Barclays Global Healthcare Conference 2021

Mar 11, 2021

Okay, and good afternoon. My name is Carter Gould, Senior Biopharma Analyst here at Barclays. Welcome to day 3 of the Barclays Global Healthcare Conference. I'm pleased to welcome CEO, Robert Yang of Vohr Biopharma to their virtual stage here. Robert, thank you very much for joining us today. You're going to give a presentation. We're looking forward to it. We recently initiated ONVAR, really transformative approach to addressing potentially a number of diseases, but certainly AML is at the forefront right now. So with that, I will turn it over to Robert. Thanks again. Thank you very much, Carter, and for the opportunity presented at this conference. And so as Carter mentioned, we are trying to take a totally different view on cancer and cancer targets. And we'll show you a platform that we're using, which is built around what we call engineered hematopoietic stem cells, EHSCs. Now these are the same cells that repopulate your blood system that produce anything from red blood cells and platelets, all kinds of immune system cells, macrophages, etcetera. So they're quite magical cells. And that being said, these cells are also being used in cancer treatment in transplantation. Now what we're doing is we are gene editing these cells and inherently making them protected from certain targeted therapy. And that in itself is a very simple but elegant solution that we think will be able to transform the lives of patients with AML and other liquid tumors. And so that means we can we'll hopefully enable the use of treatments such as CAR Ts and other targeted modalities and dose them with curative intent. A lead program that we'll talk to you about is called VOR-thirty 3. This is a program that has already received IND clearance and we'll be treating our first patient quite soon. And then we also have a complementary CAR T therapy that we call vCAR33. This is a CAR T that targets the same target that we're deleting out called CD33 and that construct is already in the clinic in a Phase III trial. And we'll be combining these in what we call a treatment system. So let me talk to you a little bit about tumor targets and what we're doing there. Now, you know that tumors express all kinds of different targets, they're very attractive to pursue on a targeted therapy basis. The trouble is that the vast, vast majority of these targets are not unique to the tumor cells. There's still some expression in healthy cells and particularly for disease like AML, where the very cells that create cancer are stem cells derived cells from the blood system. So a lot of the cell surface expression in these tumor cells overlap with the very same stem cells that are necessary for survival. And that overlapping toxicity called on target toxicity not only causes difficulty with therapeutic window, but also has led to a lot of failures in the field. So for example, on the right side, Pfizer's Mylodog, which was actually the first ADC ever approved by FDA, essentially has almost no therapeutic window. When this myelotag is used even at relatively low doses, it still causes Grade 3 or 4, cytopenias in virtually every patient you treat. Seattle Genetics is a fairly spectacular failure that occurred due to safety issues in Phase 3. And there's other examples as well. So when you take this traditional paradigm and you take the fact that you can make the modality as prudent as you want or as targeted as you want, you will never address this fundamental issue of on target toxicity. But instead, let's flip it on its head. Let's think about a way that you could use healthy cells and manipulate those in order to attack cancer. So what we're doing is we're embracing a platform made of 3 elements, hematopoietic stem cells, the same cells that repopulate your gut system, and we are genome engineering these cells to inherently make them treatment resistant permanently, all of those cells and their progeny. So then we're coupling them with the 3rd leg of the stool, which is targeted therapies. And you end up with this phenomenon where you can edit out these targets from healthy cells and thereby expose the cancer cell in ways that would not have been possible otherwise. These healthy cells still function the same, but the cancer cell can now be targeted in a much more specific manner. So let's show how this works in terms of standard of care. In many cancers such as AML, you need to receive cells from a matched healthy donor to replace the disease marrow within these patients. This could be a relative or it could be a stranger that is HLA matched. Those cells are harvested and provided to the patient in a transplant and now the patient has someone else's marrow in them. Unfortunately, a lot of times the cancer occurs in these patients and now you're stuck. You're stuck because firstly, your marrow is susceptible therapy having just been engrafted. But secondly, that this marrow also expresses the same targets that you are pursuing to target the cancer. So instead, what we are doing is we are sourcing those same cells, but instead of putting them straight into the patient, it goes through a simple and elegant manufacturing process that engineers these cells to no longer express these targets, therefore, render them inherently treatment resistant. And so when those cells engraft into the patient, you now essentially engineered the patient. That patient now has a treatment resistant marrow filled with these EHSCs. And so when you come in with targeted therapy, whether you give it on a therapeutic basis or even on a prophylactic basis, you can now treat these patients in a much more tumor specific manner. Now we're starting with acute myeloid leukemia. It's really the most common form of acute leukemia in adults. And unfortunately patients do very poorly even though hematopoietic stem cell transplant is a standard of care. What this chart shows is that patients who are MRD negative, meaning that they have no molecular markers of disease that's detectable from their marrow, generally do fairly well, but you can still see roughly 30% of those patients will relapse post transplant. Now around 40% of all transplant are in these top 2 lines. These are patients who you can pre identify even before transplant where they have MRD positive disease or frank active disease in marrow, but are still transplant eligible. And you can see, unfortunately, roughly 2 thirds of these patients relapse within about 12 months. And it's also the survival upon relapse is extremely poor. So what we're doing is we're starting with a target that's very well known in AML called CD33. CD33, you can see, is broadly expressed in bulk AML cells. It's also expressed in what people call the leukemic stem cell. It's really the most validated clinically validated and popular target in AML. So what we're doing with CD33 are 2 different things. Firstly, we are editing out CD33 from the stem cell in a program that we call VOR33. So this is allogeneically sourced from a healthy donor CD33 deleted EHSC. We just cleared AUS. IND for this by FDA, And this study will be dosing VOL33 with Molotag, Pfizer's ADC that targets CD33. We're going to demonstrate 2 very important aspects in this trial. Firstly, that our cells behave like regular stem cells. They repopulate the blood system and therefore engraft in the patients. Above all, do no harm, and we expect to have that data around the end of this year. Secondly, we are expecting that these cells and their progeny are truly protected from myelotag, which is normally quite myelotoxic. And we'll be hoping to share that data towards beginning of next year. Now another thing we're doing in the CD30 fibrilum is a CAR T. This is a CAR T that's already being studied in a pediatric Phase III trial in AML. We'll be starting our own adult study quite soon. And so what our vision is that we would marry these 2 together that eventually patients could start therapy with VOR33, have essentially a treatment resistant bone marrow that's established and then come in with VCAA33, hopefully a potent and specific therapy against CD33 that you could dose either in a therapeutic setting upon relapse or MRD positive disease or even potentially in a prophylactic setting. Now we don't want to stop there. What we wanted to be doing is establishing our EHSCs as a new generation of standard of care transplants. And this is where we want there to be no reason why you'd use a regular transplant, which is now 50 years old or more in technology and instead use these gene edited transplants that gives so much more treatment optionality for patients in the future, whether you're dosing with a CAR T therapy like our own d CARD33 or with other modalities such as bispecifics and K cell therapies or ADCs. This is what our programs look like in a pipeline. Again, we will be enrolling our first patients soon with WRAT33 and demonstrating that these cells engraft and are protected from Molotov around the end of this year to beginning of next year. We think there's ways to expand within AML such that you could think about haploidentical donors or reduced intensity conditioning regimens with a lot of different opportunities for patients. We also think we can expand into related conditions such as MDS or NPM related to AML and also we believe very strongly express CD33. The CAR T as I mentioned is already in an investigator sponsored trial and then we'll be marrying this up in what we call a treatment system. Now this is all very CD33 centric. What I will show you is that we've made some good progress in other targets that show similar phenomenon such as CD123 and CLO1. Intellectual property wise, we're very proud of our portfolio. We now have over 20 patent families covering our approach, including 6 allowed or granted U. S. Patents that cover everything from platform, different targeted therapies and gene targets as well as ways that you could put these therapies together. Now our founder is Sadafam Mukherjee. He is the famous author of Evan for Oral Maladies and also someone who has a very productive AML lab at Columbia University. He pioneered this approach, but also 2 other labs had orthogonal validation here. Sargill's lab from UPenn as well as Hans Peter Keene's lab from the Hutch. And the findings in all of their papers very much corroborate with each other. So 1 question is CD33 is obviously there for a reason. What happens to the cells if you delete out CD33? This is an experiment which is in mice where you engraft human cells into a mouse, a xenotransplant mouse, where you can now look at cell populations as well as cell function in these animals. What you see in the top here is that when you delete out CD33 versus control cells that still express CD33, there's no change in cell populations here. We've zoomed into myeloid cells on the bottom left where CD33 is a myeloid biased antigen. And again, there seems to be no difference in cell populations as a result of deleting out this gene. We can also look at function and functionally these cells look identical whether it's in terms of phagocytosis or in terms of cytokine production of differentiated cells. But actually what makes us even more confident about the biological redundancy of CD33 is this phenomenon. When you look at human genetics, such as the NOMAD database at the Broad Institute, we could identify 65 individuals in that database who we believe have never ever expressed CD33 in their entire lives. These individuals are homozygous loss of function, meaning that both copies, those alleles of CD33 prevent expression of that protein. And in fact, some of these people we know have lived long and productive lives in that database. And so this gives us very interesting human genetics evidence that CD33 deletion may well be safe. Now if you could delete CD33 safely, can you truly protect these cells from therapy? We believe so. So in fact, this was data that went into our IND. You can see that in in vitro experiments with typical sigmoidal plots, we can obtain almost a tooth log difference in cellular protection when you dose Mylotog in increasing concentrations. Similarly, on the right side, this is an in vivo experiment looking at cells that strongly express CD33. And what you can observe is that dosing monologue to these cells almost completely obliterates those cell populations versus a very nice preservation of these cells where you delete out CD33. It's not rocket science, but deleting out CD33 and then applying a targeted therapy that attacks CD33 expressing cells nicely protects these cells. And so in order to actually implement this in the clinic, we've established a cell manufacturing process that is not only simple, but also elegant. What we're doing importantly in this process is that we're not introducing any new genetic information into these cells such that you don't need any complicated processes there or viral vectors. Secondly, we are not expanding these cells. If you expand hemopoietic stem cells, they can sometimes lose their stem like phenotype. And so we want to minimize the manipulation and handling of these cells. As a result, we have a process that's very simple. We simply prepare the material. We then isolate T cells from the graph that you could potentially actually use for CAR T. But then we gene edits the purified stem cell populations with a simple 1 step genome editing step. And then that establishes our EHSC product. We've routinely done this in under 48 hours and then including release tests and shipping we're envisaging a vein to vein time of 7 to 10 days. When we gene edit, we can do this efficiently. You can see here in our experiments across 2 different lots of guide RNA and across 6 donors, we can routinely get over 80% efficient gene editing of CD33. And then when the edit does occur in the vast amount of cases, it is biolylic edit such that none of these cells nor their progeny should express CD33. So this is what our clinical protocol looks like. We are firstly taking matched healthy donor material creating VOR33 and then on the patient journey treating patients who are high risk of relapse, they all receive myelodulation conditioning and they receive our VOR33 product. Importantly, here we are measuring platelet and neutrophil levels where at day 28, it's a long established measure to understand whether these stem cells engraft into patients. So that engraftment measure is a very short term endpoint. Similarly, we are dosing old patients with Mylotog around day 60. And Mylotog is very well known to cause profound cytopenias within days of administration. And so roughly around 7 to 10 days post myeloid therapy, we're assessing these patients for platelet and neutrophil levels, which will hopefully demonstrate that these cells in their progeny are truly protected from myelotag. Of course, we'll follow-up these patients and see how they do on a clinical basis, particularly looking at relapse free survival, where again, you're expecting 2 thirds or more of these patients to relapse within 12 months of the transplant. You can see the leading sites that we're targeting in this first in human trial. Now vCAR33 is our in house directed CD33 directed CAR T. This is a CAR T that was in license from the National Institutes of Health developed by renowned T cell expert, Terry Fry. This is already in the pediatric study in the relapsed refractory setting of AML and we'll be planning and starting our own adult study soon against this with this construct. And then again, we will be then eventually marrying the 2 together where patients would receive VAS 33 and then receiving vcard33 either in a prophylactic or therapeutic setting post transplant. And that of course is being dosed with a true curative intent. Just briefly in terms of reimbursement, we're very encouraged that Medicare made some significant changes that are in our favor. Not only are CAR Ts now independently reimbursed under their own DRG with fairly healthy commercial rates, but also there's now a carve out that exists that applies to the processing and acquisition of hematopoietic stem cell transplants. That carve out will make transplants a lot more generally affordable for hospitals, but it may well be a mechanism by which we can be reimbursed for our next generation transplants. Now to talk a little bit about the future. I've talked a lot about CD33, but what I will mention are 2 other targets that we're very excited about CD123 and CLO1. I'll also talk about different approaches in multiplexing that can actually use multiple targets simultaneously. And then of course, the very future could be where we could really embrace this whole modality of hematopoietic stem cells towards other conditions even beyond malignancies. But firstly, let's talk about these other 2 targets. This slide summarized a plethora of data about these 2 other targets called CD123 and CLO1. These are both also strongly expressed in AML and we can edit these targets efficiently such as what you saw with CD33. The deleted cells for these targets are in graft normally in mice, and the cell populations look the same, including all the lineages of white blood cells. And then we can look at functional assays of these cells and the function seems to be perfectly preserved even in the face of the gene edit. What you see on the right here, a simple in vitro proof of concept experiments where if you co culture these cells with CAR Ts, either targeting CD123 here or CLO1 on the bottom, you can almost perfectly preserve these cell populations compared to wild type cells that still express these targets. Now this shows that CD33 may not necessarily be a unicorn phenomenon that there may will be other targets that are similarly biologically redundant and you can delete these targets out and therefore make them much more tumor specific in the same way we're doing with CD33. Now we're not stopping there though. What we think is also potentially quite interesting is where we can do a multiplex edit. Now multiplex editing is where you're editing more than 1 gene locus at a time. And in this experiment, what you're seeing is that we've deleted out both CD33 and CLO1 from the very same cells. What you're seeing in this experiment is that with these dual deleted cells, we can then apply 2 different CAR Ts at the same time, a CAR T targeting CD33 and another targeting CLL1. And what you can see is that wild type cells that will retain expression of both are very strongly killed off. Single deleted cell populations, deleted either for CD33 or CLO1, are also killed off by the CARs, but then a very nicely preserved population of cells that have the dual deletion where they are perfectly intact even in the presence of 2 different CAR Ts. We think this approach could be really interesting where if you're ever worried about tumor escape mechanisms down regulating a single target, this could well be a great solution for that. In addition, you could think about treatment combinations or sequential treatments such as maintenance and rescue that could well be optimal for patients. This is how we're panning out in terms of looking at different clinical catalysts. Again, we're expecting to show engraftment data around the end of this year, shortly followed by Molotov protection data with VOR-thirty 3. The vCAR-thirty 3 will be reading out over time around 2022. And then we expect to combine the 2 in the treatment system. Additional milestones may well be expected for other targets or programs as we advance those. So in summary, Volf Biopharma is a cell therapy company where we really are taking a fundamentally different approach to treating cancer and approaching cancer targets. EHSC as a platform will allow us to create treatment resistant bone marrow transplants that will inherently change the way that you could apply targeted therapies post transplant and really hopefully dose these treatments with curative intent. We'll be we're already entering the clinic with a cleared IND with Vorf33. We have a very complementary CAR T therapy that we can couple to that and then we'll be combining these together in a treatment system. Starting in AML is a fantastic treatment opportunity for patients who really don't have any good treatment options at this point. But we think this is a true platform that you could leverage other targets and it really expand out beyond AML in other hematological malignancies. We just recently raised an IPO with gross proceeds of over SEK200 1, 000, 000 and good amount of runway. And we look forward to using those proceeds to advance transformative therapies for patients. Thank you very much for your time.