Immutep (ASX:IMM) Presentation, IMP761 Preclinical Results in Autoimmune Disease, March 2019

Company Presentations

Immutep Limited (ASX:IMM) CEO, Marc Voigt, CSO & CMO, Dr Frederic Triebel discuss the latest clinical results and commercial options for funding development of IMP761.

PRESENTATION:


Moderator: Good day ladies and gentlemen and thank you for joining us for the Immutep investor call. My name is Clive Tompkins and I will be your moderator today. At this time all participants are on a listen-only mode. We will conduct a question-and-answer session at the end of the conference. I will now like to hand the call over to Marc Voigt, Immutep’s CEO to start the presentation.

Marc Voigt: Thank you, Clive and welcome everyone. We appreciate your time on the webcast. As many of you may know, Immutep is the leader in the development of LAG-3 related therapeutics. This is a very promising area of biotechnology and immunology and one that is receiving increasing interest from big pharma. In the last few years, Immutep has spoken a lot about how LAG-3 therapeutics can act in immuno-oncology as an immune stimulant. We have described our pipeline of trials with our anticancer drug, eftilagimod alpha or IMP321. These clinical trials include AIPAC, TACTI-mel and our newest trial, which dosed its first patient recently, TACTI-002 and the investigator-initiated trial INSIGHT. We will host a separate webcast soon regarding a development update for eftilagimod in cancer. Today, we would like to focus on our autoimmune strategy and more specifically our newest product candidate, IMP761, which is currently in preclinical development There is a significant unmet medical need in autoimmune diseases and a meaningful market for existing therapeutics. For example, Humira, a leading autoimmune therapeutic, is expected to of achieved over US$20 billion in sales in 2018, according to Global Data. Now refocusing on Immutep, we are looking to leverage LAG-3’s role in immuno-suppression, which we recently elaborated on. Immuno-suppression is the dampening or down-regulation of the body’s immune system. Immuno-suppression is a proven concept for drug development in autoimmune diseases. In chronic or acute autoimmune diseases the body’s immune system has gone into overdrive and an excessive immune response causes disease. Slide 3 illustrates how targeting LAG-3 or its ligand MHC II, can be used in different ways: to activate the immune system to fight cancer, immuno-stimulation, and to dampen down immune responses to fight autoimmune disease, or in other words immuno-suppression. You can see in slide 3, the way in which our lead product candidate, eftilagimod alpha, or efti for short, is involved in immunostimulation. Another immunostimulatory product candidate is IMP701 or LAG525 which we exclusively licensed the world-wide right to Novartis. On the right-hand side of this slide, we illustrate how LAG-3 is involved in immunosuppression. We highlight our existing worldwide exclusive license with GSK in this area. What we would like to focus on during this webcast, is the potential of LAG-3 in immuno-suppression as the desired biological activity of drug intervention in autoimmune diseases. Immutep believes that targeting LAG-3 to cause immunosuppression could lead to multiple treatments for a number of different diseases, or indications. Still focusing on the right-hand side of the slide, you can see that we have two products candidates, IMP761 and GSK’781 which we call IMP731. This is a depleting monoclonal antibody and is licensed out to GSK. Here we will concentrate today’s discussion on IMP761. IMP761 is a humanised IgG4 monoclonal antibody. It is an agonist antibody, so it binds to a specific epitope, or part of an antigen molecule, on LAG-3 and activates it to produce more LAG-3 transduced immunosuppression in activated T-cells. Through this activity, we believe that IMP761 will be able to play a role in suppressing undesired immune responses activated in autoimmune diseases.

• Let’s go into more detail now on the LAG-3 agonist and how it works. On slide 5, we have illustrated some of the main autoimmune diseases, such as multiple sclerosis, asthma, rheumatoid arthritis and psoriasis. The therapies currently available for these auto-immune diseases, such as anti-TNF antibodies, aim to fight the symptoms of the disease by treating general inflammation in the body. Immutep feels that the future direction of autoimmune therapeutics should be focused on developing more targeted immunosuppressive antibodies that address the root cause of autoimmune diseases instead of treating the symptoms of the diseases. In the case of IMP761, we believe that this can be done by silencing the specific autoimmune memory T cells that are known to accumulate at the disease site. This would be a shift in medicine from fighting the symptoms of autoimmune disease, to fighting its cause. I would now like to hand over to Dr Frederic Triebel, Immutep’s Chief Scientific Officer and Chief Medical Officer, whose team developed IMP761 and he will take you through the results of our in vitro and in vivo testing of IMP761.

Dr Frederic Triebel: Thank you, Marc, and hello everyone. I plan to give you an overview of the concept and present results from our in vitro and in vivo testing of IMP761 in the next sections of the webcast.

Turning to slide 6, this slide gives an overview of IMP761 as it helps to increase the down-modulation of T Cell receptor signalling. At the site of chronic inflammation, the T cell receptor of auto-immune memory T cells are known to be stimulated by the same self-peptides repeatedly, causing the disease. You can see this on the left-hand side of the diagram, where the memory T cell is being stimulated by a self-peptide presented to the T cell receptor by antigen presenting cells or APC. After a while, the T cell becomes exhausted and expresses more LAG-3. LAG-3 is recognised as a marker for exhaustion of memory T cells. In our studies, we have used LAG-3, a marker for exhausted memory T cells, to target these self-reactive T cells in vitro.

On the right-hand side of the diagram, you can see IMP761 is engaging LAG-3. Since LAG-3 is a co-inhibitory receptor this agonist mAb increases the down-modulation of T cell receptor signalling by LAG-3 and as a consequence the auto-immune T cells are not stimulated by the self-peptide any more. In other words, IMP761 blocks the activation of overreacting auto-immune memory T cells whatever the kind of epigenetic reprogramming these T cells have been through, depending on the specific disease setting. Importantly, this mechanism of action for a potential treatment works upstream from current therapeutic approaches, which focus on the consequences of epigenetic reprogramming, like the production of TNF in rheumatoid arthritis.

So, that gives you an overview of why we have developed an agonist antibody, named IMP761. IMP761 increases LAG-3 down-modulation of T-cell receptor signalling in autoimmune T cells. You can also appreciate how this new drug concept fits into the landscape of current treatments for autoimmune diseases. On slide 8, we show the results of our in vitro tests wherein IMP761 inhibits CD8 T cell proliferation. The left-hand side of the slide is a diagram of typical proliferation, or cell division, when CD8 T cells are stimulated to proliferate by a peptide mixture, called CEF and stained with CFSE, a fluorescent dye. Here you can see a doubling of cells at each cell division. You can also see that the dye is passed onto the daughter cells but becomes lighter as it is diluted out with each cell division.

On the right-hand side, you can see three graphs that enable us to compare the cell counts at day 5 of the cell culture for three cell treatment groups:
- The first, in the top graph, are unstimulated CD8 T cells
- The second group, in the middle graph, is CD8 T cells that have been stimulated by the antigen mixture, and;
- The third, in the lowest graph, is stimulated CD8 T cells that have also had IMP761
The dominant peak represents undivided parental cells. The section to the left of this peak is the area of interest as this represents the number of cells with lower CFSE staining. These cells have divided 2, 3 or 4 times during this 5-day culture, shown by further dilution of the dye. You can see in the top graph that there is a low CD8 T cell division rate of 3.7% in the unstimulated cells. This illustrates our base rate of cell division in the absence of added antigen. In the middle graph where the CEF antigen pool mixture has been added, the cell count is much higher and CD8 cell division reaches 36% at day 5. This indicates a strong response of these healthy blood donor memory T cells, primed in the past by the influenza, EBV or CMV viruses. Both the top and middle graphs serve as controls that help us understand what happens when we add both the antigen and IMP761, as per the lower graph. Here, you can see that IMP761 is able to cancel out most of the proliferation of T cells that would have been stimulated by the CEF antigen. You can see that the same area to the left of the peak now only reaches 8.6%. This demonstrates that IMP761 is an immunosuppressive antibody for antigen-specific memory T cell proliferation in vitro.

Having covered the in vitro results, in this next section on slide 10, we would like to look at the in vivo, or animal model results. The in vivo results from our studies in non-human primates, were previously announced to the ASX, but in this section, we will go into them in a bit more depth. The top left section of the slide outlines the timeline for our work in non-human primates. We commenced by vaccinating 18 male cynomolgus monkeys with BCG vaccine, and gave them a follow up vaccination 2 weeks later.

BCG stands for Bacillus Calmette-Guerin and is a live vaccine that gives variable protection against tuberculosis. The animals were then tested for their cellular response to the intra-dermal injection of tuberculin, an antigen which is part of the BCG vaccine. All animals had an erythema of various sizes at the injection site, showing that T cells specific for tuberculin have infiltrated the skin, showing the vaccination worked in all of them. This is similar to the testing called intra-dermal reaction or tuberculin test. This test is used in children previously vaccinated with BCG in areas of endemic tuberculosis to assess whether the vaccine induced a strong T-cell mediated protection against tuberculosis.

At day 0, we treated 6 of the animals with a subcutaneous injection of IMP761 at a dose of 0.3mg/kg of body weight. 6 further animals were injected with a lower dose of IMP761, at 0.03mg/kg, and the remaining 6 were given a control injection of the excipient PBS. We then challenge them a day later for a second intra-dermal reaction to tuberculin to evaluate the effect of IMP761 on the antigen-specific T-cell response. In the bottom left of this slide, we explore the pharmacokinetics and pharmacodynamics results of IMP761 in the animal model. The median maximum circulating IMP761 concentration was 165 ng/ml in the low dose group, a concentration which was found to be clearly immunosuppressive in vitro. In addition, all animals in the high dose group had more than 1 µg/ml in their serum at 24 hours post injection. Consequently, the concentration of IMP761 in tissues like the skin, expected to be lower than in the blood, should still be high enough to inhibit tuberculin-driven T cell activation in the dermis.

On the right-hand side of the slide, you can see the tissue samples which compare the first tuberculin test in the top row which took place before the IMP761 or the PBS control injection, to the second test, on the second row, which took place after the injection. T cell infiltration at the site of the tuberculin test is indicated in the images by the green immunofluorescence staining. You can see that there are fewer green CD3 positive cells which are the T cells in the skin biopsy when the animals had received IMP761 at both dose levels compared to PBS. This indicates that IMP761 is inhibiting in vivo the activation of memory T cells reacting to the presence of the injected antigen.

On slide 11, you can see the measurements we took from the tissue samples from the tuberculin tests before and after the IMP761 or PBS injection. This enabled us to quantify the inhibition of inflammatory T cell infiltration. The left-hand graph shows the percentage of site tissue where CD3 positive T cell infiltration was inhibited following the PBS or IMP761 injections. You can see in the left-hand column that the group of animals that received the PBS control had no inhibition of CD3+ cell infiltration compared to the first tuberculin test. In the middle and right-hand column of the same graph, you can see that compared to PBS control, CD3+ T cells infiltration was inhibited at both low and high dose of IMP761. Looking at the next graph, we see the same analysis but evaluating infiltration of the tissue by CD8 T cells. Again, the PBS column shows no inhibition. The lower dose of IMP761 also yielded no inhibition of CD8 T cells. However, at the higher dose, IMP761 inhibited the infiltration of CD8+ T cells. Given the results that have shown us that the high dose of 0.3 mg/kg is able to significantly decrease T cell infiltration at the tissue site, we decided to perform a multivariate analysis for this group and compare it to the PBS control group. You can see this analysis on the right-hand side of the slide. In this analysis, we included the inhibition of the expression of the three different T cell markers, CD3, CD4 and CD8, on the one hand, and the inhibition of erythema size, the size of the redness of the skin, on the other. You can see that compared to the PBS group, the high dose IMP761 showed a significant decrease of T cell infiltration in the skin biopsy for all three T cell types and, that it also yielded a smaller erythema size. Well, that concludes the preclinical results that we wanted to share with you. I’ll now hand you back to Marc, who will run through the main conclusions from the studies and talk about what they mean for Immutep’s plans for IMP761.

Marc Voigt: Thank you, Frederic, for taking us through the preclinical results. Coming now to the conclusions on slide 12. From these results we are encouraged that IMP761 has potential to treat the cause of autoimmune disease, rather than just the symptoms, as many existing treatments do. Our in vivo evidence showed that IMP761 caused the down-regulation of human T cell proliferation and activation.
From our in vitro experiments, we know that IMP761 causes down-modulation of T cell infiltration in a non-human-primate animal model. In other words, IMP761 is able to decrease inflammation at the tissue site. These studies indicate that IMP761 has great potential as a new therapy that could be used to treat the causes of autoimmune disease. IMP761 can prevent localised inflammation caused by the overreaction of memory T cell to a self-antigen present in the corresponding tissue. What this means for Immutep, is that we are confident about taking IMP761 into clinical development subject of course to all relevant preclinical and regulatory steps. There is of course much technical and regulatory work for us to complete. We have already commenced cell line development for GMP manufacturing and will announce further details as preparations progress towards clinical development.

I would like to thank you all for your time and now I will pass you back to our moderator to commence our analyst Q&A session. Clive.

QUESTIONS AND ANSWERS:

Moderator: Thanks Marc. So everyone, the time we have allotted for the Q&A session is approximately 10 minutes. Panellists will aim to answer as many questions as possible, including those that have been submitted by text, with more webinars scheduled over the coming months.
Our first question comes from Jason McCarthy. Jason please go ahead.

Jason McCarthy (Maxim, US): During your talk you insisted on the peculiar mechanism of action of 761, where it’s working upstream of the current therapies. Does that mean that 731 could potentially replace some well-established first line therapies, like Humira, like TFN antibody, in the long run?

Marc Voigt: Frederic would you like to answer that one?

Dr Frederic Triebel: I would say yes. Certainly, in the long run; of course it will take time to replace Humira in rheumatoid arthritis and maybe IMP761 will first be tested in other phase II indication first and not specifically in rheumatoid arthritis. But from a clinical point of view, yes absolutely. As you’ve seen on the slide six these T cells are undergoing epigenetic reprogramming and therefore they are becoming TH1 T cells, T cells that produce TNF and then you use Humira. But of course, if you can work upstream as discussed before, you will block that.

Clive Tompkins: Next question comes from Matt Cross. Matt please go ahead.

Matt Cross (Jones Trading, US): First one was just on the results obviously you’re representing today offering some initial evidence of the agent’s agonist mechanism, playing out as expected, in that the T cell infiltration is substantially reduced, when you’re introducing 761. But one of the kind of critical downsides of alternative approaches to treatment for autoimmune diseases, you alluded to a little bit, has been the overcorrection of this effect, which the patients are left in some degree of immuno compromised state.

Just wondering if you could kind of speak to both the durability of these T cell dampening effects that you saw, and to what degree animals experienced any kind of infection or other injury related side effects?

Marc Voigt: Frederic I’ll hand this one over to you as well?

Dr Frederic Triebel: It's difficult to say how long you will see immunosuppression. Of course, as long as the product is above a certain threshold in the blood, y You should see that. You have to consider here that we use a tuberculin antigen part of BCG which is an infectious agent and it is known that T-cells reacting to non-self proteins like infectious agents, viruses or tuberculosis have a very high affinity for antigenic peptides. In autoimmune disease the avidity of the T-cell receptor for the peptide is much lower, therefore we expect to have a better immuno-suppression effect. We use here both in vitro and in vivo infectious agents. These are not self-antigens, but non-self strong antigens because this is the only way to see something meaningful in vitro and in vivo and then we are trying to inhibit as much as we can. But we expect to have a continuous effect, probably a stronger effect on this self-peptide triggered T-cell signalling.

Clive Tompkins: Next question comes from George. George please go ahead.

George Zavoico (B. Riley, US): One of your slides showed that both IMP761 and 731 caused immune-suppression by different mechanisms. The 731 you said you partnered with GSK. One of them, yours, down-regulates the t-cell activity. But the depleting anti-body 731 is designed to eliminate the activated t-cells. So what are the advantages and disadvantages of these two approaches and could they possibly be used for the same auto-immune indications, going forward?

Dr Frederic Triebel: Yes these two antibodies are based on the same concept which is LAG-3 being expressed on the few T-cell reacting to self-antigens. So on the one hand with the depleting antibody you get rid of these bad guys, on the other end you use a softer approach you just down-modulate the bad guys. I see these two approaches being complementary. To know which one is going to be used in which indication is much too early to say. But clearly at ECCO last month in Copenhagen GSK scientists in collaboration with Oxford University have shown very interesting data with LAG-3 positive T cells in the mucosa of ulcerative collitis patients. This validates LAG-3 as a interesting target, a target one could use. Now the two mechanisms are clearly different. For the depleting LAG-3 antibodies there is no way of back walks. When you kill the T cells they are not there. There is no way you can reverse or stop any adverse event. With the agonist it's a softer route. You don't kill the cells you down regulate them as long as the product is given let's say by sub q injection every month. You have the effect of immuno-suppression.

George Zavoico: Would one way of looking at that be you'd used a depleting anti-body perhaps for more serious disease and flares and the agonistic one, softer approach, for maintenance and durability of response. Is that one way of looking at it?

Dr Frederic Triebel: That's a possibility. I mean auto-immune disease it's a very large field with more than 80 different disease entities. And even if you look at a single identity like multiple sclerosis, obviously there are several subsets where there are patients doing good and others not at all. It's only the clinicians looking at the therapeutic index which is the ratio between efficacy and safety who will decide at the end.

Sam Slutsky (LifeSci, US): In terms of the non-human primate studies that you just showed, both the low and high doses appear to immuno-suppressive. I'm just curious how you expect this to translate in the Phase 1 Study and how you think about dosing going forward?

Dr Frederic Triebel: The Phase 1 Study is going to be a proof of concept study and that doesn't mean that the indication is chosen for a lead ondication in phase II, like for instance psoriasisis just an easy indication to look at pharmacokinetics, safety as well as first hints of efficacy. And we will start with a very low dose. Less than 0.1 mg/kg s.c. This will give us some indication but again we will have to look at the pharmacokineticsprofile which could be different in human compared to cynomolgus monkeys.

Brigitte de Lima (Goetz Partners, UK): What drove the precise election of the species used of cynomolgus monkeys as opposed to any?

Dr Frederic Triebel: Here it took us since 1992, years and years to develop two agonist antibodies. Which was one of the two for this product candidate. And this was done years ago. It is very difficult to develop an agonist to LAG-3. And in fact we don't have any surrogate antibody specific for mouse LAG-3. The one we have is directed against human LAG-3 and it cross reacts with cynomolgus monkey LAG-3because the two species are very close. And also we think that it is much better to have data in non-human primates because the two immune systems are very similar. These are wild species, not laboratory mice. They are living in a normal environment and not protected like mice in an animal facility.

We do think that what we are doing here with tuberculin reactive T cells in vivo in a tissue like the skin can really tell us something about the immuno-suppressive capacity of the candidate product.

Dennis Hulme (Edison, Aus): Does Immutep (ASX:IMM) intend to develop IMP761 up to Phase 3, or is a licensing deal being considered at the present time and what are the financial implications of those choices?

Marc Voigt: Actually we would not intend to license IMP761 early, let's say as early as LAG 525525] or GSK 781 so we are very committed to this product candidate. We will move this one forward on our own. Of course we have different types of collaborations one could take into account that's for sure. If we could go all the way to Phase III especially this could be very challenging in some auto-immune diseases and remains to be seen. But at least the next steps towards clinical development and also Phase I, Phase II are within our valued chain and our sweet spot.

Clive Tompkins: Do you have any idea on time-frame from pre-clinical phase to late stage for 1MP761?

Marc Voigt: The pre-clinical development will take from where we are right now round-about let's say 18 months, maybe a little bit longer. Of course, this depends on the GMP manufacturing, this depends on the regulatory interaction and regulatory pre-clinical packages so toxicology and then late stage of course a bit more difficult to define. This will depend of course also on the choice of indication. But in general, I can promise that we would like to move this one forward to clinical development as soon as we can.

Moderator: A follow up question. How will this be funded?

Marc Voigt: We have of course with IMP761 a product candidate which is part of our business plan, meaning also part of our current funding is allocated to 761. We publicly guided the market to our cash reach, to mid of calendar year 2020, so we are going to see a number of our inflection points in that period and let's see how we will fund IMP761 beyond that period of time.

Moderator: Another question still in the same vein. Any forward intention in terms of diluting the stock to raise capital?

Marc Voigt: This is in bio-tech of course is somewhat inherent part of the business model to do from time to time when the opportunity presents itself. Capital raise - right now I believe we are comparably well financed and we see as mentioned already a minute ago a number of important value inflection points especially regarding Eftilagimod Alfa and we will come to that more specifically in the webcast in very due course regarding Eftilagimod. So I can never say no for an unlimited time in future but currently I feel that we are very well funded.

Clive Tompkins: And now we have a question about IMP321 regarding Metastatic Breast Cancer results in second half of this year. What is the time frame on commercialization and generating an income there?

Marc Voigt: A good question however I would like, and the team, we would like to address this in the upcoming webcast. Maybe just one statement. Right now, we believe that the first data from Eftilagimod in metastatic breast cancer, so our APAIC clinical trial will be announced in the fourth quarter, this calendar year, of course it’s a moving target. In terms of any commercial movements we would like to wait for the next webcast.

Clive Tompkins: And one final question. Does Immutep intend to develop 761 itself or is it looking for help?

Marc Voigt: So first of all in any case we will move this product candidate forward. Of course, there might be collaboration settings with the industry. We have already a number of collaborations with the industry in our other product candidates which we may or may not pursue. This depends on our business development interaction, let's see. But in any case we are not dependant on any partnership to move this product candidate forward.

Clive Tompkins: That's the last question there Marc. I'll leave you now to wrap up the webcast.

Marc Voigt: On behalf of the Immutep team, I’d like to thank everyone for listening today. We are very pleased with the results and are glad to have the opportunity to share them with you. Thank you also to those who participated in the Q&A session. We are very pleased to have such a strong interest in the Company. Especially from very, very good analysts I have to say. A copy of the webinar will be available shortly on Immutep’s website, Finance News Network and other media channels. With that I would like to close. Thank you and goodbye.

Ends