Good morning and welcome to the Candel Therapeutics conference call, where the company will be discussing top-line results for its phase III and phase II prostate cancer clinical trials. At this time, all participants are in a listening mode. Following the company's formal remarks, we will open the call for questions. Please be advised that this call is being recorded. You can find information on the replay of the call and further information related to today's announcements on the Candel Therapeutics website at candeltx.com. At this time, I would like to turn the call over to Ted Jenkins, Vice President, Investor Relations and Business Development at Candel Therapeutics. Mr. Jenkins, please go ahead.
Thank you, Operator. Good morning, everyone, and thank you for joining us on today's call. Earlier today, the company issued a press release announcing the top-line results from the phase III trial of CAN-2409 in patients with intermediate to high-risk localized prostate cancer. This press release can be found in the news and investor section of the company's website. And before we begin, I'd like to remind you that during this call, management will make forward-looking statements, including statements about Candel's future business and development plans, expectations regarding the potential efficacy and commercial potential of Candel's product candidates, the anticipated timing of communication with regulatory agencies, potential learnings from preclinical studies and other clinical data, the ability of the phase III trial to inform and improve future clinical development plans, and Candel's ability to advance its product candidates into later stages of development.
Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties I described here and those described from time to time in our SEC filings. Our results may differ materially from those discussed on today's call, and we undertake no obligation to update statements regarding the future or to confirm these statements in relation to actual results unless required by law. Joining us on the call today to discuss these results are Dr. Paul Peter Tak, our President and Chief Executive Officer, Dr. Garrett Nichols, our Chief Medical Officer, Dr. Francesca Barone, our Chief Science Officer, and Charles Schoch, our Interim Chief Financial Officer. Following the prepared remarks, we will open the line to your questions. With that, I'd now like to turn the call over to Candel's CEO, Dr. Paul Peter Tak. Paul Peter.
Thank you very much, Ted, and good morning, everybody. Thank you all for joining this morning. We are very pleased to announce positive top-line results from our phase III clinical trial of CAN-2409 in intermediate to high-risk localized prostate cancer. The study met its primary endpoint, so let's go to slide four. We have enrolled 745 patients in this randomized clinical trial. The patients were randomized to receive either, in total, three administrations of CAN-2409 or placebo, each followed by the pro-drug, which is valacyclovir, for two weeks, and then everybody got standard of care radiotherapy. The primary endpoint is disease-free survival, as agreed with the FDA under the SPA, the Special Protocol Assessment, which has been unchanged, so we'll present the primary endpoint and multiple secondary endpoints, so first, there was a statistically significant and clinically meaningful improvement in disease-free survival.
The treatment goal is really to avoid recurrence of the disease in these patients. We had a hazard ratio of 0.7, a p-value of 0.055 in the intention to treat analysis, and we had a median follow-up time of 50.3 months. This has been a very big project, and it took several years, actually, to follow these patients. In addition, we observed 14.5% relative improvement in DFS, disease-free survival rate, at 54 months, which was the pre-specified time point according to the protocol. This is also in line with the key experts' expectations. We've done extensive market research repeatedly, and this is considered a clinically meaningful benefit. It basically means that there's an improvement in the percentage of patients that will achieve disease-free survival over time. Also, CAN-2409 showed a highly significant effect on prostate cancer-specific outcomes. Again, we try to prevent the recurrence of the disease.
There was also a significant increase in the proportion of patients achieving a prostate-specific antigen, PSA, nadir of less than 0.2 nanogram per mL in the active treatment arm compared to the placebo arm, and you see the p-values on the slide. Importantly, we also performed a central blinded evaluation of the post-treatment biopsies obtained after two years because the histology is the gold standard to detect cancer cells, and it could show a pathological complete response rate of 80.4% in the CAN-2409 group compared to only 63.6% in the placebo arm, and you see the highly significant effect here.
In line with previous studies that we presented over the years, there's a compelling safety profile with, in fact, a lower incidence of serious adverse events and treatment-related SAEs in the active arm versus control, although we saw quite common, as you would expect, minor flu-like symptoms that typically lasted less than 24 hours. Let's go to the next slide. I don't see the next slide. Sorry. Yeah. So we are focused on intermediate to high-risk localized prostate cancer. So why is that? What's the unmet need, and what is our approach? So if you go to slide six, first, I want to mention this is a huge unmet need. There's no new treatment that has been approved for early localized prostate cancer in more than 20 years.
Prostate cancer is the second most common cause of cancer in men in the U.S. and in many other parts of the world. The third would be all the skin cancers grouped together. You see the incidence on this slide. If you focus on intermediate-risk prostate cancer incidence in the U.S., 75,000 patients each year. The high-risk patients, 30,000. So it's a very substantial proportion of patients. Usually, these patients get either radiotherapy or radical prostatectomy, which is surgery. So these are called together radical therapies. About half of these patients currently choose radiotherapy. That might change over time.
If we can get approval for the indication that we will seek for the combination of CAN-2409 combined with radiotherapy, where we can actually increase the percentage of patients that achieve disease-free survival, in other words, a curative intent, it's possible that the treatment algorithms will change and that more patients will actually choose that regimen compared to surgery. But even if it wouldn't, it's still half of the patients, so very big numbers here. Of course, we don't know a price. If the medicine will be approved over time, we will negotiate with the payers. But based on the currently available treatments in prostate cancer, you can see that the range is in the order of $150,000-$250,000 per year. Together, we believe this is a $10 billion+ opportunity. Most importantly, of course, what could this mean for the patients? Again, there's a big remaining unmet need.
Despite the radical therapies that I just described that are available to patients, 30% of the patients will actually have recurrence of the disease, and many of these patients will receive ADT, androgen deprivation therapy, which is hormonal therapy, which is associated with a very significant negative impact on quality of life. These patients may live longer, but they pay a price in terms of quality of life, many side effects, short-term side effects, as well as long-term side effects as well, and/or they receive chemotherapy, so that's exactly what we try to avoid by increasing the percentage of patients that will have no recurrence of the disease. Next slide. So how does it work? We've made a beautiful video that you can find on our website that explains it, but I will explain the mechanism of action very briefly.
CAN-2409 is a replication defective adenovirus that we inject into the prostate. It will deliver the HSV thymidine kinase gene, so that means there will be local expression of this enzyme, herpes simplex virus derived thymidine kinase, and then we give the patient the course with a tablet, which is valacyclovir, which has been approved a long time ago, and it's, in fact, generic. The interesting thing is that valacyclovir will be converted under the influence of the local enzyme activity in the tumor into a toxic metabolite, into a nucleotide analog that will kill the tumor cells in a highly immunogenic way, and because we're using adenovirus at the same time, we give a very strong pro-inflammatory signal to the tumor because that's what adenoviruses do. In other words, you create the optimal conditions for in situ vaccination against the patient's own tumor.
Therefore, we educate, we teach the patient's own immune cells how to recognize and how to kill the tumor cells, which should lead to durable anti-tumor immunity. Next slide. This is the single most slide that I'm going to show you today because we have a lot of human data. It's still important, actually, to really understand the approach that we've taken in the phase III trial. What I show you here is that we implanted prostate cancer cells in the flank of the mouse, that's the orange circle. At the same time, we injected cancer cells intravenously, leading to the formation of distant metastases here in the lung. Then we had different therapeutic regimens.
If you look at the left side, you can see the effect on the tumor in the flank, so the locally treated tumor, so it's like the prostate cancer in the phase III trial. You can see when you look at the purple line, the effect on tumor diameter. We can show here synergy between radiotherapy and CAN-2409 treatment. You see exactly the same when you look at the distant metastases. There's actually an abscopal effect in the mouse, as we've also shown in the non-small cell lung cancer clinical trial that we presented earlier this year.
So there's synergy between radiotherapy and CAN-2409, which is explained by the fact that radiotherapy will induce DNA damage, and valacyclovir will be converted into nucleotide analogs under the influence of CAN-2409 and will therefore induce cell death in the cells exhibiting DNA damage or that are proliferating, in other words, the tumor cells. So there's a strong mechanistic rationale for this combination in prostate cancer. Next slide. So let's now look at the planned indication. The planned indication is a newly diagnosed localized prostate cancer in patients who have intermediate to high-risk disease in conjunction with standard of care radiotherapy to prevent prostate cancer recurrence. And you see the definition of what's intermediate and what's high-risk prostate cancer. This is all standard classification as used in clinical practice. How do we administer it?
Everybody will get standard of care radiotherapy plus or minus short-term ADT, which is less than six months of hormonal therapy up to the discretion of the treating physician. We know that about half of the patients got short-term ADT, and we stratified for this in the statistical analysis. The patients received three injections in total. Let's go to the next slide. Here you can see on the left side that we inject each quadrant of the prostate. We inject in total four times 0.5 mL of CAN-2409 into the prostate. Here we infiltrate the whole prostate. Why is that? Because it's known that prostate cancer is a multifocal disease. There may be small lesions that may have been missed even with the prostate biopsy. We want to infiltrate the whole prostate so that we target all these lesions.
And this procedure is actually simple and well tolerated and aligned with normal clinical practice. The whole procedure takes about 15-20 minutes. It doesn't need to be in a high-profile academic center. In fact, most of the patients involved in our clinical trial were involved in community centers. There's no special equipment needed. The whole procedure takes about 20 minutes. And it's also, of course, important to ask the patients, how do they think about this? All of these patients underwent prostate biopsy because that's how you make the diagnosis. So we asked the patients, how did the study procedure where we inject CAN-2409 into the prostate compare to the prostate biopsy that you've undergone, often even repeatedly? And as you can see on the right side of the slide, most patients indicate it's the same or better tolerated. We use a thinner needle.
It's a simpler procedure than a standard of care diagnostic biopsy. So let's go to the next slide. So we're now going to have a more in-depth discussion of the design of the trial and of the data. So I'm going to introduce my colleague, Dr. Garrett Nichols, who's the Chief Medical Officer. Garrett, over to you.
Thank you, Paul Peter. I'll now present the results of our phase III clinical trial of CAN-2409 in patients with newly diagnosed intermediate to high-risk localized prostate cancer. Slide 12, please. So we enrolled 745 patients and randomized two to one to receive either three injections of CAN-2409 into the prostate gland, each followed by a 14-day course of valacyclovir, or three injections of placebo followed by a 14-day course of valacyclovir.
Both of these were in combination with standard of care external beam radiotherapy with or without short-course androgen deprivation therapy or ADT, which in this case was less than six months. As Paul Peter said, randomization was stratified by NCCN risk group and planned use of ADT. The primary endpoint for the study was disease-free survival. This was defined as the time to cancer recurrence or death due to any cause. The key secondary endpoints included prostate-specific antigen or PSA, freedom from biochemical failure, prostate cancer-specific outcomes, and overall survival. Next slide, please. Here I'm showing the details of the DFS primary endpoint, which was designed to capture treatment effect in early prostate cancer.
Disease-free survival is defined as the time from the date of randomization to the date of cancer recurrence proven by biopsy, clinical or radiographic evidence of local or regional failure, distant metastasis, or death from any cause. The study was powered 90% to detect a 15% relative improvement in DFS between the treatment arm and the control with a two-sided alpha of 0.05. This endpoint has been validated by the FDA with its granting of a special protocol assessment or SPA that was reaffirmed in 2019. Market research with payers and key external experts confirmed that the DFS improvements that we had targeted would be clinically relevant. Next slide, please. So we screened 774 patients and randomized 745 two to one to receive either CAN-2409 or placebo injections. 496 were randomized to receive CAN-2409 plus prodrug and 249 to receive placebo plus prodrug.
17 patients in each arm were randomized but not treated, and a similar proportion of patients did not complete treatment on each arm when one considers the two to one randomization. Thus, the treatment was completed by 441 patients on the CAN-2409 arm and 213 patients on the placebo arm. Included in the ITT analysis were 496 patients on CAN-2409 and 249 on placebo. Included in the safety analysis, those who received at least one injection were 479 patients who were randomized to CAN-2409 and 232 patients who were randomized to placebo. Next slide. The demographics and baseline characteristics of the randomized patients are shown here. The median age of patients in the study was 69 years. We had a great representation of patients of African-American descent with 18.8% on the treatment arm versus 11.2% on the placebo arm.
We had 9.5% of patients that identified as Hispanic or Latino, and in terms of baseline risk groups, we had approximately 85% of patients who were intermediate risk and approximately 15% who were high risk. The median PSA at baseline was 6.8 nanograms per mL in the CAN-2409 arm and 6.5 nanograms per mL in the placebo arm. In terms of baseline Gleason score, 12.1% of patients on the CAN-2409 arm had Gleason scores greater than seven versus 10.8% on the placebo arm. Approximately 50% of patients on each arm planned to receive short-course ADT. Next slide, please. In terms of outcomes, the top-line readout exceeded key external expectations. Again, the phase III trial was powered to detect a 15% relative difference between active and placebo arms. The observed 14.5% relative improvement was considered clinically meaningful, as indicated by the quotes on the left from KOL interviews.
Furthermore, as I'll show in the next slide, the DFS difference increases over time beyond 54 weeks. Next slide, please. This slide displays those top-line results. In the intention-to-treat analysis of the primary endpoint of DFS, I'm showing CAN-2409 plus prodrug in blue and placebo plus prodrug in red. As you can see, the Kaplan-Meier curves start to separate at two years after randomization and continue to separate during the period of follow-up with a median of 50.3 months of follow-up. The hazard ratio for disease-free survival comparing the CAN-2409 arm to the placebo arm was 0.7. In other words, a 30% risk reduction for either recurrence of prostate cancer or death due to any cause. The p-value is 0.0155, which is highly statistically significant. Next slide, please.
CAN-2409 also improved the rate of pathological complete response in biopsies that were conducted two years after the completion of radiotherapy when compared to the placebo control arm. Post-treatment biopsies were centrally reviewed by at least two blinded independent readers. At two years after the completion of radiotherapy, the negative biopsy rate was higher on the CAN-2409 arm, 84.4%, when compared to the placebo arm, 63.6%. This difference was significant with a p-value of 0.015. Next slide, please. Here I'm showing the forest plot that displays DFS outcomes, disease-free survival outcomes in key subgroups. Any data points to the left of the vertical line and in the green favored CAN-2409 treatment. Any data points to the right favored placebo treatment.
As you can see, all of the point estimates lie to the left, indicating that the point estimates for PFS for all subgroups identified by race, age, ethnicity, NCCN risk criteria, or the use of ADT were favorable with CAN-2409 when compared to placebo treatment. Next slide. CAN-2409 also demonstrated significant improvements in prostate-specific outcomes, either the recurrence of prostate cancer or prostate cancer-related deaths. Here we show the same type of separations of the Kaplan-Meier curves, but the separation is even greater when excluding death due to any cause. The hazard ratio is 0.62, or a 38% reduction in the risk for prostate cancer recurrence or death due to prostate cancer. The p-value is highly statistically significant at 0.046. Next slide, please. In addition, we are also reporting key secondary endpoints.
From this study, we saw a significant increase in the proportion of patients that achieved a prostate-specific antigen or PSA nadir of less than 0.2 nanograms per mL in the treatment arm when compared to the placebo arm. The proportions of patients who met this criteria were 67.1% in the CAN-2409 arm versus 58.6% in the placebo arm with a p-value of 0.0164. We also demonstrated an improvement in the freedom from PSA failure, which was numerically lower in the 2409 arm with a hazard ratio of 0.84. The overall survival in this study, as expected, was similar by treatment arm. There were only two deaths due to prostate cancer over the 10+ years of follow-up.
In this study, 50 patients in this elderly male population died, but due to other causes that were unrelated to treatment and not able to be modified by CAN-2409, such as cardiovascular disease, accidental death, etc. Next slide, please. We've shown that CAN-2409 in combination with standard of care radiation with or without short-term ADT is generally well tolerated. The table to the left shows treatment-related adverse events that occurred in greater than 5% of patients in either arm. The top three in the CAN-2409 arm were chills, influenza-like illness, and fever, which were as expected given the pro-inflammatory mechanism of action for CAN-2409. These were commonly mild to moderate in severity and self-limited. Looking at the prostate-specific side effects, these include in the table urinary frequency, urinary urgency, and urinary tract pain. These were more commonly observed in the placebo arm compared to the CAN-2409 arm.
Importantly, the incidence of treatment discontinuations due to adverse events was lower on the CAN-2409 at 6% when compared to the 5.4% in the placebo arm. The incidence of serious adverse events was also lower on the CAN-2409 arm, as was the incidence of treatment-related serious adverse events. Here we're reporting 2.2% on placebo versus 1.7% on the CAN-2409 arm. So in summary, we are thrilled to announce that the phase III study of CAN-2409 in patients with localized prostate cancer has met its primary endpoint, delivering a 30% reduction in disease recurrence or death due to any cause. The results were even more impressive when we focused on prostate-specific outcomes, where CAN-2409 treatment reduced the risk of cancer recurrence or death due to prostate cancer by 38%.
Importantly, CAN-2409 delivered these outcomes without untoward toxicities, which is of utmost importance to urologists, radiation oncologists, and their patients as they consider treatment. Next slide. This wraps up the presentation of the phase III results. I'll now turn my attention to the results of the phase II active surveillance study that we're also reporting out today. Next slide, please. This is a smaller study that enrolled 190 patients in a different population. These patients had early-stage localized prostate cancer and are undergoing active surveillance. We randomized 190 patients two to one to receive two injections of CAN-2409 followed by valacyclovir in active surveillance or two injections of placebo plus valacyclovir in active surveillance. In this study, our primary endpoint was progression-free survival that was either demonstrated by an upgrade in tumor Gleason grade, tumor volume, disease metastasis, or death due to prostate cancer.
Importantly, in this monotherapy study, the safety profile for CAN-2409 was generally consistent with the phase III trial. There was a numerical improvement in the percentage of patients with negative biopsies at one year post-treatment and the time to radical treatment compared to the placebo arm. However, these differences did not reach statistical significance. There was also not a statistically significant difference in PFS between the CAN-2409 arm and placebo. This was a small exploratory phase II study of CAN-2409 monotherapy without the synergy of radiotherapy in a different patient population with a different endpoint, all of which may have contributed to the results. The data from this study will be further explored, and we look forward to presenting the data comprehensively at an upcoming medical conference. I'd now like to hand it back to Paul Peter, who will give us closing remarks.
Thank you very much, Garrett, for reviewing the data. As I mentioned earlier, this data gives us great confidence in the future progression of prostate cancer management. Before taking any questions, I want to take this opportunity to thank the patients, their families, and caregivers, our clinical collaborators, our advisors who all participated in our clinical study. This has been an immense amount of work. We recognize this big effort it takes to be part of these studies as a patient with the hope of improving not only your own outcomes, but also the outcomes of future patients. None of the progress we make as drug developers will be possible without their participation and support. And we are truly inspired by their partnership. And we remain committed to honoring their contributions to our continued efforts to deliver meaningful solutions for difficult-to-treat tumors.
I also want to thank our dedicated employees who work very, very hard at Candel. Their relentless pursuit of excellence drives our passion to develop vital immunotherapies designed to improve survival, to improve cure, to improve quality of life where appropriate in patients with early to late-stage disease. I also want to thank our loyal shareholders. We thank you for your trust and support, especially focusing on a whole new modality. It always takes time to change the paradigm. So a big thank you for trusting that we will deliver on results and get to the scientific answers. And we look forward to our continued partnership with you as we are on this journey together moving towards the future. With that, we are ready to take some questions, and I'm going to hand over to the operator.
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question is from George Farmer with Scotiabank.
Hi. Thanks for taking my question and congratulations on the wonderful results. Certainly, it's been a long time coming. My question is on maybe some elements of the trial that we didn't talk about that might be interesting to investors and certainly to the medical community as well. And maybe you can talk about the drug's impact on the frequency of patients that actually developed metastatic disease. And of those patients, was there anything different about the disease in the drug-treated patients versus the control? And also maybe the impact on the frequency of prostatectomy.
Yeah. Absolutely. First, great to hear from you again. And thanks for the question. I'm going to ask Garrett to take this question.
Thanks, Paul Peter. In the phase III study, the outcomes for disease-free survival were either recurrence of prostate cancer as determined by a positive biopsy, clinical treatment failure, or death due to any cause. In terms of treatment failure, which included local, regional, or metastatic distant metastasis, the rates of treatment failure were 3% on the CAN-2409 arm and 4.4% on the placebo arm. Again, a reduction in the incidence of clinical treatment failure by those definitions.
Okay. And again, prostatectomy, was there any difference there in the patients in the two arms?
Yeah. Prostatectomy is typically not used in these patients post-failure of radiotherapy. It's either radiotherapy or prostatectomy.
There may have been some patients who underwent prostatectomy, but I don't have that information in front of me right now. Yeah. It's also difficult from a technical perspective to do actually a radical prostatectomy after radiotherapy.
Great. And also, I was struck by this. You saw a difference in the PSA nadir, but the magnitude really didn't correlate with the magnitude of the actual clinical outcomes. Do you have any comments on that? Are you seeing it that way as well?
Yeah. I mean, I think the PSA nadir is just one of the biochemical biomarkers that predicts response or predicts the effectiveness of radiotherapy in this patient population. The addition of CAN-2409 increased the nadir, which would be predicted to be correlated with outcomes. But ultimately, the recurrence of cancer that is biopsy-proven is the most important endpoint.
These individuals often have to undergo further therapies down the road. And obviously, this is an important thing to prevent: cancer recurrence, metastasis, and the need for future therapies.
I'll add something from a clinical perspective. PSA levels are followed in these patients because it's a soluble biomarker. So you can just draw some blood and test it. And then if it is detectable or becomes detectable and/or increases, then that's the indication typically in clinical practice to take a biopsy. So the gold standard ultimately is actually the histology. So we are happy that these results are consistent, but most important are the histologic findings there.
Great. Thanks very much.
Yeah. Thanks for the questions.
Our next question is from Kemp Dolliver with Brookline Capital Markets.
Hi. Thanks. And good morning. You had a modest number of patients that did not complete treatment during the trial.
Can you talk about the main reasons for that and whether there are any patterns with regard to, say, this subpopulation versus the intensive treatment population?
Thank you. Garrett?
Yeah. I'm pulling that back up. That was in the CONSORT diagram. Importantly, the reasons for incomplete treatment on the CAN-2409 were AEs or complications which weren't necessarily related to CAN-2409. That was in 5.2%. These may also have been related to radiotherapy or the ingestion of ProDrug. If we look at the rate of incomplete treatment on the placebo, it was actually higher at 6% due to AE or other complications. So for the most important and the most frequent reason for lack of completion, that was balanced, if anything, favored the CAN-2409 over placebo.
Great. Thank you. And what's your thinking with regard to filing the VLA? Has it changed in the last month or so?
No.
The timing would be about. Go ahead. I'm sorry.
Y eah. The timing would be the same. So we aim for VLA readiness in Q4 2026.
Great. Thank you so much.
Thank you for the questions.
Thank you. That concludes our question and answer. I will now turn the call back over to Dr. Paul Peter Tak.
Thank you, Operator. Also, many thanks to everyone who has been listening to this call and for participating in the call and for your questions. I wish you all a great day. Thank you very much.
This concludes today's teleconference. You may now disconnect your line at this time. Thank you for your participation.