Uforståelig og trist! 
3 Likes
Jeg vurderer det samme selv etter å ha sett dagens webcast. Dessuten må Staten ta cirka 35,5 prosent av mitt personlige tap, og det er da noe. Den skattefordelen er i det minste uomtvistelig. 
Ved å si nei til fusjonsforslaget og sparke styret kan man i beste fall få 60-70 øre per aksje? Og om man er så dum at man støtter forslaget er vi fort nede på 20-30 øre per aksje etter fusjonen, så kommer det etter hvert en omvendt splitt og stadige emisjoner for å holde det “nye” selskapet i live? (Nevnte prising er basert på at 70 prosent av alle biotech-selskaper worldwide prises på linje med eller lavere enn sin kontantposisjon, ifølge TheObserver.)
North er påfallende stille. Og jeg ser heller ikke helt hvordan aksjonærgruppen skal klare å tilføre merverdier utover de 60-70 ørene man sitter igjen med ved å forkaste fusjonsforslaget?
2 Likes
Betimelig og berettiget spørsmål. Men vil det gi oss mer penger i kassa? Neppe. Veldig vanskelig å vinne frem med slike søksmål i Norge. Biotech er dessuten high risk i utgangspunktet…
Norsk biotek er faktisk i en krise. Flere selskaper har vært styrt av grådige og inkompetente nisser med null respekt for folks tilitt og penger.
Basert på webcasten i dag så er det enda tydeligere for meg at det er rom for å forhandle frem en bedre deal (hvis det er dette dere ønsker).
I min verden, når man har en asset innenfor onkologi med lovende kliniske fase 1/2 data så er det dette tidspunktet BP kjøper deg opp. Lykkes du ikke med det så investerer Venture Capital deg eller du børsnoteres på NASDAQ. Lykkes du ikke med det finansierer eksisterende eller noen nye i en rettet emi penger for neste value inflection. Det er ikke da man har 20 mill norske kroner på bok og skal merge med et annen selskap for å komme på OSE.
Nisser as!
17 Likes
Nano satset hardt på “Dress for success”, med doktorgrader i styre og ledelse plassert stort sett alle andre steder enn i Oslo. “Neste gang” kommer jeg til å se etter trauste nordmenn på kontoret her hjemme før jeg satser pengene mine på et selskap.
9 Likes
Som f.eks Ronny og Anders i PCIB. Er bare å ønske lykke til…
Det de sa for et år siden:
Presenter Speech
Jan Egberts (Executives)
Good afternoon, ladies and gentlemen. Welcome to our Nordic Nanovector R&D Day. My name is Jan Egberts, and I’m the Chairperson of the company, Nordic Nanovector. Unfortunately, I was really looking forward to meet you all in person today in Oslo. But I guess, unfortunately, because of the – all the corona-related travel restriction, that’s not possible. However, we’ll make the best out of it with using the more modern technology, it’s the webcast and obviously, we will also be available for more intimately answering all your questions.
Obviously, corona had a major impact on our company. We have kept you updated about our recruitments, which suffered quite significantly in the first half of last year, which really starting to pick up now, which is very encouraging. Over the past months and years, we have been sharing a lot of information about our progress with PARADIGME, the clinical program with Betalutin.
I think it’s now also very important to kind of switch gear a little bit and share what our organization has been doing over that period in earlier-stage R&D projects because I think there’s a lot of very interesting things we’d like to share with you.
Here today with me are – is Erik Skullerud, our CEO, with his team, and they will share with you some of the progress I just mentioned that we have made. We’re also very privileged to have Professor Dr. Leo Gordon with us today, who is going to share his experience as a clinician with some of these patients. Professor Leo Gordon, he’s the Abby and John Friend Professor of Cancer Research and Professor of Medicine. He’s also the Co-Director of the Hematology Malignancy Program, the Division of Hematology Oncology at Northwestern University School of Medicine. So very pleased with all the people, and I think you’re going to be very impressed with the progress we have made over the past 1.5 years.
So having said that, I’d like now to hand over to Erik, who, together with his team, will share you some of the projects I just mentioned earlier. Erik, please go ahead.
Presenter Speech
Erik Skullerud (Executives)
Thank you, Jan. And also from my side, a warm welcome to all of you. It would have been great to have been in Oslo, just like we were a couple of weeks ago. But as Jan just pointed out, there are a lot of issues on travel at the moment. So we’re joining you from different places around Europe. There’s a couple of us that are sitting in Switzerland. There’s a couple of us that are sitting in Belgium and some of us are sitting in London at the moment. And obviously, Dr. Gordon is sitting over in the U.S. So it’s really a global conference that we are about to embark on.
I don’t know how many of you there are, but we are equally happy to see all of you. As a matter of, first, giving you a little bit of a snapshot of the agenda, if I could have the next slide. We are obviously going to go through quite a few things during the presentation. We’re going to start with – I will give you a couple of reflections on where I see us moving to as an organization, as a company. As you will know, I joined the company 8 weeks ago. I’ve had a chance to thoroughly get familiar with the organization, with the people and with the exciting pipeline that we have. So I’ll give a little bit of a background on where we want to get to.
We will then introduce Professor Gordon, who will be talking about follicular lymphoma treatments, the treatment paradigm and the unmet medical need. And that will be followed on by our new incoming CMO, Dr. Pierre Dodion, who will also talk to you about the Betalutin program. But this time, we will tell you a bit more about our plans on Betalutin as a product and eventually Betalutin as a pipeline of its own. Because I think it’s fair to say that there are several indications that makes this asset really interesting moving forward.
Marco Renoldi, my Chief Operating Officer, will share with you a program that we’re in the midst of working on our commercialization and the potential how we overcome barriers to success. And it’s a really interesting project in the sense that here we take, first, the U.S., but then also other countries, and we look at what are the barriers that we need to get across over and above your normal commercialization barriers. This is a really interesting project that we are collaborating with other big industry partners on.
Lars Nieba will give you an update on how we’re moving forward, both with our supply chain and our manufacturing. For those of you very familiar with biologics and radio immunotherapies, you will know that the process that you bring these products through your manufacturing is just as important as the clinical development itself. And we will [ update ] how we’re doing that. So we’ll share insights with you on that.
We will also, and then finally, as our last part of the presentation, jump into a couple of presentations that will be aimed towards our pipeline. Our CSO, Jostein Dahle, will do a part of this. And Maureen Deehan, our Head of Strategy and Business Development, will also take you through each – a couple of assets. So I think we have a very interesting program ahead of us. If I can have the next slide, please?
And just to share with you, first of all, this is our management team. And as you will recognize here, we have an extremely experienced group of people that we’re working with. They have been in large pharma corporations. They have worked with small biotech. Several of them has also worked as consultants and worked in 2 companies. So a wide experience, both in number of companies and also the expertise. And I’m really proud to be leading this group of people.
Also today will be the first time, as mentioned, you will meet our incoming CMO. You’ll see at the bottom here, Pierre Dodion. And let me also now give a big thanks to our outgoing CMO, Christine, done a fabulous job for us, and we’re really happy with what you have done, Christine. And she is in the midst of a transition to Pierre.
Next slide, please? So first, a little bit of an update on PARADIGME. I’ve seen, over the last couple of days, quite a few questions from you online. Are we going to give an update on PARADIGME and on the inclusion? I’m assuming that all of you will now be familiar with the program itself. This is what we have become famous for over the last couple of years. We have spent a lot of time on updating you, and you will see the study design in front of you. So I’m not going to go through any more than that.
I am going to use a little bit of time on the lower line here where you see what we reported in our last quarterly call, 102 patients included or enrolled in the study. This is now 10 days or 8 business days ago. And today, I’m able to add on to this number. But let me spend a few minutes on just telling you a story around the last 2 weeks.
So we’ve had 2 patients that have been in later stage screening and inclusion, if you want, into the study in this time frame. Both of these looked really good until approximately mid last week, end of last week. One of the patients in late screening fell through on one of the inclusion criteria and, as such, had to be dropped from the study. The second one, I’m happy to announce, is virtually being treated as we speak. They have their first medication happening in about 36 hours from now and has been cleared through enrollment. So the new number for us now is 103. That’s 1 more patient included over the last 8 business days.
So that is the status of PARADIGME. We will mention PARADIGME on a couple of locations in the presentations to come. But I think it’s fair to say that today’s focus is more going to be around what are we doing, to Jan’s point earlier, over and above. So next slide?
The starting point of this is really our own proprietary CD37 platform. As you will be familiar with, this is something that we have worked on since the inception of the company. CD37 is a really important target in beta cells. And for you to believe that this is a viable and an interesting strategy, let me make a couple of comparisons.
On a beta cell, which is basically the main attack point for cancer treatments in hematological cancers, you have CD20 and you have equally numbers of CD37 antigens. What does that actually mean? Well, if you believe that companies such as Roche, that has made a huge impact by understanding and developing the CD20 platform, if you believe that, that is possible for others, I would suggest it’s definitely possible for us. We’re the leading CD37 company arguably around the world at the moment. You see over that line, we have 5 different assets in our development, 5 different attack points, if you want, towards CD37 as a target, all with different attack points, attack angles and different ways of altering – or attaching, sorry, to the target – to the CD37 target.
Obviously, Betalutin is the one that is the furthest on the development horizon. But during the presentations today, as I mentioned earlier, you’re also going to hear more about the other 4 and we’re going to give you an update on where we are with them. But just to make it very short, Humalutin, the next one from the left, is a product that really fits very well into our life cycle thinking as far as Betalutin is concerned. This could be a fast follower in hematological indications. It has a slightly different backbone, and we’ll speak to that in a second. And it is a product that we have developed until IND stage.
Alpha37 is – has the similar antibody as Humalutin, but a different payload associated with it. And Jostein will talk both about Humalutin and Alpha37 a little bit later on.
The last 2 over on the right-hand side here are, if you want, our 2 new babies. It is on the far right, the CAR-T program that we announced just a couple of weeks ago. Maureen is going to touch upon this program in much more detail a little bit later, but we are super excited about this program. Why? Because we are, in this case, able to collaborate with arguably one of the most distinguished research institutions in the world, especially when it comes to CAR-T. This institution, University of Pennsylvania, were the ones that initially developed the CAR-T technology, licensed it out to Novartis and is the base for the Novartis product the way that we see it today.
The last of our assets is a pure humanized CD37 antibody. And this is in early-stage development. We are really interested in how this is going to take us forward as this is a product that may give us also inroads into other indications. And as you can see in the vision statement on top here, over and above what we have done so far in hematological cancer, we are also expanding this vision and including immunological disease or autoimmune disease as something we want to focus on. So not only do we have 5 different molecules/assets in development, we also target wider disease areas as we move forward.
It is pretty obvious that we cannot do this alone. So on to this strategy, we’re also bolting on an additional development strategy, if you want, in the sense of seeking partners for these different molecules. You will probably be aware that we have such collaborations with Orano Med on Alpha37. As mentioned earlier, we announced a collaboration with University of Pennsylvania for the CAR-T molecule. And we’re actively looking for other partners as well in parallel with the commercialization partner – partnerships that we’re looking at for Betalutin. So this is something that we don’t need to spend additional resources on but we use what we have.
And again, if you think about how much resource are we actually spending on this today, the vast majority of our resources is focused on PARADIGME and on Betalutin. That is where our priorities are, and that’s what we have to deliver first. But I hope you agree with me that the vision that I put forward to you right now is clear. It has a focused strategy behind it based on the CD37 platform. And when we are successful in bolting on partnerships to this, it is something that is also going to create future value for you as shareholders.
Next slide? I’m not going to spend a lot of time on this because other speakers will touch upon this in more detail. But as you can see here, from left to right, you have the same molecules. And from top to bottom, you have, kind of, how do you describe the different CD37 therapies that we have under development. If I could have the next build, please?
Three of these are really based on our heritage radioimmunotherapy background. It is something that we are really good at. It also shows you that although we’re starting from the CD37 attack point, we equally have a chance of adding on additional nuclear payloads on them as well. It also shows you, from left to right, that we are evolving the antibodies somewhat that we are using from a murine to a chimeric in these 3 boxes. And again, Maureen will touch more upon this in detail, what does that actually mean.
You can also see here that we’re using IV as the administration form for these 3 assets. And finally, they’re mainly focused on to hematology, although arguably, you could say that an asset such as Humalutin may also be used in immunological disease. But for now, we have focused on hematology for the development of all of these 3 assets.
The next, please? For the antibody, the humanized CD37 antibody, this will obviously be targeted towards subcutaneous use like most other antibodies. It will have a wider area that it could be used in the sense that here, you have a product that potentially could be used in hematology but also in autoimmune disease. It can also be used in addition to our other assets in hard-to-treat tumors, you could imagine as a baseline treatment, Betalutin, for example, and then iterative treatments with an antibody to enhance the efficacy of the radiopharmaceutical itself.
And finally, if I could have the last build, the CAR-T program, which again focused on hematology, and are also, I would say, cutting edge as far as oncology/hematology treatments are concerned. What we obviously hope here is to add value for you as shareholders, but also to actually take the next step in development of CAR-T treatments. This is for us a next-generation treatment when it comes to CAR-Ts. Again, Maureen will talk more about that in her presentation.
Next slide? So as a last slide, before I hand over to Professor Gordon, I just try to depict here where are we with these different programs. You are all aware of the third line development that we’re doing for follicular lymphoma. The row below is the first step towards a Betalutin as its own pipeline, if you want. We obviously have shown interesting results from the Archer-1 study.
We are currently talking to regulatory authorities for what we would need to do as a confirmatory Phase III program based on our BLA approval for Betalutin in third line. That discussion is ongoing. Pierre will talk more about what that looks like and what we are doing moving forward. But the next time we speak to the FDA is towards the end of first quarter 2022.
And we have plans that we’ll share with you today around how we’re moving forward on our DLBCL strategy. You have both programs, the additional 2 radio immunotherapies here, both Humalutin and Alpha37, both of them targeted in – towards other NHL indications. And there, we are now – Humalutin is already at the pre-IND stage. We are just finalizing the final steps for Alpha37 as well in the same frame of getting this to a pre-IND stage. And I’ve just shared with you some of the top line details for the humanized antibody as well as the CAR-T program that we are embarking on with University of Pennsylvania.
So with that, I will stop, and I will introduce Professor Leo Gordon to you. We’re very, very honored Professor Gordon that you have been willing to spend your time with us today. And for those of you who don’t know Professor Gordon, I think most people online would be familiar with your background. He is an Abby and John Friend Professor of Cancer Research, a Professor of Medicine, a Co-Director for Hematological Malignancies Program at the Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine in Chicago.
We’re very honored to have you here, Dr. Gordon. Thank you for taking time for this and floor is all yours.
Presenter Speech
Leo Gordon (Attendees)
Thank you so much. It’s a pleasure. It’s an honor to be with you. So I think – can I have the first slide? Thanks. So my task today really is to review with you some of the treatment algorithms in patients with relapsed follicular lymphoma and to really kind of find perhaps a niche or find an unmet medical need for those patients.
Can I have the next slide, please? So in order to do that, I thought it would be worth discussing a little bit with you some features of follicular lymphoma, talk a little bit about the incidence of this disease, where it fits in the spectrum of the non-Hodgkin’s lymphomas and the spectrum of the B-cell non-Hodgkin’s lymphomas. Talk a little bit about how one makes the diagnosis, going about making the diagnosis under the microscope and at the bedside. Talk a little bit about certain biological features which might be important and might predict for a favorable or an unfavorable course. And that has a lot of impact, I think, on where we go with second and third line treatments and whether – when and if to expect the need for second and third-line treatments.
We’re going to talk about management algorithms clearly for relapsed patients in second and third line, but I thought it would be important at least to review with you some of the first-line options because the first-line options sometimes – there are many choices for first-line options, and they will impact what we do in second and third line. I will try to focus somewhat on patients who are a little bit older or might be too frail for very intensive therapies or for some of the newer treatments that I’ll also mention, CAR-T, stem cell transplantation, things of that sort. I’ll talk a little bit about the evolving landscape, what else is out there, what’s going to be there and focus on some recently approved agents, perhaps PI3 kinase inhibitors which are being used more and more in patients with follicular lymphoma.
So next slide. So this – on this slide, this is sort of a pie chart of where follicular lymphoma fits. We can see that it’s probably the second most common type of B-cell lymphoma. We estimate probably closer to 80,000 cases of non-Hodgkin’s lymphoma in the United States in 2021. Most of those are B-cell non-Hodgkin’s lymphomas. And this is the sort of, for the most part, the pie chart representing the B-cell lymphomas, diffuse large B-cell lymphoma. DLBCL is the most common type. Follicular lymphoma makes up maybe 22% to 25%, maybe a little bit more now of the B-cell lymphomas.
Some of the discussion we’ll have, although we’re focusing on follicular lymphoma, many people feel, and I’m among those that patients with marginal zone lymphoma, although maybe a somewhat different biology and has very similar presentation and the treatment algorithms for marginal zone lymphomas, over the years, have mimicked the treatment algorithms for follicular lymphoma. And so some of the things that we do in follicular lymphoma may also apply to marginal zone lymphoma.
Next slide, please? So as I mentioned, it’s the second most common lymphoma in the United States. We have grades which are determined by what the cells look like or what the biopsy specimen looks like under the microscope. I will say that the recent practice of making diagnosis by fine needle aspirates or even by small core biopsies has limited our ability to make accurate diagnosis, and that’s something, while very popular, at least here in the U.S. in hematology oncology, it’s along with our pathology – hematopathology colleagues, that’s something we kind of try to discourage as much as we can. We often have to repeat biopsies in patients that are seen in consultation for second or third opinions.
The grading can be difficult, and that’s why we need more tissue and needs – I think I would not say may need, but I think does need hematopathology expertise and review. We think of grade 1, 2 and 3a lymphomas as the indolent type, the type that we’ll talk about today, the follicular grade 3b we tend to view as similar to DLBCL, to diffuse large B-cell lymphomas, and that sort of sets it apart as a different category.
So while we will say that advanced stage follicular lymphoma is not curable with standard therapy, this is a disease that people can live with. They may lead a normal life span with follicular lymphoma and may die of other disorders or other causes. So in many ways, when I – at least when I discussed this with patients that we’re seeing, I might compare this to diabetes or compare this to other chronic disorders. And they may not be life-threatening. And in fact, when we see people for the first time, when the diagnosis is often made incidentally on a CAT scan that’s done for other reasons or by physical exam on a routine visit, we stress the fact that this is something that actually may not need intervention right away.
Can I have the next slide, please? So this is from the NCCN Guidelines, which we put together every year and, in fact, update many times a year. This just gives us some clinical features that we’re using for prognostication. And there are 2 major criteria that are basically determined at the bedside, the so-called GELF criteria, which was developed in Europe. It was developed for clinical trials for now the [ Lisa group ]. And basically, these were eligibility criteria for clinical trials. I think this has begun to be used or has been used over the years as a way of predicting perhaps a worse outcome and maybe are specific indications for treatment.
I don’t know that we use them that way all the time, but there are features there that I think are important. The number of nodal sites, the involvement of – the number of lymph nodes that are involved. Any nodal or extra nodal, that means a mass outside of a lymph node greater than 7 centimeters often is an indication for treatment. The presence of B symptoms, of fever, sweats and weight loss. The presence of a large spleen, although I will say that we see many patients who have a large spleen who don’t necessarily require treatment. The presence of pleural effusions, fluid in the lung, or peritoneal ascites, fluid in the abdomen, might be an indication for treatment. Cytopenias, low white blood count or a low platelet count related either to the large spleen or to infiltration of the bone marrow.
And then the presence of malignant cells in the peripheral blood, and many people view as an indication for treatment, although I will say that we followed patients for many years, sometimes with some cells in the peripheral blood. And if we do flow cytometry, many patients will have abnormal cells in the peripheral blood and that by itself does not mean that they absolutely need to be treated. But these are some of the criteria that are used.
The so-called FLIPI criteria developed by my colleagues in France with – and different iterations of this. Age, greater than 60; Ann Arbor stage, greater than III or IV, that is more advanced stage disease; hemoglobin level, anemia, less than 12; an LDH, lactic dehydrogenase level, which I find very useful and important in management of patients with both large cell lymphoma and follicular lymphoma as an indicator of more aggressive disease when that is above the upper limit of the laboratory normal, that is a negative prognostic factor, greater than 5 lymph node sites.
And if you can see, the right part of this chart gives you some indication of the lymph node areas and how to measure those. I will say that although the FLIPI criteria are extremely useful for clinical trials, at the bedside, it’s not commonly used, I think, to sort of make decisions about treatment. I think we tend to use a [indiscernible] I would say, which includes many of the FLIPI and GELF criteria. But I don’t think that most people are charting the number of lymph node sites at the bedside to make decisions about whether patients need intervention or not.
Next slide, please? This gives you some idea of what I talked about earlier about the grading. Basically, the grading of this disease is determined by how many large cells are present. The more large cells that are present, the more like large cell lymphoma this is and the more aggressive it might be. And you can see follicular grade 1 and grade 2 with small numbers of large cells. Grade 3a on the bottom – on bottom left and grade 3b on the bottom right gives you an indication that if there are sheets of large cells, the more large cells, the more it’s tending toward large cell lymphoma. We tend, as I mentioned, to treat grade 3b as we treat large cell lymphoma. So most of the discussion that we’ll have today has to do with follicular grade 1, grade 2 and grade 3a.
Next slide, if I may, please? So this is how the diagnosis can be made with immunophenotyping, that is specialized flow cytometry techniques that are used to distinguish follicular lymphomas from some of the other B-cell lymphomas. And there’s 2 antigens which are really helpful, CD5, cluster designation 5; or CD10 helps us make that distinction. Patients who have CD5 positive disease tend to be more likely to have margin – mantle cell lymphoma or chronic lymphocytic leukemia, small lymphocytic lymphoma. Patients who have CD10 are more likely to be diagnostic for follicular lymphoma. CD10 is an antigen that’s present in the germinal center of the lymph node, and the germinal center of the lymph node is where we think that follicular lymphoma originates.
So these are helpful. And I won’t go into any more detail about these, but I think the diagnosis, although it can be tricky sometimes, with an experienced hematopathologist with an adequate amount of tissue, this diagnosis can be made pretty readily.
Can I have the next slide, please? So this is just like a very high, if you will, aerial overview of what our – some of our goals are. We’d like to – if we decide that patients need treatment, and I will say probably maybe as many as 50% or 60% of patients that we see initially don’t necessarily require treatment because they’re not symptomatic. They don’t have bulky disease. They don’t have any of the criteria that I just showed you.
But in those patients who do require treatment, the goal is to get a good quality remission. If we can get a complete remission, that would be ideal, to reduce the tumor load and induce an initial response, to maximize that response by sometimes using some kind of consolidation. And a fairly controversial area in hematology oncology is whether patients with follicular lymphoma should have maintenance treatment or not. And that’s – and I’ll show you some data on that. That’s – it’s an evolving discussion. And actually, and I’ll show you in a minute, has been impacted quite a bit by the pandemic, by COVID.
Next slide, please? These are data from Gilles Salles from France, now at – in New York at Memorial Sloan Kettering. These are the data from the so-called PRIMA study. The primary endpoint of this was 3 years, and the study was basically randomizing patients who were treated with chemotherapy upfront for follicular lymphoma, randomized 1:1 to receive a maintenance treatment for 2 years with Rituxan given every 2 months versus observation.
And if you look at the progression-free survival end point at 3 years, there’s clearly a statistically significant difference at, say, 36 months between Rituxan maintenance and observation. And this has led to a fairly widespread use of maintenance therapy. What this study did not find, however, was, is there a difference in survival? And up until now, there has not been a difference in that trial in survival in patients receiving maintenance therapy.
Next slide is a meta analysis published by Vidal et al in the European Journal of Cancer in 2017. And with all the caveats of meta analyses in place, I will say that they did find, if you look at sort of the left graph, an improvement that was seen at about 6 or 7 years in overall survival in those patients who received maintenance therapy in green compared with those who did not in red.
So quite a bit of debate. I will say that the pandemic has made a major impact on the decisions for maintenance therapy. Just some point of interest, we know that a patient who has COVID, a normal individual gets infected with COVID, in about 20 days will clear if you do multiple PCR swabs. Patients on Rituxan take 100 days to clear.
So while Rituxan is among the safest drugs that we use in oncology, when it comes to COVID, it’s probably one of the most dangerous drugs that we use because it limits our B cell immune response. And so we have adjusted, I think, at least in the U.S., and I think this is true around the world, decisions about maintenance treatment, and we have been more reluctant to recommend maintenance treatment if there’s not going to be a major difference in overall survival. And we have even adjusted our decision-making about when to initiate treatment. I think we’ve moved that sort of line that we cross about needing treatment over to the right in the era of COVID. And – so that’s, I think, something important to remember.
Next slide, please? So these are – we get to update these, as I mentioned, NCCN Guidelines and sometimes I find it hard to follow the algorithms in the NCCN Guidelines myself. This is just one way to – another way to look at it. If you look at the top, there are some patients who present with early-stage disease, say, a single lymph node or a lymph node area. In general, the recommendation has been those patients should be treated with radiation, involved site radiation because data from the Princess Margaret Hospital in Canada suggests that you wait 10 years, you follow those patients, 50% or 60% of them may still not have recurrent disease.
So we think that radiation might be curable in a group of patients with very early stage disease. And any time I mention radiation, obviously, we always think about how this could translate to radio immunotherapy. But radiation, involved site radiation, I think, is important.
Some people might use immunochemotherapy with Rituxan or perhaps chemotherapy with or without radiation. I think that’s reasonable, but I think in really truly early-stage disease, radiation is probably the preferred treatment. You might, however, observe patients if there – if the radiation would involve an area that might not be amenable to – or safe to give. So I’m not sure I would necessarily give somebody with a mediastinal, behind the sternum, presentation involved site radiation for stage I disease. Those patients might be observed.
And if the disease then progresses in the yellow vertical bar here, then they can progress either without transformation. They may stay follicular lymphoma or they may progress with transformation in the green box on the right if they’re transformed to large cell lymphoma. And overall, about 30% of patients will transform to large cell lymphoma if followed long enough clinical trials. And those patients should be treated as large cell lymphoma, clinical trial, chemotherapy with rituximab, possibly with radiation. And then those patients then are candidates perhaps for allogeneic or autologous stem cell transplant or even now CAR-T therapy with the 3 agents that are now approved in large cell lymphoma.
If patients have either bulky stage II or more commonly advanced disease stage III or IV, as most patients with follicular lymphoma present, if you look at the brown box on the left, and then the brown box in the middle, clinical trial, of course, if the clinical trials are available. Bendamustine and Rituxan has, I think, replaced R-CHOP, Rituxan and CHOP chemotherapy is the most commonly used regimen in follicular lymphoma based on the data from the German studies. Rituximab alone, probably my most commonly used regimen in patients who might need treatment and have stage III or IV disease. The R-squared regimen, that stands for Rituxan and Revlimid (lenalidomide), an IMiD which is active in this disease. And sometimes local radiation and then I think most commonly, observation.
I will say once you’ve made the decision to treat, that’s when we talk about whether we should do maintenance or not. There were data from actually my colleagues from the Netherlands in the early FIT trial using radioimmunotherapy as consolidation, using Zevalin as consolidation. And since this is a discussion of Betalutin, I’ll say, and I’ll say this many times, whenever I mention radio immunotherapy, it’s a bit of a pipe dream because we don’t have radioimmunotherapy anymore. Zevalin is, at least at the moment, not available, at least in the U.S., and I don’t know if and when it will become available. So either consolidation or extended dosing maintenance therapy with Rituxan with the caveats that I mentioned during COVID.
And then if you look at the bottom left in the gray box, elderly or patients who are – we don’t think can tolerate aggressive chemotherapy, may be treated with Rituxan alone, and that’s a commonly used regimen that’s what will be my probably first-line treatment for the most part. Chlorambucil or Cytoxan, these are oral – can be oral alkylating agents or perhaps radioimmunotherapy, again, if we had it. There were data from the group at the University of Michigan with an I-131 radioimmunotherapy where – that was given safely and with excellent results. But again, that’s not available either. So that’s a general overview.
Can I have the next slide? I wanted to focus on the patients who we didn’t think were candidates for aggressive treatment, just to come down on this. Again, Rituxan or – which is again my first choice, chlorambucil or radioimmunotherapy were available, that can be followed by either observation or Rituxan as a maintenance treatment. If patients then progress, either after just their initial induction therapy or after a maintenance therapy, once again, they can progress with transformation. And I think a re-biopsy with a good sample of tissue, but not a fine needle aspirate but a biopsy can make the distinction most of the time between transformation to large cell lymphoma, DLBCL or just progression with follicular lymphoma.
If they’re transformed, then we should be treating them like large cell lymphoma. If they’re not transformed, then we have some options. Some of the things that we didn’t do in first line or we thought we couldn’t do in first line, we might begin thinking about now doing in second line. So rituximab, lenalidomide or Revlimid and Rituxan are R-squared, once again, radioimmunotherapy if available, possibly PI3 kinase inhibitors, local radiation or sometimes best supportive care.
If they don’t respond or progress at that point, really that is an unmet need and I’d even say the first relapse is an unmet need. Shall we think about resurrecting radioimmunotherapy? Shall we think about radio immunotherapy in combination? These are patients who might not be candidates for something like CAR-T therapy, although we’ve seen and in recent data that patients who are older, say, over 65, and treated with CAR-T have a similar outcome with similar toxicities to patients who are younger. So I think it’s not out of the question, but more difficult.
Next slide? So just to go over once again for first-line therapy, bendamustine-Rituxan, Rituxan-CHOP, Rituxan with CVP, basically CHOP without the Adriamycin, Rituxan and Revlimid, R-squared or obinutuzumab, which is a different monoclonal from Rituxan, probably maybe with a little bit more efficacy in chronic lymphocytic leukemia and suggestion based on some recent data that it might have more activity than Rituxan actually together with lenalidomide. And then for patients, again, who are – may not be able to tolerate Rituxan alone, chlorambucil and Rituxan and possibly radioimmunotherapy.
Next slide, please? Consolidation or extended doses, Rituxan maintenance with the caveats, obinutuzumab maintenance as in the so-called GALLIUM trial where it was given after chemoimmunotherapy, obinutuzumab was given for 2 years of maintenance. And other options of a shorter maintenance course. In Switzerland, they did the initial Rituxan and then the Rituxan every 8 weeks for 4 doses. So basically a shorter course of maintenance therapy.
Next slide? So I think one thing to point out about second-line treatment, there have been some recent data that sort of substantiated I think most investigators feeling that if patients relapse within 24 months or early after their initial treatment, the outcome may not be as good. And those – and that’s been confirmed in a trial that Carla Casulo published from sort of a data analysis of – sort of a large data subgroup of patients and then was substantiated by the Mayo Clinic Group that patients who have progression of disease at 24 months, or the so-called POD24, have a worse outcome.
So in general, second-line treatment is whatever wasn’t done in first line. So if you gave R-CHOP first line, then bendamustine-Rituxan; if you gave bendamustine-Rituxan, then R-CHOP or R-CVP or Revlimid and Rituxan, possibly Revlimid and obinutuzumab. And in more frail patients, single agents, I think, is the order of the day, Rituxan alone, obinutuzumab alone, chlorambucil alone, Cytoxan alone or possibly, again, radioimmunotherapy alone as a single agent.
Next slide? So this represents the current thinking and state of the art, if you will, for the POD24 group. These are patients that I mentioned who relapse within 24 months. There is a large intergroup trial led by the Southwest Oncology Group, comparing either obinutuzumab, the alternate monoclonal – anti-CD20 monoclonal antibody with CHOP if patients had prior bendamustine and with bendamustine if patients had prior CHOP. The second arm is umbralisib, one of the PI3-kinase inhibitors, we’ll talk about in a moment. And the third arm is Revlimid, the IMiD plus obinutuzumab.
Just to remind you, I’ve talked a little bit about Revlimid, where that came from. So Revlimid is an IMiD. It’s – you may be familiar – you probably are familiar with, its cousin, thalidomide, which was used in the '50s and '60s as a sleeping aid and led to birth defects – significant birth defects. It was kind of obviously put on the shelf for many years, but resurrected again as thalidomide and then the 2018, '19, '20 version lenalidomide. And what was forgotten about thalidomide early on is that it had major immunologic effects, enhanced T cell function and had effectiveness in B cell disorders. And so that’s why it’s used and it’s a very active agent. So this is the current landscape of POD24.
Next slide is talking about landscape. This is – basically gives you some rough estimate, we won’t go into these in any detail, about some of the agents that are being either approved – were approved or in the pipeline for follicular lymphoma after second line. These include some of the bispecific antibodies. It includes some third and fourth generation BTK inhibitors, Bruton’s tyrosine kinase inhibitors, which would seek to improve upon the results with ibrutinib, which is down on the bottom left in a red dot on the slide with only about a 30% response rate, disappointing response rate in follicular lymphoma. So I think people are trying to look at the next generation of BTK inhibitors to see if we can improve the response rate. And this gives you some idea of what’s being tested. What’s approved is in blue and pipeline therapies are in red and in orange.
Next slide. Third line and subsequent treatment. PI3 kinase inhibitors, copanlisib, duvelisib, idelalisib and umbralisib is fourth line. I’ll talk a little bit about those in a moment. The EZH2 inhibitor, tazemetostat, it’s approved now by the FDA in third line if patients have the EZH2 mutation that can be relatively easily tested for on tissue specimens. But interestingly enough in an unusual FDA approval, what – if patients are wild-type, not mutated, the clinician has the option to use this drug if they determine that there are no other options for treatment. And how that’s defined, I think, is [ truly ] loosely, obviously, and in the eye of the clinician.
So basically, I think tazemetostat is available and approved for anybody with follicular lymphoma, whom the clinician feels has no other good options. And then CAR-T therapy based on data from the ZUMA-5 study, which I’ll show you in a moment, axicabtagene ciloleucel, or Yescarta, is now approved in the U.S. by the FDA for follicular lymphoma and certainly has some promise.
Next slide. We’ll go to third line approved and pipeline therapies, a similar matrix with ibrutinib now being tested together with the checkpoint inhibitor, nivolumab, on the bottom left, and then some of the other drugs, the PI3 kinase inhibitors, I mentioned, duvelisib, umbralisib and idelalisib. And then on the right part of the slide, you’ll start to see some of the CAR-T agents. The allo agents are – now people are beginning to look now at off-the-shelf allogeneic CAR-Ts. And I would say, not for necessarily elderly or infirm, but these are patients that might go to transplant if they’re younger and healthier, but the allo CAR-Ts and the autologous CAR-Ts may be reasonable options for those patients, even older patients.
Next slide. So the PI3 kinase inhibitors, the first generation idelalisib; second-generation umbralisib, another experimental drug; and then dual PI3 kinase inhibitor, duvelisib, are the ones we’ll touch on briefly.
The next slide. Umbralisib is inhibitor of PI3 K delta and casein kinase 1e and a difference in structure and other characteristics from idelalisib and duvelisib, which are approved in follicular lymphoma. This is the most recently studied and generated quite a bit of excitement.
Next slide. We’ll show you the study that generated that excitement. The issue is that this drug has to be given until unacceptable toxicity or in the study, of course, withdrawal of consent. The primary endpoint was safety, the maximum tolerated dose and some PK, pharmacokinetic, data. Secondary endpoints were what we’re all interested in, overall response rate and duration of response. I will point out something if you look at the bottom of the slide, and this I’ll bring up as we talk about these in a minute, infection, Pneumocystis jirovecii, prophylaxis was permitted but not mandated. I think it should have been mandated.
Next slide gives you a waterfall plot of the responses. And you can see and if you focus on the pink, in follicular lymphoma, you can see that there were reasonably good responses, better than 50%, say, in a significant number of patients, but most of the responses were between 5% and 50%. That’s really quite meeting the mandate for at least a partial response.
So next slide. So this summarizes some of the PI3 kinase inhibitors, the competition, if you will, for – or some of the competition for radioimmunotherapy. It’s given daily orally, but grade 3 to 4 hepatotoxicity is reported. Diarrhea and colitis in about half the patients – more than half the patients. About 10% of patients had grade 3 or life-threatening neutropenia. Skin reactions in a small number and about 10% of patients had PJP or cytomegalovirus infection. And so I would advise that everybody on these drugs should be on PCP prophylaxis with Bactrim, at least, and should be checked on a monthly basis for activation of cytomegalovirus infections, just like we check our allogeneic bone marrow transplant patients. And these drugs interact with CYP3A inhibitor. So there’s a fair number of drug interactions that we have to be aware of with this drug.
Next slide. Duvelisib. Similar. It’s twice a day dosing, but hepatotoxicity, diarrhea and colitis, pneumonia, skin reactions, infections again with PJP and cytomegalovirus. And again, concerns about the use of concomitant drugs, which are CYP3A inhibitors, for example, azoles. And if you look, there are many, many drugs over-the-counter that are CYP3A inhibitors that can interfere with duvelisib.
Next slide. Copanlisib, recently presented – published by Martin Dreyling from Munich with exciting data, except this is a drug that’s given intravenously on day 1, 8, 15 and then every month – well, actually, 3 weeks out of every month forever. It’s just an IV drug given every 3 weeks out of 4 forever until progression. Hyperglycemia is an unusual – and hypertension are unusual complications. But again, infections with PJP and cytomegalovirus and, again, interaction with certain other drugs. So the activity of this is 50%, 60% responses and maybe 30% complete responses.
And when people – we’ve been in meetings where people take a poll of what would be your choice of agent for relapsed follicular lymphoma, everybody says PI3 kinase inhibitors. And then everybody says, what would be your choice if you didn’t have to give it for the life of the patient on an IV basis 3 out of 4 weeks, and I would say radioimmunotherapy.
So next slide. Histologic transformation. I mentioned earlier, these patients can transform and they may be candidates for CAR-T therapy, we’ll finish in just a moment. I wanted to highlight this a little bit because I think this is here to stay. And I think exciting data, the chimeric antigen receptor, which is where CAR comes from, is basically mimicked after the normal T cell receptor.
And this has evolved where there is now at the – if you look at the right side of the slide, the scFv is the place where the – in the next slide, I’m sorry. Yes. So this mimics the T cell receptor. So the chimeric antigen receptor on the right, the scFv, is the place that recognizes the target antigen for the most part, CD19, but studies now with CD20, CD22, all of the approved drugs are CD19 targeted and follicular lymphoma is ubiquitous positive for CD19. So a perfect target. And people are now manipulating the co-stimulatory signal in yellow on the right, whether it’s CD28 or 4-1BB or OX40 impacts on how active this construct will be.
Next slide? I wanted to show you the data on ZUMA-5. These are data that Caron Jacobson from the Dana-Farber presented recently. If you look at the overall response rate, 76% – 92% overall response rate in 104 patients. If you look at the follicular group, it’s very similar. This is all patients. It’s made up follicular and marginal zone, but in the middle part of this graph, follicular lymphoma, 84 patients, 80% complete remission rate, 94% overall response rate. And so excellent data.
Next slide? The duration perhaps is not as good as we’d like. Starts falling off at about 10, 11, 12 months. The advantage of this treatment, just like radio immunotherapy, is it’s one and done. It’s a onetime treatment. And there probably are some patients that are going to be cured we hope by this approach. And so I think this is here, and I think it’s actually – since there are preclinical data suggesting synergy between cellular therapy like CAR-T and radiation, I would envision some trials where radio immunotherapy might be combined with CAR-T therapy.
Next and last slide. So this is just what we saw earlier. We tried to do is talk about the incidence of this, the diagnosis, little bit about biology and talk about first, second and third line treatment with a bit of a focus on patients who are older and perhaps couldn’t tolerate more aggressive treatment. The evolving landscape, I think many agents out there, I certainly think doing this for many years now that there is a role that has been missed for radio immunotherapy, either as a single agent or perhaps in combination with other agents. And some of those might be the recently approved agents, such as CAR-T therapy. So I want to thank you for your attention, and I appreciate the opportunity to talk about this. Thanks very much.
Presenter Speech
Erik Skullerud (Executives)
Thank you so much, Dr. Gordon and – for that highly educational and interesting presentation. I know you have patients to tend to. You have your rounds. So we’ll not be able to do a Q&A today, but really appreciate your insights. Thank you so much.
Presenter Speech
Leo Gordon (Attendees)
Thank you very much. I appreciate the opportunity.
Presenter Speech
Erik Skullerud (Executives)
Next, we’ll let our new incoming CMO, Pierre Dodion, give you some insights around our program on Betalutin post third line FL. So Pierre, I’ll let you take it on from here. All yours.
Presenter Speech
Pierre Dodion (Executives)
Thank you very much, Erik. And while we are loading the slides, I would like perhaps to express my – the privilege to be able to speak to all of you. As you know, I joined the company relatively recently and I’ve really – I’m really impressed by the number of activities, interesting activities that have been conducted and that will be pursued in the future. I’m looking forward to collaborating with all of you with my colleagues at Nanovector. And also, of course, with the investigators who are participating to our clinical program.
So task this afternoon will be to evaluate the potential of Betalutin beyond what we are already doing, i.e., the PARADIGME program, which, as you know, is conducted in the third-line setting in follicular lymphoma. So if you move to the – next slide, please? This is a schematic conceptual cartoon, trying to illustrate where we could go. The blue box represents symbolically the current activities in third-line follicular lymphoma and one expansion pathway is quite clearly to go to earlier lines in the treatment paradigm first and second line, but also possibly down the road in the first-line setting.
On the other side, we could also expand and this is shown by the curve pointing to the right top corner. We could expand to diffuse large B-cell lymphoma, DLBCL starting with advanced disease, i.e., patients in the third-line setting but, year ago, nothing prevent us to expand further to earlier stage of DLBCL. And of course, DLBCL has a special place in the overall landscape of non-Hodgkin’s lymphoma because as indicated conceptually by the slide, this is the largest non-Hodgkin’s lymphoma subtype.
And finally, nothing prevent us to move as well to smaller indication and representing here the particular case of – among others, but particular case of marginal zone lymphoma. So let’s address first, follicular lymphoma. If I can have the next slide, please and the next one – move to the next slide, please? Very good. Thank you.
So the treatment – could you go backwards by 1 slide? Great. Thank you. So we are focusing our interest on – in terms of clinical development on the patients in the second line setting and more specifically on frail patients. This has been discussed in details by Dr. Gordon, but typically, those patients, elderly patients, patients with co-morbid conditions, typically, do not tolerate aggressive treatments like combination chemotherapy. And very often are treated with single-agent treatment, in particular, single-agent rituximab. Hence what I’m showing here is that single agent rituximab for these patients is not at all a bad option. If you look at the efficacy data on the left side, you can see a complete response rate of 5% to 15%, a median progression-free survival of approximately 14 months.
So it does work to some extent. But clearly, there is ample room for improvement. And the curve on the right side is an illustration coming from one of the most important study in this field testing single-agent rituximab in red versus the combination of rituximab plus lenalidomide, the so-called R2 program, which was presented by Dr. Gordon in his presentation.
Next slide, please? The other attractive feature of rituximab is that overall, this is a well-tolerated drug. You have in the top part of the slide, the list of adverse events that can be induced by rituximab, things like infusion-related reactions, fever, lymphopenia. But the most important point is that in the vast majority of the cases, up to 90%, these events are actually mild or at times moderate.
And at the bottom of the slide, I’m also drawing your attention as it has been done by Dr. Gordon to the fact that besides rituximab, there are other single agents that are being used in that setting, for example, chlorambucil, with or without rituximab, cyclophosphamide with or without rituximab and ibritumomab tiuxetan. So in some of this rituximab does work, and this certainly used in these frail patients, the second-line setting. It is reasonably well tolerated, but there is clearly ample room for adopting better treatments.
If we move to the next slide, we have a nano vector piloted the combination of Betalutin plus rituximab in this patient population. This has been performed within the so-called Archer-1 study. So we are talking here in terms of patient population of follicular lymphoma were received at least some of them more, but at least one prior regimen and with the primary objective to evaluate the safety and tolerability of the combination of Betalutin plus rituximab. And of course, we have also looked as a secondary objective to preliminary antitumor activity.
In the middle of the slide to have the study scheme, in the middle box, you can see the administration of Betalutin followed by preceded and followed by rituximab as per the FDA approved regimen. And then followed by continuation of rituximab in those patients who achieve at least stable disease or partial response or complete response. The results of that study are summarized in the bottom of the slide. And actually, we have generated quite attractive data with actually all the 7 patients achieving a response. And this includes 5 complete responses, not bad at all for patients – population of patients with resistant disease. And these response seems to be quite long lasting. 6 patients have still an ongoing response. And out of these, 5 patients have passed the 2-year or 24-month assessment.
Furthermore, the combination of Betalutin plus rituximab showed actually a very good safety profile, not really different from that of single agent Betalutin. So the data suggests a pretty good – a pretty attractive level of activity with an excellent safety profile. And quite obviously, these results play an important role in forming the design of our confirmatory Phase III study in follicular lymphoma.
So coming to that, a particular study, if we can move to the next slide, please? We have been evaluating several options for the next phase of the clinical development of Betalutin in pace with follicular lymphoma in the second line setting and more specifically in frail patient who are not eligible for aggressive therapy. And for those who are curious, you can see at the bottom of the slide, a partial list of these aggressive treatment options. These are pretty much identical to those mentioned by Dr. Gordon. You can see there CHOP with or without rituximab, the combination of bendamustine, et cetera.
So if I consider all patients in the second-line setting, some of them will be eligible for these aggressive treatment regimen, but many others will not. And these patients not eligible for aggressive therapy are those who will be randomized in our study between rituximab alone, the standard of care and the combination of rituximab plus Betalutin. The primary endpoint is likely to be progression-free survival.
The beauty of this approach is that this program will be – will serve, number one, as confirmatory randomized trial as part of the possible post-approval commitment that we might receive from FDA in the third-line setting based on the PARADIGME study results. But as I said, will also constitute a data set that could lead to the approval of Betalutin in combination with rituximab in the second-line setting. So that realizes typically the label expansion that I was talking about in my introduction.
As mentioned by Erik in his introduction, we are in close contact with regulatory agencies, in particular with the FDA to finalize the various elements of this study design. So more to come, but suffice to say that we are very excited by this approach.
Next slide, please? Let us turn ourselves now to DLBCL or diffuse large B-cell lymphoma. Next slide, please? Just a quick reminder, as already mentioned, DLBCL is the most common form of non-Hodgkin’s lymphoma. And about 30% of the non-Hodgkin’s lymphoma, at least in the U.S., are DLBCL. And it is typically an aggressive form of lymphoma that involves the lymph nodes as well as other organs.
I’m not going to go into the details of the treatment of DLBCL. Suffice to say that for newly diagnosed patients, the goal is truly to cure them. And this is typically achieved by a combination approach combining multi-agent chemotherapy, the so-called CHOP regimen combined with rituximab. Many patients also receive high-dose chemotherapy followed by stem cell transplantation. Unfortunately, many patients despite this aggressive treatment still relapse and moved to the so-called second and third line setting. And despite many, many years of clinical research, the treatment of these relapsed patients remains a challenge. Therefore, this group of patients is a significant unmet medical need.
You have at the bottom some indication about the commercial opportunity for second and third line of DLBCL. And you can see that this is by no means a small group, about 23,000 patients per year for second line, 11,000 patients per year in the third line, and these are the data for the 6 key markets, EU-5 and the U.S. So that is approximately 50% more than the market of second line follicular lymphoma. That is just to show you the importance of the DLBCL patient population.
Next slide, please? This is intended to give you a very brief snapshot of the treatment approach for DLBCL as Dr. Gordon focus mainly on follicular lymphoma. As I said on the previous slide, the first-line treatment is typically a combination of chemotherapy and rituximab. In the second-line setting, there is a quite long list of agents with relatively poor activity. This may be changing now with the introduction of newer regimen, but it remains also an area of intense clinical research. And I will show you in a moment some recent data about 2 particular classes of newer agents. And then in a third line setting, the situation is even worse and it’s typically an area of clinical research.
Next slide, please? I’m sure that many of you have heard about CAR-T cell therapy, bispecific antibodies. And I’m mentioning these 2 classes because they represent examples of treatment with, yes, quite substantial activity. If you look in the middle of the slide, you can see there, the objective response rate, the complete response rate, progression-free survival data, overall survival data. And when one is talking in refractory patients or relapse patients about complete response rate of 40% to 50%, 2-year survival of 50%. One cannot deny that this is indicative of pretty good activity.
However, at the same time, the toxicity of this agent is quite substantial, and this is featuring the bottom part of the slide, Grade 3-4 toxicity failures or cytokine release syndrome, neurotoxicity, infection, neutropenia. And you can see that virtually for all of these, we are talking about ranges between 5% and 20%. Accessibility may also be an issue. These treatments are not necessarily given in every single medical center and also the financial burden in terms of acquisition costs may be quite tremendous. I’m sure that you’ve all heard about the cost of CAR-T cell therapy.
Now you may perhaps remember what Dr. Gordon said about a third class, i.e., the PI3 kinase inhibitors. And in fact, I could have easily added third column about the PI3 kinase inhibitors as a class because it’s providing pretty much exactly the same picture. Some very good activity but also quite substantial toxicity. And quite obviously, yes, one would wish to be able to administer these treatments to every single patient in the third or second line setting, but the reality is that elderly patients are simply unable to tolerate these quite aggressive treatments.
Next slide, please. It’s just providing more details about what I said as an overall approach. And I’m not going to spend too much time here. But fundamentally, in the second line setting, you can see that there is no one combination that has been approved, tafasitamab plus lenalidomide combination. CAR-T cells are moving along as well as bispecific antibodies. But clearly, there is still a need for better combination therapies and very importantly, that have an acceptable safety profile, especially for frail patients.
And in the right column, I’m providing data on the third line setting, again, some information about CAR-T cell treatment that we already discussed. Some information about drugs called polatuzumab and loncastuximab. But bottom line is that, again, these refractory patients, particularly in the third-line setting may very well represent a unique and very attractive spot for Betalutin, especially in elderly and frail patients, and therefore, provide us a way to enter the DLBCL segment.
Next slide, please? Just like in follicular lymphoma – I may have the next slide, please? Previous one? Yes, apparently. Yes. Thank you very much. We have also initiated clinical activities in the field of DLBCL. This particular study is named LYMRIT 37-05. And in fact, we have performed a Phase I study in 18 patients with relapse or refractory DLBCL patients, 16 of them were evaluable with the goal, quite obviously, to investigate the safety profile to determine the maximum tolerated dose in these patients and also to detect initial signs of activity. And you have the kind of dosages that we’ve explored in – as part of this study in the 4 boxes that are displayed on the slide.
Next slide, please, is actually showing the critical results of that study starting from the bottom. Importantly, we have been able, indeed, to establish recommended Phase II dosage. And the exact numbers for lilotomab and Betalutin are indicated on the slide.
In terms of safety and tolerability in the high top corner, we found that Betalutin is actually very well tolerated and complete in a consistent manner with all previous studies. And then finally, and importantly, as illustrated in the left top corner, we did see interesting clinical activity. In particular, we reported 2 complete remissions at 2 highest dose levels, again, considering the kind of patient resistant refractory DLBCL review that is very encouraging.
Next slide, please
[fortsetter]
Where do we go from there? Well, one very attractive option in our mind is to combine Betalutin with other agents. And this has been also – this has also led to successful development for some of the drugs, 3 of which are listed on slide, tafasitamab on the top, polatuzumab in the middle, naratuximab at the bottom. You can see in the middle, the kind of efficacy data achieved with single agent, and we are showing here the overall response rate, 26%, 56% and 22%, respectively.
And then on the right, you can see the clear increase in terms of activity when these drugs are combined with patented drugs, in particular, tafasitamab with lenalidomide, polatuzumab with rituximab and bendamustine, and finally, naratuximab with rituximab leading to a response rate of 60%, 63% and 50%. So at times more than the double of the response rate achieved with the single agent.
If we move to the next slide, we think based on all those considerations that – the most important, the most attractive option is to explore a combination of Betalutin in the third-line setting in the form of an exploratory Phase II study. To be complete, we have explored other options, in particular, escalating the dose of Betalutin further which, by the way, could be actually achieved as part of the proposed Phase II study or exploring Betalutin is consolidation agent. These options are there. But again, we feel that the combination approach is really the best one.
And coming with that to my next slide, which basically recap that, again, you can show the next slide, please, that third line DLBCL in frail patient is really the focus of our clinical research in these patients. We are working on the identification of ideal combination partners, taking into account both efficacy – existing efficacy data with also tolerability data. As I said, we could very well increase the dosage of Betalutin, and we are engaged in multiple consultations with external experts to optimize the study design. Thank you very much.
Presenter Speech
Erik Skullerud (Executives)
Thank you so much, Pierre. Two pieces of logistical information before we move to Marco. So first of all, we’re going to have a break after Marco’s presentation, so that we can get a little bit of coffee or bio-break for people. And secondly, if you have questions, please free to submit them, and we will handle that at the end of the session for everyone. But without further ado, I want to move to Marco Renoldi, our COO, who will speak to you about one of the initiatives more on the commercial side that we are developing at the moment. Marco?
Presenter Speech
Marco Renoldi (Executives)
Yes. Hello. Good afternoon, everybody. I think it would be a shame if we were unable to use the great clinical development work that the company has done so far and make it available to patients. For that reason, over the past few years, we’ve invested time, resources to understand both the drivers and the barriers to the integration of radioimmunotherapy into the continuum of care for lymphoma patients in preparation for launch. So I will share today the findings from the most recent initiative. May I have the next slide, please?
I think, as we all know, radioimmunotherapy is a targeted approach to cancer care, with the potential to improve both progression-free survival and quality of life in many tumor types. And we’re proud to have generated data with Betalutin that makes us confident that radioimmunotherapy can make a difference also to NHL patients. But on the other side, we are also aware, and I think Dr. Gordon mentioned, that some radiopharmaceutical therapies are underused despite the significant potential they can offer. So our effort has been targeted to understand the barriers to adoption and most importantly, to find solutions.
Some of these barriers, we are well aware are not necessarily related to the product. Rather, they are systemic. And so the solution, the mitigation can only be obtained through policy interventions, which require a coordinated effort. And for that reason, we are, indeed, partnering with medical societies, patient advocacy groups and also with other biopharmaceutical companies that operate in this space.
May I have the next slide, please? In 2019, a U.K.-based health policy organization, named HPP, started a very interesting project with one specific goal to raise awareness around targeted radiopharmaceutical therapy, which they called radioligand therapy. And actually, radioimmunotherapy is 1/4 of radioligand therapy, and Betalutin is one example of radioimmunotherapy. And the key findings of their preliminary research are shown in the blue chart on the right of this slide.
And what they found – what HBP found with this research was a set of barriers to integration of radioligand therapy into cancer care. I think it’s reassuring to see that what HPP found out really validates the previous research we had done in this space. The same barriers we had previously identified and had started to work on. And I will just name a few, which I believe are particularly relevant.
Number one, the low awareness of this technology amongst the younger generation of physicians. Number two, the insufficient number of authorized users, for example, nuclear medicine specialists who can deliver the medication. Number three, the unclear referral models through which patients are basically referred from hematologists, oncologists on to nuclear medicine specialists.
Next slide, please? For the above reasons in late 2020, we decided to partner with HPP. We felt they had done a really neat job. We decided to partner with them and together with another important pharmaceutical company, we decided to co-fund to provide funding support to their follow-on project. The goal of the new project was to develop in collaboration with a series of international experts from both the U.S. and Europe, and Dr. Gordon was one of them, an assessment framework.
Basically, one assessment framework per country that would allow the evaluation of the readiness level in each specific country to integrate novel radioligand therapies, radio immunotherapies, but most importantly, because that’s what is important to guide any required changes.
Next slide, please? The readiness assessment framework is designed to generate thorough situation analysis for the U.K. and one for the U.S. This situational analysis contains a clear articulation of the barriers, requiring policy interventions, but in addition, a series of background document that explore in depth specific domains. To name a few, governance, regulation and reimbursement, service provision and so forth. If I can make a parallel, it’s almost like a CT scan.
So the situational analysis identifies the problems and indicates the most laser-focused approach for removal of the problems. So you will agree with me that this is a unique tool as we prepare to launch our product because it will ensure that eligible patients can benefit from the treatment.
Next slide, please? I would like at this point to share with you a glimpse, just a very high-level overview of the most important findings of the U.S.-based situational assessment. You see on the left, certain barriers, which were spotted. And for each of the barriers, a clear set of intervention plans was identified. You see that on the right. We call them policy implications or policy interventions. And this is the beauty of this approach that we can identify areas, barriers where we can directly act upon. And I’d like to focus on the 3 ones which are highlighted in red on the left – on the right column.
Number one, our effort to ensure that treatment guidelines include any approved radioimmunotherapy as soon as technically possible. And so we hope that as we prepare to file our BLA with the FDA, we will be able to ensure that guidelines include Betalutin for treatment of lymphoma patients. Second, to ensure the awareness of this treatment collaborate and partner with patient advocacy organizations to create very patient-friendly information, so the patient are aware of this novel type of treatment and appreciate the advantages that one only administration can provide to them. And number three, last but not least, supporting medical societies to develop easier, more streamlined referral and treatment pathways.
And our goal is very simple. Our goal is to create a multidisciplinary approach so that hematologists who normally see the patient and nuclear medicine specialist who need to receive these patients for the treatment with radioimmunotherapy can have a seamless dialogue and we can ensure a consistent approach across different settings of care, both in academic sites and in the community practice.
Next slide, please? I think we are proud of this project. We are proud to partner with HPP. We are proud to be a co-funding partner with another important pharmaceutical company because we are together in an effort to drive policy change. I think we believe that creating a more receptive environment to radioligand therapy or radioimmunotherapy, whatever you want to call it, will ultimately benefit patients because those who are eligible for these therapies will be granted access.
Next slide? So I hope I’ve been able to share with you the most important findings from this project. I wish to thank you for your attention. And I’d like to suggest for those of you who are interested to learn more to please visit the website, radioligantherapy.com. Thank you very much.
Presenter Speech
Erik Skullerud (Executives)
Thank you so much, Marco, again, for this great presentation. I hope you’re starting to get a feeling, the multitude of different areas we’re working on the different dimensions that we’re working on. Before we break for a short break, let me take this opportunity to give a big thank you to Marco. Some of you will not know, but he is going in retirement as of the 1st of January 2022. And he has obviously been a cornerstone in a lot of the efforts that we have done as a company since I believe, back in 2014, Marco. So a big thank you for that.
We obviously wish you all the best for your retirement. But I’m equally happy to also say that you have decided to stay with us for 2 days a week on a consulting basis, so we won’t lose your great knowledge and your great contribution. But for now, thank you. All the best for your retirement. We’re going to take 5 minutes break, guys. I’ll be back at 3:45. I know some of you have to fill up on popcorn and Coke. I believe I saw in social media. So feel free to do that, and we’ll be back in 5 minutes and continue with Maureen’s presentation.
[Break]
Presenter Speech
Erik Skullerud (Executives)
All right. Are we back online? I think we can move on with the next few presentations. So I hope you can hear me out there? Yes. Great. Thank you. So we’re about to get started again on the second part of our presentations for today, a little mistake from my side just before we went into the break. We’re going to move to our manufacturing/supply chain now and have Lars give a short update on what we are doing with that and how we are progressing with that. This is an important part of how we develop our readiness for the upcoming BLA as well and then move to Maureen after Lars. So without further ado, Lars, all yours.
Presenter Speech
Lars Nieba (Executives)
Thanks, Erik. I tried to look like Maureen, but it didn’t work out. That is why we had to change. So – but seriously, thanks. Good afternoon, everybody. It’s pleasure for me to be here on stage and to walk you through our journey to BLA and to launch readiness.
Can I ask, next slide, please? So what does CMC stand for chemistry, manufacturing and controls. So what does it cover? It covers all aspects from production, so including quality and regulatory. So why is CMC important? Now the easy answer in essence is what Erik also mentioned earlier is, without the substance, you can’t treat the patient. But seriously, CMC has become more and more important for regulators and many successful clinical programs failed to receive immediate approval due to CMC issues.
We, at Nordic Nanovector, are working hard to avoid this. CMC is important to us because it impacts our patients. It is important to our IP and of course, later on for our margins. We have regular meetings with the health authorities, and it is really an integral part of our company. So that is why the overall CMC strategy is really important for our overall success. As you know, we have no own manufacturing capabilities.
Let me have the next slide, please? But here are our key partners. So that covers more or less where we are active in. So we are a Norwegian company. We have 2 partners in Oslo and one is Diatec, the other one is IFE. We do have a partner in Germany, which is ITM. We have 2 partners in Spain with Liof and 3PBio. We also have partners in the U.S. with Macrocyclics and we are in close interactions to finalize the contracts also with Cardinal Health for our later on distribution. So what you can see, our supply chain is already pretty global.
Can I have the next slide, please? So let me walk you and give you an overview about our journey to launch. So first of all, the PPQs, what is PPQ stands for? Its process, performance, qualification. It is a requirement to demonstrate and validate the robustness of our process and very importantly, in a suited facility, which is GMP conform.
So next in line is then that we have to prepare all of our documentation for submission, the so-called BLA preparation, and we have to prepare our facilities for a so-called preapproval inspection. In parallel to that, we have to set up our commercial supply chain.
We have to define all of our business processes to that to be able to supply in all countries. We have to define, for example, something like top policies having the right planning systems in place and so on and so forth. And where, of course, Marco and Erik are very keen on is that we are already at time of approval for an immediate launch so that we can really supply and give the medication to our patient. And last but not least, as I mentioned, it’s also important for our margins. We already start focusing today on our efficiency and effectiveness of the entire supply chain to not only have a robust process but also to reduce costs.
May I have the next slide, please? So I know it’s a reminder for most of you. Here’s our manufacturing process. As most of you are aware of, we have 2 independent products. The one is called lilotomab and the other one is called Betalutin. Let me start first with lilotomab. So we start with our production in Oslo at Diatec, where we produce the crude. We then moving further to the drug substance, to purification at 3P in Spain. And then we do have the filling at a company called Liof. So that is our final product for lilotomab.
For Betalutin, we do have the first step – the first 2 steps are the same. We then add DOTA, chemically to it, which is supported – which is brought by Macrocyclics to Spain. And we then do have the filling for the so-called lilotomab-satetraxetan at Liof and then we couple it with lutetium, which is coming from ITM in Germany, and we do have our final product done at IFE with Betalutin. So what you can see is that is our overall manufacturing process, which we are currently validating.
Can I have the next slide, please? And as mentioned before, it is not only important to have a good and robust process. It is also extremely important to have good facilities for the so-called pre-approval inspection, of course, but also in general, for producing GMP. Let me go and give you an impression about where are our partners.
So let me start with Diatec monoclonals in Oslo, I wanted to say here in Oslo, but unfortunately, we are here in Switzerland and instead of being, of course, in Oslo. And what is Diatec? We have developed together with Diatec, a robust production process. And we have invested together into the production facility, which is GMP certified by the Norwegian Medicine Agency. We have Class B and C room. So overall, I think we are making very good progress here for both the process and the facility.
Can I ask the next slide, please? Moving on in our value chain, we move to 3PBio, which are in Pamplona in Spain. The facility itself is GMP certified by the Spanish agencies, for the manufacture of biological products and also the release of sterile products. But more importantly, for us, 3P has invested into a new state-of-the-art facility, which we just visited, which really looks great and our product is produced now in the new facility, which is really good news for us.
Let me walk you to the next partner, next slide, please, which is Liof, which is about 80 kilometers away from Pamplona. And also there, Liof is GMP certified by the Spanish Health Authorities and for aseptic filling and release of sterile products. Liof has a state-of-the-art filling line, and it was already inspected by the FDA in a pre-approval inspection, and also there have very good quality, what we are getting.
Now let me – let us move back to Oslo. Can I have the next slide? IFE. IFE has also done a lot of work over the last years. This has invested into a new manufacturing line for our Betalutin production. The picture here is showing actually, the very new line, where we are very proud of. Our product will be manufactured in that line. And of course, IFE is also GMP certified by NoMA. So overall, I think we have not only a robust process, but I think also all of our partners have really good facilities in place and where we can do a lot of work in.
Now going to the next slide. And as mentioned in the beginning, the one thing as a process and the facilities, which is also very important, is really to bring the product to the patient and that is the supply chain. Now how have we set that up and what is important to look into in the supply chain if we are setting up a commercial supply chain? And what you can see here is, how we will move our product from place to place. Now we started Diatec with the crude. We will go by plane then to Spain, that it is and that we can produce there, see bulk drug substance. And then we will move it to Liof, which is 80 kilometers away, again, by plane back to Norway. And then we would – and we have to bring it from IFE very fast into the U.S. As you know, we only have about 7 days of shelf life after the production.
So – and we have a very strong partner chosen in the U.S. for commercial supply chain. We want to move ahead with Cardinal Health, which do have a lot of radio pharmacists, and they are very active in the U.S. and very well known for that, and we are happy to have them as a partner. And from there, we can bring it into various administration sites in time.
As the supply chain is not only is that what you also need to be aware of that you have to look on critical raw materials, your safety stock policy, your secondary sourcing and so on and so forth. Underneath, you can see some of these very important. But of course, it’s only a snapshot, a glimpse on where we are looking for. One thing is, for example, the monoclonal antibody medium for production at Diatec. The other part, of course, is the DOTA that it is in time at 3P. What some people are forgetting is the primary packaging. You need to think about we have vials and stoppers, which looks very basic. But of course, we have to have enough room for them. Because if we don’t, then we can’t fill. So all of that, we would need to look into it.
There are other premier packaging sources. There’s also some additions to some buffers like Recombumin and all of that needs to be looked on. And of course, lutetium always have to be fresh there in time. And we are working very close, not only with ITM, but also, of course, thinking about second suppliers and so on and so forth.
And finally, at the administration side, what you should also not forget is infusion filters. And there’s a long list, which we are currently looking on and how we prepare ourself to be ready for the launch and the commercial supply.
And can I the next slide, please? Now where are we? You always hear a lot from [ Malene ], where we are, that CMC is working on the PPQs and so on and so forth. Now we are fully on track with our process, performance, qualification. We are also on track in preparing for our BLA submission. As you have seen, we have already started to set up the commercial supply chain because it takes also a while if all of, say, things are really in place for the launch. So, of course, we haven’t done the launch, but we start to prepare for it. And where everybody is interested later on is to having good margins. And we are already thinking about how to improve our cost of goods. So that is at conceptual stage.
With that, I hand over back to you, Erik.
Presenter Speech
Erik Skullerud (Executives)
Thank you very much, Lars. I think as you can see, one thing is the clinical development, the PARADIGME study. It walks hand-in-hand with our CMC, our manufacturing, development. This is really a hand in glove. It is a matter of really ensuring that on one hand, we get the clinical results that we have. But on the other, that we also do the right things in order to ensure that the product gets developed and produced, manufactured well. So this was a bit of a glimpse into what Lars and his group is working on at the moment.
Now we’re going to switch gear completely. We’re going to let Maureen take over and talk to you about our 2 most recent little babies, on first the monoclonal antibody that we are developing, a humanized antibody. And on the other, our CAR-T co-development or our collaboration rather with radio University of Pennsylvania. So Maureen, on to you.
Presenter Speech
Maureen Deehan (Executives)
Many thanks, Erik. Yes, I’m very, very excited now to have the opportunity to give you some headline information on where we are with these discovery programs.
Next slide, please? Can I have the next slide, please? Apologies. Thank you. So this is a build slide. So B cells also known as B lymphocytes are a type of white blood cell, and these play an extremely important role in adaptive immunity. Hit the button, please. There are multiple antigens present on B cells, CD19. Next, again, please? And you’ve heard both Professor Gordon and Pierre talk about these today and also – hit the button again, please.
CD37. So yes, CD20 is very well recognized and as we all have heard of rituximab. Rituximab was actually approved in 1997 for cancer. And you’ve also heard today about some CD19 therapies, such as Monjuvi and the CAR-T therapies, Yescarta and KYMRIAH.
But at Nordic Nanovector, we focus on CD37 because it’s also a major antigen on B cells. You will see from my subsequent slides that other people are active in this space. But where we really have an advantage is that we’ve been working in this biology for over a decade.
Next slide, please? So now I want to talk to you about the B-cell development process, which is shown in the upper most panel of this cartoon. And you can see from the far left from the stem cell and the bone marrow to the far right in the plasma cells, there’s multiple stages that are involved. And when you look at the middle panel in this figure, you can actually see that individual B-cell lineages can be associated with particular B-cell malignancies as shown in green.
And what I’d like you now to focus on, please, is in the bottom panel where we show levels of CD20 and CD37 expression and CD19. And what’s really important is that CD37 expression in the B-cell lineages overlaps identically with what you see from CD20. So you see expression from the pre-B-cell to the early plasmablast, where the CD19 is expressed broader. And why we think CD37 is a better choice of candidate is that, you don’t really want to be with the therapy knock out all of these early Pro-B cells because it’s still important to be able to mount an immune response. So CD37 expression is very attractive for a novel therapeutic.
Next slide, please? What I want to do from this slide is just also to remind you that despite the fact that CD37 is almost exclusively expressed on B cells, that there is also an immunomodulatory potential, that there’s also an impact on other important immune cells such as macrophages, T cells, dendritic cells and neutrophils. And now there’s a lot of literature that really explains that CD37 has an important role not only on the B cells, but it can also impact these other important immune cells.
Next slide, please? So to date, you’ve heard all about our important role in working on radioimmunotherapy. Now with the radioimmunotherapy, what we do is, we use the CD37 antigen as a docking station. So the radioimmunotherapy molecule is an antibody with the chelator and the radioisotope. And essentially, what happens is that the radioimmunotherapy comes along, docks onto the CD37 receptor. And then the radio activity can be incorporated within the cell and also kill other cells in the environment.
Now this is a very clever and effective way of targeting B cells. But what I want to do next is explain to you how now by exploiting a humanized anti-CD37 monoclonal antibody approach, what we actually do is, we target the CD37 receptor pharmacology.
Next slide, please? And so to do that, I just want to do a little bit of a recap, refresher on antibodies. So this is a diagram of an antibody structure. And an antibody is composed in green of 2 identical heavy chains and in blue, 2 identical light chains. And through disulfide bonds and noncovalent interactions, you have this typical Y shape that you can see in the figure. So that’s what you’ll recognize as an antibody. And I want to bring your attention to the 2 circles on the top, the variable region, which circles around those square boxes and then in the bottom in red, the constant region.
Next slide, please? Okay. So as this next slide is – becomes visible, what I want to do next is to talk to you about the different types of monoclonal antibody. So what you can see on the left-hand side is that there are mouse murine antibodies, monoclonal antibodies. And the first murine monoclonal antibody approved was in 1986, and it was an anti-CD3 antibody for a kidney transplant indication and also Betalutin, our antibody component of Betalutin, Lilotomab is also a murine antibody.
Then when we move across to the chimeric antibody, you can see in the cartoon I explained previously. What you can see here is in the chimeric, the area that I called the constant region in yellow is actually now from a human and the blue, which is the variable region is from the mouse. Then moving to the right, when you actually have the situation where more of the variable regions are human and you have less than in the chimeric, that is the humanized antibody. So you have predominantly a human structure. And could you hit the dot, please? And again? And also again, please?
And really, what this means is why we’re really excited about having a humanized antibody to complement what we have is because with murine antibodies and potentially with chimeric, there is the increased chance of having immunogenicity. So therefore, that dose limit you because there is a risk if you give multiple injections. So one of the key reasons why we are pursuing a humanized anti-CD37 monoclonal antibody is because it will support multiple injections which will be important for some acute indications, but it also moves us into a market for chronic diseases because we know that in the chronic disease situation that often you have to repeat your administration. So this is why we are particularly excited about this approach.
Next slide, please? So we’ve been working on this program, and I now want to just give you an update on where we are. So we’ve generated multiple anti-CD37 leads with different vector functions. That means different killing mechanisms. And I’m going to talk to you – I described that a little bit better in the next slide. Where we are from the process is that we are finalizing our lead candidate selection. And that is based on a range of criteria, including in vitro activity, in vivo activity, manufacturability assessment because Lars wants to make sure we choose the antibody with the best characteristics to take forward for production. And also, we are ranking our leads based on other anti-CD20 and other anti-CD37 antibodies.
So now in the slide that we’re looking at, in this cartoon on the left-hand side, that’s your typical Y-shaped antibody that I’ve explained to you. And I want to let you know that these monoclonal antibodies have got 4 mechanisms by which they can kill a tumor cell when they engage. So if we start at 11:00 on the blue tumor cell, what you can see happen is, you can see the antibodies inverted. You see the arms are now interacting with the receptor – CD37 receptor on the tumor cell. And the tail is sticking out. And what can happen is, this type of engagement causes receptor signaling of a lot of death signaling pathways. So you can have a direct death effect.
If we move around in clockwise, then you see a process called antibody-dependent cellular phagocytosis. And what happens here is that the tail SC interacts with the cell, the green cell called a macrophage and it tells the macrophage, eat me. So then the macrophage is involved here and starts to eat the tumor cell.
Moving around to 3:00 on the right-hand side is also another process called complement-dependent cytotoxicity. And what happens here is that the antibody engages with a protein called C1q and causes this cytotoxicity. And then if we move down to the bottom left, the fourth process is called antibody-dependent cellular cytotoxicity. And what happens here is that the antibody engages with other immune cells called natural killer cells. And what happens is, it can elicit these natural killer cells to release granules, which kill the cell.
So we filed a patent for – on our leads. And where we are just now is, as I told you, we’re choosing our lead candidate. And because it’s commercially sensitive, all I can tell you at the moment is that we have come up with a series of leads, which – where we’ve optimized each of these killing functions. And I can let you know we’ve come up with some really interesting molecules. But where we are just now is that because it’s commercially sensitive, what we will do is we look forward to presenting further data to you in 2022 on the lead candidate that we’ve selected.
Next slide, please? So in oncology, I’m using this slide really to point out to you that for a monoclonal antibody, the top 10 therapy areas for monoclonal antibodies are shown in this figure. So you can see here that for oncology, almost 4,000 monoclonal antibodies are being developed for oncology indications.
Next slide, please? So the reason why we are developing the humanized anti-CD37 is because we want to utilize this antibody and the benefits it has to strengthen our radioimmunotherapy platform and namely to strengthen Betalutin because we believe you’ve heard from Pierre, he’s got ideas about how to do some combination treatments with Betalutin and some of these more aggressive and difficult-to-treat tumors where we know that a single injection such as we see in follicular lymphoma might not be enough. So Betalutin could be a good induction therapy, but because, again, the fact that it’s based in a murine antibody, we really feel that we might not be able to give multiple administrations.
So where this monoclonal antibody will prove extremely beneficial in oncology is that, we’ll be able to treat some of these difficult-to-treat subsets of patients such as the relapsed refractory DLBCL patients are also it gives us the opportunity to try to go to earlier lines and to have a treatment for frontline NHL. So we could use the humanized monoclonal antibodies. The maintenance therapy after administration of Betalutin with the aim of extending both the rate of response as well as the durability. So therefore, you heard Dr. Gordon talk about it, and you also heard Pierre and that’s this idea here, but we could actually use the monoclonal antibody as a maintenance therapy.
Next slide, please? So we have the opportunity in oncology, but because B cells also have an important role in immunology and in fact, immunology is the second highest therapy area for monoclonal antibodies, we intend to also explore this market opportunity and also because autoimmune diseases, in particular, have been predicted to be – have a market share of $150 – sorry, $150 billion in 2025. So we truly believe that this is an area that we should explore for our humanized anti-CD37 antibody.
Next slide, please? And why? Why do we have reasons to believe that we should do this? Because of some analysis that we did a couple of years ago in-house, with Clarivate Analytics, where we worked in a program where they looked at CD37 expression in a whole range of different autoimmune diseases. And what we came up with was the 5 listed on this slide as being areas where CD37 is expressed at higher levels. So we have Sjogren’s syndrome. We had severe asthma, colitis, psoriasis and systemic lupus erythematosus. So what we are doing now is considering doing further data mining to really look to see other sensible immunological diseases that we could target from both a scientific and clinical rationale basis.
Next slide, please? And also, we want to look at what the large pharma, Erik mentioned this earlier. So large pharma have been extremely successful in their anti-CD20 approach to extrapolate into autoimmune diseases. So we want to look and see if there’s any lessons learned for us in CD37. And in this slide, I just want to recap for you where the CD20 molecules are playing currently. So rituximab has a marketing authorization for RA but also for other immunological diseases. And in fact, rituximab is in clinical trials for progressive multiple sclerosis.
Obinutuzumab, the kind of second generation anti-CD20, is not currently an FDA approved to treat lupus but may be described off-label, but it’s also being looked at for lupus nephritis because it’s one of the most serious complications of the lupus condition.
And in addition, moving to the right-hand side, the Novartis molecule, ofatumumab, is in clinical trials for progressive multiple sclerosis and also rheumatoid arthritis. So again, what we will do is utilize the expertise that the larger pharma are working in this area, too, to really come up with a sensible plan. First indication will be for an oncology but to look to further extrapolate into some of these other autoimmune diseases.
Next slide, please? And it’s not just those that share opinion in the value of CD37 as a target. There are other companies also active in this area. So GEN3009, the Genmab molecule, which I’m sure you’re all aware of. It’s a biparatopic duohexabody molecule, and that was recently partnered with AbbVie and needed Phase I/II for hematological cancer.
And in the summer this year, we became aware of another molecule from a company called Sound Biologics, PSB-202, which is actually CD37, CD20 bispecific antibody, and that’s a Phase I for hematological cancer. And the molecule that I’m sure you’ve heard you’re most aware of because it’s been around longest is the CD37 ADC from Debiopharm, which was in-licensed from ImmunoGen, and that’s currently in Phase II for hematological cancer. So again, different molecules are in clinical development that targets CD37, but our molecule will have a different properties, and we will be able to share that target product profile with you in 2022.
Next slide, please? So again, just a summary, the patent has been filed. The lead candidate selection is ongoing. And as I explained, the first indication will be hematology, and we have an IND date planned for 2023.
Next slide, please? So on my last couple of slides, I want to talk to you now about our CD37 DOTA CAR-T cell approach. We’re working with you, U Penn. Erik already told you earlier. One of the reasons we were particularly enthused about working with U Penn is that they are the pioneers of a CAR-T cell therapy. And of course, the first CD19 CAR-T cell came out of that U Penn and that was the first CAR-T licensed by Novartis. So we know they’re an excellent group to be working with.
Next slide, please? So the collaboration aim is to harness that CAR-T experience and also to utilize the CD37 expertise that we have at Nordic Nanovector and as I explained to you over a decade of experience there. We’re also interested because the CD37 CAR-T cell landscape is less competitive. You heard Dr. Gordon already say there’s a lot of molecules that are CD19 CAR-Ts.
So we think this is a good space to play in. And also, we believe that the U Penn technology may have an important safety feature, and I’ll describe that in the next slide. And what’s exciting for us in this collaboration is that we will have the option to license in this CD37 DOTA CAR-T cell therapy.
Next slide, please. Okay. And the next slide is really just to highlight the unique properties of this technology. And if you can hit the button on this. Thank you. So the U Penn have an immune – sorry, a universal immune receptor T cell, UIR T cell. And what this is, if you think back to what Dr. Gordon said, he said, essentially, you have this single gene Fv molecule, and you have CAR and T-cell signaling elements fused to it. And you also heard that he said that new generations are really working in the T cell signaling part. So the difference here with this UIR is in addition to having the binding domain, the T cell signaling, there’s also a DOTA binding domain. And DOTA is a cumulate molecule. So what happens is that the patients in this – the blood is taken from the patient. The white blood cells are collected. And basically, the T cells are collected. And this construct is introduced into the T cells. And then they can be infused back into the patient. And unlike the CAR-T cell technologies that Dr. Gordon and Pierre has mentioned to you earlier today, normally, when you do that, when these T cells are put back into the body, they start to proliferate. But with the technology we are using, they cannot because they have a DOTA binding requirement.
If you could please hit the build again, please? So what happens for us – and again, please. So what we have in our system is that we have an anti-CD37 DOTA antibody. So again, taking you back, the T cells are in the body, they can’t do anything. This anti-CD37 DOTA antibody is injected in. This antibody binds to the CD37 cells on the B cells. And the DOTA is exposed. So then the T cells can engage with the DOTA, and then they can start to proliferate. So this really does have the opportunity to mitigate existing limitations. And you saw some of this already mentioned, a series of adverse events by Pierre.
So what this means is by being able to titrate in the amount of antibody you use, you can regulate the degree of T cell proliferation. And what that means is that you can have some control over potential toxicities, such as cytokine release syndrome and also neurotoxicity that some patients experience with these agents. So this project has just started. We’re really excited to see what data we have. And in conclusion, we’re excited to be able to present on both projects next year to you. And I really hope as investors that you’re excited to see that we’ve got some new molecules with new angles, new target product profiles. And hopefully, these new molecules will complement what we already have in our platform and also build on it.
And that all that leads me to do now is to thank you very much for your attention.
Presenter Speech
Erik Skullerud (Executives)
Thank you very much, Maureen, for that in interesting presentation.
I hope you appreciate our 2 latest additions to our pipeline. We are excited about this. We believe this adds very nicely to what we already have.
But in order to complete that picture also from what we already have, I’d like Jostein Dahle, our CSO, to take you through an update on Betalutin as well as Alpha37.
Jostein, please?
Presenter Speech
Jostein Dahle (Executives)
Yes. Humalutin is a CD37 targeted therapy for the treatment of non-Hodgkin’s lymphoma.
Next. In Humalutin, we have used a chimeric version of the lilotomab mouse antibody that is used in Betalutin, the NNV3 antibody. It binds equally well to the CD37 antigen as lilotomab. The blue part of the antibody is human, while the red part is marine. So 70% of the most sequences have been removed. And therefore, the antibody has lower immunogenicity potential, higher therapeutic effect and longer half-life in blood than lilotomab. For Humalutin, we used the gold standard lutetium DOTA peculation of lutetium 177 as in Betalutin. The intellectual property rights are covered by a composition of matter patent and a combination patent application. GMP processes have been established to manufacture NNV3 and Humalutin for clinical trials. And our regulatory dossiers have been completed. So Humalutin is our next-generation anti-CD37 radioimmunoconjugate that is tailored for treatment of non-Hodgkin’s lymphoma.
Next slide. In our most therapy experiment, NNV003, in the orange curve, was more effective than lilotomab, in the blue curve. In this study, we injected 100-microgram of the antibodies 2 times a week for 4 weeks to each mouse. So we used quite high doses, but they were tolerable. The mice were injected intravenously with REC-1 mantle cell lymphoma cells before the treatment started, and we got 100% survival while treatment with NNV003 and 60% to 70% with the lilotomab, while all the mice in the untreated control group died because of cancer between 50 and 70 days after start of treatment. Human antibodies bind very well to most effector cells, and like Maureen talked about. And that is why we get an effect in this therapy experiment, while most antibodies do not bind to human effector cells. So in humans, or patients, we do not expect and also we haven’t seen any therapeutic effect of lilotomab, while we expect to see an effect of NNV003. This higher therapeutic effect of NNV003 than of lilotomab might enable use of NNV003 for both pretreatment and pre-dosing. So we don’t need to use rituximab like we do for Humalutin.
Next slide. With a radiolabel antibody, Humalutin, we use much lower doses of antibody, only around 4 microgram as compared with 800 microgram in the experiment with only naked antibodies on the previous slide. So here, we also have exactly the same mouse model as in the previous slide. it’s actually a leukemia model since we inject cells intravenously. And we actually do not expect so good effect of Humalutin in this model because the range of the beta particles is too long for treatment of single cells in the blood. It’s better suitable for larger tumors. You can see in the green curve that when we treated only 4 microgram or 0.167 milligram per Kilogram of NNV003, we still get some effect of the naked antibody, around 40% survival. So it’s quite potent on its own in this model. The greater is the untreated control group. And you see that all the mouse dies within 70 days of the cell injection in this experiment also. The orange curve shows the effect of a nonbinding antibody and the red curve shows effect of nonbinding antibody labeled with lutetium. And as you see, there’s no effect of these 2 treatments. They just follow the gray control curve. In the light and dark blue curves, you see the effect of treatment with Humalutin. There was a significantly increased survival compared with the control groups, but the effect was not significantly higher than the effect of NNV003. Okay. So we could have increased the dose as you might think, but we have used skid mice in this experiment, and those mice are inherently very sensitive to radiation. So therefore, we couldn’t go higher than 100 megabecquerel per kilogram.
Next slide. So in this experiment, we have changed to another mouse type, new mice, that tolerates radiation much better, so we can go up to 500 megabecquerel per kilogram. In addition, we have changed our subcutaneous tumor model with tumors under the skin on the few flanks of each mouse to resemble a lymphoma tumor. Even though we have used the same cell line here, REC-1 cell line again and much higher doses of the NNV003 antibody. We get no effect of the naked antibody in this model, as you see in the 2 green curves, and also no effect of the nonbinding antibody of a radio label nonbinding antibody in this aggressive model. You see it’s much more aggressive than we have it on the flanks, when we have tumor cells on the flanks than when we inject intravenously, or the mice dies because of cancer after around 30 days of the cell injection. The reason for no effect of the antibody this time is probably that it only binds to the outer surface of the tumor and do not reach the inner cells of the tumor, which then grow as they want. The better part, it goes from Humalutin, on the other hand, they reach the inner tumor cells. And here, you really can see the benefit of the cross-valuation that 1 beta particle can hit multiple tumor cells. So therefore, the effect of Humalutin is significantly higher than all other treatments in this aggressive tumor model.
Next slide. A way forward for radio immunotherapy can be in combination with other drugs. In this study, we have looked at the combination of Humalutin with olaparib. Humalutin results in DNA damage and Olaparib inhibits DNA damage repair. So this should potentially be a very good combination.
Next. So a beta particle from Humalutin induced a single-strand break in the DNA. And next, the cells will start to repair the break by recruiting a protein called PARP to the damaged side. But then, next, Olaparib will inhibit PARP, and we get that unrepaired bulb, double strand break, and the tumor cell dies.
Next. So that is the double strand break. So next, we tested the combination treatment in 7 different NHL cell lines and found the combination to be robustly synergistic in 4 of 7 cell lines.
Next. Conditionally, synergistic in 2 cell lines and antagonistic in 1. We have not been able to find out exactly why the combination was not synergistic in a DOHH-2 cell line, but this could, for instance, be related to different DNA repair pathways involved in this cell line.
Next slide. In preparation for clinical development, we have made a GMP-grade companion diagnostic for Humalutin. It is based on the NNV003 antibody label with the PET trace of the zirconium 89. That emits a positron instead of an electron, and can therefore be used for PET dosimetry instead of using Humalutin. The benefit with this is much better image quality, lower radioactive dose to the patients and shorter imaging protocols than when using Humalutin itself. So far, we have shown that imaging with 89 zirconium and imagery can accurately predict whole body distribution of Humalutin in mice by comparing data for the 2 molecules. We have developed a GMP procedure for manufacturing. And the molecules are ready to be used in the clinic to predict radio immunotherapy distribution in patients. With clinical 89 zirconium and NNV003 imaging, we can help identifying response to Humalutin, we can predict Humalutin mediated toxicity to help in healthy tissues, and we can optimize those regimens for Humalutin.
Next slide. So the key takeaways are that Humalutin has lower immunogenicity, which may allow for multiple dosing. We have developed a robust GMP manufacturing process and completed preclinical and CMC dossiers. A high therapeutic effect of NNV003 than of lilotomab may enable use of NNV003 as pretreatment. And we have shown therapeutic effect of Humalutin in different animals models and a synergistic effect when combined with the PARP inhibitor Olaparib. As zirconium 89 and NNV003 companion PET diagnostic has been developed for dosimetry studies in the clinic.
Next slide. So in the second part of the presentation, I will present the status of our pipeline candidate, Alpha37, for treatment of chronic lymphocytic leukemia and non-Hodgkin’s lymphoma.
Next slide. Alpha37 also consists of the chimeric anti-CD37 antibody NNV003. But this time, we have conjugated it with the chelates TCMC, which chelates Alpha particle generating chelates lead-212 much better than DOTA. So this is a collaboration project with Orano Med. Lead-212 is an Alpha particle, generating radionuclide with a 10.6% hours half-life. An alpha particle consists of 2 neutrons and 2 protons and has a charge of plus 2. So it interacts very strongly with biological material, and therefore, you only need 1 to 2 alpha particles to kill a cell. An Alpha particle has a very short range of less than 100 micrometer. Alpha particles are therefore optimal for treatment of disseminated disease like CLL.
Next slide. NHL has already been covered by the other speakers, but I would like to go a little bit into the treatment and unmet medical need in CLL. So CLL is currently mainly treated with the Bruton’s Tyrosine Kinase inhibitor ibrutinib, both in first line and second line of treatment, but anti-CD20 antibodies in combination with chemotherapy and with the BCL-2 inhibitor venetoclax are also used in first line. Venetoclax is also used along in second line. And anti-CD20 antibodies are also used in combination with venetoclax or in combination with the PI3 kinase inhibitor, idelalisib, in second line. So there are already many treatments available for CLL.
Next slide. However, there are still large unmet medical needs in CLL. In a new report by Decision Resource Group, treatment options against new targets and with new mechanisms of action for the high-risk patients with p53 mutations were highlighted as an unmet medical need. Alpha37 is a new treatment with a different target and a unique mechanism of action that currently have oral treatments. One unmet need is also discontinuation of ibrutinib therapy because of adverse events and intolerance. So a well-tolerated radioimmunotherapy can be an alternative treatment for these patients. Another unmet need is a lack of complete response, especially in old and frail patients, in the high-risk patients and in patients treated with chemotherapy. And as you know, CLL cells are very radiation-sensitive, so – and they also have a very high CD37 expression. So radioimmunotherapy will potentially give higher complete responses. The kinase inhibitors are oral therapies, and they pose compliance issues because the patients have to take the tablets every day until disease progression. A single injection with radioimmunotherapy will secure compliance. And then we are finished with the treatment. So there are absolutely unmet medical needs in CLL that can be met by radioimmunotherapy.
Next slide. Market analysis shows that there is a significant opportunity in second line and third line setting of CLL, the total of around 27,000 patients. There are around 10,000 high-risk patients with p53 17p-mutation in second and third line. And there are around 11,000 patients in first and second line that discontinue ibrutinib therapy. The available treatment options in high-risk and ibrutinib refractory patients are not satisfactory. So the entry indication for Alpha37 should be in these 2 settings because here the unmet need is high and the regulatory pathway will probably be easier.
Next slide. Therefore, the preclinical development strategy was designed to evaluate effect of Alpha37 in ibrutinib resistant and ibrutinib sensitive mouse models. In an ibrutinib-resistant mouse model, mice were treated with daily high doses of ibrutinib. And you can see in the green curves, there was no effect of ibrutinib because the curves overlap with the gray curve, which is the untreated control. So this data confirms that the model was ibrutinib resistant. The lead-212 label cetuximab, it’s not binding to the cells. And there was a small effect of this treatment, as you can see in the purple curve. The effect of Alpha37 was very high in this experiment, with 100% survival when we treated with 15 microcurie of Alpha37, as you can see in the yellow curve. The orange curve shows treatment with 20 microcurie Alpha37. And here, the treatment became a little toxic, so the maximum dose should be 15 microcurie for these mice. NNV003 did not have any effect in this experiment, as you can see in the blue curve, because we used TCMC conjugated antibody, and that destroyed the binding to the effector cells. The data indicate that Alpha37, our next – the data indicate that Alpha37 has potential in ibrutinib resistant refractory third line CLL.
Next slide. Okay. So then we tested on ibrutinib sensitive model. We treated mice that had been intravenously injected with tumor cells, with increasing doses of alpha37, and with the nonbinding antibody, cetuximab, labeled with lead-212. This model is about 5x more sensitive to ibrutinib. Median survival was not reached for Alpha37 treatment. And after 27 weeks, the survival was from 70% to 90%. For the controlled treatment, the median survival was only around 7 to 8 weeks. You can see in the purple curve that there was no effect of the nonspecific cetuximab antibody, 212-lead in this experiment and no effect of the NNV003 TCMC conjugate either. The data indicate that Alpha37 can have – next, the data indicate that Alpha37 can have potential in ibrutinib sensitive second-line CLL.
Next slide. So in the end of 2019, we started a project for Phase I trial and got Eurostars funding for it as well. The goal of the project was to finalize the package of work and documentation that is needed for starting a clinical trial. We are getting very close to reaching that target now and have only the last part of the finalization of the GMP methods for production of the antibody conjugate and Alpha37 itself and the documentation around this left to do.
Next slide. So the key takeaways are that Alpha37 is an alpha particle emitting anti-CD37 targeted therapy for CLL. It is superior to ibrutinib and effective in both ibrutinib resistant and sensitive mouse models. The preclinical data and the unmet medical need suggest to focus on high risk and/or ibrutinib resistant refractory CLL as the entry indication, because here, the unmet-need is high and the regulatory part may be shorter. There is a clear unmet medical need and market opportunity for Alpha37 above and beyond this entry indication. Yes. Thank you.
Presenter Speech
[Fortsetter]
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Erik Skullerud (Executives)
Thank you, Jostein. So in conclusion of today, first of all, a big thank you to the team for giving these updates. I hope you share our excitement over what we’re trying to achieve with our wider CD37 platform. Again, we have seen examples of this in the past. We have seen other companies do similar things to what we are starting the journey that we are on.
And let me give you one other example. There was a company called 47, who did very similar things to what we are doing, but for a CD47 rather than CD37. This company got acquired by Gilead and is now a big part of Gilead’s success. So I think, again, if you look at where we are, our attack points, our unique area of focus, it’s a good starting point. Hopefully, we have also been able to give you a feeling for the different parts, the different angles that we have, these 5 different molecules that we can use to target the receptor in different ways, both some that have been in development for a while and others that are fresh off the bats that we have great faith in for the future. And the third part is, in the area of which diseases we can targets for patients, we have already done a lot of work in hematological disease. But we are also looking at how we can expand this to autoimmune or immunological disease. And that is where molecules, such as our humanized antibody, will find its place, in the sense that these diseases will likely need iterative treatments over time. And as such, a humanized antibody will be a better fit potentially than a radio immune therapy.
So all in all, again, thank you for taking the time today. Thank you for joining us on a day that seems fairly lackluster in other ways, with the stock markets around the world going down significantly on the base of news that we saw this morning from Moderna. So obviously, we’re interested in that part of how the world is working as well. But we hope that all of you are safe. We hope that all of you are enjoying what we’ve been able to share with you today. And we look forward to your questions. So I’ll probably now – let’s open the channel for questions. What we’ll do is I’ll try to answer as many as I can, but I will obviously add on people in the team as we need over the next few questions. So if I may ask for the questions, please.
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Frazer Hall (Attendees)
We’ll get started with the Q&A session. [Operator Instructions]
So just to begin with, we have a number of questions around PARADIGME. But the first question is asking, why are you not publishing the preliminary complete response, partial response and medium duration of response data together with top line data for PARADIGME?
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Erik Skullerud (Executives)
Yes. So thank you for that question. This is obviously an equation of what data do you have available when we have our preliminary results. And that will purely be on the primary end point. More analysis will need to be done for the secondary endpoints, and this will take time. Hence, we can only give updates on the preliminary end points when we initially give the results. We will not have the data in a detailed enough fashion to say anything about these other end points upfront. And again, feel free to look at how other companies are doing this. This will be exactly the same as any other company that is finishing their pivotal trials. Unfortunately, this has to take time.
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Frazer Hall (Attendees)
The next question relates to screening numbers and is asking, since you’ve previously mentioned in presentations the number of patients in screening, can you give us a rough estimate on how many there are in screening at the present time, given your previous statements that the patient pool is one of the most promising that you’ve seen with regards to PARADIGME?
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Erik Skullerud (Executives)
Yes. I don’t think we have given any numbers as such. But we stand by our comments around that we see we see a good number of patients in screening. As I mentioned in my update on PARADIGME when we did our Q3 update, it takes about 3 months for us to get from the first time we see a patient until they are officially included. So again, as an example of what I just mentioned previously today, the patient that we are enrolling as we speak has been on our radar for quite a while, but it’s only now that we are able to say that they’re actually included. There are several other examples of this, but we have not nor will we talk about the exact numbers. And again, the example I used on the patient that actually did not enter this study is hopefully a good example. And I hope you understand why rather than going in and talking about all of these numbers in detail, we would probably not give you a very confident answer if we were to do so, because they fluctuate a lot. And some people go into the study, a lot of people also do not go into the study. And again, that is the nature of doing clinical research. Some patients will find their way into the study, others will not. But from a totality point of view, we do see a lot of patients in screening also as we speak.
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Frazer Hall (Attendees)
Just moving on to a question around enrollment for PARADIGME. Given the current enrollment update that you’ve given for PARADIGME at this point in time, how confident are you in still meeting the time line with guidance for top line data in the first half of 2022?
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Erik Skullerud (Executives)
So as mentioned in the update as well, we are 8 days post our Q3 update. We are still as confident as we were in our Q3 update. And with the additional patients, I think for those of you that are more into run rates. You also see that we continue on the same road as we have been in the last few months. And may I also remind you that the quarter that we have ahead of us, last year, we included 14 patients. I’m not saying that we’re going to do that again, but it should also tell you that these numbers are fluctuating, and we may very well have such a number also coming up in this coming quarter.
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Frazer Hall (Attendees)
And a further question on PARADIGME relates to the impact of COVID. And is asking specifically whether you can provide any color on the ongoing impact from COVID. And in particular, are you seeing missed follow-up appointments within PARADIGME? And is there any issue in terms of the enrolled patients becoming infected with COVID, which can impact outcomes from the study?
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Erik Skullerud (Executives)
So my first comment, I will reiterate what I said in Q3 as well. So far, we have seen limited impact of COVID on patient numbers in the study, and we continue to see that similar picture. I think it’s also fair to say that due to the emergence of the Omicron variant, I think many of us are still waiting or all of us are still waiting to see how this will pan out. But again, as mentioned in the Q3 report, we saw a similar picture of rising numbers last year in Q3 and into Q4 of COVID patients. We saw more patients included in late Q3 and into Q4 last year. And as such, we don’t see necessarily that this would change this year. But again, I would put a caveat on that, that the new strain of the virus may affect it, but we don’t know that yet nor have we seen it yet.
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Frazer Hall (Attendees)
The next question relates to the confirmatory Phase III study following Archer-1, and asks, will this study be done by Nordic Nanovector alone, or were will be a financial or medical partner, and possibly, with the supply of rituximab for completion of that study?
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Erik Skullerud (Executives)
A very good question. And there is obviously a lot of unknowns to the answer of that. #1, will there be a partner? As we get the results of PARADIGME and assuming that what we believe will be the case, we will have partners. If they will be part of the confirmatory Phase III, it’s still too early to say. That will depend on the deal that we will be doing. On the second hand, with regards to rituximab itself, obviously, there are different providers of rituximab. You have a whole lot of biosimilar companies at the moment. So from a purely from a costing point of view, the cost of doing this study now probably will be less than what it would have been just a few years ago. But again, it’s too early to comment exactly on what this is going to look like. It depends on the PARADIGME results. It depends on partnership deals. It depends on what those are going to look like, the structure of them, et cetera. So that’s all we can say really at this stage.
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Frazer Hall (Attendees)
The next question, again, relating to PARADIGME is, can you say something about what you think would be an acceptable overall response rate to target in order to meet the endpoint for the study and get an approval for Betalutin?
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Erik Skullerud (Executives)
Short answer, no, we can’t. And from competitive reasons, we wouldn’t necessarily talk about that either. This is something that – in looking at our clinical data, and eventually, our strategies, this is something that we would need to internalize, analyze, and therefore, optimize as we go to market eventually as well.
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Frazer Hall (Attendees)
We’ll move on to a couple of questions on Alpha37. And the first of those is that, at the previous R&D day, Jostein expressed the view that the data – the early data around Alpha37 were some of the most promising data that he had seen. And the question is, is this statement still valid? Can you explain how the company intends to benefit from moving the program forward?
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Erik Skullerud (Executives)
Well, I’ll let Jostein talk in a little bit about if he still stands by his statement. I know he is extremely excited about Alpha37. And whenever we have a conversation, he keeps on reminding me about that. I think it’s fair to say, this is a molecule that we have a very good partner on, and that should speak for itself with regards to the results of it. Secondly, this is an Alpha emitter, not a Beta emitter. And as such, it is differentiated from other products in our pipeline. But Jostein, with regards to how excited you are about the data, do you still feel that way?
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Jostein Dahle (Executives)
Yes. I think it’s the best data I have seen. So the data hasn’t changed. So it’s extremely good data.
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Frazer Hall (Attendees)
Great.
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Erik Skullerud (Executives)
Thank you, Jostein.
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Frazer Hall (Attendees)
And just as a follow-up question on Alpha37. Can you give any guidance on the time line for being ready for IND approval and the start of clinical studies with Alpha37?
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Erik Skullerud (Executives)
So I think Jostein alluded to this. We are really nearing the end point of the data package that we would need. Our estimation, and we are in close dialogue with our partner, Orano Med, on this. We had a big meeting as late as this last week, is that we believe that we’ll be able to do this in the first half of 2022. It may even be earlier. But in this sense, it’s a little bit too early to say. As you did see in Jostein’s slides, we do have a few more steps to complete, but we’re making extremely good progress as we speak.
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Frazer Hall (Attendees)
And moving on to the CAR-T CD37 program. Can you describe in any more detail at what stage you’re at with regards to the collaboration with U Penn? Are there any in vitro and in vivo studies that you can discuss at this point in time? And when might we expect to hear some of the first results from these studies? And just following up on that, is there any time line for how this program is likely to progress and going forward into clinical development? Can you put any time line on that at this early stage?
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Erik Skullerud (Executives)
So with regards to the collaboration itself, the expectation is that we’ll be able to give some indication on where we’re going in the next 12 to 18 months. What that exactly will look like is more – we will assume that we will kind of show what is the molecule, what does it look like? We may even be able to give some early stage results. I believe Maureen said in her presentation that when we get to the R&D day 2022, we will likely have an update for you. More specific than that, can I not be at the moment. We did publicize the deal, was it? 2.5, 3 weeks ago now. So we’re – it’s obviously very early days. But we’re – were suggesting that at least in the next 12 to 18 months, you will see something around the – around what this is giving as results. Was there a part of the question I didn’t answer, Frazer?
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Frazer Hall (Attendees)
No. I think that’s fine. Thank you, Erik. There are a few questions around your ongoing discussions with partners. And essentially, these questions really ask, can you give any further updates at this point in time to any of your ongoing discussions with these partners?
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Erik Skullerud (Executives)
So I would say we – like I said in the Q3 call as well, we have several conversations ongoing. And I reiterate what we said back then as well. We can’t talk about which companies we’re talking to, what kind of companies we’re talking to. But for obvious reasons, we’re hoping for different types of deal, and I said that in my introduction, different types of development deals, depending on the molecule in question and depending on geographic area in question for Betalutin or for other parts of our portfolio.
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Frazer Hall (Attendees)
There’s one further specific question, just regarding the announced retirement of Marco, just asking, do you have in mind who his successor will be at this stage?
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Erik Skullerud (Executives)
I have in mind, but that’s where it will stay for now.
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Frazer Hall (Attendees)
That completes most of the questions that we have online at this stage. There is one further question that is directed at Dr. Gordon, which he may wish to answer in his absence, which is asking, which patients would you use Betalutin assuming the data holds up from the Phase IIb readout from PARADIGME?
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Erik Skullerud (Executives)
Well, it should probably be directed at Dr. Gordon. What I will say this, and I said it in my introduction for why I joined the company as well. I have very seldom seen a company that has been as prepared when it comes to how we have characterized the patient where the unmet medical need is, and how we therefore are able to target this unmet medical need. It’s very, very seldom that you can see that in a company that are in Phase IIb. That usually comes much later. So I believe the organization way before my time have done an incredible job in outlining exactly that. And I also do believe that, that is where patients should benefit the most for it. So that’s where I would hope that most physicians would prescribe it. But I don’t want to put words in Dr. Gordon’s mouth. It is probably something one would follow up with him directly on.
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Frazer Hall (Attendees)
And then just a general question, which asks, could you give any outline as to the anticipated news flow that we might expect over the coming year other than for PARADIGME?
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Erik Skullerud (Executives)
Yes. I would look at this space. We – I hope – let me take a step back. I’ve spoken to several of you, several investors via e-mail, in Norwegian and in English, I’ve spoken to some of our biggest investors around what are they expecting from us. And one of the things that they have told me over and over again is be more transparent, give us updates when you can. And as an example, I believe today is the first time that we have ever gone out with an update on PARADIGME outside of the quarterly updates. This is our intention moving forward. That’s not to say that we’re going to give updates every single week on what’s happening with PARADIGME or anything else for that matter. But we will try to the best of our ability to communicate more with you, our investors, and to give updates continuously. But I’m not going to promise that we’re going to give updates on PARADIGME inclusion every day or every week or every month for that matter. I believe that – and again, I hope I’ve been able to make that point, inclusion for PARADIGME is going up and down almost on a weekly basis. So to try and do this more often than the quarterly updates, I believe, would be foolish of us.
Secondly, with regards to other news items and what you should expect from us is we want to keep an open communication with markets. We want to ensure that you get the updates when we have the updates. At what exactly will come when, I will not be able to say now. I’m still 2 months in the job. And I know that people around me are working very hard on creating results as much as they can. But you have my commitment, that we’re going to do the best that we can to communicate as much as we can, we do.
Answer
Frazer Hall (Attendees)
We’re really reaching the last set of questions now, Erik, which really center around the competitive landscape, and are asking, first of all, can you give a broad overview in terms of an updates around the competitive landscape? And then there are a couple of specific questions which relate to how you view the indicated risk benefit profile of bispecifics, such as the CD3, CD20 at bispecifics, and relate to some other more recent data from competitor programs, and in particular, a PI3 kinase called Zandelisib from MEI Pharma, where evidently some data has been released earlier today. But broadly speaking, could you give an update on the competitive environment? And are there any specific comments around the bispecifics?
Answer
Erik Skullerud (Executives)
Yes. So again, thanks for that question. With regards to the competitive environment, we mentioned this again in Q3, in our Q3 updates. And what we see both in the last few weeks’ worth of data, the last year worth of data, and what is expected over the next year worth of data is that the positioning that we have chosen initially for Betalutin in the space of follicular lymphoma, it is still an area of significant unmet need. What have we seen get into this area already? We have seen CAR-T products. But as Dr. Gordon said, he would, and our impression is also that his colleagues, other prescribers will mainly use this in younger patients. There are still significant toxicity around these regimens. And although progress is being made in how this is managed, I think he gave a clear indication that this was only for a smaller group of patients. The other part of the CAR-T treatments in general is that they are extremely expensive, about $0.5 million per injection. And as such, this is a significant burden for payers to play – for payers to pay. And as such, again, it will remain an area of high selection when it comes to who’s going to receive these kind of products.
From a PI3K point of view, I think, again, Dr. Gordon, and I believe he presented the vast majority of data that exists in that space. On one hand, far from the same type of efficacy as what you have seen with CAR-T, but on top of that, a significant toxicity as well. That seems to be the case also in the – some of the – at least of the later PI3K inhibitors. I’m going to ask Marco in a second to talk about the data that has come out today on MEI. I haven’t been able to read through that myself, to be honest. But I think, again, it kind of confirms what we have seen with other PI3K inhibitors as well. And the last group of – or there’s 2 more group of products that Dr. Gordon was touching upon as well. One is EZ2H inhibitors. Here, you obviously have a highly selected group of patients that can utilize the drug in the sense that you have – you only have significant response rates in patients that have the mutation in the gene, to begin with, and that’s about 15% of patients. And finally, with the bispecific antibodies, again, I think he was also pointing towards the risk benefit in the sense of, yes, good response. But on the other hand, and I believe Pierre also talked about this, significant toxicity associated with them. So as such, I know it’s a long answer, but hopefully, if you look at all of these potential competitors, I think we’re very well positioned. And I would add to that as a final point, personally, I don’t see CAR-Ts as a direct competitor, nor do I see bispecific antibodies as a direct competitor. And that basically leaves us with the PI3K inhibitors as a competitor. Again, I believe Dr. Gordon confirmed this.
With regards to the latest one, maybe I’ll ask you, Marco, to talk a little bit of what you have seen in that data.
Answer
Marco Renoldi (Executives)
Yes. Thank you, Erik. I think we’ve seen the data provided by May Pharma earlier this morning about their Phase II TIDAL trial. And I think the results were not unexpected. The data, the efficacy data are aligned to the upper end of the efficacy range we have seen with the PI3K inhibitors in the past, and actually not very different from the dapples-to-apples that we have generated with Betalutin in our LYMRIT 37-01. So an overall response rate in the 70% range, if I recall correctly, the press release, and a complete response rate in the 35% range. I think the median duration of response was not reached, so not provided by the company. But I think what is important to remind is the side effect profile this agent is still associated. So 10% of the patients in the trial were discontinued due to side effects. And we saw Grade 3 and Grade 4 adverse events, which are very typical of the class. So we don’t see any really different feature in terms of the safety profile of Zandelisib. We – I read about those events that led to discontinuation in the GI tract, so diarrhea and colitis. I read about pneumonitis. I read about [indiscernible]. So a safety profile which is very much reliant on the safety profile of the PI3K inhibitor class. It’s a good class. It’s a class of agent that are effective. But is this the right drug for the patients we’re trying to serve? We don’t think so. We don’t think so. Umbralisib came to the market with a similar promise. But it was associated exactly to the same type of adverse events, the prior PI3K inhibitors were associated. And the market uptake to date seems to confirm that physicians understand that and patients as well.
Answer
Erik Skullerud (Executives)
Thank you, Marco.
Answer
Frazer Hall (Attendees)
Thank you, Marco. Thank you, Erik. That concludes the questions that we have that have been submitted online. So I’ll hand back to you for any concluding remarks, Erik.
Answer
Erik Skullerud (Executives)
Yes. Just a big thank you partly to the team here internally for their development of material, their presentations today, and the dialogue with all of you that we’ve had today. Secondly, to all of you out there that have dialed in to listen to our presentations, our discussions. We hope this was what you were looking for. As mentioned, to begin with, we’re looking for a transparent communication with all of you. We’re looking to give you updates as often as we can. We’re looking forward to a new R&D Day in 2022 to give updates on the different projects that we have outlined today. And thank you very much for your support as investors, and looking forward to the onward journey. Thank you so much.
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Fra Asmyr på AG fb gruppa
"Vi kommer med en felles uttalelse etter kveldens webcast når vi har fått områdt oss.
Svært få av de spørsmålene vi sendte inn på vegne av AG ble besvart. Vi vil vurdere å be om skriftlig svar på våre spørsmål som i sin helhet blir lagt ut her så alke får se.
Selskapets ledelse og Carnegie forsøker tegne et bilde av at det ikke finnes alternativer. Det sier de uten å gi oss nødvendig svar og informasjon.
Vi har tenkt å fortsette kampen med å få innsikt, rydde opp og sondre alternativer. Vi er en høyst motivert gjeng og flere av dere, skribenter på FA forum og TI, har tatt kontakt og vil bistå med kompetanse fra alt fra corporate til med.tech. Vi har fått en voldsom oppslutning på kort tid.
Viktigste første skritt! STEM NED FUSJONEN!
Vi vil komme med en initial plan før EGF.
STEMME NED FORSLAGET:
Mtp arbeidet vi står i så er det enkleste vei til målet at flest mulig forhåndsstemmer før 29 nov kl 1600. Det er deadline! Rekker du ikke dette må du delta ved å melde deg på. Deltagelse gjøres fysisk eller elektronisk. Info på Nanov hjemmeside.
Vi har laget og lastet opp et dokument som viser stegenev skritt for skritt. Trykk på FILER så finner du dokumentet som viser hvordan forhåndsstemming gjøres.
Merk at dersom du kjøper flere aksjer etter å ha forhåndsstemt, så blir antallet automatisk oppdatert uten at du må gjøre noe mer. Vet ikke siste tidsfrist for å kjøpe stemmeberettigede aksjer.
De som ikke får til dette av forskjellige årsaker, send mail så får vi ordnet fullmakter. Merk mail fullmakt/problem forhåndsstemming".
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Og mister like mye verdier på sine aksjer/opsjoner som oss andre og samtidig mister jobben sin i samme slengen… Blir ikke særlig lukrativt med en dårlig betalt styreplass da, spør du meg…
Noen som har vurdert å kreve en granskning av selskapet?
Lite å ta dem på juridisk, grunnet side 2 i rapport og presentasjon.
Men det burde vel gi litt glede, å finne ut av om dere har blitt ført bak lyset?
Hvilken Partner er det Skullerud har hatt samtale med? ( om det har vært noen)
Å burde de vurdert tiltak under avlesningen av tidligere data?
Fra nye Algeta, til å gi bort alt for 24% eierskap til et selskap med 20 millioner på bok, å en 439 millioners verdi vurdering.
Pr d.d er NN sterkere stilt økonomisk en APIM. Men priset til 1/20 av verdi basert på pipeline.
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I kommunikasjon med Skullerud 20. Jan 22 uttalte han følgende til meg:
“ Som du sikker pgså vet, jobber vi mulige partnerskap med andre firmaer hele tiden. Vi har mennesker i organisasjonen som jobber fulltid på dette. Hvordan et partnerskap kan se ut er ikke mulig å si, men vi har hatt, vi har og kommer til å ha diskusjoner for å få et optimalt samarbeid på plass. Slik farmaindustrien ser ut i dag, sitter mange store firmaer og venter på kliniske studieresultater før de går inn. Det er derfor det viktigste for oss er å bli ferdige med innrullering i PARADIGME.”
I kombinasjon med at styret på dette tidspunktet fortsatt ikke slipper informasjon som antyder at virkningen av Betalutin er dårligere enn tidligere antatt, så er min oppfatning at Skullerud kommuniserte at hvis bare Paradigme fullføres, ja da ville vi komme i mål.
Den generelle oppfatningen var at alle “visste” at Betalutin skulle bli medisin.
Nærmest som en ren formalitet, var vi likevel avhengig av fullført Paradigme fordi industrien alltid stilte krav til formalitetene ved kliniske resultater som grunnlag for inngelse av partnerskap.
På den måten er det en mulighet for at de forledet aksjonærene til å tro, at til tross for at Paradigme hadde en veldig treg innrullering (som ble begrunnet med vanskelig tilgang til pasienter grunnet corona), så var det ingen indikasjoner som ga grunn til å tvile på Betalutins virkning.
Ikke vet jeg, men jeg ville ikke bli det minste overrasket om en intern granskning nå ville bekreftet at langt tidligere tilbakemeldinger fra innrullerings-sitene klart antydet manglende virkning av Betalutin som årsak til fraværende innrullering og at styret bevvist holdt tilbake denne informasjonen i påvente av ny emisjon i februar 22.
I så tilfelle ville det bekreftet at selskapets styre bevvist har forledet sine eiere.
Personlig mener jeg også at kursutviklingen i forkant av selskapets melding om Betalutins manglende virkning klart antyder at noen aksjonærer har visst mer enn andre.
En kan alltids i ettertid argumentere at Betalutins manglende virkning var åpenbar på et tidligere tidspunkt pga indikasjonene med fraværende innrullering i Paradigme, men i forhold til styrets informasjonsplikt, så er det uansett ikke et holdbart argument.
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Dette er egentlig hovedtemaet for meg. Jeg har en veldig klar følelse av at dette var nøyaktig hva tyskeren fant ut så snart han fikk tilgang til onedrive, brukte en måned for å verifisere, og så bare beinet straka vegen ut fordi det var åpenbart at ting var monsterfucked.
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Og der var gårsdagens rally visket ut, 10hi.
Det meste tyder på at dem satt allerede med informasjon før siste emisjon…og allikevel hauset dem opp for og hente inn 250 millioner’ dem tegnet snaut aksjer selv…som ble mye diskutert.Alvorligt …og bare tragiskt hele greia
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Markedet var vist ikke imponert over Webcasten…
1 Like
Hvor finnes dette dokumentet/ bruksanvisningen som er lastet opp? Du sier trykk på FILER. Hvor da?
Det er linket fra et FB innlegg, trenger du guidance på hvordan man stemmer før EGF?