Hi, everyone. Thank you for coming to the Jefferies Healthcare Conference. My name is Nora. I'm on the healthcare team at Jefferies, and I'd like to introduce Paul Talk, the CEO of Candle Therapeutics.
Thank you very much, and hi, everybody. As you will notice, I lost my voice. I had meetings with 18 investors today, and we're even not raising money at the moment. So I lost my voice, so I hope you can still hear me. Candelto Reputex is focused on developing viral immunotherapies for difficult to treat solid tumors. You can find this language on our website. And here you see a summary of the company. So our lead asset is called Agla Timogen, formerly known as Ken 24-9. It has a unique mechanism of action. It's the first in class. It's an off-the-shelf product. It's a pan-solid tumor therapy, but it leads to an individualized anti-tumor immune response, specific for the patient's own tumor. And we feel quite comfortable that it is a pan-solid tumor strategy because we've shown mechanism of action, proof of mechanism, proof of concept, positive phase 3 placebo-controlled trial in prostate cancer. We have data in lung cancer, in pancreatic cancer, in other indications as well. And I'll speak today mainly about newly diagnosed localized prostate cancer and will very briefly mention the non-sponsor lung cancer program. We are about to start a global phase 3 study in that indication as well. But we also have data based on a small randomized controlled trial in borderline resectable pancreatic cancer where we see a total separation of the overall survival curves. We got all the designations that we hoped for from the FDA, as you can see. I will just briefly mention we also have another investigation on medicine that's, I think, equally exciting. but in an earlier stage of development, which is called Linosepaturev, formerly known as CAM3110. It's a different mechanism of action. It's also a viral immunotherapy. But this is a true oncolytic virus, but it's a next-generation replication-competent herpes simplex virus that has been designed to replicate specifically in the tumor while sparing the healthy tissue. And we tested in probably the most difficult-to-treat form of cancer, which is recurrent glioblastoma. And we've seen beautiful effects where we see, even after a single injection, doubling of expected median overall survival. We've studied the molecular and immunological changes. We published this in Nature. And more recently, we presented data where we injected this multiple times, each preceded by a brain biopsy. So we've learned a lot about the tissue response in the brain of patients. we published this in Science Translational Medicine and we are on the cover and I think we have shown there the first pathological complete response in history in recurrent glioblastoma so this is a big unmet need, big commercial opportunity in an area that has been a graveyard for the industry where we are planning now a randomized controlled phase 2 study but this is also an enabling indication for other tumors outside the brain So here again, like for Agla Timogen, the strategy could be to create a pipeline in a product. In terms of corporate highlights, we have a very strong executive team with decades of experience in drug discovery and development. We are supported by a very strong research advisory board with people like Jim Ellison, Carl Jung, Phil Kenthoff, Roy Herbst and many others. We are in a good financial situation. We have a runway into Q1, 2028, and potentially we can get into commercialization based on the current financing. So how does aglatimogen work? Very briefly, this is a replication-defective adenovirus that we use to deliver a gene that's actually derived from herpes simplex virus. It's the HSV thermodincarnase gene. So, for example, in prostate cancer, we inject this into the prostate. It's a very simple procedure, very thin needles like a flu shot, but then in the prostate, much less traumatic than a standard-of-care biopsy. And it leads to infiltration of the prostate by aclatymogen. And we delivered this HSV-thymidine kinase gene. That means you get local enzyme activity. You get local activity of HSV-thymidine kinase. And then we give the patient two weeks of a tablet, which is valacyclovir. This is a generic drug, and we use it as a pro-drug, because valocyclofere will be activated under the influence of HSV-ethyminin kinase, so specifically in the injected prostate, and this will be converted into a toxic metabolite, a nucleotide analog, that will be specifically incorporated in cells that exhibit DNA damage, or that are proliferating, in other words, in tumor cells. And there's a synergistic effect with radiotherapy, because radiotherapy will induce DNA damage. So that means you get highly immunogenic cell death in the tumor microenvironment, leading to the release of a whole variety of cancer antigens and cancer neoantigens that are specific for that tumor. And then at the same time, the adenoviral serotype 5 capsid proteins will give a very strong pro-inflammatory signal. In other words, you create the optimal conditions for in-situ immunization against the patient's own tumor, which leads to a local anti-tumor immune response and also a systemic anti-tumor immune response. You don't need to do this again and again. In prostate cancer, this treatment is basically a one-off treatment consisting of three courses, almost like a vaccination approach. In non-sponsored lung cancer, we just administered this twice by bronchoscopy. Again, aligned with normal clinical practice, simple procedure that takes less than an hour. We've dosed aglactimogen to more than 1,000 patients, so we feel quite comfortable when we speak about safety and tolerability. I spoke already about the designations. On the right side, I just show you that we've also shown clear monotherapy activity. This is a patient actually with newly diagnosed lung cancer. You see this enormous tumor. We only injected aglartimogen, followed by valacyclovir. Three weeks later, you see a reduction in size by 50%. So very briefly, Lino-Zapatarev, I mentioned it. We tested in recurrent glioblastoma. We got fast-track designation and orphan-track designation in this indication as well. We've now dosed it to more than 62 patients. So we call it a phase 1b trial, but I would say it's actually a phase 2 trial, but now we added ARMS. And you see on the right the responses that we get in terms of clinical outcomes. You see here a patient with recurrent multifocal gliobastoma. You see two tumors, one with a wet arrow, and then next to it there's another white lesion. This patient refused all further standard of care, but he only agreed to a single injection of linozapaturev in the large lesion with a wet arrow. And you don't need to be a radiologist to see that if you go from the left to the right, There's a dramatic improvement at the site of the injection, but also at the uninjected lesion. And this patient could go back to work. Some of you may have seen that there was recently an interview by a patient who participated in this trial, who gave an interview to Parade, which is a journal that's read by tens of millions of people. This is an exceptional patient, but this patient had a similar story. Recurrent glioblastoma, the memory was wiped out, she was close to dying. She got a single injection of this replication-competent virus, and she's still alive after almost six years and leads a normal life. I'm not saying that we see this in all patients. This is an exceptional case. We see a few of these cases. Now we try to learn how can we optimize this. So together we've created a pipeline focused on value creation, which is largely de-risked. We have proof of concept in humans for each of these indications and for each of these investigational medicines. I also want to highlight that since I joined this company almost six years ago, we've always done what we said that we would do. We've never missed a single catalyst. I'm not going to say that it will never happen, but I will do anything we can to identify risk and mitigate risk. And you can see we're also on track this year. And in the red square on the right, you can see what we are planning for the rest of this year. Initiation of a phase 3 clinical trial in metastatic progressive non-small lung cancer, new biomarker in Q3 in newly diagnosed localized prostate cancer. In Q4, an update of the potential long tail of survival after linozopaturev in recurrent glioblastoma. Just imagine that we are even starting to think about this because these patients typically all die within 6 to 9 months. And most importantly, BLA filing. In Q4 of this year, we're still on track for aglatimogen in newly diagnosed localized prostate cancer. So why are we focused on newly diagnosed localized prostate cancer and what is the problem that we try to solve? We focus on patients with intermediate risk or high risk, with a single high risk factor, newly diagnosed localized prostate cancer who want to be cured. These patients elect to undergo radical treatment with curative intent, and they can choose between radical prostatectomy, which is surgery, or radiotherapy. And we focus on the patients who choose radiotherapy. So the outcomes in terms of recurrence are similar. There's a risk of recurrence of about 30%. And how the complications kick in, that difference, and that the patients are able to undergo surgery, All these factors determine, are they going to choose one over the other? So we are focused on the 65,000 patients per year in the U.S. alone that will choose radiotherapy with curative intent. And the problem is, as I said, in 30% of the cases, the disease will come back. We want to increase the proportion of patients that will achieve their goal of living free from cancer. So this is not about living longer with cancer. This is about living without cancer. We try to delay or avoid the need to use long-term selfish anti-cancer therapies like long-term ADT, androgen deprivation therapy. This is chemical castration. Patients hate this. We try to avoid the local or metastatic progression of the disease. You may still be alive with prostate cancer, but it may be alive with a very strongly impaired quality of life. So that's the treatment goal. there's no competition in this space nobody's done such a study and one of the reasons is it takes forever to do such a study it took us more than 10 years the good news is it's behind us and it's positive so this field is wide open it's a very big opportunity this was the design of the clinical trial so by design everybody got external beam radiotherapy standard of care we left it to the treating physician whether the patients would get short-term ADT defined as not more than six month and we ended up with about 50% of the patients getting ADT and the other 50% did not and we stratified for this in the statistical analysis. So we had 745 patients and we randomized them two to one to receive either three administrations of aglatimogen into the prostate or three administrations of placebo into the prostate. Everybody got valacyclovir which is the product which does not nothing in itself on cancer and as agreed under the SPA the special protocol assessment agreed with the FDA the primary endpoint is disease-free survival which basically means the absence of any evidence of cancer this is the right endpoint in a curative setting so here you can see the procedure this is a simple procedure in the hands of a urologist or a radiation oncologist this can be done in an outpatient clinic you don't need to give sedation In many cases, you even don't need to give local anesthesia. And we basically infiltrate the prostate by giving 0.5 mil in each of the four quadrants of the prostate. And the reason is that prostate cancer is often a multifocal disease. There may be small lesions. And we have shown that if you use this approach, if you look at the bottom left of this slide, all the green color represents, as shown by immunofluorescence, the distribution of aglutimogen after local administration. so this was the treatment regimen we started by giving the first administration of agletymogen which can often be combined with for example the placement of a spacer that's increasingly used then we give two weeks of the tablets valacyclovir then you see the start of the radiotherapy patients come to the clinic anyway so at that moment they get the second administration of agletymogen another two weeks of valacyclovir And then the third, so there's like a second booster of aglatimogen, again followed by valacyclovir. The primary endpoint was disease-free survival, as I mentioned. So what does that mean? This is an event-driven endpoint. And per protocol, we took a two-year biopsy of the prostate, which is not part of normal standard of care. Why not? Because it's not very pleasant to undergo a prostate biopsy. But it's the most objective and sensitive way to detect cancer cells, and it will actually precede biochemical failure, so PSA levels going up, and also PSA levels in themselves are not completely reliable, so the PSA was not accepted by the FDA as an endpoint. So this is the gold standard to detect cancer cells, is take a biopsy and look under the microscope. So if the biopsy was positive at two years, that's an event. Patients are in normal clinical practice followed by PSA measurement. If there's a continuous rise in PSA, it will lead to additional diagnostic workup, imaging, and or biopsy. If that was positive, that's an event. If the patient would develop metastases, which is unlikely in this time frame, it would be an event. On the right side, if the patient would die independent of the cause, that would be an event. If a patient died in a car accident, as happened, that was counted as an event. If a patient overdosed on drugs, as happened actually one and a half year after the trial, people do crazy things, that's an event, right? That also means we diluted the signal with events that have nothing to do with prostate cancer. But still, we achieved our end point. This is generally well tolerated. You can see a lot of detail, actually, in the paper in the Lancet Oncology that was published yesterday. today, so this is really very new, right? And you can see that you see flu-like symptoms in about one-third of the patients. These are typically mild, last one or two days, and that's it. You can just compare it actually to, for example, COVID-19 vaccination in terms of these flu-like symptoms. Otherwise, if you look at the serious adverse events, as shown on the top of this slide, there's no increase when you compare aglatimogen compared to placebo. Some people will say, well, Well, numerically, it looks even better in the aglatimogen group. Well, that is statistical noise, right? But there's no increase. This is the primary endpoint, which we convincingly achieved. Hasard ratio of 0.7, p-value of 0.055. And that means basically a 30% risk reduction or a 30% improvement in disease-free survival. So from how I described DFS follows the key secondary endpoint, which is prostate cancer-specific DFS. And this is shown here. So here you exclude the deaths that are completely unrelated to prostate cancer. As you mentioned, we had only two prostate cancer-related deaths in this trial with a median follow-up of 50.3 months. That's what you would expect. One in the active treatment arm, one in the placebo. I want to remind you, 2 to 1 randomization, but we should not read too much into this at this time. But you see, it looks even better, has a ratio of 0.62, and it's very highly significant. So this is actually a better way of looking at it. It means 30%, sorry, 38% reduction for prostate cancer-specific events. We did an exploratory descriptive analysis. So, again, I want to warn that we should not read too much in it. This study was not statistically powered to detect differences in subsets. But what you hope to see is that all the trends are more or less in the same direction and that the hazard ratios tend to be lower than 1. And that's exactly what we see. If you look at the patients who did not receive endogen deprivation therapy, you see hazard ratio is 0.56. If you look at the patients who did get ADT, hazard ratio of 0.69. So the conclusion is we observed the benefit of our glitimogen compared to placebo on top of standard of care radiotherapy, independent of the use of short-term ADT. And the same is true for the use of the specific type of radiotherapy, because there has been evolution. And there was what we now call conventional EBRT, but later there was a new regimen which is called hypofractionated EBRT. Basically, that means you give exactly the same overall dose, but you give it in fewer sessions, which is more patient-friendly because they don't need to come that often to the clinic. It does not impact outcome. It does not improve outcome. It's just more patient-friendly. And therefore, in 2019, we submitted an amendment to make it possible to use moderate hypofractionated EBRT. And then again, we interacted with the FDA that confirmed in writing that the spa remained intact and here you can see that in the same exploratory descriptive way i looked at the hazard ratios does it actually have an impact whether you use hyperfractionated ebrt versus conventional ebrt well you look at the hazard ratios they all look smaller than one some people might say it looks even better for hyperfractionated ebrt again i want to caution against over-interpreting the data. My conclusion is we've shown the benefit of aglatimogen versus placebo independent of the specific type of radiotherapy. Then I spoke already about the pathological complete response that we looked at, right? We took a two-year biopsy, and this basically means the total absence of tumor cells in your biopsy. As you can see in the placebo group, this was achieved in 63% of the patients. This is what you would expect based on the literature. We saw a statistically significant increase in the proportion of patients that had a pathological complete response at two years with a value of 80%, which is very high. And so why does this matter? Because it's known based on previous studies, and I'm showing you a published meta-analysis comprising 22 clinical studies where two-year biopsies were used in radiation therapy studies in localized prostate cancer that has a highly significant relationship between having a positive biopsy at two years and subsequent biochemical failure. If you look at the top of the slide, tenfold higher odds of developing biochemical failure over time, threefold higher odds of developing metastatic disease, and after even more extended follow-up, a fivefold higher odds of dying from prostate cancer so many people will say prostate cancer you know many of these patients die with prostate cancer which is true because it's also associated with cardiovascular disease and other conditions but at the same time it's true that this is the second most common cause of death due to cancer in man it just it just takes longer than when you look at pancreatic cancer or lung cancer and other cancers but after 10-15 years it's still a major killer. That's not the main goal of our treatment. We want to achieve cure. And I would say if you're cured, you won't die because of prostate cancer 15, 20 years later. But here you can see that the two-year biopsy is very predictive. So I said in December 2024, when our data read out, I believe that over time we're starting to see a separation between aglatimity and versus placebo. If you look at biochemical failure, time to metastases, and the time to salvage anti-cancer therapies. And that's exactly what we just presented. So these are data that we presented two weeks ago in the plenary oral session at the AUA, American Urology Association, meeting. A very big session. And you can see that the impact on prostate cancer-specific DFS is durable. The hazard ratio even looks a little bit better. Still very statistically significant. of 39% improvement in prostate cancer-specific DFS after prolonged follow-up. Here we have a median follow-up of 58 months. Here I'm showing you the time to salvage anti-cancer therapy on the left and showing you the time to biochemical failure on the right. So it's almost boring. All the figures look the same. You see the consistent separation between agladymogen versus placebo. This is also interesting. We're looking here at the time to metastases and you see here a hazard ratio of 0.58. Again, very clear trend towards improvement if you compare aglatimogen versus placebo. Then I asked my team, well, let's now look at the largest subset, which is 85% of the patients had intermediate-risk prostate cancer. It's still a very large group. So we have here 635 patients with intermediate-risk prostate cancer. And again, I just show you one slide because all the others show also the separation. I just want to highlight here, we look at the time to metastasis, look at the hazard ratio, it's point one, we're showing here 90% improvement in the time to metastasis, which actually achieved a very statistical significance if you look at the confidence interval as shown on the bottom. So this is a very exciting, supportive piece of information that we do not necessarily need for the file because we have already, we had to read the readout of our data in December 2024, but all of this is very supportive from a scientific engagement perspective and shows the meaningfulness of the two-year biopsy. So this is what I just showed you. We also have other secondary endpoints that were all positive. You can find far more detail in the Lancet paper, Lancet oncology paper, and also on our website. I just want to speak briefly about non-small cell lung cancer. So here we start actually at the other side of the spectrum. So in prostate cancer, after approval, hoping that we will get there right, and planning for success, we will probably move into oligometastatic disease, and after that into metastatic disease. In fact, we have already some evidence that it also works in advanced prostate cancer, patients with failed radiotherapy. In non-small cell lung cancer, we have the reverse strategy. We start with progressive metastatic non-sponsor lung cancer. And this is a big unmet need, as you see on the right side of the slide. But immune checkpoint inhibitors have really changed the field and have really improved outcomes. Still, it's a huge unmet need. After one year of immune checkpoint inhibitors, 60% of the patients will actually show progression. And there's a lot of activity in this field. But we don't believe that there are great compounds in the pipeline of the industry that I'm aware of. that show very promising benefit risk for the patients so to make a long story short you can find it in far more detail on our website this is what we find this is a representative patient in our trial you see this huge tumor right more than 11 centimeters at baseline growing despite ketruda and despite chemotherapy and you see the real diameter of the tumor on the top right of this slide, right? So before the first injection with aglatimogen, you can see this tumor is growing and this patient has an extremely poor prognosis. Then we give the first administration as shown by the red arrow. You see that the tumor is starting to decrease in size, right? It's not an immediate dramatic decrease because it's an immunotherapy. We replace tumor cells by immune cells. There's an element of pseudoprogression as we've shown in serial biopsy samples. Then we give the second administration that's like the booster right you see the second red arrow and you see that there is consistent control we basically change progressive cancer into a chronic disease with an acceptable quality of life this patient lived until 56.4 months which is extremely long right and we've seen very clear abscopal effects so you don't need to inject all the metastases you just choose one or two tumors that are easily accessible typically by bronchoscopy to educate the patient's own immune cells how to recognize and eliminate the tumor cells and create a new state of immune surveillance. So these data were presented very recently. We have shown that we have observed doubling of expected median overall survival, even a little bit more than that, with just two administrations of aglotymedia and without changing anything else. But then we asked the question, is there a long tail of survival? And these patients will get a normal standard of care docetaxel, second-line chemotherapy, which has quite a lot of toxicity, and the median overall survival with standard of care has consistently been reported as less than one year. Here we showed that after two years, 50% of the patients were still alive, which is very long, and you see several were alive, three, four, up to almost five years. The interesting thing is, all these really long-tail survivors have non-squamous, non-small cell lung cancer. And we've shown that there's a differential immunological response if you compare non-squamous to squamous. So if you focus here on the population with progressive disease at baseline, with non-squamous disease, you can see we observed a median overall survival of 25.4 a month. If anyone has seen better data in the industry, please drop me an email, because we are not aware of it. So these data are extremely promising. And we got faster designation from the FDA, and we've designed this phase three clinical trial that is going to start imminently. We will include 500 patients with metastatic, progressive, non-squamous, non-small lung cancer who failed on ketruda and cisplatin-based chemotherapy. So you know they have a very bad prognosis. We randomized them to either stay on the ketruda that they failed on, but we gave them two administration of aglathymogen to convert non-responders into responders. as we've shown in the phase 2 study, or you stop the immune checkpoint inhibitor, K-truda in this case, and then you give the patients docetaxel, as you would do in normal standard of care, and the primary endpoint is overall survival. So I'll stop here. This is my summary, and I would like to thank you for your attention. Thank you very much.