021 and tail more patients from the 201, 202 formulation. We expect to define or select recommended Phase 2 dose in 4Q 2021, expansion cohorts in the Q1 of 2022 and will start a checkpoint inhibitor combination study in first line, head and neck squamous cell carcinomas in the first half of twenty twenty two. Our prostate cancer program named HV300, is expected to have an IND in the Q3 of 2022 and then move on to the clinic.
And looking at the ability to drive novel programs forward, we would expect to be able to deliver one additional IND Prahranan starting in 2023. This concludes our presentation, and I'm very happy to open up for Q and A at this point.
Thank you very much. We now turn to the Q and A. And the panel have been joined by Hookeeper CFO, Reinhard Candera and Chief Business Officer, Christine Baker. And the first question comes from Aspik Gunewarden. Aspik, if you would like to unmute your microphone and please go ahead.
Pertz. Hi, guys. Did you hear me okay? Yes. Hi, Huki.
Hello. And thanks for taking the time to give us the update and yearn for Staying up quite late on your side of the world there. First off, really interested to see
the kind of response that you
guys produce here and I'd say hats off to producing that kind of data. I wanted to get some ideas. So of that 8 patients that you are treated with the HP-two zero two, TUL-one, about how many of these actually got into that Huquipa's 40% antigen specific CDAPositive T cell compartment range. Just curious if you could maybe give us an idea about that. I know it's up to So That patient regarding to the 40% was kind of an extreme outlier.
I would say what we are currently seeing for the What we have seen for the 202-two zero one, for the moment, as we can extrapolate, is probably in the double digits, but that patient is kind of at the extreme range of what we observed. Got it. And then guys, just look at the spider, I mean, you have some patients who are in the state of the disease category, including some blocking the heterologous prime boost. I'm just wondering, have you looked at extensively at biopsies in these patients to see if there's maybe some sort of information that may be offsetting tumor volume reduction kind of like almost in a on-site sort of progression happening? We haven't seen any, I would say, information, any of the tumor biopsies that would do that.
We really haven't seen any I mean, I resist this with the following patients with Exyceline, we can rule out pseudo tumor progression from initial inflammation. We haven't seen evidence of that. Got it. And then last one for me is the focus much of the focus today was on the 3QW dosing. I'm just wondering, are you suggesting that Huquipa's.
QW, maybe the piece of response is not as great or I'm just wondering why is it that the QW looks so much better then? Not only clinically that those patients not do as well, but also from a CD8 T cell levels, we did not Huquipa's. So there are a couple of independent factors that are both pointing to
And the next question comes from Andrew Berens. Andrew, if you would like to unmute your microphone, please go ahead.
Thanks. Can you hear me?
We can.
Great. A couple of questions from me on the regulatory pathway based on what we're seeing today. You mentioned accelerated approval as a pathway. And I was wondering what you think the bar is for approval. I mean, I assume it's based on OR and you're citing an 18% ORR, but Your confirmed OR rate is not really 18%.
It's half of that since that one patient didn't confirm. And then when I look at the spider plots and the swimmer plots, it doesn't appear that some of the actual response those two responses are durable. What type of durability do you think you need to show for accelerated approval? And then lastly, it seems like most of the efficacy that you're seeing Hukipa's stable disease, which could lead to a PFS benefit eventually. Do you think a randomized trial might be a better strategy with PFS versus going for accelerated approval on response rates.
Yes. Those are all good questions. I think our plan Huquipa's. For the moment, it's to progress our data as we continue to our recommended Phase II dose. I think all the points, Juarez, are exactly the way I'm seeing the situation.
I think we'd like to both get the response rate as well as the, I would say, the durability up to where it's solidly in the 3 to 4 months range. So the response rate that I today is a solid 18% fully objective to really get where you want to go. We can think about it as a monotherapy Phase II. We are, I would say, optimistic that as we're seeing with as our data is increasing with dose escalation, that we will have those kinds of numbers in the near future. And we'll be discussing that path with the FDA probably in the Q4 of this year as we think about the motor therapy in the advanced settings.
Okay. What do you think the bar is that you need to show in terms of the ORR And the durability for an accelerated approval.
Historically, the accelerated approval has usually have had in first line has been quite I think in general, as we can show in these advanced treated patients that we can have a 20% or higher bar, Huquipa. Considering that the historical response rate has been dramatically less and the second line is only 13% to 18%, That would be sufficient, I think, to discuss with the FDA.
Okay. And I guess, we haven't seen any responses with the combination therapy yet or the alternating therapy yet. Where are you on the dose escalation part. I mean, how much higher do you plan to go? And when should we expect to see some formal responses?
I can't say when you expect
to see formal responses. The recommended Phase II dose for the program will be defined by year end. We are currently just dosed 2nd dose level 2 of the 20 2,201 and a dosing dose level 3 as well. And the question is, can we go higher or depend on the data?
Okay. And what type of T cell response are you seeing with the alternating therapy now Relative to the 40% that you've seen.
Yes. We haven't updated or disclosed any information of
Okay. Thank you. Thank you, Andrew. And the next question comes from Brian Abrahams. Brian, if you would like to unmute your microphone and please go ahead.
Thanks. Can you guys hear me okay? Yes. Great. All right.
Well, thank you so much for taking the questions and
for the presentation. I guess, the first question would be following up on the patients who received alternating 201202. And When we look at the SPIDER plot, it looks like the patients who responded to monotherapy 201 seem to respond relatively early in the course of treatment. Whereas for 201, 202, it's still relatively early, but you haven't yet observed responses. And you've described that you're seeing pretty robust double digit antigen specific T cell levels.
So could you maybe, I guess, square those and help us understand What would be the outlook then for those patients, at least on the first dose? Is there preclinical or other mechanistic data such that the speed of response despite the higher initial T cell levels might differ for this alternating regimen versus the immunotherapy.
Yes. I think despite the current supply, it's really not the best way to look as there are a lot of lines there. And I think the early the lines overlap in that kind of early left side of the bar. I think if you look at the waterfall plot, I think that might be the easier place to look at in the slide deck that we just showed. And if you look at the waterfall part, Is there any way that I can have my slides back?
Yes, we can. Which slide would you like?
It's a waterfall plot. Just can you fast forward?
Yes. You can give it a go.
If you look at the waterfall plot,
33.
33. Thank you. You could see there that the red guys are 202-201s. So they are showing responses early. I think they're a little bit probably overtaken by the many more blue bars in the spider plot.
So I would say you're looking at the first scans, and we'll see what happens with further treatment.
Okay. Fair enough. Sounds like it's still early. And then are there any data on how chemotherapy might affect T cells and I guess what the time between systemic therapy and starting on 201 or the combo would be and I guess I'm just curious if there's any influence on T cell levels or activity and what the implications for that It might be for exploration in an earlier line setting, including frontline settings.
Yes. We And how it affects our cVAP cell inductions, if that's the question you're asking, I would say. We haven't seen any evidence. All of our patients have, I would say, respond very nicely to our therapy. They all get significant expansions.
So we haven't seen, I would say, any relationship between the 2. We are actually in the middle of starting an investigator initiated trial, looking in kind of an early setting of a direct combination with chemotherapy and HP200 to see how the concurrent use of chemotherapy may affect our viral vectors. So the chemotherapy has been known to both promote active immunization. So we'll see how that goes. We have not seen any evidence to date regarding this.
Got it. One more quick one, if I could squeeze it in. Are you guys planning to explore Any additional dosing intervals, perhaps just given what you've seen with the wider space intervals leading to more robust clinical and immunological responses. Thanks.
Our protocol, I would say, is open to allowing us to explore different dose schedules. So the clinical as written is flexible, and we have the option to explore a 4 week dosing schedule as well. So for the moment, we are still discussing with the investigators whether this is worth pursuing or not. One of the problem with extending the dose intervals is, of course, you run against the time frame that You have to get in therapy until relatively quickly before the tumor progresses. So you can imagine dosing once every 3 months at the 1 quart for this patient population unless you're 1 Peartson.
So A, we have the option B, we are currently discussing whether with investigators whether this is an option we want
Thank you, Brian. The next question comes from Alec Stranahan. Alec, if you would like to unmute your microphone, please go ahead.
All right, perfect. Can you guys hear me?
We can.
Perfect. So, hey guys, thanks for taking my questions and congrats on the update. Wondering if there's any demographic differences you point to in the 4 efficacy patients in the 2 vector arm that can maybe explain the lack of objective responses or do you think it's really more driven by a shorter duration of follow-up? And Additionally, whether you think the one patient that received KEYTRUDA, which is now in the PR, will you continue to follow this patient and provide updates maybe later this year.
So as far as we can tell, there is no difference in demographics Any of the patients at all. They're all, I would say, fairly homogeneous. They're all heavily treated or progressive CPIs. As to the patient in question, we will, of course, update on all patients as we do at all of our updates. We have been shown wonderful plots and stroma plot for Endo work.
So it's biocarb plots for all of our patients. So sure, absolutely.
Okay. And then just one point of clarification on your registration plans. Do you expect that you'll take forward the 2 vector approach? Or will the studies that you've highlighted be just the 201 model therapy with or without PD-one or will this really depend on the data update Linda this year.
Well, I think our general philosophy at room has always been and remains the same. We will take the 200 program as, quote unquote, mode of therapy. And by mode of therapy, we mean either 201 or 202201 into the post CPI space. We believe the fact that no active immunizations ever worked in that space and the fact there's no standard of care in that space really gives us a shot in terms of getting our drug approved in that setting. At the same time, we believe that our clean safety profile, the synergy we are already shown with CTI's mix and the fact that we're the only active mutation therapy to show monotherapy efficacy makes us the ideal partner for CPIs in situations where CPIs are approved.
Now so we're going to go both CPI and then CPI approved indications with CPI. And the only question that resolved will be a little bit unresolved is the 201, along with 202201, And I think we will make that decision and recommendation as part of our recommended Phase II dose guidance, which we'll have at the end of this year.
Okay. That's helpful. And then, one final question, if I may, and it's more of a science y question, I guess. I thought it was interesting that in the facts plots, You showed that the 2 vector therapy generated a much higher level of TNF alpha T cells. So wondering what in the 202 vector you think Maybe driving this.
The well, for the record, what we're showing is the upper right corner of the facts box we're showing is a TNF alpha interferon gamma double. So They are just in general generating the double vector generating, in general, just more, polyfunctional CDAT cells. In other words, that 201 homologous and then versus 202201 cortical heterologous. The heterologous gives us simply many more polyfunctional antigen specific CD8 T cells. This has to do with the fact that when you have different vector back They minimize competition against the same backbone when you reintroduce, therefore, allowing expansion of the target antigen in common.
That's the entire theory behind the heterologous or kind of the alternating dual vector approach.
I think we will keep just the single application of 201 versus 202 on one of the slides.
I mean, I was thinking more about the 2 vector strategy. I mean, I would be interested to hear what you've observed with just 202 alone in terms of
the polyfunctional T cells as well.
Well, in AACR, Alex, we show what happens after one dose of 201 versus one dose of 202. Huquipa. So we put too much stock in those two numbers. So let's say, preclinical, we both saw they both give us about 4% to 5%. Clinical results.
We saw 1 D3, 1 D8, but they're both given the same range. I would not say there's a difference shot per shot. I'd say the real difference comes in when you actually boost with a different vector versus the first.
Okay. All right. That's very helpful. Thanks again for taking our questions.
Thank you, Alex. The next question comes from Roy Buchanan. St. Roy, if you'd like to unmute your microphone and please go ahead.
Okay, great. Thanks. Thanks for taking my questions. Impressive T cell results. So it's good to see.
I guess I had a question, maybe I missed it, but the patient with a 40% induction of directed T cells. That patient is not considered a partial response because of the lymph node progression or why is that? No, the patient had a 20% response to 202201, but then they investigated kind of concern about a subagial lymph node, inflating inflammation and then that's to get actually added pembrolizumab. Response, but that was with pembrolizumab added after the first scan. So therefore, as monotherapy doesn't count as a PR.
Got it. Okay. That makes sense. And then, I guess, do you guys have any data or information on vector directed T cells for the combo, The 201, 202 alternating sequential. I mean, how many T cells I know you're showing T cells against HPV, but do you know how many are against the arena virus?
We do. We do know how much is against the Orenavirus, but we haven't formally kind of compiled that information. What I can tell you is, basically for the for the heterologous combination, it is less than for the antigen itself, hence, I guess, I presume. Okay, great. And then I guess you guys have any early data on durability of the T cell responses?
We some of the patients that we saw, we showed data concerning with the max responses. That is actually up to 84 days. So we know that the TBA T cells, 1 induced, actually stay quite up there, with some after at least their 4 treatment cycles. Great. Perfect.
And then I had one last one for Doctor. Zamarin. I'm not sure if maybe this was in his review or not, but I mean, I'd say there is some validation for T cell theory for HPV, right, in the cell therapies, some early data with some good response rates. But I think they also use Interleukin 2. Just wondering if you could maybe comment more broadly on the cell therapy approach.
And then If you think maybe that was potentially the end of the continuum too or just your thoughts there.
Yes. No, absolutely. So that is T cell approach. So they infuse a relatively smaller population of T cells into the patient. And in fact, the patient needs to be lymphodepleated to make room for the T cells to expand.
And IL-two is applied specifically to allow for expansion of these T cells. In this case, the question does Well, what if we actually add some IL-two to boost up the efficacy of this current agent? It seems like the expansion is quite high. It's actually I mean, if we do talk about 40% of the peripheral blood T cells being specific for the antigen, That's higher than you would achieve with an adaptive cell therapy approach. So I think the T cells Granted that it's only been seen that 40% is an outlier, but even if we're talking about the teens, It's still much higher than what we did here for the cancer vaccine studies.
So I don't think a cytokine that would necessarily stimulate the response Huquipa would help here with the peripheral blood of these T cell proliferation. And the question is like whether it would to help with the effect of function of the T cells once they actually make it into the tumor. That's a good one. And Certainly something to think about if the current strategy of combination of perhaps immune checkpoint inhibitor doesn't pan out.
Okay. Thank you.
Thank you, Roy. And the next question comes from Vikram Parohit. Vikram. I believe you're dialing in on the phone. You should be able to speak now.
Give it a go. And you may have to unmute. There you go.
Great. Can you hear me?
Yes.
Great. Thanks for taking my question. A couple from my side. So first, you mentioned that 38 patients that were dosed over 20 discontinuation. I just wanted to get a sense of how the discontinuation rate compared to when you would have initially expected a model when we were starting out the study.
Well, the patients discontinued usually for progression. So there are no surprises. They were all kind of end stage third line more advanced cancer patients. So I'm actually surprised that patients are staying on therapy and responding to drug as long as they are getting the advanced nature of these patients. Okay.
All right. Understood. Secondly, now that you've had a couple of months since the last update in December to presumably learn more about the 2 patients who did have responses for 201 monotherapy. Have you come across any patient specific factors that might explain that may have played into these patients' responses, especially the partial response for the patient that did not pass away. Yes.
No, it's a great question. Clearly, we to scrutinize those patients in every way we can, and the short answer is no. We do not yet see kind of a predictor marker either from a clinical perspective, from a treatment history or by any kind of tissue or biology, Any other kind of markers that actually explains why those particular patients responded better. What I can tell you is and kind of the message that I try to kind of send along the way is that we are the patients where we have higher CDAT cells Okay. That's helpful.
And maybe one last question from my side. For the T cell responses you're seeing. Are there any migration markers that you've been tracking to help to get a sense of whether these PD-two cells have been traveling through the tumor sites or anything about sort of the contracting that you could kind of give us some color on? No, we have not been tracking the CD8 T cells. We've been measuring them either directly or in the from the board, we're Okay.
Understood. Maybe if I could squeeze in one last question. Thinking about the update that we're supposed to get in the by the Q4, I think you mentioned, both for 201 and 201-two zero two based on your sensitivities that you're enrolling and based on how high you think you can dose the 201 monotherapy. How many patients and how many dose levels with the data do you think would be reasonable to expect by that time. I think we should be able to get through 3 dose levels for both programs Okay.
That's helpful. That's it for me. Thank you.
Stifel. And the final question comes from Swayampakula Ramakanth. If you would like to unmute your microphone and please go ahead.
Thank you very much, gentlemen, for doing this. Really appreciate it and thanks for taking my questions. Most of them have been answered. I have a couple of quick ones. Just trying to follow-up on the migration question.
How many patients have the data for antigen specific CD8 positive T cells the tumor biopsies. And do these correlate with the T cell response that you saw in the PBMCs? We only have 2 sets of biopsies that correlate with our 2 sets of paired tissue biopsies that correlate to the For all CD8 T cells and for the 2 for those 2 where we have correlates between both blood and tissue, they do correlate. Okay.
Thank you for that.
And then the last question from me is on the dose level Yes, that was used in the 201, 202 combination. How does that correspond with the monotherapy? The dose for the dose is a little bit confusing. Dose Level 1 For 202-two zero one is the 2nd dose level of 201 monotherapy. In other words, Hukipa.
We used for 201, we used the highest dose we cleared from the monotherapy at the time we started the combination. So at that time, that dose was dose number 2. So numbers help. So for 2,01, monotherapy, the first dose is 0.05 dollars 10 to the 5th. The second dose is 0.05 dollars 10 to the 6th.
However, for dose level 1 for the 202-two zero one, The 202 is delostat 1x10 to the 6 and the 201 is delostat 5x10 to the 6. Okay.
That's helpful. Thank you.
Thank you very much for doing this for us. Thanks.
Thank you very much. And we have one more question, one final question and that's from Ostika Gunawarden. Stifel, if you would like to unmute your microphone and go ahead.
Hi, guys. Thanks for starting me in. Just another quick one here. I'd like to think ahead to the next update. What are you planning on including in that next update?
And in terms of I'm really curious to get more of the translational data in terms of the patient numbers. What should we look forward to in that? Well, so thank you. The way I've been thinking about this. I think at AACR, we, I would say, gave us some initial immunogenicity, then the blood we follow-up at ASCO, I would say with a lot more.
I would say here, we're presenting some early tissue. We're going to present, I would say, Hukipa's story a little bit further in terms of this relationship between what we're seeing in the blood and what we're seeing in the tissue. I'd like to push a little bit more into The second thing in the next update, I think, will be important and will be the recommended Phase II dose. I've already commented on the fact that I'd like to do a formal update on 3 dose levels of 2 0 1 and likely 3 dose levels of 20 two-two zero one and contrast and compare those 2 in order to make some final recommendations. Finally, I'd like to, at the next our recommended sorry, the next update, also talk about a little bit more about How we're seeing our CPIs combinations.
We've made I would say, we've alluded to the fact that we've had several patients on CPIs. We haven't really discussed it. We're going to probably put on a fair amount of more even before we conclude dose escalation, And I'd like to write an update on that at the next update. Got it. Thank you very much.
Stifel.
And that was the final question. And if I could perhaps hand back to Jorg just for your final remark.
Yes. So I would like to thank everyone for participating in this meeting. We believe that we've made great progress and we will continue to push hard to develop all immunotherapies to change the life of patients.