Telix Pharmaceuticals Limited (TLX) Earnings Call Transcript & Summary

Good morning, and good evening, everyone. My name is Kyahn Williamson, SVP of Investor Relations and Corporate Communication at Telix. Thank you for joining our educational webinar on our neurologic oncology portfolio. Before we commence, I want to note that today's presentation includes forward-looking statements. These forward-looking statements are based on current assumptions, actual results could differ materially. We do advise you to read the safe harbor statement. Today, you'll be hearing from Richard Valeix, CEO of Telix Therapeutics for a portfolio overview, and this will be followed by Dr. David Cade, Group Chief Medical Officer at Telix for a clinical update on our Therapeutic and Precision Medicine candidates in the neurologic oncology portfolio. This will be followed by a discussion with key opinion leaders in the field, Dr. Josef Pichler and Dr. Nelleke Tolboom, who David will introduce more fully during the session. Following the discussion, there will be a live Q&A where both David and Richard will be available to take your questions. With that, I'd like to hand over.

Thank you, Ky. I'm Richard Valeix, the CEO of Telix Therapeutics. As you can see, Telix has one of the deepest pipeline in the radiopharmaceutical industry. But let's focus today on the neuro-oncology portfolio. This is an area where innovation has been stagnant for the past 2 decades. And we believe, based on the clinical evidence generated to date that we are well positioned to bring new therapeutic options to patients and become a leader in this field. Within neuro-oncology, our lead candidate is an iodine-based compound named TLX101 therapeutic, which is the subject of a pivotal Phase III trial named IPAX-BrIGHT. David, our Chief Medical Officer, will speak today about this and other trials for this candidate. We are also exploring an astatine-based candidate, TLX102 therapeutic. It's an alpha-emitter in an earlier development phase. One of the key features of our candidates is the ability to cross the blood-brain barrier. Our molecule is designed to overcome this challenge, and we develop a simple IV route of administration, which is a breakthrough innovation considering all the other therapeutic options, which are very invasive. Our key opinion leader will talk more about this today. In -- as a leader in radiopharma, we are dedicated not only to treat disease, but also to diagnose patients. It's what we are used to call the [ theranostic ] approach. And this is the reason why we have developed an imaging agent for glioma, TLX101 diagnostic, expected to be branded as Pixclara or Pixlumi, depending the geographies. This is currently under regulatory review in the U.S. and in Europe. While being developed as an agent for imaging and glioma initially, it is also intended to be a patient selection tool to make the patients eligible for our 2 therapeutic candidates. Next slide. With this slide, I just wanted to show the importance of a theranostic pair, an imaging agent associated with a therapeutic compound. On the left part of the slide, before treatment, you can see how clear the image with FET-PET or Pixclara is compared to MRI, showing a more extensive and active disease. On the right part of the slide, after treatment with TLX101 therapeutic, the new images illustrate in that case, a near complete response, showing the power of theranostic to see it and treat it. More on this later in the presentation. But let's move on the total addressable market in the next slide. Our neuro-oncology franchise addresses a significant unmet need. Gliomas and glioblastoma represent an underserved patient population that has not seen any new therapies over the past 2 decades. It's also a sizable and growing patient population with increasing diagnosis rates, supporting long-term growth. This creates a compelling commercial opportunity for Telix. Our initial focus is on later line patients, more precisely in recurrent glioblastoma. It's the focus of our Phase III therapy study, where we have an orphan drug designation granted. We pursue also the opportunity to expand into earlier lines of treatment, and we have just completed a Phase I study in this setting. We see the opportunity to expand into multiple indications and broaden the market opportunity, including into another indication, leptomeningeal disease or LMD, with our alpha targeting therapy. The patient number on this slide illustrates the potential of this complete disease area. But with that, I will turn over to David Cade, who will provide a clinical update.

Well, thanks, Richard. Much appreciated. David Cade is my name, and I serve as the Group Chief Medical Officer at Telix. I look forward to going into our clinical programs in a bit more detail. Let's go to the next slide. Thank you. Now before I go into our current clinical trials, I think it's important to recap the previous key studies that we've undertaken and completed with TLX101, which comprise the IPAX-1 and the IPAX-Linz studies. Now both these studies evaluated TLX101 in combination with standard of care external beam radiation therapy in patients with glioblastoma. And of course, both these studies were done in the recurrent disease setting. Now this is a population of patients who have very few effective treatment options available to them, and we clearly need new and better options. And I can summarize these 2 trials very simply, I think. Firstly, both studies confirmed that TLX101 is well tolerated with a quite benign safety profile. And then secondly, both studies indicated encouraging overall survival durations. In other words, when we measured overall survival from the time of first diagnosis, overall survival was in the range of 23 to 32 months. And then when we measured overall survival from when treatment with TLX101 was initiated, overall survival is in the range of 12 to 13 months. Now both these durations, depending on either from time of initial diagnosis or time of initiation of treatment, both of them are very encouraging overall survival durations. Now more recently, we reported the completion of patient enrollment into a third study, which is IPAX-2, which is our study of TLX101 in combination with frontline standard of care in newly diagnosed patients. And while follow-up for IPAX-2 is still ongoing, this study has been particularly pleasing with no dose-limiting toxicities even at the highest planned 10-gigabecquerel dose regimen. And I look forward to reporting the outcomes from IPAX-2 later on this year. Now let's move to IPAX-BrIGHT and IPAX-2 in a little more detail, which I'll go into in the next couple of slides. So if you go to the next slide. Now here, I think this really nicely lays out IPAX BrIGHT, which is our registration-enabling Phase III study that's evaluating TLX101 in combination with lomustine in patients with recurrent glioblastoma. Now lomustine is an oral alkylating agent that's been around a long time. It's primarily used for patients with recurrent glioblastoma once it progresses following standard frontline care, which will typically comprise of maximal surgical debulking by the neurosurgeon followed by chemoradiotherapy. Now lomustine is commonly used when disease recurrence occurs, but there's still no established standard of care in this disease setting. And hence, we really need quite desperately new options. And as you can see, IPAX-BrIGHT is a 2-part study, where in part 1, we're evaluating 3 cycles of the highest dose of TLX101 at 4 gigabecquerels plus lomustine at 90 milligrams per meter squared. Now if this combination is tolerated, we'll proceed quite rapidly with an expansion cohort of another 12 patients before we proceed to Part 2 of the study. Now Part 2 is where it gets really interesting, here, we'll assess the combination of TLX101 plus lomustine versus lomustine alone as a control in a randomized treatment expansion. And it's -- because lomustine is a commonly used comparator in late-phase clinical trials, that's why we're using it in this recurrent setting. So this is a global study in which we already started dosing patients in Australia and Europe and the first cohort has fully enrolled quite rapidly. In Europe, we've received regulatory approvals to proceed across 7 countries, and we'll be expanding to the U.S. once FDA has granted us clearance. So let's now move to IPAX-2. Next slide, please. So this is IPAX-2, which I'll discuss just briefly as it's been -- it's just completed patient enrollment as we announced now a couple of weeks back. Now while this is a Phase I dose escalation study, it is an important study as it was conducted in patients with newly diagnosed glioblastoma and it evaluated TLX101 in combination with frontline standard of care. Now standard of care in this frontline setting, again, it's typically maximal surgical resection of the tumor, followed by chemo radiotherapy. And this is commonly referred to as the Stupp protocol. The important point being that this protocol has been the conventional approach for about 20 years now, 20 years. So as you can see, this is a dose escalation study undertaken to identify the maximum tolerated dose of TLX101 that we could give when we layer it on top of frontline standard of care. And as I mentioned earlier, we're very pleased that there's been no dose-limiting toxicities in this study. Indeed, the safety profile has been really quite benign, and we've been able to escalate to the planned maximum dose of 10 gigabecquerels. And I look forward to providing an update on this study in the coming months. Now let's go to the next slide. Now to round out the picture, and I think that's probably quite apt. I'd like to briefly cover the imaging side of our neuro-oncology portfolio. Now while conventional MRI has long been the standard of care for imaging malignant gliomas in the brain, the purpose of diagnosing and staging these tumors, MRI is also used to determine whether a patient is responding to a treatment, for example, chemo radiotherapy. But especially in this setting, when we're using MRI to work out response to treatment, there's some significant limitations with MRI, where depending on the literature that you look at, up to 40% of MRI scans are deemed equivocal. And they can't tell us clearly whether a patient's tumor is growing and progressing on the one hand or whether it's what we see is simply an artifact of treatment or what we call treatment-related change. But as you can imagine, this inability to distinguish between disease progression and treatment-related change that can lead to a delay in treatment or overtreatment or under treatment, which this group of patients simply don't have the time to be able to afford. Now if you look at these 2 images, you can see how clearly the active tumor contrast on the right-hand side when you compare Fluorine-18 FET-PET using Pixclara versus MRI. Pixclara is therefore, a critically important additional tool to support clinical decision-making in patients with malignant gliomas who need definitive decision making. Now let's go to the next slide. I think this is my last slide. Here, you can see the high accuracy in terms of sensitivity and specificity of detecting gliomas that we can now achieve with a Pixclara scan when we use it in combination with conventional MRI. Now these data come from a prospective study evaluating whether the diagnostic accuracy of MRI could be improved by the additional use of Fluorine-18 FET-PET with Pixclara. In the study, 26 biopsy samples were taken and the diagnostic performance was determined by the area under the receiver operator curve. That's that diagram on the right. That's the technical terminology that we use. So for MRI, sensitivity was 96%, and specificity was only 53% specificity, which is not good enough. The combined use of MRI and Fluorine-18 FET-PET significantly improved that specificity into the high 90s, which is exactly what we want. So Pixclara, therefore, is a very eagerly awaited tool to improve our diagnostic accuracy of gliomas, and it's currently under the review by the U.S. FDA with a target approval date in mid-September. So with that, I hope that gives you a solid foundation for our imaging and our therapeutics pipeline. And I'm looking forward now to moving into our in-depth Q&A session with Dr. Tolboom and Dr. Pichler. Well, thank you very much for joining us. David Cade is my name, Chief Medical Officer at Telix Pharma based here in Sydney, and absolutely delighted to welcome 2 of the most esteemed colleagues from Europe. Europe is probably the major contributor to the advancement of research and thinking for the way that we treat patients with malignant central nervous system and brain cancers, and 2 of the leading institutions we have clinicians joining from. So first of all, Professor Josef Pichler from Kepler University in Linz in Austria. Professor Pichler is the leading neuro-oncologist and, over many years in the field, a contributor to the advancement of our approaches to the way we treat patients with glioblastoma in particular. And also joining us is Dr. Nelleke Tolboom from the University Medical Center of Utrecht in the Netherlands. This is a leading group from the Netherlands. And Dr. Tolboom's research is focused on malignant brain tumors, but also as a nuclear medicine physician, how we image them and also, you have a very strong interest in pediatric neuro-oncology as well.

So I think I'm delighted to welcome you both. I think given that we've got quite a diverse audience. Let's start with some basic fundamentals. And I think I might direct the first question to Professor Pichler. Glioblastoma is a disease where there's never an average patient. But as clinicians, we have quite average approaches. It's a difficult disease to treat. So could I just sort of ask you if you could lay out the -- some of the basic demographics or the epidemiology of glioblastoma? And what would -- if you painted the vignette of a patient who was diagnosed with glioblastoma and the way that you would manage them, how does that look?

Okay. I will give you a short overview of the current state of GBM epidemiology, a little bit about the standard of care therapy and perhaps some future strategies in this devastating cancer. So here you see that GBM is increasing burden. However, survival rates have not improved about the last 20 years. You can see it on the graphs, we have a little rise up, the annual incidence and average survival is not really good. It was not really better in the last 20 years. We have spent a 25,000 new brain cancers, CNS tumors every year in the U.S. with 18,000 death per year. GBM is the most common and most devastating type of brain cancer accounting for about 50% of all malignant brain cancers in total. So the median overall survival of these patients rise from 2006 to now, to this date only for 15 months at the beginning of the year 2000 and rises a little bit up to 18 to 20 months. Today, the median progression-free survival is within 1 year. So it's really unmet need to have really effective treatments. And you can see it on the next slide. First-line treatment of the glioblastomas, our maximal safe resection, followed by combinational radiochemotherapy using alkylating agents, the most used agent is temozolomide. But also with this treatment, we have a progression-free survival of about 7 months and recurrence rate is very high in the first 2 years. Upon recurrence in these patients, we have no standard of care treatment. You can reoperate the patient, you can re-irradiate the patient. You can use other chemotherapies, but nothing really prolongs survival at that stage. And in the third recurrence, they treat the tumors often refractory and it is a palliative situation. And imaging modalities like how to diagnose this cancer is the gold standard MRI in the last 30 years, but MRI have some limitations, and we will further discuss these limitations with new treatment imaging modalities with [indiscernible] together. So in the next slide, you can see, in summary, the progression of treatment, the progression of diagnosis and the progression of diagnosis with imaging and with molecular, the histopathological diagnosis. We have the radiotherapy and operation, and the last millennium treatment was added with temozolomide, additional to radiotherapy from 2000 on. Temozolomide was introduced in 2010, but no study shows a prolongation of overall survival. Tumor treating field were added. It's not very widely accepted, this kind of treatment, but it has a positive study, a study outlined. Imaging modalities was less millennium, CT than the inclusion of MRI. Treatment modalities are now more and more added with FET-PET, amino acid PET, and we will discuss it in the next few minutes. So treatment is always necessarily to have the right diagnosis. Diagnosis with immunohistology is added now in an integrated diagnosis with the WHO classification based on molecule biomarkers. GBM presents a significant and persistent unmet need for patients treatment because there is no really good option to prolong survival as effective or essential. So the next slide, I will transfer to Nelleke. if it is okay, David?

Yes. Yes. Look, I think that's perfect. I think...

Because we have a new target and a new treatment option, but the structure behind is more explained by Nelleke, as a specialist for nuclear medicine.

Well, that leads me to a question for Dr. Tolboom is the brain has a special protective apparatus called the blood brain barrier, which not only protects it from undesirable chemicals also the drugs that we want to get to the brain to treat various tumors. Could -- as a nuclear medicine physician, I think it would be really relevant for you to discuss the blood-brain barrier and the challenge that, that poses and then the unique target that we are targeting. And then I'll have a -- I think, a follow-up question on imaging as well.

Thanks, David. Well, that's a very interesting question. Like you said, the brain tumors or gliomas are tumors from the glial cells or from the brain itself, and they have -- unlike other tumors in the human body, they have an added layer of defense around the blood vessels. So like you said, toxins cannot enter the body, but that means drugs can also not enter the body. So commonly, we use MRI for imaging brain tumors. And what we greatly rely on is on the enhancement that you see on MRI. An enhancement on MRI is gadolinium leaking through a leaky blood-brain barrier like we see in the core of a glioblastoma, so the more aggressive form of brain tumors, for instance. But around that core, where the blood-brain barrier is leaky, there are also more infiltrative components of the brain tumor, which have an intact blood-brain barrier, so which do not permit leakage of gadolinium or leakage of drugs for that matter. So that means that we -- that brain tumors are very difficult to image because we don't see infiltrative components and also difficult to treat because it's very difficult to treat those infiltrated components which are protected by the blood-brain barrier. And I think that is where the LAT1 and the LAT2 targets really are a game changer because they're on the blood-brain barrier. The brain needs essential amino acids as building blocks and the brain let's amino acids through via the LAT transporters. And that means that if you radiolabel an amino acid, for instance, with amino-acid PET -- FET-PET or with TLX101, the compound your company is using for treatment that it also gets across the blood-brain barrier because the brain does not see a difference between a normal amino acid that it needs for building blocks or the radioactive amino acid. And because the brain tumors have a higher uptake of those amino acids, they also get taken up, the radioactive amino acids get taken up by the brain tumor more, so we can visualize that infiltrative component with the compound, but also treat that infiltrative component with the compound. And that is, I think, where product and the mechanism of imaging and treating disease is so promising for this group of patients.

Dr. Tolboom, I noted that Professor Pichler was showing some of the basic epidemiology of glioblastoma. One thing that really jumps out is the abbreviated limited survival duration, as researchers and clinicians we need to come up with more options. But in that context, we have to make rapid decision-making in terms of what is the optimal treatment. Could you maybe talk about the conventional imaging, CT and MR -- and yes, in the molecular imaging that in Europe as clinicians, you have broad access to, but in the United States clinicians do not have broad access to molecular imaging. So maybe if you could talk about FET-PET and what does that bring?

Right. So brain tumors are imaged mainly with MRI. And after the initial diagnosis, patients get sequential MRIs at set time points to see if a treatment is working. How -- if the tumor is stable or if they have recurrent or progressive disease. And while MRI really is the hallmark of imaging for brain tumor imaging. It does a fantastic job. It shows the infiltrative component like we just discussed, but you also have other modalities with MRI and FLAIR sequences also newer options with MRI like perfusion and metabolic MRI. MRI only shows part of the puzzle, in my opinion. And amino-acid PET really is an additional, very valuable tool. It's not in the game to replace MRI, but it does really show really additional value to MRI, for instance, in patients where MRI can sometimes have a problem in distinguishing if a patient is having -- if new enhancement on an MRI, if that is due to the treatment itself or due to the radiation and the chemo or if it is in fact, a tumor progression. And as you might understand, there is a very -- it's very crucial to differentiate between the 2 because they are treated very differently. And that is where amino acid PET really can aid the diagnostics in patients. So amino acid PET is not out there to replace MRI, but it really is an additional, extremely valuable tool for instance, in the follow-up of patients during their treatments.

Yes. Look, that's very clear. Well, I think both of you are trialists, you're very significant trialists, in fact, contributing to the literature. I might turn back to Professor Pichler. You were the principal investigator on the IPAX-Linz study, named after your institution. But TLX101-Px, which is iodine-131 I-PA, a therapeutic agent, and you did that study in recurrent glioblastoma. What -- I might start by asking you about the trial, what led you to initiate that trial. And what was the purpose that you were trying to examine?

Yes, IPAX-Linz was initiated because I've mentioned it before, we have no standard of care, standard of therapy in the recurrent setting and IPAX-1 was the study first in patient Phase I study with different doses of Iodofalan. And I want to add some information with a couple of patients additional to this first-in-man study. So we conducted the study and closed it with 8 patients treated with much high doses than in the IPAX-1 trial. We administered 4-gigabecquerels before the re-irradiation and 2-gigabecquerels after re-irradiation. And radiation therapy was applied with 18 fractions of 2 grays. So that was the same as in IPAX-1. The inclusion criteria comprised patients with recurrent GBMs in first or second recurrence, that was different to IPAX-1. And also our reoperation was allowed in this setting. It was also not allowed in the IPAX-1 study. But after reoperation, have to see a residual tumor in MRI or in FET-PET, as mentioned Nelleke, that the MRI and the FET-PET have different signatures because sometimes we see no tumor under MRI because the blood-brain barrier is intact and infiltrating tumor part and -- but we see it on the FET-PET. And when we see it on the FET-PET, we have a target for Iodofalan. So we have the option also in the operated patients. The primary outcomes was a safety and tolerability because of lack of -- a lot of patients and secondary endpoint comprised progression-free survival and overall survival also. So I can share some outcomes if you want?

Yes, I think that's important. Yes, if you could talk about the impact, I mean, it was a small Phase I study. You mentioned 8 patients. What would say the impact was to your outpatients? And what did you -- what should we take away from IPAX-Linz?

I think the impact was we gather more data, additional to IPAX-1 treatment -- IPAX-1 treated patients. And also, we got further informations on the feasibility of the treatment and also on toxicity of the treatment. And I will state that the impact of the patients is very good because the treatment is very well tolerated. The only hinderance for the patient is that they have been isolated for a couple of days. But they have no relevant adverse event occurred or no serious adverse events, only 3 patients experienced adverse event with leukopenia grade 2 or the lymphopenia 3 and 1 thrombocytopenia grade 3. One patients have fatigue and the most other events were very, very mild. So in this primarily palliative situation of recurrent first or second recurrent GBM patients is very important that the patient has not to suffer from the treatment and we can guarantee with the treatment of IPAX, they don't have to suffer from the treatment side effect. That's the impact of the patients primarily.

So this is a patient from your study. I think I believe you presented this at the European Nuclear Medicine Meeting last year. Could you give this as a vignette of one of your patients a case study of the dilemma that you face with this patient that you were trying to address on the study? And if you could step us through the case, I think that would be very illustrative.

Yes. You see in the slide that the patients have a recurrent tumor. Clearly seen on the right image, but also very impressive seen on the FET-PET scan. And when you administer the iodine, phenylalanine, you see a clearly uptake in the tumor. And this patient have a partial response after this treatment and a good quality of life during the whole until she died due to the tumor. So I think it's impressive when you see that the patients are -- the treatment with Iodofalan have a very clear uptake, and we see we hit the target, really. We can treat it, and -- but we have to look for the optimum dose in this treatment. We don't know it now. I think a higher dose than IPAX-1 is necessary for relevant treatment. The combination of the Iodofalan therapy with the radiation therapy has in my opinion additional effect in enhancing the treatment effect in strand break of the DNA of the tumor. So for the future, perhaps not only the single treatment is -- Iodofalan is the key of treatment, I think we have to find perhaps some additional component -- additional treatment combined with this kind of radiation, internal radiation.

Okay. Well, I might turn to Dr. Tolboom. As I mentioned at the opening, University Medical Center Utrecht is one of the leading Western European institutions to malignant brain tumors, you've been doing some extraordinary research. Dr. Tolboom, I think you've treated -- approaching 20 patients. What types of patients do you treat? I believe it -- it includes adults and pediatric patients, and it includes glioblastoma and other forms of malignant brain tumors. So if you could maybe summarize what is your patient case load like? And maybe you can talk about the types of patients you're treating?

Well, we're very fortunate to be able to collaborate with Telix, obviously, to get our hands on this promising compound. So we have been treating a lot of patients in studies, but also outside of the studies as compassionate use. So in certain instances where there was absolutely no other treatment for the patients, and we have been treating mainly patients with a glioblastoma. So the most aggressive form of glioma but also indeed to pediatric patients, we're looking into that. We're adjacent to the largest pediatric oncology hospital in Europe. So we collaborate with them a lot. And like Professor Pichler mentioned, the high clinical unmet need for glioma patients, it is as high for pediatric and neuro-oncologic patients. So aside from the pediatric patients, we've also treated some patients not with a glioblastoma, so not the most aggressive form of glioma, but with maybe a little bit less, but still aggressive and fatal glioma. So we've been getting more and more experience on the treatment and also for Nuclear Medicine wards around the world where the theranostic concept is getting very popular. So we're treating a lot of patients, but these are mainly patients -- adult patients and also prostate and neuroendocrine tumor patients. And that is a whole different ball game to these neuro-oncological patients, which take, I think, real teamwork and expertise care with neuro-oncologists and the oncologists in our center and in the center like Professor Pichler. So we've been mainly treating glioblastoma but also pediatric cases and higher grade gliomas.

Okay. I think that summarizes it very nicely. Now we -- Professor Pichler talked about Phase I trials, IPAX-1 that's been done and IPAX-Linz, that has been done. Now we'll get on to IPAX-BrIGHT, which is a multicenter international Phase III trial, which we need to understand where iodine-131 I-PA, TLX101-Tx might contribute in the future. But case studies in this setting, this is an orphan disease glioblastoma. So case studies remain highly relevant to inform our ideas about research. You reported a near complete response in I believe, a treatment refractory patient, again, just recently. Could you step us through that case study and the relevance of the findings from that case?

Right, right. This is -- I think this is a super exciting case for -- well, especially for the patient, but I think for the whole field, really, because we have to understand that glioblastomas are such aggressive tumors that even like slowing down the disease, progression of disease is -- would be -- is fantastic or stabilizing let alone, having a near complete response that is the blew us all away. So this is a 56-year-old male, who was a treatment refractory. So he had past treatments for his glioblastoma. As you can see in the top row, you see the MRI before on the left side and then the MRI after on the right side. If you look at the MRI, you see in the left parietal lobe, you see an enhancing mass, and that was his tumor. It couldn't be resected due to the location. So surgeons always look at the tumor, is it safe to resect or do we cause too much debilitating symptoms for patients. So this patient had dysarthria due to the location of the tumor. He had several lines of treatment that and the tumor was progressing again. Then he came to us and got a FET-PET, which you see in the bottom row on the left side. And there you see the intense uptake of the tumor. And what is very interesting is that if you look at the area with high uptake, where the white arrow is, you also see that the uptake is also in the regions that do not show so much contrast enhancement that we see on the MRI like we discussed before, contrast enhancement is leakage over a leaky blood-brain barrier, but glioblastoma and gliomas have infiltrative components, which make it very hard to target disease. And as you can see that the FET does come there. So that's also where the TLX101-Tx also will come -- so it also treated the infiltrated component. So this patient got treated with 1 cycle and he tolerated it extremely well. I think his only complaint was -- maybe a little bit of boredom of being in our isolation rooms. And then he came back and after 4 weeks he got another cycle. That's what we typically do, give patients 2 cycles. And then in between we waited a while to see how well he tolerated in. And it's good to realize that this patient got 2x 5 gigabecquerel, which is much higher than has been given before in case studies, but also in IPAX-1, 2 and Linz. And then he got lomustine, which is a chemotherapeutic for a while. That's not something that is -- it differs a little bit in Europe. Some countries, I believe Germany, gives it standard as a second line in Holland, it is offer, but it's not always given. So this patient did receive it, but the lomustine is so toxic that his bone marrow -- his platelets dropped. So he was taken off the lomustine again and then patient was still in clinical such good shape after a couple of months that we decided together with the patient and their treating neuro-oncologists to give him 2 cycles more. And we followed them up for months. And then this is what you see after I have to -- I think after something like 22 months, you see his MRI on the right and the FET-PET in the bottom. And if you look at the MRI, you hardly see any contrast enhancement anymore, which is, that alone is something we never ever see. And then to prove that his tumor is in fact decreasing and that is not just the enhancement going away, which we have seen in the past before with treatments like bevacizumab in other patients, you see that the uptake on the amino acid that is also going down. But more importantly, this patient is still alive. He's doing very well. His quality of life has increased massively, and his speech problems, so dysarthria has also improved a lot. So for us, this is something we would never ever have dreamed of to see in a patient. And even though it's only 1 patient, and this has to be replicated in a large trial like the IPAX-BrIGHT. For us, this gives us a lot of hope for the future for these patients.

I think that's a very articulate story for this patient. As I said, orphan disease case studies like this are informative that we don't tend to pay a lot of attention to case studies in the common cancer, as you know, prostate cancer for men, breast cancer for women, or colorectal cancer, second most common for both men and women. In this orphan disease, these types of outcomes are informative and they do contribute to the design of the trials that we must run phase III multicenter randomized trials. Now both of you are principal investigators on IPAX-BrIGHT. I might -- I recall Dr. Pichler, probably 3 years ago now, I was in Linz with you contemplating how we might design a Phase III trial, and it got named IPAX-BrIGHT as all big Phase III trials do. They get a good name. Could you maybe talk about -- share your thoughts on the design of IPAX-BrIGHT? And what we are aiming to learn from running that study, which is now underway and enrolling patients, I might add.

Yes. IPAX-BrIGHT is the next study, I think the next step forward in our recurrent setting because the recurring setting is that we have the most unmet need for effective treatments. And as I mentioned it before, in IPAX-BrIGHT, we will combine 2 treatment modalities because it is combined in this dose-finding first part of the study with lomustine, as Nelleke mentioned it in the patient before. We know that lomustine has no really effect on overall survival in the recurrent setting over the last 40 to 50 years, but it's an alkylating agent, crossing the blood brain barrier, we know it. Have a little bit more toxic effect on the bone marrow as temozolomide, but it's not very complicated drug in oncology. For oncologists, this is very mild -- mild drug, I will say. So we will combine it because I think 2 mode of actions will be better for treatment. And the mode of action is an alkylating agent different to radiotherapy in double-strand base and are also in repair mechanisms because lomustine has a limitation of the -- of chemo resistance in tumors with unmethylated MGMT promoter, that's a chemotherapy-resistant mechanism in glioblastomas affecting about 50% of all glioblastomas. And this alkylating agent has not another good effect in this type of tumors. So -- but in the other side, the 50%, we have an option with the combining for an enhancing effect because also what [ we said ] to temozolomide when it was given only in the adjuvant setting, is that not did effect as it was combined in the concomitant setting, temozolomide in combination with radiotherapy. That was the effective part of the Stupp regimen. And so I also think IPAX-BrIGHT is good for the next phase to combine 2 treatment modalities in the recurrent setting.

Okay. Look, I think that designs -- it's a very simple design, isn't it? And I think it's going to answer a fundamental question. You made the point earlier on, Professor Pichler that upon first recurrence -- yes. And 90% of patients or thereabouts do recur. So pretty much the entire population that we treat with maximal surgical debulking and postoperative chemo radiotherapy. Once we've done that, what is it, it's a median of 7 or 8 months, and they -- 90% of patients do recur. So we need something there. But I do note that the National Comprehensive Cancer Network, the NCCN guidelines in the U.S. recommend a clinical trial which can include unproven agents as being best treatment upon first recurrence. So clearly -- we clearly need new options and we're hoping that this randomized trial will address that. I've got a follow-up question for Dr. Tolboom. You talked earlier on about using -- well, you talked about the limitations of contrast MRI and sort of 30% or 40% of MRIs being equivocal, and we need FET-PET to adjudicate in that setting. But could you comment maybe on the role of a theranostic approach where we use F-18 FET-PET for patient selection, and then Iodine-131 I-PA for treatment, but for genuine theranostic pair there. What is the role for theranostics in glioblastoma?

Well, I think the beauty of the theranostic treatments with you have the imaging for patient selection and then almost the same compound for treating the disease that you do really see that there will be target engagement in this particular patients because if you need to -- if you use histology, that can be from -- that can be either older from their previous surgery or you need invasive ways to get the histology. So I think this is a very elegant, noninvasive way to determine that the target you're actually trying to attack is visible in the patient. And I also think, this is a little bit a side step. If we look at -- for instance, the Alzheimer's disease field where a lot of studies have failed because they failed to incorporate -- well, they incorporated a lot of patients and then when the amyloid PET came about -- they discovered that actually, in fact, I think 1/3 of the patients did not have Alzheimer's disease so they were treating these massive cohorts of patients that were heterogeneous. I think with the possibility of amino acid PET, you can really make sure that your cohort is really the right cohort for the treatment because we don't want to do a trial where we're, in fact, treating patients who do not have progressive disease at that time, but who have pseudoprogression, for instance. So I think the theranostic pair, the imaging and the treatment is really crucial for noninvasive target selection and making a real homogeneous cohort for a trial.

Yes. So Dr. Tolboom, there's a renowned nuclear medicine physician here in Melbourne who describes conventional imaging with CT or MRI is lumpology, the study of lumps and do they get bigger or smaller when we treat them. You're a nuclear medicine physician and you have the benefit of molecular imaging. So when you use F-18 FET-PET to select patients or when you use it to determine response to treatment, how does that help you in having the discussion with the patient about whether they are a good patient treatment and whether they're responding to the treatment that you'd offer them?

I think that's a great question, David. I think it takes away a lot of the uncertainty, for instance, with the amino acid PET, and what we discussed previously, sometimes it can be very challenging to see on MRI if a patient is progressing or if it's due to treatment-related effects. And I'm not saying amino acid PET is perfect, but it does add another piece to the puzzle and help in kind of taking away a lot of the uncertainties. We, as imaging specialists, but also treating physicians like Professor Pichler, but especially the patients have because it's very difficult to get like the result of your scan being like we're not sure what it is, come back in 3 months, and we'll do another one. And as far as treatment selection, I think the amino acid PET is really helpful in showing the patients exactly where the treatment will go and that we -- and the reasons why we think it is promising. So it really helps in visualizing for patients, a little bit of their patient journey. So it does make a big difference in my opinion.

Yes. I think 1 final question, just to frame it this way is I noted when Professor Pichler showed some of the epidemiology, the 1-year, the 3-year, and the 5-year survival rates for patients have been stuck in first year. We're probably stuck in neutral, really. We've gone nowhere for really the last 15 years. I think those rates haven't materially changed. So Professor Pichler, if we take a -- if we look through the theranostic lens, is what is an aspirational question, what really excites you about what we might see over the coming 18 months, 24 months as we run IPAX-BrIGHT. What do you think the potential might be?

My statement on this test, there are 5 main reasons for brain tumor still defines us. There's an infiltrative growth, the tumor heterogeneity, the tumor macro environment, the blood brain barrier, and the treatment resistance to the repair mechanisms after alkylating chemotherapy. Simplified, we need a new strategy. In the last 2 decades, all treatment failed. The blockade in targeted therapy, multiple pathway blockade, immunotherapy fails, local treatment, also high-end immunotherapy with CAR-T cells. The radiopharmaceutical treatments in brain tumor are at the beginning and have potential to change really the therapeutic options in this devastating disease. And it excites me in this way that it's had a favorable safety profile. We see the exact release to the tumor target, overcoming the blood brain barrier, and we have an option for monitoring with FET-PET.

That's crystal clear, crystal clear. Dr. Tolboom, you have a passion for your patients, you care deeply about them and their quality of life. So what again, aspirationally, what would excite you over the coming sort of 18, 24, maybe 36 months as we run IPAX-BrIGHT. A lot of these patients, I do hope all have extended survivals. Time will tell but what are you looking for?

Well, as Professor Pichler also nicely put it, but I think there is so much to gain for these patients, and we're not there just trying to elongate their lifespan, but also doing that with really good quality of life. And I think radioligand treatments like we know from treatments for patients with prostate cancer in patients with neuroendocrine tumors really have the potential to be able, hopefully, to slow down disease progression with really good quality of life so that would be -- that's the Holy Grail for these patients. And I'm really excited for IPAX-BrIGHT. I think that's to have the first ever theranostic trial in neuro-oncology being run at the moment is really exciting. It's like a milestone for neuro-oncology research. And hopefully with combined -- for other amino acid that take other CNS diseases that take up amino acid PET like other brain tumors or maybe pediatric brain tumors, there could be future trials, combining them also with agents that are being used in these diseases and also looking into other radionuclides. So in the future, I hope we will have a radioligand therapy that will be given in an outpatient clinic. Patients will get the radioligand and then be able to go home and enjoy their life with their loved ones with only minimal side effects and minimal radiation safety rules. That would be my aim.

I would add something. I also think that we are in the beginning of the treatment with the ligands, perhaps with alpha emitters, we spoke Nelleke, because it's an outpatient treatment possibility, and so we have a lot to do in the next years. And the quality of life in this patient is very important, especially in the pediatric population and also involved in the pediatric, neuro-oncology tumor boards. And I think we have treatment options in midline gliomas, in pontine gliomas who are never can be resected, and that's for the children will be a really good option, I think.

Well, look, Dr. Tolboom, Professor Pichler, I think it's not available really the Netherlands and Belgium and Germany and Austria, your European countries are leaders in radiopharmaceutical development, not just in urological oncology but in neurologic with the neuro-oncology. I think Australia is part of that group as well of major contributors in radiopharmaceutical development, I hope. And what really shines through is your ambition for your patients and for advancing what has been a drug development stalemate for 15 to 20 years. And I think collectively, we're going to do that. You both have massive patient case loads. I am very well aware of that, I'll be to both your institutions. They're enormous. So I won't keep you away from your patients, you've got a lot to do. I'd like to thank you both on behalf of the audience for your time and I've learned something and I hope the audience has, too. So thank you very much.

Thank you, David.

Thank you.

We will now proceed to the Q&A session of the investor call with Mr. Richard Valeix and Dr. David Cade. [Operator Instructions] Your first question today comes from Andy Hsieh from William Blair.

Thanks for putting this together. Super informative. I just wanted to dig a little bit deeper into the case study with a complete response. For the outside world, we don't have a lot of background information about how commonly you see that in the relapsed setting for glioblastoma. So could you paint a picture for us just in the real-world setting how common or maybe I should say, uncommon do you see a complete response using the standard of care, just to juxtapose that with 101's potential activity there.

Yes. Thanks, Andy. It's David. Yes, thank you for the question. Essentially in the recurrent disease setting and I made the point during the call that almost all, so about 90% of patients ultimately recur after maximal safe surgical debulking and postoperative chemo radiotherapy almost all of them recur, unfortunately. When we use a salvage treatment in that recurrent setting, and there is no standard salvage treatment. Complete response is exceptionally rare. So it's as rare as being as close to 0 as 1 can possibly get. So to have an agent that has clearly activity to be able to deliver either stable disease or partial response or in this instance, again, it was just a single vignette complete response is clearly meaningful, given that the survival duration is approximately sort of 7 to 9 months with lomustine if you pick 1 of the standards, Andy. So lomustine in a recurrent setting, overall survival of that 7 to 9 months, so anything that provides disease control, complete response, partial response, stable disease, it's clearly important. And that is currently almost no patients get that.

Your next question comes from David Dai from UBS.

And I also want to [ congratulates you ] on the great presentation, very informative, learning more about the neuro oncology programs. So David, just a quick question on the IPAX-BrIGHT Phase III trial, given that there is 2 limited therapeutic advances for GBM over the past 2 decades. What levels of benefit would be considered meaningful clinically that would actually change the clinical practice and establish the 101 as the new standard of care?

Yes, David, great question. Best way to -- there's 2 parts to the answer. So the first part to the answer is that the last major advancement in the treatment of glioblastoma with a European and Canadian trial. It was an EORTC cooperative group trial in -- it's a bit embarrassing to say for all of us in the field, 2005, so 21 years ago that added concurrent and adjuvant temozolomide to postoperative radiotherapy. And in 2005, the stupp regimen, so-called STUPP regimen became the new standard of care with temozolomide, concurrent and adjuvant added to radiotherapy. And that was done on the basis of a 2.5 months improvement in overall survival, if you got temozolomide versus if you didn't. So I think survival went from something like 12.1 to 14.6 months, so a nominal 2.5-month improvement in overall survival by adding that in the recurrent setting. So that's the quantum of improvement in survival duration that changes the standard of care, and we've been stuck in that year since 2005. So the second part of the answer is really, what does lomustine give today in this recurrent setting? It gives somewhere overall survival in the range of 7 to 9 months. And as we discussed in the webinar, the 2 trials that we've done, they're small trials, the Phase I trials, IPAX-1 and IPAX-Linz, had survival durations in the order of sort of 11 to 12 months. So we're looking at sort of a 3- or 4-month improvement in over survival and IPAX-BrIGHT is aiming to at least be able to identify that at a minimum and ideally longer. So it's a comprehensive answer but I hope that addresses that, David.

Your next question comes from Laura Sutcliffe from Citi.

I got a question on the IPAX-BrIGHT trial and hopefully, I get away with this as just one. Is the output of the IPAX-BrIGHT trial, what you would look to submit to regulators with a view to an indication that just captures the recurrent setting. And can maybe you also just give us some color on this setup whereby you have a dose-finding component as part of a Phase III? Why have we chosen to do it that way? And would you need anything on top of that for any of the major regulators?

Laura, thanks for the excellent question. And I would love to ask Richard to contribute because he's a very experienced drug developer. But maybe I'll just kick off and then hand to Richard. To the first part of your question, we will start in the recurrent, first recurrent disease setting because that's where we don't have any standard options, as we mentioned during the call. The NCCN guidelines list Phase I trial as being an option for patients with recurrent glioblastoma. And obviously, Phase I can include trials of the agents that are right at the start of their drug development journey totally unproven. So that's not adequate. We need to improve upon that. And then from there, we typically -- if a study works in that recurrent setting, typically we would then run future studies that move it upstream and Richard can talk about that because he's done that a lot before. And then just the second part of your question, we're aiming to optimize the dose of TLX101, so optimizing the amount of activity to inject and optimizing the dose simultaneously of lomustine, what drug dose to give. And that's the first -- that's a part of Part 1. That's the objective of Part 1. I won't bore you with the details, but that's called a Bayesian design, and that's what the FDA we've, I guess, been in very deep discussions with the FDA to design the first part of the trial to optimize the dose of the radiopharmaceutical when given with the drug. And that's sort of a hot topic with FDA probably the last 18 months to 24 months, picking the right dose for a radioligand therapy to take forward into Phase III. Richard, do you want to add anything to that about starting in the refractory population and going upstream from there. You've done that a bit.

Yes. Thank you, David. So you're totally right, and you summarized well. When we interact with the FDA, they advise us to go for the last line treatment. As you know, classically, in oncology, that they don't want to let us start earlier. They just want to test the product in the last line setting. That's also the reason why they say that. And as Dr. Pichler highlight, where he said, a combination therapy will be ideal because we are addressing in IPAX-BrIGHT recurrent glioblastoma, which is the most aggressive type of gliomas concept. So having 2 compounds and evaluating the optimal dose that was really the recommendation from the experts and from the FDA. So that's the reason why we start with the last line with this dose adaptation as a part 1 and then after that, the dose expansion, which we authorized to obtain this indication in the marketing authorization. But clearly, we have the ambition to expand the use of the 101 in earlier lines of treatment. And the previous studies that we have conducted with external beam radiation therapy goes in that sense plus additional indications with the alpha such as leptomeningeal disease. So it's the beginning of the development of this compound, but we had to start from somewhere and this is the basic oncology to start with the last line treatment.

Okay. So just to confirm, the FDA is happy with this trial design?

Yes, I confirm that we designed the clinical trial following the interactions that we had with them.

Your next question comes from David Stanton from Jefferies.

I'm referring to Slide 12 on your deck around the Pixclara or the potential Pixclara drug. Can you talk to us about the sensitivity and specificity of 93% and 94% that you've talked to there. Is that basically new data that you've now submitted to the FDA...

Dave, the last part of your question dropped. Do you wanted to state the last part?

Pardon me, it seems David is disconnected.

Okay. Well, maybe he did get most of you guys, I think, 85% or 95% of his question now. So let's give it a shot. Yes, the Pixclara, so Fluorine-18 FET-PET will be used as well as MRI or as we would say, as an adjunct to MRI. And Dr. Tolboom made the point that F-18 FET-PET is not intended to replace MRI, it's an adjunct. And when they are used together, the sensitivity and specificity is over 90%. And so that is part of the clinical data package that was included in the refiling of Pixclara to the FDA where we have the goal PDUFA approval date of the 11th of September. So I think that's the last of the questions. I'll hand back to Richard for any final remarks.

Thank you, David. So perhaps to complete the question from David Stanton, that -- it's true that the sensitivity and specificity will be amazing combined with MRI. And the ambition is really to start with first indication for the characterization of recurrent gliomas. But we can see also there a fantastic world of opportunities to expand these indications. We had the ambition to move the diagnostic tool Pixclara in the adjuvant radiation treatment planning in glioblastoma and also, more importantly, a reservoir of patients, if I can say like that, in the brain metastasis indication when we have the diagnosis and the evaluation of the brain image, that's 100,000 patients a year that will beneficiate from this new diagnostic and monitoring tool. But let's move to the last slide, perhaps and conclusion of the session, if we don't have any more questions.

No. There are currently no more questions at this time.

Okay. Perfect. So let's look into the key takeaways. Can we have the slides on the screen? Okay. So the key takeaways of the session. I would say that we within Telix, we have this fantastic opportunity to develop this theragnostic couple of Pixclara, and the 101 compound with Iodine. That's the first -- we are the first company with these 2 compounds under development in such advanced stage. So very proud of that. We can see that even Pixclara is now included in the NCCN guidelines as a recommendation, not yet improved, but proud of that. We are also developing our therapeutic candidates with -- as you saw, the beta therapies with Iodine but also with the ambition to move with the Alpha area. The actinium isotope that we are already proceeding in the preclinical stage study. And with the ambition to move in 2027 with the first human -- with the [indiscernible]. So that's a novel mechanism of actions. And all the preclinical data and clinical data are very encouraging. Perhaps something that we did not address during the presentation is the fact that in Europe and more especially in Netherlands, within the center of research, they have treated more than 20 patients, which is massive. And if I have to provide you milestones during the year, let's fix meeting during the EANO Congress, European Association of Neuro-Oncology in October 2026 because we just received the information that we'll have 12 patients from the EAP that will be presented and accepted as an oral presentation by Dr. Tolboom and [ Dr. Brett ] from Utrecht. So that's very encouraging. And the medical community will be exposed to this small cohort of 12 patients. So as I mentioned previously, we will address multiple indications with these compounds in the oncology setting, which is really 1 of the pillar of the indication that we develop within Telix. We have a deep radiopharma expertise. We control the manufacturing to the distribution and the recent success story with our compounds for the diagnostic of the prostate cancer has demonstrated that we are well positioned to build a success story also in neuro-oncology after urology. And that's perhaps the last word I wanted to share with you. David, you have something to say, please?

No. Look, I'd just like to thank the audience for their time and attention. I hope it's been a valuable deployment of your time, and that they shed some light on both the precision medicine and theragnostic -- therapeutics parts of Telix's portfolio. I personally think this is a very exciting set of assets where we have a very significant opportunity with a proximal event to improve the lives of these patients. So thank you for your time and attention.