Okay, great. We are ready. Good afternoon, everyone. Welcome to the second day of the Cantor Fitzgerald Global Healthcare Conference. I am Imogen Mansfield, I am a biotech analyst here, and I am delighted to be joined by the CEO of Candel Therapeutics, Paul Peter Tak. Welcome, Paul Peter.
Thank you very much. Great to be here.
To get us started, could you give us a two-minute overview of Candel Therapeutics and the current state of your programs?
Yeah, absolutely. Candel Therapeutics develops viral immunotherapies for very difficult-to-treat solid tumors. We have two investigational medicines in the clinic. The first is called aglatimogen besadenovec. I will call it aglatimogen for short, and we are preparing for BLA submission. We have achieved a primary endpoint in a pivotal placebo-controlled phase III clinical trial in newly diagnosed localized prostate cancer patients who seek curative treatment through radiotherapy, and I guess we will come back to that. We also have positive data for aglatimogen in non-small cell lung cancer. Recently, we announced that we have started our first global phase III clinical trial in therapy-resistant non-squamous, non-small cell lung cancer patients with progression despite immune checkpoint inhibitors, pembrolizumab, KEYTRUDA, and cisplatin-based chemotherapy.
These patients have a very poor prognosis, and we have very encouraging phase II-A clinical data that are currently under review at the scientific journal and that are really the basis for the design of this phase III study. We also have positive data in borderline resectable pancreatic cancer. For the same asset, we have paused this program because we cannot do everything at the same time. The data were very encouraging. We got also Fast Track designation, Orphan Drug Designation, and it reinforces the notion that this is a pan-solid tumor off-the-shelf therapy that induces an individualized anti-tumor immune response specific for the patient's own tumor. That is the first asset, and then the second is called linoserpaturev. Actually, it is equally exciting, but it is in an earlier stage of development.
We call it phase I-B, but you could easily call it phase II-A because we have now dosed 62 patients with recurrent glioblastoma brain cancer. These patients are probably the most difficult to treat, and we have very encouraging data that we published in Nature and in Science Translational Medicine. This has also the potential to become a pipeline in a product because there is a possibility to not only go into recurrent glioblastoma, which is a huge unmet need and commercial opportunity in itself if you have something that seems to work, but we could also expand into indications based on other indications based on the biomarker called Nestin. That is where I will pause.
Of course.
Most important, we are preparing for BLA submission.
Yes, and that is where we are going to spend most of our time today, talking about your Q4 BLA filing. Before we dig into the key investor debates around this, could you just give us an overview of the data that we have seen so far in localized prostate cancer for aglatimogen and what gives you confidence in the commercial potential there?
Yeah. We have conducted a study in 745 patients with intermediate or high-risk prostate cancer who elected to undergo external beam radiotherapy, EBRT, with curative intent. These patients get radiotherapy on the prostate, and the goal is to eradicate the tumor. The problem is that despite this radical treatment, there is a chance of recurrence of at least 30%. It is quite high. We try to increase the proportion of patients that will achieve their goal of living free from evidence of recurrence with all the complications over time, like symptoms due to local progression of the disease, symptoms due to metastatic disease over time, the toxicity, and the side effects of long-term cell-rich anti-cancer therapies, especially long-term androgen deprivation therapy (ADT), basically chemical castration, which has a very negative impact on quality of life in at least two-thirds of the patients. Patients hate it.
That is what we try to avoid. We designed a clinical trial in agreement with the FDA, conducted under a Special Protocol Assessment, SPA. That basically means that there was basic alignment about what the trial looked like, including the primary endpoint, disease-free survival, DFS, which is the right endpoint if you treat patients with prostate cancer with curative intent. It is an event-driven endpoint, and we have achieved that with a hazard ratio of 0.7; that means 30% improvement in disease-free survival. That includes all events, including death, completely unrelated to prostate cancer. Think of an accident, a car accident, or somebody fell off a ladder and died.
Or a heart attack or a stroke. All of that was included despite that, because you dilute the signal by doing this. We still achieved this with statistical significance. What follows is that the key secondary endpoint was prostate cancer-specific disease-free survival. That is when you exclude death not related to prostate cancer.
and then the results look even better. We have achieved that, convincingly supported by other secondary and exploratory endpoints. Very importantly, we did a two-year biopsy, which is not part of standard of care, but this is a research tool. It is the most objective way to detect cancer cells and also the most sensitive way. We observed a pathological complete response at two years in the patients who had received aglatimogen in 80% of the patients, compared to 63% in the control group who only received radiotherapy. Again, statistically significant. Why does that matter? Because we know based on the literature that this is predictive of subsequent clinical outcomes, and that is what we have shown, and we can discuss that further.
Great. Remind us how aglatimogen is administered with radiotherapy in localized prostate cancer.
Yeah. It is a simple procedure, actually, to inject aglatimagene into the prostate. Non-clinicians may find needles scary, but actually it is super simple. There is no place in the body that cannot be easily reached with a needle. The whole procedure takes 15 to 20 minutes in an outpatient clinic, is often better tolerated than a standard of care diagnostic prostate biopsy, which is a completely routine procedure. So what we do is the urologist or the radiation oncologist; they are the treating physicians. I think it is important to understand this. They are used to manipulate the prostate. They put needles or spacers into prostate every day. This is a simpler procedure than a standard of care biopsy.
They inject 0.5 mil in each of the four quadrants of the prostate in an outpatient procedure, and that leads to a diffuse distribution of aglatimagene in the whole prostate. Then we give the patient a tablet called valacyclovir for two weeks, and that leads to massive immunogenic cell death. We kill the tumor cells in such a way that they are subsequently recognized by the immune system and leads to in situ immunization against the tumor.
We do that three times in a patient's life. Think of it almost like a vaccination regimen, although aglatimagene is not a vaccine. We do that the first time, and often it can be combined with the placement of a spacer, which is often used by the radiation oncologist to separate the prostate from the rectum with a gel so that you get less side effects during radiation therapy on the gut, on the rectum, or other procedures that they do.
Other procedures, yeah.
It's not always done. The second injection is given at the start of the radiotherapy. In principle, the patients are coming to the clinic anyway, then they undergo this simple procedure. The third injection is given always at least two weeks apart during radiotherapy. Typically they're halfway. It's a very patient-friendly approach. We've tested this with surveys that we sent out to patients. Most patients indicate it's better tolerated or the same as a standard of care biopsy. You only do it three times in a patient's life with the goal to induce durable anti-tumor immunity.
Well, that's our first debate, which you've answered, which is the impact of logistics and patient discomfort here. Anything else you can share about how this is impactful for a patient in terms of the pain? You've done a lot of work on this with patient surveys.
Yeah. First, it's not very painful, and in principle, you even don't need local anesthesia in many of these patients. You can give local anesthesia, so it's a very minor procedure. I think it's very important to understand this. It's also important to always think through normal clinical practice. This is very much aligned with normal clinical practice because the patients are treated by physicians who put needles into prostates every day, and it's simple and well-tolerated. It's not a recurrent or recurring treatment year after year. It's a one-off treatment consisting of three courses, and off they go with the goal to get durable anti-tumor immunity. As we've shown, with now a follow-up of a median follow-up of about six years, we meaningfully improve patients' lives.
So what do these patients want to achieve? They want to live free from cancer. We've shown that the two-year biopsies, that we achieve this pathological complete response. This is a goal in itself. Just think about this through the lens of cancer-related anxiety, the fear of recurrence. Think of what it means when there is local progression of the disease, which leads to symptoms, and over time when there are metastases, which leads to symptoms. So patients may still be alive after 10, 15 years. There's a big misunderstanding about this, I think, in the field. They say, well, prostate cancer is not really a problem because median overall survival is about the same at 10 years, independent of what you do.
There's a big impact of having recurrence, local and metastatic progression, and then actually needing salvage anti-cancer therapies like chemical castration, leading to a very impaired quality of life. Ultimately, it's important to note that if you don't have prostate cancer anymore, you won't die because of prostate cancer 15, 20 years later. I would argue if you're diagnosed at 65 and it's possible to get complete eradication of the tumor, then it actually does matter that you don't die because of prostate cancer when you are, let's say, 80 years old. I think this is often forgotten. These are some of the aspects I want to highlight in terms of the clinical relevance of the findings.
Yeah. So how impactful is it for the physicians that you speak to not have to use long-term ADT in the recurrent setting and to patients?
Yeah, this is a great point because this refers to one of the major unmet needs in the field of urology and radiation oncology and medical oncology. Patients, patient advocates, patient organizations, radiation oncologists, urologists, the medical oncologists consistently indicate that while long-term ADT works in terms of improving survival and may be indicated, it has a very strong negative impact in terms of toxicity. First, it can be contraindicated because of cardiovascular disease. Second, it will have an impact on the mood, mental state, on sexual function. It will therefore also impact not only the patients but also the patients' partners. Hot flashes, think about all these side effects. This is a very big problem. If you are able to develop a medicine that will reduce the need or delay the need for long-term ADT, this would be extremely clinically meaningful.
From KOLs, we hear very high levels of support and intended use very often of aglatimogen at AUA. Both of the doctors at our table planned on using it on 100% of their patients.
Yeah.
Your biggest supporters joke about the Candel brainwashing effect that you seem to be having with all of these KOLs. Can you tell us more about that and those discussions of how even some of the most skeptical people in the field have become convinced that—
Yeah
Aglatimogen will be?
Yeah. I'm not necessarily the type of CEO who likes to hype things. We have a very scientific and very rigorous approach, and what we've chosen to do is to present the data, and we've presented at big oral presentations at ASCO, at ESTRO, at the Prostate Cancer Foundation, at the American Urological Association. I opened the session, the plenary session in the ballroom at SITC. We've presented this data at very high-profile events, actually. It was all peer reviewed, right? This has helped, I think, to convince the key external experts about the relevance. Next, we submitted the data to one of the most high-impact journals in the field of oncology, The Lancet Oncology, paper was published. All of this has helped, I think, but we do need to educate people because they've never seen a medicine that improves disease-free survival.
They've never seen medicine that helps patients to live free from evidence of recurrence before. Disease-free survival has never been used for approval in prostate cancer, so you need to educate them about what does that actually mean, right? They don't take two-year biopsies in standard of care. Why not? Because it's not very pleasant to undergo a biopsy. That's the reason. But it is the most objective research tool and also the most sensitive tool to detect cancer cells. Right? This is the gold standard to detect cancer, is to take a biopsy and look under the microscope, is there cancer? Better than looking at PSA levels or even imaging.
There's a lot of novelty that we needed to explain, that we did through all these oral presentations, also through high-impact publications, and actually by interacting with SABs, learning from the field, working closely with, for example, the Prostate Cancer Foundation, listening to patients. That's probably why some people became really excited and started to mention aglatimogen as the next viral KEYTRUDA. These were not my words, but it is true that some people got very excited based on the data and really deeply understanding the significant unmet need.
Let's talk about another debate around the DFS endpoint. Can you tell us about what was included as an event in the DFS?
Yeah.
You've talked about prostate cancer specific, but what were all of the different events that—
That's a great question. Disease-free survival is an event-driven endpoint. It was agreed under the SPA with the FDA, which is intact. If there would be tumor cells in a two-year biopsy, that would be an event, and this was all externally, centrally read after completion of the study, so did not influence the study, and this is extremely objective, done by very experienced readers of histologic specimens. Second, if there was clinical evidence of local progression of the disease, it had to be confirmed by imaging and/or biopsy. This was all defined in a very rigorous way. For example, in normal clinical practice, these patients will just be followed by testing PSA levels, typically every three months for the first two years, and then if everything looks fine, then you increase the interval to six months, and then after five years, you do it annually.
If it goes up, that's called biochemical failure. The FDA did not agree to use that as an event. Why? These patients still have a prostate, right? These prostate cells can be irritated, definitely during the first two years, as a result of the radiotherapy. It doesn't necessarily indicate cancer, but it would lead to diagnostic workup, which could be imaging or biopsy showing evidence of cancer. That would be an event.
If the patient would develop metastasis due to prostate cancer, that would be an event. If the patient would die, independent of the cause, that would also be an event. With a median follow-up at the time of data readout of 50.3 months, you don't expect that many patients will have died because of prostate cancer, because typically it's a slowly growing tumor. Indeed, we only had two prostate cancer-related deaths, both in the high-risk group, one in the active treatment group, one in the placebo group. Remember, this was two-to-one randomization, so maybe it's good, but the numbers are extremely small.
We should not conclude anything here. Then we had 50 deaths completely unrelated. All of these were events. If you take all of this into account, we observed this hazard ratio of 0.7.
You got a Special Protocol Assessment with the FDA for this novel endpoint. It was a while ago, so 2010? What gives you confidence that that will be upheld when you file the BLA later this year?
Yeah. First, it took a while to do this study because you need to follow these patients sufficiently long to actually demonstrate the events. The good news is, therefore, nobody else has done it, and there's basically no real competition in this field, and this field is wide open. In 2019, there was a new way of using EBRT, external beam radiotherapy, which is called hypofractionated EBRT. It basically means that the patients would get the same total dose of radiotherapy, but in fewer sessions. It's more patient-friendly because the patients don't need to come to the radiation therapy so often. It does not improve outcome. It's just more patient-friendly. In 2019, we amended the protocol to make it possible for patients to choose moderate hypofractionated EBRT. Then we discussed that with the FDA, and the FDA confirmed in writing that the SPA was still intact.
We have always conducted the study completely consistent with the SPA that has been agreed with the FDA, so there's been no deviation, and the FDA agrees about this. Then also we went to the FDA, I call them the new FDA, but now they're not so new anymore, with the data in hand. After data readout in 2025, we presented the data to the FDA, and they granted us RMAT designation. Regenerative Medicine Advanced Therapy designation, which is a big thing actually, and which indicates, I think, that the FDA was very supportive, that this is a relevant indication, and that these data are potentially clinically meaningful.
You're planning on filing the BLA by the end of the year. Do you expect an Advisory Committee? Has this come up in your discussions with the FDA?
Yeah, this has not come up in any of the meetings. This has not been discussed, but also it would have been atypical to discuss it because typically this is discussed after submission and after review of the data.
Okay, cool. You had a Type B pre-BLA meeting earlier in the summer. Are there any notable outcomes from that meeting?
Yeah. We've had two types of meetings. One was about manufacturing. The last Type B meeting about manufacturing lasted six minutes. That is because there was alignment about what the FDA wants to see, so that was all great, and we didn't want to waste anyone's time. Then we have had meetings focused on the clinical aspects of what we plan to submit which is completely consistent with the SPA.
I think the review will be focused on disease-free survival. Did we achieve the primary endpoint? What is the clinical relevance of this endpoint? There will be a review of the secondary endpoints, like prostate cancer-specific DFS, the nadir of PSA of less than 0.2 nanograms per ml, et cetera. The second topic that we discussed is we want to review the clinical standard of care at this time compared to, let's say, 10 years ago. Of course, there's always evolution, right, over time. Although we believe, and our key external experts all agree, that there's no fundamental change in standard of care. Unfortunately for the patients, there, of course, has been some improvement in EBRT, as I just described. Less side effects, but it's still true that there's a chance of recurrence of about 30%.
Yeah.
There's a new subclassification in intermediate-risk prostate cancer that did not exist at the start of the trial. Namely, the distinction between intermediate-risk favorable prostate cancer, where, according to the most recent NCCN guidelines, ADT is not indicated, versus intermediate-risk unfavorable disease where short-term ADT, four to six months, is indicated during the initial treatment. In our clinical trial, we wanted to be as close as possible to normal clinical practice, so we left it to the treating physician, in the context of shared decision-making with the patient, whether the patient would get ADT or not, and we stratified for this in the analysis as we agreed in the statistical analysis plan before data readout with the FDA.
Most of our patients were actually enrolled relatively recently, because it took a long time in the beginning. It was very slow enrollment until there was a real uptake since 2018. Then professional investors came on board, and more centers could be open. We assumed that most patients were actually, in reality, treated according to the guidelines.
We did an exploratory analysis, looking at the question, if you would retrofit the patients based on treatment according to the most recent guidelines that actually came out even after study readout, this is an exploratory sensitivity analysis. Then we see the same pattern, actually, of a benefit of aglatimogen versus placebo. We announced to the FDA that we would consider actually adding these data as , like, a supplementary table or in a different context, as an addendum to the FDA. We have had more of a discussion about the type of data that they want to see for review, which are, again, clinical relevance of the endpoints and has there been any change to standard of care that would affect the interpretation of the data.
Before we get into manufacturing, are all of the other BLA modules ready to go? Is it we're waiting on manufacturing? Is that right?
There are many work streams all going on in parallel, and there's no white space. Some people have asked me, "Why does it take so long?" To take two years. I will say this, two years is an extremely tight timeline. We are not aware of any company that could have done it faster or actually did it faster if you just exclude the COVID-19 programs. That was an exceptional situation.
Yeah.
This is a super tight timeline. On the critical path are all the modules in manufacturing, in CMC. This is biology. All these things go in parallel. Think of the following, the development and qualification and validation of a whole variety of assays.
Yeah.
We had done already the commercial engineering run before data readout. When we pressed the button, we did a GMP run. We did multiple PPQs.
Yeah.
That's a lot of work, of course. Then you need to test these PPQs. Then we started to work on the assays that we will need for analytical comparability.
Yep.
Of course, the FDA also required that we would do an additional clinical trial, which is a small experimental medicine clinical trial called PRTK-05. In this study, we inject aglatimogen into the prostate, and the goal is really not to look at clinical endpoints but to look at biodistribution and shedding. So where can you detect aglatimogen after administration into the prostate, and for how long, and in which body compartments? Of course, we have done all of this already in the past.
We could show that after a few months, you cannot detect it anymore. That is what you expect. Why? Because it is a replication-defective adenovirus. It cannot replicate. Second, actually, we kill all the cells that we transduce because we give valacyclovir. That is how it works. Ultimately, the medicine that remains are the patient's own immune cells that have been educated how to recognize and kill the tumor cells. We are working on all these things. We are on track with PRTK-05.
The good news is, I was quite happy that we were going to do this trial because I like deep experimental medicine data, and we used this actually to collect biosamples that were not requested by the FDA but that we can use for sophisticated immunological biomarker research. We have done this already for aglatimogen in glioblastoma. We also had the glioblastoma program for aglatimogen with very encouraging results that we published. We have very interesting immunological biomarker data in non-small cell lung cancer.
Although we have shown that aglatimogen leads to massive infiltration by CD8-positive tumor-infiltrating lymphocytes in the prostate after injection, we do not have these data for, let us say, induction of central memory in the blood after aglatimogen administration in prostate. We are doing all sorts of studies right now.
Yeah.
We are on track to deliver new biomarker data in Q3. I know it is already Q3, so we need to have this data before October.
Okay.
No pressure, but I think we are still on track. It is possible that we will actually have additional interesting biomarker data even during Q4 of this year.
Cool. Just quickly back to manufacturing. We did a very helpful webinar with your wonderful team. You were waiting on the final PPQ run. Has that been done yet? Are you able to tell us?
Yeah, I will tell you that we have completed the third PPQ.
Cool.
Obviously, we need now to test this extensively and see if this is sufficient.
Yep.
We have completed this.
How much overlap is there with the assays that you do for release testing and that you've done already for the scale-up process, and what gives you confidence in success on analytical comparability?
Yeah. First, there is an enormous amount of assays that we have developed and that we needed to qualify and validate. This is a lot of work. A lot of these assays that are needed for the analytical comparability will also be used for release testing, but not all of them. We will need less assays actually for release testing than we will need for the comparability studies.
In terms of how you've got to this point for PPQ of scaling up, it sounds like you have tested potency, which is one of the more important ones, as you've been making sure that the process is the same as your prior process.
Yeah.
I guess, are there other assays where you see overlap and you've had to already test them in the scale-up process?
Yeah. Maybe it's good to explain what analytical comparability actually means.
Will do. Absolutely. Yeah.
It's very pleasant actually that we don't need to do another clinical trial. The FDA agreed that we would just do analytical comparability. That means that we're just comparing the new product to the old product that was used in a clinical trial in the lab. You ask questions like, what is the identity of the molecule? What is the quality? What is the potency? What is the titer, et cetera. That altogether is an enormous amount of assays.
Yeah.
We are doing. We started to do this.
You started the assays now?
We have started to do this, but there's still a lot to be done as well.
Yeah.
This is all work in progress. Again, this is biology, but we have initiated this work.
Great. Quickly, before we have to leave the stage, can you remind us of the milestones that we should be expecting for the rest of the year?
Exactly. What follows from what I said is we hope to disclose immunological biomarker data based on PRTK-05 this year and also so-called digital histology data based on the randomized control phase III trial. We expect to present data on long-term survivors; potentially, I don't know the data yet, for lenvatinib plus bevacizumab in recurrent glioblastoma. Just asking the question, could there be long-term survivors in patients who have failed neurosurgery and radiotherapy and chemotherapy? It's already a radical question, and we hope that we will have some interesting data in Q4. Then most importantly is, of course, an update about the BLA submission that we plan for the end of this year.
Great. Thank you so much, Paul Peter.
Thank you.