Morning, everyone. Thank you for being here. Once again, warm welcome to day two of the 2024 Global Jefferies Healthcare Conference. My name is Axel Dotter. I work with the Jefferies Healthcare Investment Banking team here in London. Pleasure this morning to introduce Paul Peter Tak from Candel Therapeutics. So without further ado, I will let you get along with your presentation. It'll be a 20-minute presentation and then five minutes towards Q&A at the end if you guys have any questions.
Thank you very much. A very good morning, everybody. I'm very excited to share the programs that we are working on. We are at a very important inflection point as a company. We'll have data read out in about 900 patients next month. This is great timing to hear the story. What are we doing at Candel Therapeutics? We are focused on the development of viral immunotherapies for very difficult-to-treat solid tumors. This is the language that you can see on our website. This is a new modality. We are focused on the intra-tumoral delivery to induce systemic anti-tumor immunity. It's a new approach, but it's coming to fruition. It always takes time for any new modality to start to see the results. We've seen the same with ADCs, radioligand, cell and gene therapy, CAR T cells.
You can see success across the field actually with different viral immunotherapies for different forms of cancer, like Replimune, focused on skin cancer, CG Oncology after many years of work, very encouraging data in bladder cancer, very successful IPO as well. But also the first pharmaceutical companies are moving into this field. I think a prime example is J&J. They have created a large unit within J&J focused on intra-tumoral approaches, including viral immunotherapies. So let's focus now on Candel Therapeutics. We have some unique viral immunotherapies in the pipeline. The first is CAN-2409. As you will see, this is an engineered virus that we combine with a small molecule with a tablet to induce anti-tumor immunity. So it's not an oncolytic virus, but it is a viral immunotherapy that will lead to durable anti-tumor immune responses. And we create a pipeline in a product for this medicine.
It's an off-the-shelf product that leads to an individualized anti-tumor immune response. The second is CAN-3110. This is a true oncolytic virus. It's a next-generation replication-competent HSV, Herpes simplex virus. We test it in probably the most difficult-to-treat form of cancer, which is recurrent high-grade glioma. Most of these patients will have recurrent glioblastoma. We have very encouraging results. I'll show you something. We published this in Nature. But here again, there's the opportunity to create a pipeline in a product through expansion of indications based on the molecular mechanism that I will discuss in a minute. And then we've also created the enLIGHTEN Discovery Platform. We can make in a relatively short period of time completely new viral immunotherapies that can be combined with other approaches, for example, with CAR T cells. That's why we have a partnership with Carl June at UPenn.
I'm proud to say that he reached out to us, actually. So we're developing a viral immunotherapy here to help to get his CAR T cells delivered intravenously into the solid tumors in pancreatic cancer. So this is where we are open for business, for discovery partnerships. So let's now see how CAN-3110 works. So this is the HSV, as I told you. I'm going to play a little video which will explain this in about 60 seconds.
Candel Therapeutics is developing cancer immunotherapies based on engineered viral gene constructs able to modify tumor microenvironment, kill tumor cells, and generate systemic immune activation against tumor-specific antigens. CAN-3110 is a modified herpes simplex virus carrying a single copy of a viral gene known as ICP34.5 that enables the virus to replicate despite cellular defense mechanisms. This gene is engineered to be under the control of the promoter for Nestin, a protein that is highly overexpressed in high-grade glioma and other aggressive cancers outside the brain, but not in healthy tissue. This modification allows CAN-3110 to replicate almost exclusively in tumor cells, causing immunogenic death. The ability of CAN-3110 to replicate specifically within the tumor leads to significant tumor oncolysis with release of tumor antigens and local inflammation, resulting in a long-lasting immune response against the tumor in both injected and uninjected lesions.
CAN-3110 is currently in an early-phase clinical trial in recurrent high-grade glioma.
We've published the data for the first 41 patients who received a single injection of CAN-3110 into the tumor because of recurrent high-grade glioma last year in Nature. We could show that after just one injection, we could achieve doubling of the expected median overall survival, and since then, we have completely reproduced these findings in an independent cohort of patients with exactly the same results. We got Fast Track designation and orphan drug designation from the FDA based on these data, and then we asked the question, well, what would happen if you would give multiple injections? Could it be even better, so we've started to do this work. We have now presented, two weeks ago, the data for the first six patients who received up to six injections into the tumor. This is feasible. This is generally well tolerated and safe.
We don't believe that you need all the six injections, actually. It's maybe two, three, or four. We are trying to figure out the optimal dosing regimen. But what we could show is, and we presented this in a press release and presented this at the scientific meeting, that out of the six patients, three are still alive after more than one year. This is ongoing. One patient now more than 18 months. Well, there's an expected survival in this population of less than six to nine months. So we see dramatic clinical responses all supported by beautiful immunological biomarker research. So what does it mean for a patient? This is a patient who had recurrent multifocal glioblastoma, failed neurosurgery, failed chemotherapy, failed radiotherapy. So this is the end of the journey for this patient. And he refused all further standard of care.
But he did agree to a single injection of CAN-3110 into this tumor with the red arrow. We did not touch the other tumor. So there are two tumors here. And you can see when you go from the left to the right, you really don't need to be a radiologist to see that there's a very strong decrease in the size of the injected and the uninjected tumor. This patient could go back to work. So we see dramatic changes in these patients. Another example is shown here. This is the typical story of a patient with glioblastoma. You see the initial lesion. Then the patient undergoes the gross total resection to remove as much of the tumor as possible. And then, unfortunately, these tumors basically always recur. So there's a tumor recurrence on day minus 47.
Then very shortly after that, the patient undergoes the second neurosurgical resection of the tumor. As you can see, just two weeks later, there's already, again, progression of the disease. So that's typically how it goes, and that's the end of the story, but not for this patient. She received on day zero a single injection of CAN-3110. Then three months later, you can see that the timelines are shifting now, right? She was still alive after three months. There was another scan, and it appeared that there was progression on the scan. Therefore, she underwent biopsy, and it appeared that we had actually largely replaced the tumor cells by immune cells. This is pseudoprogression, but there were still tumor cells present. And therefore, she underwent a third neurosurgical procedure to debulk the tumor, and this patient continued to improve over time.
She was considered cured after two years. This is an empty space on the scan, and she tragically died actually in a car accident without even being the driver. This is one example. This is also included in the Nature publication. We see now more examples. We actually invited the patient into the company to talk to our employees. This patient is now alive after three and a half years after diagnosis, and we see every time on the scan that actually the tumor is a little bit smaller, so the virus continues to be active as long as it sees Nestin, so we believe there's a big opportunity here in a field where everybody else has failed, but also an opportunity for expansion of indications.
We just presented last week at SITC, the Society for Immunotherapy of Cancer, very encouraging data and a preclinical model of melanoma where there's also Nestin overexpression, very strong anti-tumor immunity. This is also in the paper. You can see that we fundamentally changed the T cell repertoire. This is not just a virus killing the tumor cells. We induce actually as a next step an anti-tumor immune response. Here, I'm showing you data on the bottom right of this slide based on the TCR, T cell receptor repertoire analysis. There you can see that the broadening of the anti-tumor immune response where we teach the immune system how to recognize the variety of cancer antigens and cancer new antigens that are specific for the tumor. If you are able to induce such a response, this is associated with further improvement in survival.
For more details, I refer to the Nature paper, so let's now focus on CAN-2409 because that's where we have a lot of data coming up, actually, and this works in a different way, and I'm going to show a quick video to explain how this works.
Candel Therapeutics is developing viral immunotherapies for cancer that are able to kill tumor cells, modify the tumor microenvironment, and generate systemic immune activation against tumor-specific antigens. Our most advanced candidate, CAN-2409, is an adenovirus that has been engineered to deliver a gene encoding an enzyme called thymidine kinase into the tumor cells. The enzyme converts valacyclovir, an FDA-approved oral small molecule drug, from its inactive pro-drug state to a form that is toxic to cancer cells. Incorporation of activated valacyclovir and tumor cell DNA results in termination of DNA synthesis and permanent cell damage and death. When administered together, CAN-2409 and valacyclovir cause immunogenic cell death where tumor cells release tumor-specific antigens that are recognized by the immune system. At the same time, the adenovirus itself provokes the release of inflammatory mediators that recruit immune cells, which are educated how to recognize the patient's tumor neoantigens.
This effectively results in vaccination against the injected tumor and the uninjected distant metastasis. CAN-2409 is currently in late-stage clinical trials, and it has been designed to improve patient survival while maintaining quality of life.
We have dosed CAN-2409 to more than a thousand patients. So we have very extensive experience. I think it's quite unusual for a biotech company. We are already in phase 3. And we are currently focused only on indications where we already have proof of concept, not only in mice, but actually in patients which are pancreatic cancer, non-small cell lung cancer, and early localized non-metastatic prostate cancer. For each of these indications, we got Fast Track designation for pancreatic cancer, also orphan drug designation based on the data, this year. And the phase 3 clinical trial in early localized prostate cancer is conducted under an SPA, Special Protocol Assessment, agreed with the FDA, which basically means that the FDA has agreed in writing that they agree with the primary endpoint.
And this phase three clinical trial should, in principle, be a registration or clinical trial if we achieve the primary endpoint. So again, I will just highlight here, we have to read out of two randomized clinical trials, in the next month, in December. I'll show you the trial scheme. And I will just mention this. We've shown that CAN-2409 can be used as monotherapy, very appropriate. And we've also shown it can be combined with radiotherapy, chemotherapy, surgery, and immune checkpoint inhibitor where it makes sense from a standard of care perspective. This is just a proof of mechanism clinical trial in a patient with early non-small cell lung cancer. You see this tumor is nearly 15 centimeters. That's a huge tumor. We injected it with CAN-2409. We gave the pro-drug. We did not do anything else.
Three weeks later, there's already a reduction in the tumor size by 50%, half the size of the tumor. So let's now look at the data in a little bit more detail. We presented earlier this year the data based on a small randomized clinical trial in borderline resectable pancreatic cancer. So what does that mean? It's a clinical diagnosis. There is, in principle, resectable pancreatic cancer. That's the only hope for cure. So think of major surgery like a Whipple procedure. Then, on the other hand, unfortunately, many patients have locally advanced disease or metastatic disease. And then in between is borderline resectable pancreatic cancer. These patients have a tumor that's invading a blood vessel. Therefore, they can't be operated on yet.
The hope is that by giving them chemotherapy induction treatment followed by chemoradiation, that the tumor may shrink and they may become operable, which is the case in about half of the patients. So that's what we are focused on. We randomize these patients to receive either this optimal standard of care plus two to three administrations of CAN-2409 to educate the patient's T cells how to recognize the tumor or standard of care alone, exactly the same standard of care. And we focus on the hardest, primary endpoint, which is overall survival. That's what matters to patients. That's most important to the regulators as well. And you can see what we observed. It's a complete separation of the median overall survival curves with a median overall survival, in the active treatment group of 28.8 months compared to only 12.5 months in the control group.
Patients, they're completely comparable in terms of baseline prognostic factors. This paper is currently under review at Nature Medicine. You can find it actually online already, if you want to see more detail. So we see these dramatic changes even in patients who have metastatic disease. We have a patient here, which is patient 2042. You can see stage four disease. So, during the attempted surgery, it turned out that this patient had liver metastasis. This patient is actually still alive five years after diagnosis with metastatic disease. Everybody who knows anything about pancreatic cancer knows that this does not happen in the natural course of the disease. And we've shown that we can change the balance between the tumor and the immune system, even if we're not able to cure these patients. Nobody can cure these patients. So that's very, very encouraging.
It's explained in part by the fact that we fundamentally changed the tumor microenvironment. You will know that this is a very immunologically cold tumor, sometimes called an immunological desert based on the absence of immune cells. Here you can see that we can induce massive infiltration by immune cells. We've also published this previously in a separate phase 1b clinical trial in pancreatic cancer. You can see that we see organized lymphoid structures that are shown by immunofluorescence, resemble tertiary lymphoid structures. TLS, this is now like the holy grail in immuno-oncology because this is known to be associated with improved outcome and improved response to treatment across multiple solid tumors. We fundamentally changed the tumor microenvironment. Completely consistent with these data, we saw very encouraging overall survival data in patients with stage three or stage four non-small cell lung cancer.
In fact, 90% of these patients had stage four disease. Most of these patients had progressive disease at baseline despite chemotherapy and despite first-line treatment with an immune checkpoint inhibitor. So these patients don't have placebo effects. They have progressive metastatic disease despite optimal standard of care. These patients are going to die within 10-12 months with optimal standard of care dose of chemotherapy. You can see here that we have actually shown that in this population, in the patients who received two injections, and which is critical because it's a vaccination regimen, you need to get the second, the booster basically, that we can double the expected median overall survival. And I'll show you just one slide. There's a lot of biomarker data. But here you can see that this is based on flow cytometry, right? And analysis of the peripheral blood mononuclear cells.
Everything above the dotted line, the red line, is statistically significant. And you can see that the changes in the CD4 positive T cell memory compartment and the CD8 positive T cells are associated with subsequent improved survival. So these are the patients where we have been able to teach the immune system how to recognize the patient's own tumor. And it's completely aligned with the randomized trial in pancreatic cancer. So we are preparing now a large randomized phase two B/phase three clinical trial in non-small cell lung cancer as well. So let's now focus, in the last few minutes, on prostate cancer. This is a very big opportunity. Of course, there's been a lot of work going on in prostate cancer. It's all in later stages of the disease.
In fact, there's no new treatment that has been approved for early localized non-metastatic prostate cancer in more than 20 years. And this is still a huge unmet need. This is the second most common cause of cancer in men, as you probably know. And, although many patients may die with prostate cancer, for example, due to cardiovascular disease, this is still also the second most important cause of mortality due to cancer. So this problem has not been resolved. And we focus on two sub-indications. Patients with early, low to intermediate risk prostate cancer who elect to undergo active surveillance. So these patients actually don't want to get radical prostatectomy surgery or radiotherapy yet because they don't have a lot of signs and symptoms yet due to their cancer. If you undergo, for example, a radical prostatectomy, the complications and side effects will kick in immediately.
Think of urinary incontinence, erectile dysfunction, loss of quality of life, depression. These are all extremely common. These patients have a kind of active wait-and-see approach, but it's not great to know that you have cancer and you're not being treated. After one year, one third of these patients will have cancer-related anxiety. They're worried about the growth of their tumor. The second point is a slowly growing tumor is still a growing tumor. After five years, more than half of these patients will actually undergo radical therapy at that time point. They will face the complications at that point. 1/3 of these patients after radical therapy will still have progression of disease. There's a real need for a relatively simple intervention that is well tolerated by patients that will change the balance between the immune response and the tumor.
That's the first indication. That's why we have a phase 2B clinical trial. We inject these patients twice with CAN-2409 or placebo. And we try to stop the tumors from growing. The primary endpoint is progression-free survival. The second sub-indication in early disease is in patients with more aggressive disease, intermediate to high-risk prostate cancer. They will need to undergo radical therapy. These patients in our trial elect to get radiotherapy. And we try to increase the percentage of patients that will be cured. That means the primary endpoint is disease-free survival. We've done very extensive market analysis. This is like pushing against an open door. It's a huge commercial opportunity. Why do we believe that this may actually work? I'll show you one mouse slide today. We have a lot of mouse data.
But here you can see a model of prostate cancer where we implanted the prostate cancer cells in the flank, but we also injected the tumor cells intravenously, leading to the formation of lung metastasis. If you just treat locally, just the flank, then you do not only see the reduction in the size of the tumor as you would expect in the flank, but also a very clear abscopal effect in the mice. You see that this leads to systemic anti-tumor immunity, as we've shown in lung cancer and in other indications in patients, actually. Very promising mouse data. This is based on the phase 1B clinical trial that we previously published in early localized prostate cancer. This is monotherapy during a period of three weeks.
We inject CAN-2409 into the prostate, which is actually a very simple procedure, 15-20 minutes in an outpatient clinic, simpler than a standard prostate biopsy, and then you can see that after three weeks, there's massive necrosis of the tumor cells associated with CD8 positive T cell infiltration. This is a key part of the immunological mechanism, so how about the clinical effects? This is based on the phase 2A clinical trial that we previously published, that we reviewed extensively with the FDA. This was the basis for the SPA, the Special Protocol Assessment that we got, and we're looking here on the y-axis at the percentage of patients after follow-up that were still free from failure. It's basically progression-free survival. So all the orange bars represent patients who received CAN-2409 combined with optimal standard of care.
All the other bars represent published studies from the same period of time with exactly the same standard of care, and you can see there's a consistent improvement in the groups that received CAN-2409 compared to standard of care alone after more than five years of follow-up, so we have very extensive follow-up in these patients, so this gives us hope that this may work also in early localized prostate cancer. We also have other trials. I won't show all the data because of time, but now let's look at the design of the clinical trial, so this is the phase three trial. We have 711 patients enrolled in this trial. Everybody gets radiotherapy, and then the patients in the active treatment arm will get three injections of CAN-2409 into the prostate or three injections of placebo. Everybody gets the prodrug valacyclovir.
Primary endpoint is disease-free survival. Let's now look at the clinical trial in the active surveillance population. So low to intermediate risk prostate cancer. By definition, these patients don't get any active treatments. They will just get two injections of CAN-2409 into the prostate or placebo. Everybody gets valacyclovir. We try to stop the tumors from growing. Therefore, the primary endpoint is progression-free survival so that these patients don't need to undergo radical therapy in the future and face all the side effects and complications. So what have we achieved for CAN-2409 this year? As I mentioned in the randomized clinical trial in pancreatic cancer, overall survival of 28.8 months compared to only 12.5 months in the control group, completely in line with these data in progressive therapy-resistant non-small cell lung cancer, median overall survival of more than 20 months.
I'm not aware of any program where the standard of care or anything experimental in the pipeline of the industry that has achieved a median overall survival of more than 20 months, and we believe this is very encouraging. Then we hope to see significant improvement in progression-free survival in the active surveillance population and significant improvement in disease-free survival, cure in the patients with more aggressive disease. We've consistently delivered on everything that we said that we would do. You can see what the plans are for this year. These data are imminent, but then it's not over. After January the 1st in Q1, we'll have the final overall survival data in lung cancer and in pancreatic cancer, plus an enormous amount of immunological, biomarker data. Also we will have the mature overall survival data for the repeated injections of CAN-3110 in glioblastoma.
So this is my summary. I'll just stop here because my time's up, and I would like to thank you all for your attention. Thank you very much.
Anyone? Sure, sir.
When are you expecting to file the prostate product in the U.S.?
The BLA? Yeah. So, after the moment of a positive readout, and that's what I'm hoping for, and that's why I'm going to buy some shares myself extra, this week, then we will have about two years to get BLA ready, which is largely based on manufacturing. Manufacturing is pretty straightforward of a replication defective adenovirus. So think of the AstraZeneca vaccine for COVID-19. It's the same methodology. But, we didn't want to write the big checks actually until we have seen the data. So it will take about two years. Thank you.
Anyone else? Okay, perfect.
Or I lost the audience. Yeah, go ahead.
No, thank you so much. Thank you, guys, for joining.