All right. Good morning, everyone, welcome to B. Riley's Oncology Conference. I'm Kalpit Patel, a research analyst here at B. Riley, it's my pleasure to introduce our next company, Candel Therapeutics. With me, I have Paul Peter Tak, the company's President and CEO. Paul Peter, thank you very much for joining us today. Maybe we can start with a brief overview of your approach for fighting cancer. Curious to hear how your approach is differentiated relative to historical attempts for utilizing oncolytic viruses. I'll pass on the mic to you.
Okay. Thank you so much, Kalpit, and hi, everyone. Candel Therapeutics has 3 platforms. 2 are clinical platforms. Third, we have a newly created discovery platform. The first is an investigational medicine called CAN-2409. It's actually not an oncolytic virus. We call it a viral immunotherapy. It's a way to immunize the patient against the patient's own tumor. We induce an immune response that is specific for the injected tumor, but that also has a clear effect on the uninjected distant metastasis. It's a form of in situ vaccination, so you don't need to inject all the tumor metastasis. You don't need to give it very often. It's much more like COVID-19, like a vaccination schedule where you give 2 or 3 injections in the patient's life, actually, with durable responses.
We are testing it in multiple indications, and that's why I call it a platform. The second is an asset called CAN-3110. That is a true oncolytic virus, but it is differentiated from every other HSV, every other herpes simplex virus, because it contains the so-called ICP34.5 gene. Everybody else has knocked this gene out because of safety concerns. The problem is that if you do that, you have a safe virus, but actually you also sacrifice efficacy. We've reinserted an allele for this gene under the control of a tumor-specific promoter, so it replicates, and it exerts its aggressive action against the tumor cells only in the tumor while sparing the healthy tissue. We've tested this concept. We were the first to do this in humans. We've now experienced in more than 41 patients, there's no dose-limiting toxicity.
We see some transformative clinical responses in recurrent high-grade glioma. Here again, we can expand into other tumors outside the brain with a diagnostic biomarker, which is nestin. That's why I call it a clinical platform, which is very differentiated from other HSV gene constructs. The third is a newly created discovery platform that we call ENLIGHTEN. It reflects the name of Candel, light. We just unveiled this platform at the same time that we announced a discovery partnership with Carl June and Neil Sheppard at University of Pennsylvania to create synergy between CAR T-cells used for solid tumors and new viral immunotherapies that we designed to create synergy and to convert non-responders into responders.
We could do the same in discovery partnerships with pharmaceutical companies to create synergy with their cell therapies or antibody-drug conjugates or immune checkpoint inhibitors to convert non-responders into responders. That's also where we are open to business.
Okay. Okay, good. Let's talk about, you know, your efforts in lung cancer with CAN-2409. You have two cohorts that you're testing initially. Maybe explain the rationale behind that specific trial design and why you chose only to enroll patients with stable disease and progressive disease into this trial.
We focus here on an area of high unmet need. For each indication, we look at the medical unmet need, the scientific rationale. We've done extensive market research to look at the commercial opportunity, developability, et cetera, et cetera. At this time, we focus on patients with stage 3 or stage 4 non-small cell lung cancer. They can't undergo operation. They're not resectable tumors, and they have already been treated with immune checkpoint inhibitors for a prolonged period of time, at least 18 weeks. Then at some point, the conclusion is these are immune checkpoint inhibitor inadequate responders. Most of these patients have also failed chemotherapy. The therapeutic options are extremely limited in these patients, so there's a huge unmet need. That's where we now test in 2 sub-cohorts patients with progressive disease. That's arm 2.
These patients may have exhibited an initial response to immune checkpoint inhibitors or may have had stable disease. At some point, the tumor starts to grow again. That's why the prognosis is so poor. Again, there are no real therapeutic options for these patients. We give them two administrations in total of CAN-2409, and we've shown that we are able to convert progressive disease into stable disease. I guess we'll come back to that. Arm one is an area that's a little bit more exploratory because they actually have stable disease during continued immune checkpoint inhibitor treatment. You may make the case that patients do not like to have a stable tumor. They want to see a decrease in the tumor.
That's where we start to explore whether we can create synergy also in this population that has a slightly more favorable prognosis.
Okay. In the initial data, you showed a 25% in that cohort, with stable disease and then a 12% ORR in the cohort with progressive disease. Give us some perspective on these results and what the expected outcomes would be with, you know, salvage therapies, whether it's chemotherapy or anything else.
Yeah. Most of these patients will get chemotherapy in the context of standard of care. The best publication that shows exactly the same population has been published in 2018 by Gandara and colleagues. What they did is they included a similar patient population and then switched them to atezolizumab. This is the so-called OAK study. This is the best benchmark. Key experts in the field all agree about this. What they observed is an overall response rate of 7%. That's the benchmark. The results that we see are extremely encouraging. I should also mention that with immunotherapies, ORRs are not necessarily the best endpoint. These have been developed to evaluate the effects of chemotherapy, kinase inhibitors, radiation therapy.
Big lesson from the field of immune checkpoint inhibitors, as the pioneering field in immunotherapies has shown that there may be patients who initially do not have an ORR and a response according to the RECIST criteria, but you are able to stabilize the disease. These patients live longer with a high quality of life, and that's the goal for the patients. That's also a meaningful endpoint, which is survival.
The fact.
We see in our study, very high disease control rates, which basically means patients who fulfill the RECIST criteria, plus the patients where it was possible to convert progressive disease into stable disease. We actually see this in arm 2, patients who had progressive disease in 77% of the patients. This is unheard of and a very encouraging result, and the expectation would be that that will translate into improved progression-free survival. I guess we'll come back to that.
What's the benchmark for disease control rate? I know you mentioned, 77% in cohort two, but what was the DCR in that other study that you're referring to?
Yeah, that's 56%. 77% is really much higher than what has been published before in this population.
Okay.
Very encouraging.
Got it. You know, oftentimes when investors look at these, combination-based studies, you know, when you have, you know, a checkpoint inhibitor on board, you have chemotherapy, added as well, how do they delineate the benefit of what your, you know, specific agent is doing? Are there any certain pieces of translational data that suggest the outcome is driven by 2409?
Yeah. First we know that if you select patients with therapy-resistant disease, as we do, that you will not see placebo effects. You don't see regression to the mean, and there's no effect of expectation bias. If you see results and you compare it to baseline populations, as I just described for the OAK study, then you can compare whether this is clinically meaningful. You're right, translational results are very important as well. We've done very deep immunological studies. We know based on mouse models, extensive preclinical work that we've done in the past, that the effects of CAN-2409 are mediated by CD8 positive cytotoxic tumor-infiltrating lymphocytes. If in animal models you deplete these antibodies, then it doesn't work anymore. Ultimately, the effect is mediated by CD8 positive tumor-infiltrating lymphocytes.
That's exactly what we show in the ongoing non-small cell lung cancer clinical trial. We've shown a very significant increase in the number of these CD8 positive T cells at the site of the tumor. They get closer to the tumor cells. We've done a proximity analysis, and we can also show that there's an increase in the number of circulating CD8 positive cytotoxic T cells. These are the cells that have been educated how to recognize the tumor cells. They're looking for metastasis. Indeed, we see an effect on uninjected lesions in two-third of the patients. That is very significant. You can also measure in the serum the levels of so-called soluble granzymes. They are cytotoxic enzymes produced by these cytotoxic T cells that have been trained how to eliminate the tumor cells. Highly significant results there as well.
The mechanistic data clearly underscore the specific effect of CAN-2409.
Got it. maybe let's zoom in on the four partial responses that you had in the trial. Are any of those responses still ongoing? Do we have a more recent update?
This study is still ongoing. In 2 of the 4 patients, although they were having an inadequate response to immune checkpoint inhibitors, we still have a continued response. In 1 patient, this is now already more than 14 months. Extremely encouraging result. When we look at patients who had progressive disease, but who convert into stable disease, so they do not fulfill the RECIST criteria, but they stabilize. We now have patients who actually have a prolonged follow-up and continue to do very well clinically. I can show you, let's see if that works technically. I can show you what that means for a patient.
Mm-hmm.
Here you can see an example of a patient in this study where we have mapped the real tumor values on the top right of the figure. Right? You can see the actual values in millimeters based on the CT scan. You see the tumor continues to grow over time. On the x-axis, we show time in month, so we have long follow-up here. You can see what happens after the first injection with CAN-2409. A dramatic decrease in the tumor size, and you can see the illustration on the bottom. You can see after the second injection, gets even better.
We have now followed for more than a year, and we can see that this patient continues to do well with the treatment that was well-tolerated, easy to administer, and that really leads to prolonged progression-free survival.
Yeah. Paul Peter, on this chart, on that graph, upper right graph, were there other drugs that were administered at the same time, when you saw that tumor reduction or was it just, CAN-2409?
Yeah. What we did is the only change, the only variable is CAN-2409.
Okay.
This patient had been treated with immune checkpoint inhibitors for more than 18 weeks, has progressive disease. You don't expect further improvement. We continue the same immune checkpoint inhibitor.
Okay.
The single variable is the administration of CAN-2409. We're looking at the real effects of CAN-2409 treatment in this patient with an initially inadequate response.
Yeah, that's fantastic. Okay. You know, you took an early look at the progression-free survival at, you know, in cohort 2 for the 26 patients, and you saw median PFS of 8.1 months. I guess, how does that compare to-
Yeah.
You know, just to standard therapies?
It's a great question. First, we have actually shown that we've mapped the individual tumor growth trajectories, we can show that initially they're all growing, then we can stabilize it in nearly all patients. We've shown, as we discussed, that this translates into high levels of disease control. We don't propose that this will be the primary endpoint of the future pivotal trial, it gives us confidence that it works because disease control is expected to be a surrogate marker for progression-free survival. In December, we were able to show for the first time the effects on progression-free survival. As you mentioned, in Arm 2, this is 8.1 month. What would you expect based on the literature in this population? Not more than 4-5 months. A very meaningful improvement in progression-free survival.
In arm one, although the numbers are still small in arm one, the results look even better. We see progression-free survival of more than 11 months. Again, we need to be cautious because that's a small cohort, but very encouraging. Progression-free survival is expected to be a surrogate marker for overall survival. Now we're following these patients, and we expect to have these data over time. Patients need to live long enough actually to have these data. It's a very consistent and very encouraging data package.
Got it. You mentioned an update, I think you said December of this year. Should we expect more patients worth of data, or is it just gonna be more of a, you know, a more mature data from the current set of patients?
We presented the most recent data, the very fresh data in December. This is available online. If you go to the website of Candel or go to the IR site, you will find the R&D online virtual event with speakers like Jim Ellison, Ben Sharma, Roy Herbst, Nina Kyokai, and others who speak about our programs as world-class leaders. That was the last data cut. What are we going to present in Q3 of this year? We will have prolonged follow-up, we will have more mature progression-free survival data of at least six more months. That's very meaningful. We might see some initial overall survival data based on case reports, as I've just shown you. We will have more patients as well.
Arm 2, we aim to include in total 40 patients, and we expect to reach that point around April 1st of this year. We'll have more patients in both arm 2 and in arm 1. We will have more mature data in terms of survival data, and we will have more immunological biomarker data.
Got it. Maybe how are you leveraging these results for, you know, planning a potential pivotal study? Have you engaged with the regulators at all, or is that after you have the update in 3Q?
Yeah. We started to speak to key experts. We've made the decision that we're going to prepare a potentially registrational clinical trial, which will be a, well, we're doing the work, but that's most likely going to be a randomized clinical trial where you randomize to a standard of care chemotherapy, which has very disappointing results, but that's the standard of care. Primary endpoint will probably be progression-free survival and or overall survival. There's a very clear regulatory way forward. We will start to talk to the regulators when we have more mature progression-free survival data so that we can finalize the design of the study.
Got it. Maybe before we move on to the next program, one quick question on the administration technique. This is an intratumoral injection in the lung and the lymph node lesions. I guess, discuss the mechanics of delivering your therapy and sort of the viability of doing this on a large scale.
Yeah. That's a great question because I think this is a source of enormous confusion in the external world. CAN-2409 is a systemic immunotherapy delivered locally to one or two of the tumors. You don't need to inject all the tumors like what happens with less effective oncolytic viruses. We've shown that there is an effect of at least 5% decrease in uninjected lesions in two-thirds of the patients. Very strong data. You don't need to inject all the lesions. You don't need to give the injection every week or every other week. It's probably two or three times in the, in the life of a patient. It's a true vaccination strategy. How do you administer it? In the lung, this is done during diagnostic bronchoscopy, which is a 15-minute straightforward procedure in an outpatient clinic.
If you can deliver this in a procedure that's generally well-tolerated and patients live longer for several months, this is a patient-friendly approach. If you compare it to chemotherapy with all its side effects, or even immune checkpoint inhibitors, where the patient needs to come back to the hospital every three to six weeks, depending on the dose, and then all the side effects of these treatments. This seems to be a very acceptable procedure. It's aligned with normal clinical practice, 50 minutes in the outpatient clinic, and you don't need to repeat it very frequently.
Got it. Maybe switching to your prostate cancer program, with, you know, same agent CAN-2409. You know, in the earlier study, the phase II-A, you enrolled patients with all risk levels, and then now in the phase III, it's newly diagnosed patients with intermediate and high risk only. I guess, help us better understand the decision-making for just focusing on these patients in the pivotal study.
Yeah. Initially we've done, and we've published this meta-analysis, where we certified patients based on their risk as shown by histology. There's low risk in prostate cancer, intermediate risk or high risk prostate cancer. We compared CAN-2409 with optimal standard of care in open label prospective phase II-A clinical trial, compared to comparable open label prospective cohort studies that had been published in the same period of time with the same standard of care. We could show a consistent improvement in the percentage of patients that were free from failure over time. Free from failure basically means progression-free survival, with the death censored. This is sometimes used in phase II-A clinical trials. It's a generally accepted endpoint. Now we have designed two different randomized clinical trials based on these results.
We were actually granted an SPA based on this analysis, Special Protocol Assessment, agreed with the FDA about the endpoint. The first is a fully enrolled phase III clinical trial in patients with intermediate to high risk prostate cancer. That's where we combine three injections of CAN-2409 in total into the prostate with optimal standard of care, which is radiation therapy plus or minus hormonal therapy, androgen deprivation therapy. About 50% of the patients will get hormonal therapy. We certify for this. What is the rationale behind this? We know that prostate cancer is the second most common cause of cancer in men in the U.S. Despite of all the treatments available for metastatic disease, this is still the second most common cause of death, of mortality due to cancer in men in the U.S.
Still a huge unmet need for a treatment that could lead to cure of prostate cancer. Because we focused on cure by creating synergy, potentially, by using this as a new adjuvant, we focus as a primary endpoint on disease-free survival. That's the goal. We have enrolled 711 patients, so most of the work has been done already in the past and has been paid for in the past. We follow these patients, and this study will read out at the end of next year.
Mm-hmm.
We are in phase III with a fully enrolled clinical trial that will read out already next year. The other population that we are focused on is in the so-called active surveillance population. They have low to intermediate risk prostate cancer, and these patients do not want to start with the currently available treatment because of the side effects. They don't want to face the side effects of radiation therapy or surgery, prostatectomy, or hormonal therapy, that has a lot of side effects and a negative impact on quality of life, before they actually face the signs and symptoms due to their cancer. The slowly growing tumor is still a growing tumor, and over time, most of these patients will need so-called radical therapy. They will get radiation therapy, et cetera.
One third of these patients after radical therapy will still have progression of the disease. There's still a big unmet need. That's where we position CAN-2409. We give in total two injections in the patient's life versus placebo. We follow these patients, and the goal is to show progression-free survival. We can't do disease-free survival because we expect that in the placebo group, there will be patients who have progression of the disease, natural course of the disease. Here again, this is a phase II clinical trial, fully enrolled, 187 patients, is expected to read out at the end of this year. We will do some work during this year to look at the number of events, it's an event-driven endpoint, which will inform us about the optimal readout of this clinical trial.
Okay. For the prostate cancer program that's in the phase III, you know, in the event, let's say you hit stat sig, is there also a delta between the active and placebo arms for that primary endpoint that might be viewed clinically meaningful?
Yeah, absolutely. We have 90% power to detect a 15% difference in disease-free survival, which gets us probably to a difference between around 75% versus 90%. In other words, we have a hazard ratio of 0.5, so this would be very clinically meaningful.
Okay. Got it. Got it. Okay. That readout is expected in Q4 of 2024. Are we gonna see all the secondary endpoints as well there, or is that-
Yes.
for later? Okay. We will.
We will. We have long-term follow-up. These studies are very difficult to do. That's probably why everybody else-
Right.
focused on late-stage disease. The good news is most of this work has been done in the past. We have to follow up, it will read out next year.
Got it. Got it. Maybe last few minutes on your second drug, CAN-3110, in patients with high-grade glioma. I guess, you know, maybe first, how does 3110 differ from 2409? What makes you think that'll get you more horsepower in terms of treating patients with high-grade glioma?
Yeah. We have actually prioritized CAN-3110 in high-grade glioma. These are two very different approaches. CAN-249 is in situ vaccination using an adenovirus that is replication defective to deliver a gene. You could see it as a form of in vivo gene therapy for in situ vaccination. CAN-3110 is a very differentiated HSV, is replication competent, and it replicates specifically at the site of the tumor under the influence of the so-called nestin promoter, which will activate the 34.5 gene that I alluded to earlier. That leads to aggressive action against the tumor cells while sparing the healthy tissues.
Okay. Okay, you showed a median overall survival of about 11, 12 months. How does that compare to standard options today?
We've decided to focus with this very new mechanism of action, first on recurrent glioblastoma. Glioblastoma is a very poor prognosis, as you know. These patients have already failed neurosurgery and chemotherapy and radiotherapy. Several of them have multifocal disease, multiple tumors in the brain. They ran out of options. Some of these tumors are as big as 5 centimeters, and they basically have a few more weeks or a few more months to live. Basically, on the population level, you expect median overall survival in this population of less than 6-9 months. If we see more than 11 months as we've seen, that's extremely encouraging. This is just after a single injection. We did that for safety reasons because we wanted because it's a new concept. We did not observe dose-limiting toxicity.
We see some very encouraging results. I'll show you one in a second. Now we are asking the question, could it be even better if we give 2 or 3 or 4, up to 6 injections? We've just dosed the first patient with multiple injections. This is extremely exciting and very meaningful to patients. I will show you what this means for some of these patients if you give me one second. Yeah. This is a patient. Actually, I posted a video with an interview of the treating physician, Professor Nino Chiocca, at the Brigham and Women's Hospital, including an interview with her daughter. This was a patient with high-grade glioma. You see the initial lesion. Patient undergoes neurosurgery. The surgeon removes the tumor. Over time, the tumor comes back. You see tumor recurrence, day minus 47.
Patient undergoes neurosurgery again, subtotal resection. Just a few weeks later, there's already a rapid progression. You can see very poor prognosis. On day zero, we give a single injection with CAN-3110. On the next scan, there appears to be tumor progression. It turns out that this is pseudoprogression.
Mm-hmm.
A biopsy was taken, and it was a mixed infiltrate of immune cells and tumor cells. This patient was followed without further treatment, the tumor disappeared completely. This patient lived an almost normal life, went on a cruise, could reconnect with her children and grandchildren. You can see it in the video. Very tragically, on day 630, this patient died in a car accident completely unrelated to the tumor. She was even not driving herself. We've seen really transformational changes. I could show you more. I just heard this morning there's another patient like this, where the tumor is regressing over time after just a single injection with CAN-3110 in a completely therapy-resistant disease. We know that this works.
Okay. That's fantastic to see this type of a response. We're assuming here also that no other therapies were given aside from what they were already on. Is that correct?
That's correct. Like, this patient actually refused all further treatment, even dexamethasone. We're looking here at monotherapy efficacy on this slide. You see a patient with two tumors in the brain. We just gave one injection in one of the two tumors. Very strong decrease in both tumors over time. This patient could go back to work.
Okay.
This is monotherapy efficacy that I show here.
Got it. Okay. I think we're at time here. Thank you very much, Paul Peter, for participating in our conference. We look forward to more updates from Candel later this year. Thanks for the audience for tuning in.
Thanks for Kalvin. Thank you all.
Thank you. Bye.