Very good. We're going to have a bit of a fireside discussion today, which I'm very much looking forward to. Before I get to some questions, I'll just provide a brief introduction for our audience. Immutep is a clinical stage company with its lead drug candidate in phase III clinical trials for lung cancer, as well as having a second asset undergoing trials for an autoimmune condition. Under Marc's leadership, Immutep has reached a point that only few peers on the ASX have achieved in the past, and that is to take a drug through its early discovery activities, conduct initial phase I and then phase II clinical trials, speak to the regulators at the FDA and EMA, get alignment there, and then finally conduct a large phase III global trial in hundreds of patients.
It is this final clinical stage that Immutep is now in, with its lead drug candidate called eftilagimod alpha being evaluated in a global phase III trial in patients with a type of lung cancer. That is my intro summary spiel, Marc. Thanks very much again for joining us. Why don't you just, to kick things off, start by reminding us about how eftilagimod alpha works through its LAG-3 pathway and how you're aiming to improve outcomes for cancer patients here in general terms. Thanks.
Yeah, thank you, Thomas. Indeed, eftilagimod is a unique approach, a unique drug, and we are activating the immune system specifically, very broad and very deep. If you have cancer, of course, you would like to have an active immune system and overcome practically cancer with fighting the cancerous cells with your own immune system. Eftilagimod is using LAG-3 as a tool to activate the dendritic cells, if you like, the generals of the immune system very specifically. This leads to a very broad immune reaction so that we have more CD8 T cells, if you like, the soldiers who are actively fighting cancer, providing the right information, see more CD4, more natural killer cells. It's a unique approach.
Very good. Let's drill into that lead program of yours. The most advanced trial that you have underway is in non-small cell lung cancer. Unfortunately, that remains the number one killer in terms of types of cancer. I think here in Australia as well as the U.S., there are many patients that unfortunately have this. Can you just, I guess, describe to us what that means in terms of the addressable market size, how many patients there are, and how many dollars are being generated by drugs in this therapeutic area today?
Yeah, as you said, unfortunately, we are talking here about the leading cause of cancer death. It's globally the largest market, also in terms of dollar terms as we speak right now. It's for those specifically addressable by anti-PD-1, the most modern immunotherapy you have marketed, it's round about up to $25 billion US dollars annually. It's believed to reach more than $40 billion US dollars by the early 2030s. It's unfortunately a steeply increasing market and a high unmet medical need, despite all progress we saw in the past decades where you had new therapies approved, but unfortunately, the median overall survival is much below two years.
Okay, very good. We'll come to the phase III trial that you're running in a moment's time. Before we get there, I just wanted to recap for the audience. You've already done some phase I and phase II clinical trial work in non-small cell lung cancer. One of those trials is the INSIGHT-003 trial, which you've recently given an update on in the last couple of months. Why don't you just take us through that trial and say the key takeaways that you're seeing from that that gives you confidence now moving into the phase III trial?
Yeah, INSIGHT-003 is an investigator-initiated study in about 50 patients run in Germany, different German centers. The primary reason to do it was, of course, to look at the safety side of things. Can you combine Keytruda, the top-selling drug in the industry, the most prominent drug in non-small cell lung cancer, in combination with chemotherapy and eftilagimod? Can you combine these different drugs? Yes, that's feasible. We know that since a while, of course. In addition to that, we saw also very encouraging efficacy. To provide you here with one update, which we recently provided in October at ESMO, the largest clinical oncology conference in Europe, we saw for patients which are suboptimally or not really reacting to Keytruda, which is about 70% of the patients, an overall response rate, meaning tumor shrinkage, in more than 60% of patients, 61.7% to be precise.
Typically, you would expect round about 40% of patients experiencing tumor shrinkage. We increased the rate of tumor shrinkage versus historic control by about 50%. That's, of course, a very good outcome. Previously, we reported also a median overall survival of more than 30 months, 32 months actually, and also a progression-free survival of round about 12 months. We saw very strong efficacy signals besides what has been in front and center, the very important safety.
Very good. Okay. This isn't a tiny trial in 10 patients, is it? Is somewhere around 50 subjects in that phase I trial?
Yes, indeed. Many of our trials are actually relatively big. If you take lung cancer here, we have about 50 patients, 51 available patients to be precise. Then we have another 114 from a study which is published and which we discussed in the past for TACTI-002. We have for non-small cell lung cancer, 165 patients in phase II trials, meaning a very robust fundament for our ongoing phase III trial.
Very good. Okay. Just before we move on to the phase III , any further updates we can expect from INSIGHT-003 in the next 12 months or so?
Certainly, in the next 12 months, you may hear the one or the other update. You need to have, of course, enough maturity in the study also to talk more about overall survival from the last group of patients. That is all ongoing. Once the data is fully final, we will update the market. So far, a great success.
Great. All right, let's move to the phase III trial, a huge area of focus internally for the company. This is in 750 patients in total, 150 sites around the world. A massive undertaking. Why don't you start, Marc, by describing to us just the design of this trial and how, I guess at a high level, what you're trying to achieve here in the two arms of the study?
Yeah. In this clinical study, we try to achieve nothing less than to change the practice in the day-to-day clinical care, how first-line non-small cell lung cancer eligible for anti-PD-1 is treated. We want to drive benefit for patients. We would like to achieve that the patients are living longer and that this therapy is approved on the market. It is a final clinical step. It is, I believe, a very well-designed clinical study. It is one-to-one randomized, meaning you have one arm with eftilagimod and one control arm with placebo, always based on the standard of care combination of Keytruda plus chemotherapy in 756 patients in, at the end, more than 150 hospitals in more than 25 countries around the globe, of course, including Australia, where the study started. It is a study which is very well balanced.
We have four different so-called stratification factors, factors where you balance a trial or recruit patients accordingly. That's the TPS score where Keytruda, where you can measure by biomarkers of Keytruda, has a chance to work very well optimally or not at all. The region, of course, also the performance status of the patients, is patient doing okay to join a clinical study, as well as the histology, meaning squamous or non-squamous cell, first-line non-small cell lung cancer. A very well-designed clinical trial.
Great. Okay. You gave an update a couple of months or weeks ago about how the recruitment is tracking in this phase III trial. We know the end goal is 756 patients. How has it been tracking so far and how are those timelines shaping up?
Yeah, it's actually the second clinical trial in my entire career, well above 20 years in the industry now, which is really delivering according to the KPIs, or actually better in the one or the other KPI, meaning the guidance we have been providing more than a year ago is still valid. The guidance prior to study start. Unfortunately, a problem in our industry is that you quite often see heavy delays in clinical recruitment with clinical trials so that the original guidance needs to be pushed out. I'm very happy to state that the operational performance of the trial is really excellent. Our guidance stands. We have been recruiting enough patients already in October to see the so-called futility analysis in first quarter next year. In a relatively due course, by the standards of our industry, we will see a very important update from the study.
We believe that last patient in will be in third quarter next year with then the first readout in terms of an endpoint, progression-free survival could be achieved by back end of 2026 to mid-2027. This is an event-driven readout, meaning you need to have enough patients progressing to trigger that readout. If that is sufficiently positive, we can already file. About a year later is the first overall survival readout. It is a trial where the operational performance is going very well. We have well above 100 hospitals already. We are continuing to roll out the study startup, but it is so far going very well.
Right. All right. I just want to touch on one of the points you mentioned there about the futility analysis. That is a pretty clear event and catalyst coming up not too far away, first quarter of next calendar year, you said. Can you just take a moment to describe what that involves and what we can expect to see when that comes out?
Yeah. So the futility analysis is the first analysis for our phase III clinical trial. It's run by a so-called IDMC, Independent Data Monitoring Committee, as well as by an independent statistician. So the company has no seat at the table. These persons will look then into the clinical trial data. They are unblinded. It's a blind, a double-blind clinical trial. As we speak, we don't know any results, of course. They will look into the data and say practically a go/no-go decision if it's a futile undertaking. If the eftilagimod arm is performing in a way that the continuing of the study is not recommended, that's practically a de-risking step for the entire clinical study. Very important to have that. It's based on overall response rate, so on tumor shrinkage, as well, of course, as on safety that will certainly also be evaluated.
Yeah, this is the basis for this futility analysis.
Right. Okay. Are you able to comment at all about, it sounds like you predefine a certain threshold that needs to be hit. If it hits the threshold, you continue the trial. If it does not hit, you stop the trial. If that is kind of a right, an accurate summary, is that a threshold that it is no worse than the control arm, or does it have to be a certain amount better than the control arm, or is that not able to be talked to at this point?
It's not specifically disclosed, but your general description is right. You have, of course, a predefined criteria. Of course, we would like to see Eftilagimod performing better than the control arm. This is something which we achieved in every single clinical trial so far, randomized, not randomized, whatever it is, we always saw a higher response rate with Eftilagimod. Of course, we hope that this continues here as well. Typically, futility analysis is not aiming, just to be clear, is not aiming for statistical significance. It involves a smaller patient population, but it gives you the first hint or first analysis, not a hint, it's an analysis if it is futile or not. Please keep in mind that this trial has been designed together with Merck from the United States.
They helped to achieve here an industry standard design with high integrity and with all the features you need to have.
Yeah, very good. That leads me to my next question, which was that Merck collaboration. For our audience, Merck sells the biggest selling drug in lung cancer in terms of dollars at the moment, Keytruda, that you're combining your product with here in this case. What exactly was their role to get this trial up and running, and how involved are they with its ongoing conduct?
Yeah, we entered into a clinical trial collaboration and supply agreement with Merck mid of last year, a very important agreement because Merck is supplying Keytruda, a commercial value there, round about $100 million US dollars. Otherwise, we would need to finance it somehow. Very difficult, $100 million US dollars. It's a big number. Even more importantly, they helped to design the clinical study. Both companies teamed up in order to design a potentially practice-changing phase III clinical trial combining eftilagimod alpha, Keytruda, and chemotherapy. We have, of course, an ongoing relationship. Typically, you have a joint development committee throughout the clinical trial, so relatively frequent touchpoints. Of course, also involvement in the design in terms of statistics and also to drive different other aspects of the trial to make it really a pharma-standard clinical trial, not a biotech exercise.
It's good as biotech is, but especially if it comes to these large clinical trials, it's very important that you have everything in mind. Also, this is what we actually did, that you involve the regulators. We have been to the FDA already last year. We have been to the German Paul-Ehrlich Institute, as well as Spanish AEMPS. Coming back to Merck, one last sentence to reflect on the importance of this clinical trial collaboration supply agreement. It has been the first time for Merck to enter into such a phase III collaboration for more than two and a half years. The last one before us, they have been doing with Gilead in January 2022.
Okay. All right. Last question for me. Let's fast forward, sorry, on this phase III trial, last question. Your co-primary endpoints are survival and progression-free survival. You said that PFS, which is the first one, might be end of calendar year 2026 to 2027, and then overall survival a year after that. Just talk to the difference of those two different primary endpoints. Do you think both of those need to be statistically significant in order for you to progress this product through to an application to the FDA and EMA?
Yeah. First of all, the description of those endpoints, overall survival, I believe is relatively clear. It's how long the patients are living. I said before that most patients, unfortunately, pass away prior to reaching the two-year mark. Of course, this is something which we would like to improve. This is typically measured by the so-called median overall survival and also then the hazard ratio. Progression-free survival is how long a patient lives without the tumor progressing. This is all standardized. There are different benchmarks. This is objectively measured according to around the globe accepted standards. Progression-free survival is reached earlier than overall survival. For instance, in the INSIGHT-003 clinical trial, let's say 12 months median overall survival and more than 30 median progression-free survival. Apologies, 12 months progression-free survival and more than 30 months median overall survival. You would like to achieve statistical significance.
The first chance that we could file with the FDA and other regulators and aim for approval is based on progression-free survival within the time frame you just mentioned. There you would like to achieve in order to file statistical significance. You would need to see at least a major trend in overall survival. If overall survival would be flat, I believe the FDA would not look favorable at this combination. If you see a major trend or let's reverse it, let's assume you do not see progression-free survival being statistically significantly positive, you still have the chance about a year later to achieve statistical significance with overall survival. The final overall survival data, which is another year later, can still achieve statistical significance.
In other words, we designed a clinical trial which has different endpoints and different times when it's reading out, very important from a risk perspective. We are not facing a binary event. We flip the cards once and then we win or lose, but we have different points at times on different endpoints where we can win and actually potentially also on major groups of patients. Let's assume it's a close shape overall, unfortunately not statistically significant, but the non-small cell patient population, typically around 70%, hits that marc, we will, of course, discuss that with the regulators and still aim for approval. It is a very risk-balanced clinical trial from my perspective.
Okay. All right. That was a great run-through of that phase tIII program. Let's shift to some of your other indications with the same drug in FD. You recently put out an update in soft tissue sarcoma. What were the highlights from that announcement and that trial?
Yeah, soft tissue sarcoma, we have there the so-called neoadjuvant settings. We treat a few weeks prior to surgery the patients. The primary endpoint of that study, it's another investigator-initiated study in 38 evaluable patients, has been met, highly significant versus the historic hypothesis, p-value of 0.001. Also the lab data, which has been recently presented at the CTOS conference in Boca Raton, has been very positive. You saw a much higher level of interferon gamma, and FD is known to drive higher interferon gamma and the interferon gamma cascade, meaning that the trial results, and actually here together in combination with radiotherapy, are very convincing, threefold higher than what you would normally expect. They are also in conjunction and congruent with the lab data, something which we saw, by the way, also in non-small cell lung cancer.
It's not only important that you drive very good efficacy, it's also important that you can link it to the underlying mode of action, something we discussed at the beginning of our conversation.
Yeah, great. All right. We've talked so far about your lead program, eftilagimod alpha. Let's shift to IMP761. This is a different candidate, not for oncology, but for autoimmune conditions, still along this LAG-3 immune pathway, sorry. You're doing a phase I trial with that product. Can you recap where that's at and what the latest data you have is from that trial?
Yeah, IMP761, indeed, another, I believe, exciting program, which has game-changing potential the way you treat autoimmune diseases. Here we are aiming at the potentially curative approach. We are aiming for the root cause of 80%-90% of autoimmune diseases. We use there LAG-3 as a marker to identify the rogue T cells. In oncology, you would like to have an active immune system. In autoimmune diseases, unfortunately, it is hyperactive and stimulated by the self-peptide and has been running out of control, attacking your own organ systems. We are at the phase I, in the phase I dose escalation clinical trial, actually a double-blind placebo-controlled phase I, where we saw first remarkable results when we treated the healthy volunteers with 0.9 mg per kg.
Prior to that, they have had a local irritation of the skin, deliberate local irritation of the skin, and then you measure versus placebo the immunosuppressive effect. We will, prior to the end of the year, update the market on how this has been continuing as we are in the dose escalation after 0.9 mg per kg with 2.5, 7, and then 14 mg per kg. It is a very exciting program. We have for eftilagimod alpha a lot of interest around it, and we will provide an update in the not-too-distant future.
Okay, very good. I mean, autoimmune conditions is obviously a bucket for a whole range of different conditions. Is there any one or two in particular that you think 761 could be particularly targeted towards?
It's a very good question. There has been a publication with IMP761 based on preclinical experiments in juvenile arthritis. Maybe rheumatoid arthritis could be the right way to go. Psoriasis is another one. We had one external discussion around type 1 diabetes. It is a broad range. At the end, we need to make the right decision here.
Okay. All right, let's shift tact a bit to your balance sheet and partnerships. Just noting here, AUD 110 million in cash at the last quarterly update. You've got a pretty strong balance sheet. How far does that get you in terms of your cash runway and how are you thinking about potential partnerships to ultimately get eftilagimod and other products through to approval and onto the market?
Yeah, strong balance sheet, cash live till end of next calendar year. We have been very good with the budget all the time. Partnerships as we had with Merck or have with Merck and with others are very important. We continue to discuss and hope that we can also deliver.
Very good. All right, we are coming towards the end of our time here, Marc. Perhaps we'll just finish on a recap of the, I guess, catalysts and news flow that we can expect from the company over the next 12 months. It seems like that phase III trial, first quarter next year, the futility analysis is a pretty big obvious catalyst. Could you just recap for us that and any others that we can expect over the next 12 months?
Sure. The key value drive of the company, TACTI-004, phase III, futility analysis around the corner in quarter one. From the same clinical trial, last patient in, we believe third quarter next calendar year. Also very important and hopefully good operational performance with a chance to see the first readout on which, if sufficiently positive, of course, we could file back end of 2026 to mid-2027, progression-free survival. We have other clinical trials which will continue to deliver data, actually by end of this year in metastatic breast cancer, the APEX-003 clinical trial, also the trial in soft tissue sarcoma, it's called FTSARC-NEO, maybe INSIGHT-003. There are a number of different clinical data points we are going to have. IMP761, another product with an important data update till end of this year as well, of course, and also in the next year.
We will continue with our regulatory interactions. We are working on a number of hopefully exciting things I can't talk about yet, but the next 12 months will continue to be extremely busy. Yeah, we will update the market accordingly.
Very good. All right, Marc. Unfortunately, that wraps up all the time we have for our presentation today. Thank you very much for running us through a whole lot of what's going on at Immutep. There's certainly many different clinical paths and streams that you've got keeping you busy there. We will be watching very closely as that all unfolds. Thanks.