Innate Pharma S.A. (IPH) Earnings Call Transcript

Ladies and gentlemen, thank you for standing by, and welcome to the Innate Pharma conference call. [Operator Instructions] I must advise you the conference is being recorded today, Tuesday, the 9th of February 2021. I will now hand the conference over to your speaker today, Dr. Mahjoubi. Please go ahead.

Thank you. Good morning, good afternoon, everyone, and thank you for joining us today. I'm Mondher Mahjoubi, Chairman of the Executive Board and CEO of Innate Pharma. And I'm very pleased to welcome you today to today's event as we welcome 2 key hematology experts to provide insight into the unmet medical need across the T-cell lymphoma space and the potential impact of our lead investigational product candidate, lacutamab. Move to the next slide, please. We don't see the next slide. So it's Slide #2. Our -- first, I would like to remind you that we will make forward-looking statements regarding the financial outlook in addition to regulatory and product development plan. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. Slide #3. The agenda of today's call. Following my brief intro, Dr. Joyson Karakunnel, our Chief Medical Officer, will provide an overview on lacutamab, a high-level summary of today's update as well as a rough outline of our development strategy. Following that, we are very pleased to be joined today by 2 key opinion leaders in the field of T-cell lymphoma: Dr. Pierluigi Porcu, who will outline the epidemiology and review the unmet need across the cutaneous T-cell lymphoma and the peripheral T-cell lymphoma landscape. Dr. Porcu is also the primary investigator of our Phase II TELLOMAK study, and he will speak to the progress in that study. The second guest is Dr. Olivier Hermine, who join us from the Lymphoma Study Association, or LYSA, and who will speak to our collaboration with this major cooperative group for peripheral T-cell lymphoma, which we announced this morning. Joyson and myself will return following the presentation from our guests to conclude and then open up for questions. Please move to the next slide, #4. First of all, I wanted to take a moment to give you some background on our featured speakers today. You all know Joyson, who joined us last year. Dr. Porcu and Dr. Hermine are 2 world-renowned experts in their field and represent leading institution in this space. We are very pleased that they have joined us today to speak to the TCL landscape and to the potential of lacutamab to improve patient outcome and address unmet medical need for this population. Please move to Slide #5. And before we move on to the main event, I would like to spend just a few minutes, provide a brief overview of the company, so you can put today's update into context with the broader strategy and development priorities. At the Innate, we follow the sign, and we are committed to developing innovative medicines for patients and to building a robust pipeline of novel antibody therapeutics that leverage the body's own innate immunity and target area of high unmet need. Over the last 2 decades, we have developed a scientific excellence in the field of innate immunity with particular expertise in NK cell biology and also in antibody generation. Actually, this brings us to our strategy and focus for 2021 and beyond, which is on Slide #6. First, we will drive the near-term value with lacutamab. We have generated our outstanding Phase I clinical data that led to the clinical development plan that we will share with you today, and there is clearly potential there to not only address unmet medical need with Sézary syndrome, but expand beyond that and address other segments of the T-cell lymphoma space. This is the short term. This is the low-hanging fruit. This is where we have to put our energy and focus in the 2021, 2022. In the midterm, second, we have to advance our innovative R&D pipeline with a particular focus on NK cell targeted approach, and in particular, leveraging our NK cell engagers, we will probably have to address this at one point in time join Q&A, but there is a growing momentum about NK cell engagement, the role of innate immunity. And we have to leverage that opportunity through our pipeline. Last but not least, we need to continue to build a sustainable business through partnership. That's how we will strengthen our financial position and further invest in our R&D pipeline. Drugs like monalizumab, avdoralimab and others will help us through the partnership to build this sustainable business. Actually, on Slide 7, you have a summary of what we have done over the last 2 decades. Scientific expertise is at the heart of Innate and today, we are very pleased to add to the list of collaboration and partnership, the LYSA Go, as we have just announced the collaboration with them on future lacutamab study. But clearly, we have a very strong science that has been validated in high-impact publication. We have a strong track record of collaboration and partnership with both academia and leading pharma industry, and that led to the robust pipeline with the innovative technical and clinical assets that we have in our portfolio today. Actually, if you move to the next slide, you have an overview on our R&D strategy. And before I get into the details of this very schematic approach of the Innate cycle, let me say that over the last almost 15 years now, most of the immuno-oncology approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors or by targeting activating pathways as with CAR-T cells or biospecific antibodies. These treatments actually have led to unprecedented success and have transformed the natural history of this disease, in many cases, yet, there is a high unmet medical need in many solid tumors, and there is a need then to identify new cells and new molecules that could be exploited as the next generation of immunotherapy. And in fact, given the crucial role of innate immune response in the immunity, harnessing these responses actually opens up new possibility for long lasting multilayered tumor control. In fact, you have on this cartoon, 2 of the approach we have followed in order to either unleash NK cells by targeting inhibitory receptor that are expressed on the surface of NK cells, and monalizumab is the perfect example of that. But the other approach that we are taking is to engage NK cells directly to our tumors, either through tumor antigen, like with KIR3DL2 or eventually by using our, as I said, NK cell technology, capturing NKp46 on one side and a tumor antigen on the other side. And on Slide 9, you have the pipeline that shows how we have turned basically this scientific excellence into a robust pipeline of proprietary and partnered assets. Of course, the focus of today's call is our lead product, lacutamab. As we go into detail of this product, you will see we have a step-wise and strategic approach to its development. But we have also balanced pipeline with partnered assets, which provide us with nondilutive revenue stream, for example, monalizumab. And finally, we maintain a healthy preclinical pipeline, our engine to fuel our future clinical portfolio. And beyond lacutamab, our primary focus as a sale is on the advancement of novel NK cell engaging molecule or NKCE. And now I'll turn over to Dr. Joyson Karakunnel, our Chief Medical Officer, who will provide more detail on lacutamab. Joyson, over to you.

Thank you, Mondher. So I will start on Slide 11. So as noted, lacutamab is our lead proprietary asset, and we are very excited about this asset. And we want to talk to you further about the development -- further development of lacutamab. So just let's start with a little bit about the mechanism of action. Lacutamab was designed to bind to KIR3DL2 on tumor cells and recruit immune effector cells to deplete the tumor. Fc receptors on the NK and myeloid cells are activated, including CD16 and CD64, inducing an antitumor cytotoxicity. This was tested in a Phase I study in Sézary syndrome, which has been published in the Lancet Oncology. The data that was generated from this Phase I trial helped to move into a Phase II study, which is called TELLOMAK, which we will go further into in the upcoming slides. This data also was able to secure us EMA Prime Designation as well as FDA Fast Track Designation in Sézary syndrome as well as Orphan Drug Designation in the EU and the U.S. for CTCL more broadly. As KIR3DL2 is expressed across subtypes of T-cell lymphomas, but not on healthy cells, we are pursuing a broad and stepwise development strategy for lacutamab. Sézary syndrome represents a niche indication with an unmet need. And from there, we want to expand into other forms of T-cell lymphomas, such as mycosis fungoides and peripheral T-cell lymphoma. So if we move on to Slide #12. So here, you see a breakdown of the KIR3DL2 expression across the different subtypes of T-cell lymphomas, specifically looking at Sézary syndrome, mycosis fungoides and peripheral T-cell lymphoma. Sézary syndrome, the expression is about 90% of patients expressed this target. Dr. Porcu will go into some of the data that we have generated from the Sézary syndrome trial. Mycosis fungoides, about 50% of the patients express this target. And we will go over a little bit on the TELLOMAK study and how we are trying to further determine the expression patterns in mycosis fungoides. And finally, in peripheral T-cell lymphoma, where it's greater than 50 -- it's about 50% of patients express the target. The incidence is also shown on the right-hand side. And in the 5 -- sorry, 7 major markets, we see that the incidence is about 80 to 200 for Sézary, about 2,000 to 4,000 for mycosis fungoides and about 18,000 for peripheral T-cell lymphoma. If we move on to Slide #13, this is the TELLOMAK study. And in the TELLOMAK study, I'm going to slowly walk you through this because there is some important information that we'll get to on the next slide. So the TELLOMAK study is a Phase II study that is evaluating lacutamab across subtypes of CTCL, specifically in Sézary syndrome, which is Cohort 1; and then cohort 2 and cohort 3. Cohort 2 and Cohort 3 are made up of mycosis fungoides patients -- patients with mycosis fungoides. In Cohort 2, these are mycosis fungoides patients that expressed KIR3DL2. And in Cohort 3, these are not patients who have mycosis fungoides that do not express KIR3DL2. Looking again at Cohort 2 and Cohort 3. It is an assignment 2-stage design. So essentially to go from stage 1 into stage 2, there is a minimum threshold that we have established. The study endpoints include objective response as a primary endpoint, and key secondary endpoints are progression-free survival and duration of response, quality of life and adverse events. Just to note, the KIR3DL2 positivity is defined as greater than 1% of KIR3DL2 expression based on IHC. In Cohort 1, just going back up to the top, this cohort has been expanded from our Phase I trial data to 60 patients -- about 60 patients. And the importance of that is, number one, it is in greater than 2 lines of therapy, including mogamulizumab. But in addition, this can serve as a pivotal trial and has been discussed with the FDA. If we go on to the next slide, Slide #14. So this is exciting data that we want -- that we want to share with you today. So we have seen early signals in KIR3DL2 patients -- in the expressing patients. Specifically, as I mentioned, Cohort 2 and Cohort 3 are based on a Simon 2 stage design that in a minimum threshold would move us from stage 1 into stage 2. And we have reached this threshold before enrolling 50% of the planned patients within the KIR3DL2 expressing patients. So once again, in Cohort #2 of the mycosis fungoides, patients where there's KIR3DL2 expressors, we have reached the minimum threshold to move into -- from stage 1 into stage 2 before 50% of the patients have been enrolled. We look forward to presenting this data at an upcoming conference in totality. Next, we'll move on to Slide #15. Also announced today were the next steps in our clinical development plan for PTCL. We are initially exploring lacutamab in the relapsed setting as it has the highest unmet medical need. In this setting, we are deploying a two-pronged approach by advancing 2 parallel clinical trials to evaluate lacutamab as a monotherapy and in combination with the standard of care in the relapsed/refractory or refractory PTCL expressing KIR3DL2. We will run a multicenter Phase Ib monotherapy trial, which will enroll approximately 20 relapsed patients to evaluate safety and characterize clinical outcomes for lacutamab in the relapsed/refractory PTCL setting. And in addition, dependent upon the data, we'll also consider starting a separate trial in combination with the standard of care. Our partners at LYSA, which Dr. Hermine will talk more about, will run an investigator-sponsored Phase II study, which will evaluate lacutamab in combination with chemotherapy, GemOx, or gemcitabine oxaliplatin, versus gemcitabine oxaliplatin alone. This will also be a multi-center, randomized study and will recruit approximately 60 relapsed/refractory patients outside the U.S. I want to emphasize that Dr. Hermine will go further into the details of this trial, and we are very excited to have him speaking with us today. As noted in our press release this morning, we anticipate that both of these trials will be initiated in 2021, the monotherapy within the first half and the LYSA study within the second half. Overall, we believe this is an efficient data-driven strategy to identify the optimal regimen for lacutamab in the relapse setting and eventually support advancing lacutamab as an earlier line treatment, including as a combination in the CHOP regimen in the frontline PTCL setting or as a consolidation therapy following standard first-line therapy. With that, I'd like to hand over to Dr. Pierluigi Porcu. Dr. Porcu is a professor of Medical Oncology, Dermatology and Cutaneous Biology at Thomas Jefferson University. Subsequently, Dr. Olivier Hermine will speak. He is a professor of Hematology at the University of Paris Descartes and Director of Division of the Adult Hematology at Hôpital Universitaire Necker Enfants Malades.

Thank you, Joyson. It's a great pleasure to be on this call this morning, this afternoon for those of you in Europe and the audience here. I'm a medical oncologist, with expertise primarily in lymphoma, particularly in T-cell lymphoma. My position is Division Director of Hematologic Malignancy and the Hematopoietic Stem Cell Transplantation at Thomas Jefferson University in Philadelphia. And professionally, I'm a medical oncologist who's been treating patients with T-cell lymphoma for more than 20 years. And I've been involved in many clinical trials in T-cell lymphoma. So next slide, please. So I'm very excited, really this morning to kind of provide you an overview of the epidemiology, the disease spectrum and, fundamentally, the clinical unmet need in both CTCL and peripheral T-cell lymphoma in the context of what Joyson just presented to you. Next slide, please. So what this slide shows is that in the U.S. in 2019, there were approximately 80,000 cases of lymphoma in general, 82,000 cases, specifically. As the slide also shows, of those, a minority of cases were T-cell lymphoma, but a significant minority because the clinical unmet need in this population is very high. Of the T-cell lymphomas, about 8,500 to 9,500 cases a year are represented of peripheral T-cell lymphoma and the cutaneous T-cell lymphomas represent 2,000 to 2,500 cases per year. Next slide. When we look at the way we currently classify T-cell lymphomas, I would like you to focus on the lower part of this slide on the left with those different columns there to show the classification, which is made according to the clinical presentation. Clinical presentation and clinical manifestations are very important in the distinction of the difference of types of T-cell lymphoma. And as you can see from the slide, depending on whether T-cell malignancies are presenting as a leukemic component, lymph nodal involvement primarily or extra nodal or cutaneous, they belong -- they are classified according to the different families. This leads to the fact that what we call cutaneous T-cell lymphoma, which is accounted on your leftmost side of the slide, which represent about 3% of all non-Hodgkin lymphomas, already classified as a separate category. And this category includes mycosis fungoides and Sézary syndrome, which we're going to discuss more in a minute. The other major category of T-cell lymphomas they included, it's called the peripheral T-cell lymphomas, which represents 8% to 9% of all non-Hodgkin lymphoma. And the most common types are those listed in the nodal family, which are peripheral T-cell lymphoma NOS, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma. Next slide. So let's focus on cutaneous T-cell lymphoma and the initial part of this conversation. Next slide. This slide presents 2 different sort of sets of information here. On the left, the table shows the prevalence and the incidence of the different types of cutaneous T-cell lymphoma, particularly Sézary syndrome and mycosis fungoides in separate sort of columns. Cutaneous T-cell lymphoma are relatively heterogeneous, and they are essentially lymphomas that present or behave primarily in the skin; however, with time, many of them actually progress to involve visceral organs, lymph node and blood. Overall, the annual incidents in the U.S. for cutaneous T-cell lymphoma is about 0.5 per 100,000 per year. This translates into an annual new number of cases of about 2,500 to 3,000 cases per year, as shown in the previous slide. Now because of the long survival of patients with cutaneous T-cell lymphoma, the actual prevalence, so at any given time, the number of patients who are living with the disease and most of them after receiving therapy for cutaneous T-cell lymphoma is much higher. It's estimated to be 25,000 to 30,000 cases per year. These are data from the cutaneous lymphoma foundation surveys that are available online. The median age at diagnosis is 55 to 60 years. The average time from diagnosis -- from disease onset to diagnosis is long because the biopsies can be difficult to read. So this is an unmet need also in the diagnosis of this disease to make an early diagnosis. Again, the table on the left shows that if you look at the U.S., the EU and then Japan as a non-North American European country, mycosis fungoides and Sézary syndrome together represent approximately 2/3 of all the cases of CTCL. And the other cutaneous T-cell lymphomas represent about 1/3. Now Sézary syndrome is a rare disease and represents about 1% to 5% of the cases of cutaneous T-cell lymphoma according to the different regions. The table on the right shows the breakdown in the different subtypes. We're not going to go through all of them. But fundamentally, this shows that mycosis fungoides in terms of the survival is the one that has kind of the best survival between MF and Sézary syndrome with all together 88% of the overall survival with slight differences according to the subtype. The 5-year survival for Sézary syndrome is much lower with about 36%. And all the other subtypes have a very good favorable prognosis with the exception of the gamma delta in the cutaneous peripheral T-cell lymphomas that are very [indiscernible], which we are not going to discuss. Next slide. Now looking specifically at mycosis fungoides, which is, again, by itself, the single most common type of T cell -- of cutaneous T-cell lymphoma, this slide is supposed to convey the concept that it is a progressing low-grade CD4 positive T-cell lymphoma. Just think about follicular lymphoma, think about other low-grade lymphomas that have a very slow course and progression. The difference is that in cutaneous T-cell lymphoma and mycosis fungoides specifically, this progression is very easily visible and can be followed because the manifestation is primarily in the skin. Now as I mentioned, mycosis fungoides has a significant tendency to progress over time. And the way we break down our understanding of mycosis fungoides during the course of the disease is that to begin on top as a state of dynamic but stable equilibrium. At that point, the immune system of the patient is normal or near normal. And the interaction between tumor cells in the skin and the immune system is balanced. This period may last many years. Eventually, over time, the dynamic state changes and the equilibrium becomes unstable. And that is generally associated with a reduction in the efficiency of the immune response. Eventually, the T-cell clones expand. The immune system becomes more defective, and the rash extends to greater and greater surface of the body sometimes eventually leading to involvement of the blood and the lymphoma. At that point, point number three, with the image shown on the right, the -- at this point, we're dealing with a very aggressive type of T-cell lymphoma with nodular growth, which implies a vertical growth, aberrant trafficking of the T-cells, defective apoptosis, progression and death, and this corresponds to the development of a very high burden of oncogenic mutations in the malignancy cells. At this point, mycosis fungoides become a very aggressive T-cell lymphoma, very difficult-to-treat and almost impossible to cure. And this is shown by the survival data on the most -- on the rightmost part of this slide. Next slide. So in terms of how do we manage cutaneous T-cell lymphoma and what is kind of going from the previous slide, how do we look at the risk of progression here? So from the previous slide, it becomes evident that mycosis fungoides is an immunologically responsive disease, particularly in the first and the second part of their natural history. The other is that multiple therapies are necessary over time. And despite the fact that the FDA has approved multiple therapies, really, the duration of response is typically low. The quality of response is typically low. And therefore, there remains a significant unmet need for additional therapy for most of these patients. Now stable disease in these patients is a meaningful endpoint because often, it corresponds to symptomatic improvement in quality of life. It's a major component of the management for this disease. If we look at the patients coming through, as physicians see them in their office, about 2/3 of the patients present with early stage, meaning that they have disease primarily located in the skin. And only about 1/3 of the patients present with more advanced stage. However, the vast majority of the patients who have early stage, particularly sort of more extensive early-stage disease in the skin, over decades, will progress to more advanced stage and eventually will require systemic therapy. And if we look at the median survival in advanced stage. So once you hit the advanced stage, the survival is short, as I mentioned before, 1.5 to 3.5 years. And this is in terms of the risk of progression as shown in the panel on the right side, which from bottom to top, shows the different risk of progression for patients with earlier stage versus more advanced stage. And if you look at the very bottom, you'd see that even patients who have the early stages of 1A and 1B in particular, over 20 to 30 years, the risk of progression is high, up to 40%. So the need for systemic therapy clearly impacts also patients who present with early stage disease. Next slide. And this, again, is to reemphasize and reinforce kind of a pictorial view of the journey of the patients here. Starts from the left. Essentially, patients who, again, 2/3 of the patients present with early stage, they will have symptomatic disease, sometimes itch, sometimes it's just a cosmetic, but most patients want to have therapy, and they will start skin-directed therapy. Now skin-directed therapy can -- there are many different types. It will be cycled. Often would be overlaid. So it would be more than one type. But eventually, over time, the patient will require cycling of different types of skin-directed therapy, sometimes with the additional skin-directed radiation therapy. And during all this time, again, quality of life remains a very important component of the management. Over time, however, it could be 2 to 5 years, could be longer, but eventually, the patient will experience relapse from a previous complete response or more often failure to maintain a partial response and will progress. And at that point, that's when the decision to start systemic therapy in these patients is made. And from that point on, really, the natural history is one of continuous cycling of systemic therapies, which are shown here in the block, with a relatively narrow treatment -- time to start the next treatment or treatment-free interval. And again, this time for the last 5 to 8 years, but at some point, when the patient develops advanced stage disease with lymph node involvement, potentially blood, the survival is short. So it's really kind of throughout the natural history and the patient journey here, a patient will continuously go from one systemic therapy to the next, often overlapping with skin-directed therapy. Now Sézary syndrome, which as we saw in the previous slide, is a small minority of the patient with CTCL; however, essentially presents with advanced stage disease de novo. These are patients who present with skin and lymph nodes and blood involved as shown in the next slide. And at that point, their survival is very short, and there are no effective therapy. Next slide, please. So the -- there are currently 6 agents approved for cutaneous T-cell lymphoma. They are listed here, to some degree, kind of, almost chronologically because with Bexarotene being one of the earliest, then Ontak, Vorinostat, Romidepsin, 2 of these are HDAC inhibitors. Brentuximab is an antibody drug conjugate targeting CD30, and then most recently, mogamulizumab, which is an anti-CCR4 monoclonal antibody. These are approved either in the U.S. by the FDA or both in the U.S. and in Europe. The table is the specific indication, which I'm not going to go through directly. What I want to point out is the efficacy and the overall response rate. And one important phenomenon to highlight here is the fact that many of the studies that originally led to the approval of these drugs were small Phase II studies. And when the same drugs were then later tested as a standard of care comparator arm in clinical trials, they actually had significantly lower response rate, which is something that you would expect. In some cases, major differences in response rate because if you look, for example, at Vorinostat, when it was approved, was approved with a response rate of approximately 30%. But then on the subsequent MAVORIC study, which is the study that led to the approval of mogamulizumab and vorinostat was the standard of care, the response was only 5%. And particularly, the response in Sézary syndrome are absolutely dismal with many of these drugs with exception of mogamulizumab in the MAVORIC study. Next slide. So when we look at the lines of therapy for patients who are -- lines of systemic therapy for patients with CTCL, it will look something like this. For mycosis fungoides, it's really kind of Bexarotene, which are retinoid. All Bexarotene-based combinations, often with skin-directed therapy at the same time and then Brentuximab, mogamulizumab, Romidepsin, Vorinostat and then a number of other chemotherapy drugs used either in combination or as a single agent. For Sézary syndrome, it's sort of the same thing, except that the efficacy of most of those approaches is quite low. And certainly, the duration of response is very, very low, short. Next slide. Okay. So now moving on to peripheral T-cell lymphoma. Peripheral T-cell lymphomas, again, if you go back to the slide that I showed at the beginning, essentially are defined as those lymphomas that primarily affect either the lymphomas or external sites or have leukemic involvement. And of those, the significant majority of them are the nodal type of peripheral T-cell lymphomas listed here in this pie chart as a peripheral T-cell lymphoma, NOS ALK-positive and ALK-negative, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma. Between the 4 of those, essentially, they account for about 2/3 of all the different types of peripheral T-cell lymphoma. Now these data are coming from the complete registry, which is a U.S. prospective registry that started many years ago. It has now completed accrual and data are gradually being analyzed and coming out in publication. I think that this is a fair representation of the distribution of peripheral T-cell lymphoma in the U.S. and probably in Europe as well, with some small exceptions. Next slide. Now because we're focusing primarily on patients with relapsed/refractory PTCL following Joyson's presentation here, I wanted to provide the audience with kind of a view of what's the progression-free survival and what is the survival in general for patients with relapsed/refractive PTCL. The short answer to that, it is dismal. And what this slide shows, it's a compilation of progression-free survival data from a number of studies, some of them sort of retrospective, kind of a single institution or registry studies and some of them actually are from prospective clinical trials. As you can see, with the exception of Brentuximab, which is shown on the right side of the slide, which is mostly applicable for anaplastic large cell lymphoma or for CD30 expressing peripheral T-cell lymphoma. With exception of Brentuximab, the responses in the progression for survival are very, very poor. We're talking about 3.7 months, 4 months, 1.6 months in the belinostat trial. So huge unmet need here. Now brentuximab has better response data, particularly in anaplastic large cell lymphoma and better progression-free survival. But you have to understand that Brentuximab is now approved in the frontline setting for CD30 expressing peripheral T-cell lymphoma in the U.S. and for CD30+ anaplastic lymphoma in Europe and, therefore, has quickly become kind of a standard of care in the front line for these populations. And therefore, it's not going to be available for second line for most patients, certainly for all patients who have anaplastic large cell lymphoma and for many patients with peripheral T-cell lymphoma as well. So this kind of opens up the need for second-line in peripheral T-cell lymphoma. Next slide. Now the standard of care for patients with peripheral T-cell lymphoma based on the information I just provided has changed recently and now can be divided between CD30 expressing peripheral T-cell lymphoma and CD30 non-expressing peripheral T-cell lymphoma. The CD30 expressing represent about 40% of all the peripheral T-cell lymphoma, and the vast majority of them are anaplastic large lymphoma. For these patients, the standard of care right now is Brentuximab vedotin and CHP following the ECHELON-2 clinical trial data, we call this BvCHP. For patients who are not expressing CD30, the standard of care remains essentially a CHOP-like chemotherapy, either with or without etoposide. Now with these approaches, the overall response rate and the progression-free survival are shown at the bottom of the slide here to the left. And overall response rate in the CD30-positive patients are pretty good, 80%. And even the CD30 negative are good. And even including complete responses, they issued a progression-free survival -- again, we're talking about frontline now, which is good for the CD30-positive peripheral T-cell lymphomas, but remain completely inadequate for the CD30-negative peripheral T-cell lymphoma. Therefore, many patients -- most patients really have to move on to second or third line therapy, and these are listed in the slide on the right side. And there's no single standard of care for patients in second-line depending on the patient situation or the physician preference or potentially with some additional considerations in terms of a subtype. People may select a combination chemotherapy with GemOx, which is very frequently used or other combination therapies or single agent FDA-approved drugs, particularly in the U.S., where those are available, Romidepsin, Pralatrexate, Belinostat or single-agent chemotherapy. And the responses are shown in the below with overall response rates ranging between 30% and 45%. And as I showed before, the progression-free survival is very short. So this is a huge area of unmet need in peripheral T-cell lymphoma, with none of the drugs listed in this slide here really having taken kind of majority of the market or showing particular strength and, therefore, becoming kind of a leading drug that will replace everything else. There's plenty of need and opportunity for additional drugs. Next slide. So when we look at the relapsed/refractory PTCL, kind of a summary about what we have just discussed is as follows. In frontline, there are good response rates for sure, including complete response rate, but even in the frontline, most patients eventually progressed, and they have to have second line or third line of therapy, with exception of anaplastic large cell lymphoma where Brentuximab clearly has been a game changer. There's really no intensive salvage therapy for patients who arrive refractory PTCL. When we look at the second line and beyond, it's a dismal situation. Some individual patients have good responses with some of those drugs, but the vast majority of them failed to respond or have durable responses. And despite all these drugs recently approved, the prognosis really remains very poor for these patients. Next slide. So we're going to focus on the KIR3DL2 now in the next few slides, and then I'll review the data from the Phase I study that Joyson mentioned. Next slide. So KIR3DL2 as both Mondher and Joyson mentioned is, it's a very important biomarker in T-cell lymphomas. It's a member of polymorphic family of innate cell receptors. So it is expressed on a small subset of innate immune effector cells but more predominantly is expressed -- high expressed on subtypes of B-cell lymphoma, which Joyson has reviewed before. I think that the interest in KIR3DL2 in T-cell lymphoma comes in parts also from data that have shown that it's a very sensitive diagnostic marker for Sézary syndrome, which has been a disease, quite difficult to pinpoint with a single biomarker or a single combination of biomarkers. And in addition to KIR3DL2 expression may actually have some prognostic impact for Sézary syndrome as well. Now because it is sensitive, and it is a good market identified Sézary cell, it is also helpful for follow-up and management of disease long term. In patient with PTCL, high expression is actually associated with advanced stage, extra-cutaneous involvement and overall shorter survival. So we all feel that KIR3DL2 beyond the fact of it is somewhat cardio therapy for lacutamab, it's a very interesting biomarker in T-cell lymphoma. And so we've mentioned the following 2 slides, this one and the next one, next slide, are going to show just the pattern of expression of KIR3DL2. This particular slide shows KIR3DL2 expression in Sézary syndrome, the top 3 panels and transform mycosis fungoides with 3 -- the bottom 3 panels. And you can see that some expression but is strongly expressed across both sites. In peripheral T-cell lymphoma, next slide shows the 3 nodal types of periphery T-cell lymphoma angioimmunoblastic NOS and anaplastic large cell lymphoma. As Joyson mentioned, approximately -- based on information we have right now, approximately 50% of the patients with peripheral T-cell lymphoma expressed KIR3DL2. And there is some heterogenerative expression here, the slide shows, and so it would be important to gather more data on exactly the pattern and the intensity and the frequency of expression of KIR3DL2 in Peripheral t-cell lymphoma. But certainly, there is plenty of data sufficient to justify targeting KIR3DL2 in peripheral T-cell lymphoma. Next slide. Okay. So I'm going to briefly review now the lacutamab Phase I data. Next slide. As Joyson mentioned, the study has been published in Lancet Oncology, so it's available to all the audience as a publication. The Phase I altogether enrolled 44 patients with cutaneous T-cell lymphoma that had failed at least 2 lines of systemic therapy. There were 25 patients with -- in the dose escalation part, 20 of which has Sézary syndrome and then 19 patients in the cohort expansion, of which 15 had Sézary syndrome. So this was a Phase I, very heavy on Sézary syndrome, which as an investigator on this Phase I, all the investigators really appreciated because those are the patients for which we have nothing really. So it's good to see these number of patients treated in a clinical trial. The trial led to the identification of the RP2D as 750 milligrams weekly times 4 and then every 2 weeks and then every -- once a month until progression. The safety signal was extremely good. The AE was not reached. There was no DLT. The most common adverse events were lymphopenia and fatigue grade 1 and 2. So as someone who had patients on the Phase I and having reviewed all the data, the drug was really striking for the safety, in addition to the efficacy so -- which is important in comparing it to some of the other available drugs. Now the panel on the right shows the waterfall plot, specifically for the patients with Sézary syndrome, which altogether were 35, both in the initial dose escalation, the cohort expansion. And as you can see, the color coating of the best global response, trpR, stable disease. And as I mentioned, stable disease, these patients actually is a valuable -- sort of clinically valuable type of efficacy. And the waterfall is impressive because there are many responses and including complete responses. Now if we look at the durational response, the progression-free survival, which are shown on the bottom parts of that panel for the Sézary syndrome patients, it's very good with a best global response of 43% essentially, a durational response of 13.8 months, which is very, very impressive. And this is true even with prior exposure to mogamulizumab, which is essentially currently the standard of care available, so it really becomes an important benchmark for any drug that wants to go to Sézary syndrome. And the response rate in patients with Sézary that did not have large cell transformation was even higher, and I'm not going to go into the details of that, but I think the problem with large cell transformation, first of all, it's difficult to define, to some degree, but -- and it's a heterogeneous population. So I think that it's important to see that the response rate remains good pretty much across the board of all the different types of Sézary syndrome. Next slide. So this is a representative patient, and you can see the information on the patient on the left side. This was on the Phase I study. The top panels are showing essentially the erythroderma inflammation of the skin and cutaneous involvement with Sézary syndrome. These patients are incredibly symptomatic with very severe pruritus. There's nothing that can often take care of the itching, except for a good clinical response. And the patient was started on lacutamab and after having failed all the therapies that are listed there and have a global PR starting at week 14. So this is a very satisfying response both for the patients as well as the clinical investigators. Next slide. So if we want to put those data that I just mentioned into context, if we look at the results in MF and Sézary patient with mogamulizumab and Vorinostat. First of all, the 2 drugs in that clinical trial that were tested in patients who had to receive at least 1 prior system therapy and not 2. Response rates are listed there, and they are good considering the clinical situation. At least for mogamulizumab, for Vorinostat are not good at all. The median progression-free survival in the trial, clearly -- very clearly favors mogamulizumab, but it's still relatively short. So we're talking about 7.7 months. If you look at the time to next treatment, which is something I alluded to in the slide where I was showing the cycling of all those different systemic therapies, is still not ready even with Moga. It was very bad with Vorinostat. So this is kind of the landscape right now in the benchmarks, as I mentioned before, that we have to consider for CTCL, particularly for Sézary syndrome patients. So there's plenty of opportunity for improvement here. Next slide. So in conclusion, have to be clear that Sézary syndrome is perhaps the area of highest unmet need in CTCL and lacutamab really has very promising activity in this subset with 43% global response. And this is highly meaningful. Of course, we're going to have to see if these data are confirmed in the TELLOMAK in Cohort 1. We are looking forward to see that. I think there's optimism, but we're just going to have to see the data. If the data holds, then I think this is going to be a paradigm shift in Sézary patients, particularly after at least 2 systemic therapies. In MF, I think, again, the activation, as Joyson mentioned, of the stage 2 is highly encouraging. And again, we're excited to see the study moving forward. We'll have to see how the responses are in terms of quality of life, in safety and all the things that are important for this subset of patients. We're going to have to see exactly what the actual magnitude of the benefit is. In peripheral T-cell lymphomas, where the unmet need is very high, clearly, there is an opportunity in second line for new therapies. And I think lacutamab clearly is a drug that we are all interested to see how it's going to perform in this population. The expression of the biomarker is there. The unmet need is very high. And again, we're looking forward to see how the therapy is going to perform either as a single agent or in combination with GemOx. Next slide. Okay. This is my last slide. Thank you very much for your attention. I'll then -- Dr. Hermine will proceed now. Thank you.

Okay. Thank you, Professor Porcu. So my name is Olivier Hermine, and I'm physician and hematologist in Paris, Professor of Hematology at University of Paris Descartes. And I'm heading also laboratory on cytopathology and mechanism of hematological disorders and therapeutic implications. So next slide, so first, I will introduce what is the landscape of -- and the organization of treatment and diagnosis of T-cell lymphoma in France. And I'm part of the LYSA, which is a Lymphoma Study Association and also on the Lymphoma Academic Research Organization. And the aim of this organizations is to define the best therapeutic strategy and prognosis for patients with T-cell lymphoma. So our next slide, our network is made of a cooperative network between like 500 lymphoma specialists in 100 centers in 4 countries: in France, Belgium, Portugal and Israel. And we have numerous international collaboration. And also, we have a strong track record for oncology breakthrough. So we can see we have a network in all France and Belgium and part of Europe to be able to include a lot of patients in study for T-cell and B-cell lymphoma. Next slide, our mission is to gather lymphoma specialist in an organized network of professionals and opinion leader. And we try to design research programs and clinical trial protocols at all stage of the disease from Phase I to IV and to have a long-term follow-up of this patient, which has been included in protocols. And we can assess clinical, biological, anatomo-pathological and epidemiological studies. And currently, we have made something like 130 research project that we published in scientific journals and in international congresses and to disseminate the information to patients, but also to the medical community in all world. Next slide. So how we are organized, we can make some clinical trials, which are made and monitored by the LYSA. And with the LYSA, we work very closely with LYSA, which is an organization of physicians involved in lymphoma. We split in different parts that we call the LYSA biology, the LYSA pathology and the LYSA imaging to be able to assess all of the aspects of lymphoma. And we collect all of this data through the LYSA, and we can assess the clinical, biological imaging and pathological data. And we use this biological material to do transactional studies and also basic fundamental study on lymphoma. And we have now a big database with almost like 25,000 patients in which we have all of the clinical data, the phenotype of the patient. And most of the biology and anatomo-pathological imaging data. And we can use this data for bioinformatics and biostatistics study to assess the prognosis and to do some theranostic studies on lymphoma, which led to publications and to a number of collaborations with academic laboratory, academic clinical department and industrial and biotech partner. Next slide. So because of this collaboration, we have some landmark that I can show you here. For example, we did some Phase II and Phase III trials, which led to show the benefit of rituximab in diffuse large cell lymphoma. At this time, this group was called GELA and which led to the registration of rituximab in T-cell lymphoma. And in addition, also, we have shown that rituximab was good for maintenance therapy in follicular lymphoma, which led also to this registration. And we made a lot of studies showing, for example, and we are the first to show the role of radiotherapy localized lymphoma and the role of PET scan to assess early the response rate of patients with lymphoma. Also, we characterize a lot of key biomarkers. And for example, Bcl-2 as a marker of prognosis in B-cell lymphoma in the early '90s. And now with the more advanced study with host genomics and plasma-derived biomarker, gene expression by RT-MLPA and immunomonitoring of blood subpopulation to assess the response rate to chemotherapy and immunotherapy. We published like more like 250 publications in high level journal, including the New England of Medicine, journal of Clinical Oncology, Blood and so on. And we present this data in main international congress, including ASCO, ASH and so on. And we contribute to the international effort to better define the standard of treatment and assessing the prognosis and the response rate of patients treated by lymphoma, including the PET scan and the clinical and biological data leading to the API and CT and so on. And also, we participate actively in the WHO lymphoma subclassification of lymphoma. Next slide, so the LYSA, we can go on the next slide. I will show you now what is the rationale to use lacutamab with chemotherapy in refractory T-cell lymphoma, which is a very high unmet medical need. So on this slide, you see, first, what we have shown and what is the main goal of Innate is to show that antibodies, which target KIR3DL2 may engage NK cells to induce the killing of the tumoral cell, which is ADCC mechanism of action of lacutamab, which is very important mechanisms. So what is very interesting is, that on -- we look on the left side on the upper panel, we have showed that there is a synergistic effect between gemcitabine and oxaliplatin, which are 2 chemotherapy used in the setting of relapsing T-cell lymphoma. And the addition of these 2 drugs led to the increased expression of KIR3DL2, meaning that we can expect to see an increase of the mechanism of engagement to NK cells to the tumor by increasing the number of antigen at the cell surface, which has been shown on the low panel, you can see here, a very synergic effect between lacutamab alone in yellow or in combination with chemotherapy, oxaliplatin to gemcitabine in the purple curve in which we can see a nice additive and synergistic effect between lacutamab and GemOx. So next slide, you can see on this slide, we have used on ATL, which is a very aggressive T-cell lymphoma, with virtually no treatment in the relapsing setting of this patient. And we have shown that these tumors were -- they are very aggressive. They express highly KIR3DL2. And when we mixed the cells with NK cells in the production of more [indiscernible]. You can see on the red curve on the left side, in positive cells, you see an increase of the lysis of the cells. And to show that this effect is highly specific when we did the same experiment on cells, which do not express KIR3DL2. We didn't see any effect, as you can see on the red curve on the right side. So based on this data and also, as I've shown Professor Porcu before on the expression of KIR3DL2 on relapsing T-cell lymphoma, we set up a clinical protocol in which we would like to test the combination of lacutamab and GemOx, which might be a standard of care chemotherapy in relapsing patients. So in this study, we will include refractory/relapsing patient who'll receive at least 1 prior line of therapy and while also KIR3DL2 positive. So we will include 56 patients, randomize 2:1. And patients will receive, in the experimental arm, GemOx plus lacutamab in 37 patients and GemOx alone in 19 patients. And we will assess the PFS on these patients. And if these patients are responding, we will use a maintenance therapy on lacutamab alone at this progression for 2 years, at least. And the follow-up, we follow this patient every 3 months to assess the progression-free survival, which will be the primary endpoint of the study. And as a secondary key endpoint, we assess the response rate, the toxicity and the rate and overall survival at 12 months because we have seen before that this rate is very low in patients with T-cell lymphoma. And we strongly expect to initiate this KILT study early in 2021. And I think I will stop here, and we'll be very happy to take your questions. Thank you very much.

[Operator Instructions] Your first question comes from the line of Yigal Nochomovitz of Citigroup.

I had a question related to Cohort 1 in the Sézary syndrome trial. I think you mentioned that the FDA could potentially allow that as a pivotal trial. Could you just let us know whether there's a certain overall response rate hurdle that you need to hit in that study for success? Does it have to be at least as good as the 43% in the Phase I or more like the 28% with mogamulizumab, if you could just expand on that, please?

Thank you, Yigal. If I repeat the question, it's in the Sézary syndrome. After these 2 prior lines of therapy, including mogamulizumab, what would be the from a regulatory perspective in order to get the adjusted. Joyson, I know it's hard to get into the details of the discussion with the health authority, but maybe you can give some perspective on what we are shooting for.

Sure. So as Mondher mentioned, I think going into the definite details of what the health authorities -- our conversations with health authorities may not be possible, but our benchmarks that we look for, keeping in mind that currently, this trial is being recruited in greater than 2 lines of therapy and mogamulizumab is in greater than 1 line of therapy. So keeping that in mind, if we see similar or, of course, better results, then I think that would be something to consider.

Okay. And I have a similar core sort of question for this KILT trial. Is there a hurdle for the PFS that you're trying to hit or beat for GemOx plus lacutamab versus GemOx?

Yes. So again, a question for Olivier about what is the threshold of activity for the combination to be considered as better than what is the standard of care. Remember, Pierluigi has shown already what is the median PFS, usually ranging between 1.6 and 3, 3.5 months. So the bar is rather low. But from your perspective, Olivier, what good will look like? Olivier? I think you're on mute maybe.

I'm sorry. I was on mute my phone. Okay. So as usual, if we can improve by 50% the PFS, for example, to go for 4 months to 6 months, it will be clinically relevant. We hope to get more, but I think 50% of increase of PFS will be a good endpoint.

Your next question comes from the line of Daina Graybosch of SVB Leerink.

I have a couple of questions. Maybe if I can take them one by one. I wonder in MF, as you use Monalizumab, if I say that correctly, is there any reason to bring it forward and use it as the first systemic therapy for any reason to bring logo or lacutamab earlier into the more chronic condition of MF because these therapies seem highly tolerable?

Thank you, Daina. I think this is a question for Pierluigi about the paradigm shift to entry now that we have active drugs like mogamulizumab and lacutamab potentially in mycosis fungoides, why would you, as a physician, move it earlier in the kind of natural history of this disease and its treatment? Or would you keep it for the later line of therapy?

Yes. It's actually, it's a great question. And a short answer to that will be, yes. I think a lot of investigators and practitioners would like to kind of move the therapy with Moga or any other drug that will get approved in its phase to an earlier phase, lacutamab being a good potential example there. I think that the -- everything depends, to some degree, on the patterns of care for these patients. Because at least in the U.S. -- I know in Europe, it's different. But in the U.S., there's still kind of a split between dermatologists and medical oncologists. And patients who have, for example, earlier-stage disease, say, 1B, for example. So still skin limit, but perhaps they have failed multiple prior lines of skin directed therapies, those patients will be systemic therapy. And it depends on which physicians they see because if they see a dermatologist, I think there will be a tendency to continue with as much as possible the skin-directed therapy, essentially to continue with any therapy that the dermatologist can give in their office. And with the exception of certain sort of institutions where there is actually a multi clinic and Jefferson is one of them, and I know there are several in the U.S., but with the exception of that, then I think the selection that is going to depend on which patient -- which physicians the patient sees. So infusional therapy, for example, is much more likely to be driven by medical oncologists compared to dermatologists. Having said that, again, we have to deal with these logistical and practice sort of limitations. But yes, I think that for patients, the more and more we learn about the long-term efficacy and safety of these drugs, the more and more they will start to be used on the front end. And certainly for Sézary syndrome, I think that we are looking -- I'm looking forward to kind of a shift where a patient with Sézary syndrome will we start receiving more effective drugs earlier on as opposed to having to wait, for example, to fail Bexarotene, ECP, methotrexate, all those things. So I think we look forward to going to move them up for sure. I hope this answers your question.

Yes, it does very much. And then I wonder, again, taking sort of the same topic, if you could talk about the experience in using mogamulizumab versus lacutamab? Are they very similar in tolerability? Do you ultimately see any reasons for lacutamab to be used prior to mogamulizumab?

Pierluigi, this is for you, too, your own experience with both the drugs.

Happy to answer. So yes, so I do have experience with both drugs. And I would say that the drugs are relatively similar in terms of the way they are administered. Of course, they're infusional. Based on the limited -- keep in mind that we have Phase III data for Moga, and we have only Phase I, with a limited Phase II data for lacutamab, so the dataset is very different. So take that with a grain of salt. I think the impression is that when it comes down to safety, Lacutamab may have an advantage. For example, with mogamulizumab, some of the adverse events include, in addition to the infusion reactions that are possible with any infusional therapy. But, for example, a type of dermatitis that can be significant, meaning requiring use of steroids to control it. It definitely has been observed in patients with mogamulizumab is not uncommon. And that has not been observed with lacutamab up until now. And another one is that in terms of the mechanism of action, mogamulizumab target CCR 4, which is a molecule expressed on the surface of regulatory T-cells, which it is -- it is a favorable mechanistic angle because it's supposed to activate immune system, and it could be one of the way mogamulizumab actually works in addition to direct targeting of the tumor cell. The issue is that with that, there is a potential for the activation of autoimmune responses. And some of those phenomenons have been seen with mogamulizumab, and there is a big sort of debate a big question about the safety of mogamulizumab in patients, for example, who then receive an allogeneic stem cell transplant, where some groups have observed the high rate of GVHD. I think the jury is still out for that, in my judgment, but those are things that mechanistically, you would not necessarily expect to see with lacutamab. So again, the datasets are vastly different, and it would be unfair to make a head-to-head comparison. But I think the signals from lacutamab are strong in terms of the safety.

Daina, do you have another question?

I'll go back in the queue.

Your final question comes from the line of Swayampakula Ramakanth of H.C. Wainwright.

Excellent presentations by both the doctors. Two questions. The first one goes to Dr. Porcu. Excellent presentation. It's very helpful to get all the background information on these diseases. In general, as you talked about so many different drugs being tested for this, these 2 indications. What, in your opinion, are the -- is the real issue that even though so many different drugs have been tested, none seem to be delivering decent efficacy or better efficacy than what you would like to see for your patients.

Mondher, it's okay?

Yes. For you, it's actually, yes, pretty straightforward.

Yes. So I think the primary reason -- thanks for the question, by the way. It's a good question. I think the primary reason is probably the disease heterogeneity of these T-cell lymphomas. You have to understand that both molecularly and clinically, we're talking about 30-plus different cancers, essentially. And we know that they're all derived from T-cells, but now that we're learning the biology, the cell of origin is very different for some of these, and a lot of them are very heavy in terms of mutations. And therefore, I think they're very resistant drugs. Another possibility, this is pure speculation on my part now. But another possible is the fact that because we know that immune responses are important to control cancer. Remember that these lymphomas essentially are cancers that really get to the core of the normal immune response because they're affecting the very sort of part of the adaptive immune response that's supposed to play a major role in controlling cancer. So I think that he has to do something with that as well, but primarily is the fact that most of these drugs are purely generic. Think about the HDAC inhibitors, for example. I mean, the [indiscernible] of that is hardly specific. And therefore, you see some good responses, for example, in angioimmunoblastic T-cell lymphoma, better responses, but you don't see responses in a lot of other types of T-cell lymphoma. So I think that's -- fundamentally, that's the reason.

Thank you, Pierluigi. Last question for Olivier, I guess, RK.

Yes, this is both to Dr. Hermine and also to yourself, Mondher. So based on the data that Dr. Hermine presented today, especially the frequent data, it looks like the GemOx combination in combination with lacutamab seems to be quite synergist, GemOx seems to be quite synergistic in PTCL. So what's the rationale for doing a single agent study by the company at the same time, the combination being done by the organization?

Yes. You know what, I'm going to first let Joyson maybe provide the overall context and rationale behind the totality of the program. And of course, then, Olivier, you can give perspective on the KILT study. But maybe Joyson, first, on why do we go with the single-agent monotherapy? What's in there? And what are the other options eventually? Joyson?

Yes. Thanks, Mondher. So a good question. So when we look at monotherapy, I think one of the main things we have to remember is we are going after the KIR3DL2 positive patients. So although we do see synergy with the combination, what we don't know and sort of goes to a contribution of component question, is what does monotherapy do itself. So because this is a subset, and it is in the KIR3DL2 positive, keeping in mind that this is the mechanism of the drug, where this is why we were confident in also beginning the monotherapy trial, in addition to the combination.