Immutep (ASX:IMM) Presentation, Clinical Results of Ongoing Melanoma Study and Update on Eftilagimod Alpha Clinical Development Strategy, May 2018

Company Presentations

Immutep Limited (ASX:IMM) CEO, Marc Voigt, CSO & CMO, Dr Frederic Triebel and Director Clinical Development, Christian Mueller present on clinical results of the company's ongoing melanoma study and provide an update on the Eftilagimod Alpha clinical development strategy.

Marc Voigt: Thank you everyone for joining us today to discuss the interim results from our TACTI-mel clinical trial and to hear an update on our clinical development pipeline. We are very excited to have this webcast - the first one for quite some time. In the past years we have really been focusing on clinical work, generating results and results are now coming in, in the next period of time, you will be hearing from us more often. On the call with me today, we have Professor Frédéric Triebel, by the way the person who discovered LAG-3 and the world wide scientist in terms of LAG-3. Immutep’s Chief Medical Officer and Chief Scientific Officer, and also Mr Christian Mueller, our Director Clinical Development will comment on different aspects of TACTI-mel. For those of you who are new to Immutep, I may just give you a very short introduction. We are the global leader in developing LAG-3 therapeutics in immuno-oncology as well as autoimmune diseases. As you are probably aware LAG-3 is an area of growing industry interest as it is considered to be the next major immune checkpoint molecule. So LAG-3 is seen to be following in the footsteps of other checkpoint molecules such as CTLA-4 and PD-1 which have of course approved products like Keytruda or Yervoy. We believe LAG-3 will be the next big immune checkpoint.

In today’s call, I would like to start off by just giving you a short overview of our lead product. Dr Triebel will then present the interim results from the first three initial patient cohorts of Immutep’s ongoing TACTI-mel Phase I clinical trial in metastatic melanoma. Next, Mr Mueller will provide some additional interesting clinical data and put that in comparison and an update on the Company’s clinical immuno-oncology combination program. In particular, he will talk about our new trial, TACTI-002, which is planned in collaboration with Merck. We will then be joined by a panel of biotechnology analysts from across the globe who will participate in the Q&A session at the end of the call.

Let’s start the presentation now, moving to slide 4 with an overview of our lead product candidate. In general, there has been a big change in the way cancer patients are being treated in recent years. This change is related to immune oncology. The reality in oncology these days is that one tries to combine different IO therapies to achieve an improved outcome for patients. Within the immuno-oncology landscape of existing treatments, the most commonly known immune checkpoints are of course PD-1 and CTLA-4. We believe that the most important checkpoint on the horizon is LAG-3 and we are going to see more results this year and next from us and other players like Bristol-Myers Squibb. And we believe that LAG-3 it is a strong candidate for a combination therapy with some of the existing cancer treatments, including PD-1 treatments. As mentioned, Immutep is the worldwide leader in LAG-3 therapeutics, and I believe that is a big statement because usually immune checkpoints are a big pharma game and here we have a situation where you won't have anyone else, not even our partners like Novartis of GSK not having that many different products that far advanced. On slide 5, we have mapped out the industry landscape, detailing all other LAG-3 modulating therapeutics that we are currently aware of. So we have four different LAG-3 based products candidates. Our lead product which is the focus of the webcast today, is known as Eftilagimod alpha, IMP321 or efti for short. Efti is already in Phase I and II clinical trials and later stage clinical development. Second, we can see LAG525, a blocking antibody, which we have partnered exclusively worldwide with Novartis. Third, GSK2831781 is a depleting antibody which is partnered exclusively worldwide with GSK and positioned in autoimmune diseases. And finally, IMP761, the world's first agonist antibody which is currently in preclinical stage studies here at Immutep.

Before we turn the page, it’s worth just highlighting here that the number of products that have been originally developed by Immutep vastly outweighs any other developer. Secondly, as ASCO is coming up this week it's important that besides our posters, also Novartis will present our LAG-3 product - they call it LAG525, at ASCO, the American Society of Clinical Oncology, conference coming up in a few days.

As mentioned, our lead product candidate is called eftilagimod alpha, or IMP321, or efti for short. It is an innovative LAG-3 immuno-oncology product candidate. We see it here - it's actually a fusion protein. We use LAG-3 itself as a tool to activate the antigen presenting cells. It's very important to understand that efti is not a blocking antibody, but a unique antigen presenting cell, or APC activator. Very often LAG-3 as a term is used inconjuction as blocking antibodies like LAG-525 for instance from our partner Novatis. But it's very important to understand that eftilagimod alpha is different and is actually unique, and this means it can have synergies with other therapies. Importantly eftilagimod stimulates the immune system and leads to an increased number of monocytes, dendritic cells, NK cells and CD8 T-cells and this we can measure in patients. Other therapies that it can have synergies with include other immuno-oncology therapies, cancer vaccines or chemotherapies.

Moving on to our clinical development program for efti, slide 9 gives you a good snapshot of where we are at the moment. We have four clinical trials with efti that are currently ongoing or will be started soon. The most advanced is our Phase II b trial in metastatic breast cancer, called AIPAC. 226 patients double blind randomised by the way. This trial is based on a chemo-immuno drug combination. We combine TACTI-mel and eftilagimod. AIPAC is focusing on primary progression free survival, the primary read out is expected in 2019. Currently we believe that this trial will be fully recruited by the end of this year. We have two posters which will be presented at ASCO next week that focus on AIPAC. Another clinical trial is our planned Keytruda – efti Phase II study, called TACTI-002. We will go into more detail on this trial later in the presentation with Mr Mueller.

As you are aware, today we are reporting interim data on the third clinical trial, called TACTI-mel. Dealing with metatastic melanoma and we will come to these results in a minute. The fourth study in the program is called INSIGHT and it is an Investigator Led Trial which will also be presented at ASCO this year via a poster. Just to mention the trials you see here we will recruit close to 400 patients so quite a number for a biotech company of our size.

I’d now like to hand over to our Chief Medical Officer and Chief Scientific Officer, Dr Frédéric Triebel. He will provide us with an overview and the interim results from our TACTI-mel phase I clinical trial.

Dr Frédéric Triebel: Thank you, Marc for the introduction. As mentioned already, efti is a good candidate for combination immuno-therapies. Slide 11 helps us understand why. The paper published in 'Nature Medicine', looks specifically at the role of monocytes in helping melanoma patients to respond to PD-1 treatment. It reports that the overall survival of these patients was better if they had higher levels of monocytes at baseline.

You can see in the graph on the left, that patients with more than 19 per cent of what are called classical monocytes (these are CD14+ CD16+ cells) representing more than 90 per cent of the total monocyte population have longer survival. We know from our AIPAC study that, besides increasing the very important CD8 T-cells, efti also increases the level of monocytes above the critical threshold of 19 per cent. The increase in monocytes from efti treatment over a 6-month period is detailed in the graph on the right. Therefore, we believe that efti, in combination with PD-1 treatment, gives patients a better chance of responding to the PD-1 treatment, especially when the combination starts from cycle one day one.

Moving onto slide 12, I’d now like to give you a brief explanation of the study design for TACTI-mel. TACTI-mel is a Phase I explorative trial. It involves a total of 24 patients, split into four cohorts, with six patients in each cohort. As you may know, the initial three cohorts have already been enrolled with most of these patients already completing the trial. The fourth cohort has a slightly different study design. Patients in this cohort start their efti pembrolizumab combination treatment from the beginning of cycle one. This amendment to the design resulted from encouraging earlier interim trial results that were reported showing that safety is not an issue here. The fourth cohort presently commences enrolment at the moment now with three patients enrolled.

Turning to slide 13, in our TACTI-mel trial patients in the first 3 cohorts have been given an anti-PD-1 therapy, called pembrolizumab or Keytruda. They receive this product for the first three treatment cycles. Keytruda is Merck’s marketed immuno-oncology product. At the fourth cycle, patients are assessed for their response to the pembrolizumab therapy. Those that are considered to have a sub-optimal response of progression are screened and enrolled in the TACTI-mel study. From cycle 5 to cycle 9 of pembrolizumab, they receive efti as an add-on therapy.

After the conclusion of the combination treatment, patients have the chance to continue on pembrolizumab monotherapy. All patients are followed up every 12 weeks to record progression free survival, or PFS, data as indicated on the slide. As you can see, TACTI-mel has a unique design. It is different from other trials in melanoma. It is this uniqueness that makes it difficult to compare to other trials, however, you will see some data in that respect later.

Moving onto the interim results that we are reporting today on slide 14. Here, you can see that the results from the patients after they have completed the combination treatment are very encouraging. Most of the patients (83 per cent) had M1c stage of disease which means the disease has spread already beyond the lymph nodes and the lung to other organs like in the liver. Almost 40 per cent of participating patients had elevated LDH which is poor prognostic marker in melanoma. Furthermore 22 per cent of the patients have been pre-treated, for instance with ipilimumab or BRAF/MEK inhibitor. This pre-treatment means they are considered to be second line patients and unfortunately have smaller chance of a positive outcome. After the combination treatment started, 50 per cent of patients had tumour shrinkage. Encouragingly, the Disease Control Rate was 66 per cent. Disease control, as per our assessment criteria, means patients had a benefit like tumour shrinkage or stabilization of disease. Of course, these results need to be viewed in conjunction with the landscape setting on the following slides to be fully appreciated. The patient response to the combination therapy was measured according to irRC. irRC stands for immune-related Response Criteria

The overall response rate after start the combination therapy is 33 per cent. It is interesting to note that we had two complete responses if measured according to RECIST. We will show these patient cases later on in the presentation. And please remember: the patients had a progression or suboptimal response to pembrolizumab prior to inclusion.

On slide 15, you will be able to see from the spider plot graph that the combination therapy takes time to deliver its full benefits to the patients. Indeed, efti is now given, not for 6 months only but for 12 months in the newly open fourth cohort. I will just draw your attention to the bottom of the graph, along the X axis. Here you can see that there are two patients that have reported a complete response. A complete response is where the target cancerous lesions have disappeared altogether. On the graph, their data reaches the X axis. The first one at 11 months of treatment and the second at 18 months of treatment with pembrolizumab. Aside from being very encouraging for us, this gives us crucial information supporting our statement that often immunotherapies are taking time to deliver its benefits. The treatment of three patients from the third cohort is ongoing, but we have shown their interim results here. Slide 16 shows the complete response from one of the patients in the first cohort. As we have reported the results from this patient on a previous occasion, I would like to go directly to the next slide which reports on a second complete response from a patient.

Turning now to slide 17, we are able to give you some more scans that show the complete response from another patient out of the 2nd cohort. The PET-scans show the patients prior to starting treatment as well as thereafter. The PET-scan was used in addition to the CT scan to show the target lesion, a nodule on the chest, is really metabolically inactive to make sure that this is a complete response according to RECIST 1.1

Now, I would like to hand over to Christian Mueller, who is our Director of Clinical Development.

Christian Mueller: Thank you, Frederic for taking us through the results from the TACTI-mel study. So what I would like to do is to put the data we have seen into perspective as the trial design we have seen is pretty unique. The next slide gives us a good understanding of how the same patient data looks if response is assessed from cycle 1 of pembrolizumab. This makes it also easier to compare to historical data generated with pembrolizumab alone.

Remember that pembrolizumab treatment started on day 1 of cycle 1, whereas the combination therapy with efti only commenced from cycle 5. So when measured from day 1 of cycle 1 of pembrolizumab, as we are now doing for cohort 4 and also in TACTI-002, we see an Overall Response Rate of 61 per cent. Furthermore, the percentage of patients that were progression free at the 6-month mark was very high at 66 per cent. Most interestingly, seven of the 12 patients (so almost 60 per cent) who came in with a progression or sub-optimal response to pembrolizumab monotherapy during the first three cycles had a benefit from the combination treatment. This means that if you look into the data and compare to others, these are very, very encouraging results and we are very, very excited and basically the basis why we decided to approach Merck and planned the TACTI-002 trial.

I will move on to slide 19 and try to fit the data a little bit into the landscape and compare it to what Pembro monotherapy, which is a very good drug in metatastic melanoma, has shown. So, as we all remember, TACTI-mel involved ipilimumab naive and ipilimumab pre-treated patients, so that's why we selected the Keynote-002, which had only "ipi" pre-treated patients, and Keynote-006, which had the "ipi" naive patients included. So that's why we used these two different trials as a comparator arm.

What we can see first of all is we had very, very late stage patients with 83 per cent metastasis stage M1C compared to the ipi pretreated arm in the keynote 002.

Overall, if starting from cycle one, day one, we had a response rate of 61 per cent according to irRC, and then, according to RECIST, pembrolizumab showed a first line response of 33 per cent, which drops to 21 per cent if you give it as, let's say, a second line treatment, and the progression free survival rate is well below the 50 per cent landmark in first line and especially second line. While we certainly should remember that this is a Phase 1 study with a limited number of patients, the results are very encouraging.

Moving on to slide 20, to give you just a brief idea of the safety profile of efti, which we believe is a very important differentiator. So far, what we have done here, we have evaluated the safety data from the first 87 cancer patients which have been treated with IMP321 or efti. I think it's important to understand this database is growing practically every day, since we are actively recruiting patients into AIPAC, TACTI-mel and most likely in the near future into TACTI-002. And we also have some studies which have been conducted early on which are not concluded yet. We are pretty confident to say that the most common adverse events are local erythema and any type of injection site reactions. Most importantly, we haven't seen any maximum tolerated dose being exceeded for the combination with pembrolizumab or any kind of chemotherapy we have combined it with. So we believe efti is really, really safe for the time being. As stated, the safety data is growing every day. I hope that has given you a very encouraging overview of the interim results we have reported so far.

So coming a little bit from the past what has been seen so far and moving into the future and talking about our new trial TACTI-002. First of all we are very delighted to say that in March this year we have entered into a clinical trial agreement and collaboration agreement with Merck, known as MSD outside the US and Canada, where we will evaluate efti in combination with Keytruda in a phase two basket trial. We are very pleased to be working with Merck on this collaboration.

Just giving you a quick overview of the trial’s study design on slide 24, we are planning to recruit 120 patients to the trial. It will take place at up to 15 study centres in the US, Europe and Australia. So it's really a worldwide trial. The combination treatment will be evaluated in patients with three different types of cancers, such as head and neck squamous cell carcinoma and non-small cell lung cancer. The study design is called Simons 2 stage design, which means that will treat a pre-defined number of patients per indication, in the beginning approximately 20 per indication, which gives us a total number of 60. If we see sufficient activity the study will be enlarged by another 20 patients to confirm what we have seen in the first 20 patients. Which will lead us in the end to 120 patients in total.

So what kind of patients are we going to include? First of all in Part A these patients will be first line non-small cell lung cancer patients. They should be PDX naive, which means they shouldnt have seen any PD-1 or PD-L1 antagonist before. Very important for this part of the trial.

In part B of the trial we will do it a different way, we will go to second line non-small cell lung cancer patients and we will treat patients who have been exposed, which will be most likely be refractive or resistant to any kind of PDX therapy and we hope here is to see a response that is more pronounced than with chemotherapy which will then be the standard of care most likely.

And in head and neck cancer we will look for patients who have received first line therapy without any PD-1 or PD-L1 antagonists. So they should be PDX naive as well. The patients will be given the combination treatment from day 1 of cycle 1, as we have done for the 4th cohort of the TACTI-mel trial. They will receive this treatment for 12 months and then will receive pembrolizumab as a monotherapy for additional 12 months. The main objective of this study will be to evaluate the patient’s response rate, as measured by iRECIST. This is a little easier for sites compared to irRC but still allows treatment beyond initial progression. Which we believe is very important if you combine IO and IO. At the moment, just to give a little set up, we are working on the trial protocol together with Merck and on the IND which will be submitted very soon. Our intention is to start the study in the fourth quarter of this calendar year, with an expectation of reporting the first data from the trial in mid 2019.

Basically that covers the summary of the TACTI-002 trial. Now I’ll hand you back to our CEO, Mr Marc Voigt.

Marc Voigt: Thanks Christian. I hope that we have given you a good overview here regarding the state of affairs regarding the TACTI-mel trial results and the new planned TACTI-002 trial in collaboration with Merck.

Crucially, we have seen that efti has a very favourable safety profile. Which is important as combination therapies are the way to go and in order to be combinable you should have a very good safety profile. So we are very glad for the time been this has been confirmed. In addition, we can say with confidence that efti is able to induce a beneficial immune response in patients. So of course this is the desired biological effect. Then by the response rates Christian reported the TACTI-mel trial the combination of efti and pembrolizumab demonstrated an encouraging response rate of 61 per cent and a progression free survival rate at 6 months of 66 per cent in melanoma. This is very, very encouraging and also in the light of the 4th cohort which is actually starting at cycle one, day one. And the TACTI-002 will see the same efti combination together with Pembro is just reported in three different settings. Thank you all again and goodbye.