Precigen, Inc. (PGEN) Earnings Call Transcript & Summary

Good day and welcome to the Precigen R&D Update and Clinical Development Call. [Operator Instructions] Please note that this event is being recorded. I would now like to turn the conference over to Steven Harasym, Head of Investor Relations. Please go ahead, sir.

Thank you, Chuck. This is a very exciting time at Precigen, and I would like to extend a special thanks to everyone joining us today for an update on our clinical programs. Next slide, please. Before we begin, I would like to remind you that, during today's call, we will make various forward-looking statements. Investors are cautioned that our forward-looking statements are based on current expectations and are subject to risks and uncertainties that could cause actual results or outcomes to differ materially from those indicated by our looking statements. Please read the safe harbor statement contained in this presentation as well as the risk factors contained in Precigen's most recent SEC filings for a more complete discussion of these risks and uncertainties. Next slide, please. I am pleased to be joined by Dr. Helen Sabzevari, President and CEO of Precigen; Pieter Rottiers, CEO, Precigen ActoBio; Dr. Nora Disis, faculty member at the University of Washington and Fred Hutchinson Cancer Research Center and one of our lead investigators for the PRGN-3005 clinical study; Dr. Kevan Herold, Professor of Immunobiology and of Medicine at Yale School of Medicine and one of the lead investigators for the AG019 clinical study. During this update call, we will focus on 2 of our technology platforms: first, the UltraCAR-T platform and the PRGN-3005 and 3006 UltraCAR-T trials in ovarian cancer and in acute myeloid leukemia or AML and MDS, respectively. We will then spend some time discussing the Precigen ActoBio platform, specifically for the AG019 trial for recent onset type 1 diabetes. Following our prepared remarks, we will open the call to Q&A with our lead investigators. [Operator Instructions] I would now like to turn the discussion over to Helen.

Thank you, Steve. I hope that this call finds all our listeners and their families safe and healthy as we head into the end of what has been a very challenging year for all of us. We are very excited to be at the point where we can give you some updates on our platform technologies as well as clinical trials. I also would like to take this opportunity to thank our PIs and KOLs, especially Dr. Nora Disis, one of the pioneers in the field of immuno-oncology, which has basically very graciously given us time today and participate on our Q&A, as well as Dr. Kevan Herold that will be participating on behalf for the program AG019. Unfortunately, we are missing director David Solomon, which has contributed tremendously and is the PI for our AML, due to their clinical obligations. We are very grateful to him for all he has done. And finally, I really would like to address our team at Precigen for a tremendous job that they have done this past year. It's truly my privilege to stand next to a team for -- and their dedication to this field and what they have really achieved. With that, I think we can go to the next slide. As you can see and we have communicated previously, we're going to be looking at 3 of our clinical assets today: basically, the 2 UltraCAR-T programs in ovarian cancer and AML, and also one of our autoimmunity assets, AG019, with the ActoBio platform, the microbial platform. We are also extremely excited about our PRGN-2009 platform, our AdenoVerse platform that, despite of all challenges this year, we were able to clear the IND and NCI. With the leadership of Dr. Jeff Schlom and Dr. James Gulley and their team, they were able to advance and also dose the patients. And we are looking forward to be reporting in the first half of 2021 on this progress of these trials. And similarly for INXN-4001, which we have finished the 1 year, basically, follow-up of the patients and we will be discussing this later on in 2021. With that, we can go to the next slide. Just to give you a perspective and a little bit of a review on our UltraCAR-T platform, in next slide, what you see is basically why we are so excited about the platform that has been evolving at, basically, Precigen, and the differentiation that our platform has compared to all other conventional CARs off the shelf, allogeneic CARs and T cell therapies and even TCRs. As you can see on the right-hand side of this slide, our UltraCARs basically have been designed in such fashion that, first of all, by using our UltraVector, we can simultaneously express number of genes including the CARs of interest; the membrane-bound IL-15, which is essential for the expansion and persistence of the cells directly in patients; and finally, a kill switch, which, in the case of any kind of toxicity, we can activate for safety purposes. The advantage of our UltraCAR platform compared to everything else is that these cells are not expanding and being exhausted outside. These cells are created overnight and infused back to the patients the next day. They have a stem-like T cell memory phenotype, which we believe they can persist and expand much longer than conventional CAR-Ts. And they have the ability to basically target a specific antigen on the tumor cell. One other aspect of this is our really manufacturing for overnight. The diagram that you see, this is the reality that is taking place currently in our clinical settings. As patients walk in, they have been apheresed. On the same day, the UltraVectors in a nonviral fashion are transfected into their own autologous T cells. And the next day, the cells are [ QC-ed ] and infused back to the patient. The importance of this manufacturing platform with the nonviral delivery is we basically do not need a centralized manufacturing anymore, and you can use any clean room of the hospital to basically accomplish this. With that in mind, if we look at the next slide, during the past year, what we have done is also introduce another important part of our manufacturing process to make the UltraCAR platform commercially scalable and viable. The UltraPorator had been designed specifically in order to handle large number of cells. As we speak, up to 4 billion cells can be transfected under 12 minutes. What is the advantage of this? The advantage is you reduce the time but also reduce any aspect for mistakes. Now you don't have to spend hours or days for this transfection but a matter of minutes. And what is very important, this allows the scalability and the global accessibility to this platform, which we are very excited. On the bottom half of this slide, for the first time you're seeing some of the data of the comparison of our UltraPorator device to others. And very clearly, despite of the fact that we keep a very high survivability, in every category that you look at as far as total T cell recovery to CAR-T cell yield or gene transfer efficiency, our UltraPorator is doing better than competitors. And we are excited about this manufacturing process, even though currently we are using UltraPorator at the heart of the manufacturing for our UltraCAR-T platform. I should mention that this device can be used for many other cell therapy or gene therapy procedures, and that is obviously within our sight. With that in mind, in the next slide, I would like to now get to PRGN-3005, which we are extremely excited about this trial as we discuss some of the preliminary interim data today. As you know that obviously this PRGN-3005 has been actually targeted for MUC16 in ovarian cancer, an unmet need. The patients in these indications have very little option. Practically every other treatment is less than 10% response; and stage 4 patients, 20% is the maximum that they have a 5-year survival. I should say that MUC16 not only is expressed highly, more than 80% of the ovarian cancer tumor cells they expressed it; but also on many other indications such as breast cancer, pancreatic, endometrial cancer and even lung cancer, there is an over-expression of this tumor-specific antigen, which allows actually our therapy to be applied to these indications as well. In the next slide, you see our UltraCAR PRGN-3005 on the right-hand side that specifically targets MUC16. But what I should mention here and I like you to focus is our specificity of our UltraCAR for the memory-bound portion of MUC16. And why do I emphasize that? The Achilles' heel for the field of MUC16 has been the issue of shedding of MUC16. Basically, if I want to give you an analogy simply, that when the MUC16 is shed to the blood, it acts like a fishing net. Any kind of therapy that you put in, it gets stuck in this net. And this is why a lot of the treatments has had a problem. Our team at Precigen has designed our CAR-T in a specific fashion that does not interact with the shed portion of MUC16 and only recognizes the membrane-bound portion that is on a tumor cell. And this makes it very, very specific as a result. So with that in mind, let's look at the design of the trial. When we started our discussions, and I should say and I'm grateful to Dr. Disis and her team with FDA, it became very sort of -- it came in life, I should say, that this was considered as far as FDA is concerned, the first in mankind ever because no one has basically attempted to manufacture directly the autologous T cells overnight and allow these T cells to grow in patients. With that in mind, the designs became 2-arm trial of Phase I, Phase Ib, the first arm infusing the UltraCAR-Ts directly intraperitoneally. The second arm of the trial was to infuse the UltraCaR-Ts IV. You have seen the criteria for eligibility on the left-hand side of this slide, which is in advanced-stage ovarian cancer patients. And I have to mention that we have not stratified upfront for the patient for MUC16. We will do that in a retrospective fashion after we basically finish our Phase I and expand to Phase Ib. And then we look at the responses according to the expression of the MUC1 -- MUC16 and also use that as a biomarker. Obviously, the first aim for this trial is safety and dose. And also, we will be looking at disease responses and correlative specifically, as I have mentioned, the expansion of our UltraCAR-T cells in the patient and persistence of these cells, which basically we believe will change the paradigm for the field of CAR-T once we show that. So with that in mind, let's look at the next slide, which shows the dose escalation at this trial. As I mentioned, this is first in mankind. And obviously from FDA and our perspective, we have started at extremely low doses, in a way, sub-efficacious doses. And you see that it's a 3 plus 3 plus 3. And today, we will be reporting on the first 2 dose levels, dose levels 1 and 2. And I want to get your attention to the number of cells that are being infused to the patients. The lowest level is between 3x10^4 to 1x10^5 per kilogram. So our patients, the 3 patients have been dosed between 6 to 7 million UltraCARs total. In the second dose level, our highest dose is at 3x10^5 cells per kilogram for the total of somewhere between 12 million to 21 million cells totally in the next cohort. If I want to put that in perspective for you, compared to what has been done in the field of conventional CAR-Ts, allogeneic off the shelf and TCRs, we are logged lower. And they have basically infused hundreds of millions, if not, billions. And as you can see in the literature, there is practically no responses at all for solid tumors at this point. One other aspects with this trial, which needs to be mentioned, is, again, there is a staggering period between the patients for their DLT observation, followed also with similar staggering between the dose cohorts on this trial. And lastly, the prior treatment of the patients. I would like to mention that the patients in this trial have been heavily pretreated. You see between 6 to 9 lines of prior therapies, which they have failed. And these patients, once they receive their UltraCAR, there is no lymphodepletion at all. Why? Because we believe that the membrane-bound IL-15 with these cells, it basically provides the full backpack that they need. And as a result, you do not need to open up a space that for these cells to have access to a cytokine milieu. With that, let's move to our exciting data. First, safety, the most important thing in a Phase I. Up to date and we are reporting on 6 patients at 2-dose cohort levels, we have seen no DLTs. We have not seen any incidence of neurotoxicity, and we have not seen incidence of cytokine release syndrome, a very clean safety profile. In the next slide, we are extremely excited about our expansion and persistence of these cells. On the left-hand side, you see the dose level 1. This is 3 patients. And what you see here that these cells, between 6 million to 7 million cells giving intraperitoneally. You see the expansion up to the points that we could follow some of these patients. And you see not only the expansion but persistence up to 90 days, yes. On the right-hand side, you have a dose level 2. These patients have received up to 20 million or 21 million cells totally IP, and you can see there is expansion and persistence of these cells. Again, I would like to stress that the picture that you see is from the blood of the patient that have received the UltraCAR intraperitoneally. So these cells are trafficking to blood and they are also expanding. And this is the snapshot of basically trafficking cells across the whole patient's body, and this is very important to be mentioned. In the next slide, always everyone asks on a Phase I, do you see any efficacy, and my general answer is Phase Is are not designed for efficacies. And that's what Phase Ib, Phase IIs and Phase IIIs are. However, what we are very encouraged about is, on the left-hand side, what you see basically here is the pie chart that looks at the response in the individual target lesions of the patients. The dose level 1, you can see that on 36% of the lesions, you have a stable disease; and 9% of the lesion, they show complete responses, again, at the dose of 6 million to 7 million cells infused intraperitoneally. The dose level 2, as we have gone up to 20 million cells, now you see that we have 44% of the lesions are stable, 33% of the lesion show partial response, and 11-odd percent of the lesions are in complete response. This is very encouraging for us, and we are moving to higher doses and expanding to Phase Ib. The right-hand side of this slide basically look at all 3/6 patients as you can see in dose level 1 and dose level 2, and the target tumor burden regression is 50%. 3 out of 6 of these patients have shown regression in their tumor lesion. This is very, very exciting, preliminary but extremely exciting for the dose level that we are in as we move forward to higher doses. In the next slide, I would like to highlight our first patient that entered to this study. This is a patient, 50 -- in her 50s. It was heavily pretreated prior to enrollment, has failed 7 prior lines. It has a disease status at enrollment, number of lesions in axillary lymph node, liver lesions, abdominal lymph nodes. Patient received 7.5 million of autologous UltraCAR-T cells, showed no DLTs, had no lymphodepletion. And as you see on the right-hand side, there was a complete response in axillary lymph node target lesion after 3 months. Eventually, the patient developed new lesions in the liver and was considered as the progressive disease. In the next slide, we have an example from our dose level 2. This is a patient that received -- basically had received 6 prior lines of therapy and had failed everything. The disease status of the enrollment of this patient was 10-plus lesions in liver, lymph node, abdominal wall, peritoneal and received total of 21 million cells. Imagine overnight manufacture received the next day with no expansion on size and no DLTs. From these patients, we also had access to the ascites of the patient from the peritoneal cavities, which now you can see actually these cells are also expanding directly there. And you see from the baseline on day 35, which we received the ascites, you can see there is a significant expansion of these cells there. But more importantly, when you look at this scan of these patients, we saw a complete response in supraclavicular lymph node of the patient at day 35. So I'm going to get your focus on the higher magnification. The lesion went from 15.2 millimeters to 9.79. We had a 13% reduction in sum of all lesions at 5 weeks. Unfortunately for this patient, eventually, again the patient has developed the new liver and lung lesion and was considered progressive disease. The next slide, this is another case of study of our dose level 2. These patients similarly had 7 prior line of chemotherapy and failed and entered to the trial with 10-plus lesions, liver, lymph node, bladder, peritoneum. So you can see the extensive disease status of these patients. Received 19 million autologous UltracaR-T overnight, no lymphodeletion, no DLTs. And as you can see on the left-hand side, when you look at the axillary lymph nodes, it went from 2.4 centimeter to 1.1 centimeter reduction. And on the left-hand side, 22 days after infusion, you can see the size of the lesion in bladder from 4.1 centimeter reducing to 2.9. There was a 19% reduction in the sum of these lesions at 3 weeks. And the overall status of the patient was considered a stable disease. Actually, 2 of the patients in the 6 achieved a stable disease such in low sub-efficacious doses. So with that in mind, as you can see, we are extremely excited about this trial as it's moving rapidly toward the next cohort and expansion phase at UW, Fred Hutch with Dr. Disis. We have shown a very good safety up-to-date as well as [indiscernible] of expansion and persistence and also the clinical activity on target lesions. And we are really happy to move to the next level as there is very little treatment options for these patients in this trial. With that, now I really would like to also go to our PRGN-3006, which is our UltraCAR that targets CD33 in AML patients. As you know, this is a very, very difficult indication. The patients that are above 65 years old and especially even 70 years old, they have less than 5% chance of surviving in 5 years, and their life span is somewhere between 1.5 to 3.5 months. Why we went to this? It's very simple. None of the other cell therapies would allow for this kind of a time line. And we knew that by being able to produce these cells, this might be the chance that these patients need. So in the next slide, it shows the target of CD33, which is our CAR and expressed arm over the 80%, 90% of the blood cells in these patients of AML and MDS. And it's considered a very good target. Next slide shows our clinical trial, the schema. And if we move to our next, again, as being first in mankind especially for hematological malignancies, what you see here, there are 2 arms in this trial, a non-lymphodepletion arm versus a lymphodepletion. This is the one opportunity that we have that we can actually directly compare here the need of lymphodepletion, which you know they are being used all across CAR-T, TCRs. And especially in allogeneic off the shelf, it's extremely heavily used and leads to a lot of toxicity. And also what we have as a Phase I, Phase Ib is looking at obviously safety, the dose and the disease responses with our correlative readouts as the biomarkers and immune readouts. In the next slide, similarly, we have started at extremely low doses similar to PRGN-3005, and today I will be reporting on basically 9 patients that they have been treated in the first 2 cohorts of the nonlymphodepleted and the first cohort of the lymphodepleted trial. And there is a staggering of 14 to 28 days between the patients for the DLT observation similarly followed with a staggering time between the first dose level to a second level. Next slide. The safety of PRGN-3006, well tolerated and has a very good safety profile. As you can see, we have seen no DLTs or neurotoxicity, low incidence of treatment-related adverse events and serious adverse events, and transient grade 1 to 3 CRS, which was resolved in 2 patients. Next slide. We are extremely excited to show this data. If you recall our journey when we were evolving this platform and we said can you imagine to have an autologous UltraCAR that you manufacture overnight and the next day the patient can receive it, and then this expands directly in the patient and persists. And you don't have to expand these months outside and exhaust them. And then when you inject them with a very high cost, then you will have maybe at best 2 weeks to 3 weeks of viability. The graph on your left hand shows the dose levels, not lymphodeletion, cohort 1; and the dose level without any lymphodeletion on the cohort 2. And what you see here, we have 6 patients, and you see expansion of the cells directly in patient followed by persistence. And the longest patient that we could follow was up to 7 months, which Dr. Solomon reported in the ASH meeting last week. And you can see that clearly these cells have maintained themselves. Similarly for a lymphodepletion, we are at the sub-efficacious dose, remembering again between 30,000 to 100,000 per kilogram. We have been dosing between 1.8 million to maybe 4 million or 5 million cells total IV in this patient. They expand and they persist. Now if we go to next slide, this is a case study that Dr. Solomon presented last week at ASH. This patient is a 69 years old female that has failed multiple treatments prior; and actually, when the patient was enrolled to our trial, the patient was in hospice. And for these patients to be at hospice, you're looking at days. Maybe worse is weeks or months. And this -- and received the total number of cells was 24 million. And the patient did not receive any lymphodepletion in the hematological setting, and we have not seen any DLT on the patient and no neurotoxicity. We also were able to get samples for the day 56 bone marrow biopsy. On the right-hand side the upper graph in purple, you have the expansion and persistence of that 24 million cells that was infused to this patient. And you can see, 7 months later, these cells are there and they are present in the green numbers. Also, what that parallel is exactly with the blast, the green line, stabilization and eventually did drop. And on top, we have added this, which you have not seen before. It's actually one of the immunological biomarkers, is the perforin expression in the blood. And for all of us immunologists, the way we consider perforin is there are little bumps, that cytotoxic T cells they release to destroy the target, which in this case are tumor cells. And you can see that there is an increase in the level as our UltraCAR-Ts have increased. In the bottom, the bone marrow, these cells obviously have traffic to bone marrow. And you can see at the readout at day 28 and 56, there is expansion and persistence, and that correlates with the drop in the blast cells. I think this is very exciting for us. This is the longest following patient that we have had up-to-date. And we are really excited as far as reporting this and which -- at ASH. As of late, actually, what we should -- I should mention is Dr. Solomon has reported another patient, which was dosed at dose level 1 with lymphodepletion. And this patient is also in response and in fact has achieved morphologic leukemia-free state. What does that mean? As you know for the AML, there is ELN criteria and according to that, it means essentially disappearance of cells with characteristics of leukemia cells in the bone marrow at day 28, and it has also held to day 56. This is extremely encouraging, again, remembering these patients received few million cells at the dose level 1 IV, not hundreds of millions, not billions, just a few million. With that in mind, now we are very excited for our PRGN-3006 as well. I believe that across the both trials, we are showing not only good safety profile but also the expansion and persistence of these cells. And even at the very early and sub-efficacious doses, signs of clinical activity on target lesions and basically stabilizations of the disease and in the case that we just report, even in the way partial response and above. So with that, obviously, we are looking forward to escalating our doses rapidly. Our investigators, and I am grateful forever to them as even during the COVID challenges they continue to treat patients. And we are looking forward to our expansion phases with our UltraPorator manufacturing as well as UltraCARs. With that, I would like to hand over now to Pieter and Dr. Kevan Herold to discuss another asset that we are very excited in our autoimmunity portfolio, AG019. Pieter?

Thank you, Helen, and thank you all for listening to the R&D updates. We are pioneering a new plan of micro-based biopharmaceuticals created on the ActoBiotics platform. The ActoBiotics platform works biogenetically in modified Lactococcus lactis, which can be given orally or topically to deliver [indiscernible] therapeutic agents. Through our platform, we are able to modify local and systemic immune and inflammatory responses. Since ActoBiotics are based on the safe food-grade microorganism, Lactococcus lactis, this approach promises safer and more efficacious treatments than injectable agents. Next slide, please. AG019 is currently being investigated in a Phase Ib/IIa study for the treatment of clinical recent-onset type 1 diabetes or T1D in patients with residual functional beta-cell mass. T1D is a chronic autoimmune disease in which the immune system destroys insulin-producing beta cells in the pancreas, resulting in a blood glucose imbalance. Approximately 10 million to 15 million people worldwide suffer from T1D, and it is reported that a global incidence of T1D is increasing by 3% every year. There's no approved disease-modifying treatment for T1D. T1D is currently managed through lifestyle modification and diet combined with insulin therapy. We are engaged in the development of a safe and convenient disease-modifying treatment to preserve or restore beta cell function while leveraging antigen-specific immune tolerance induction. Next slide, please. AG019 is formulated as an easy-to-take capsule of engineered Lactococcus lactis specifically modified to deliver human proinsulin, which is an [ ultra antigenic implicator ] in beta cell [ immunity ] and a tolerance-enhancing cytokine, human Interleukin-10 human proinsulin directly to the mucosal lining of the gastrointestinal tissues. AG019 is designed to induce antigen-specific regulatory T cells that may reduce or eliminate the destruction of insulin producing cells and has the potential to become the first disease modifying treatment [ antibody ]. Preclinical studies demonstrated that AG019, in association with a short-term treatment with systemic anti-CD3 antibody, successfully induced reversion to normal blood sugar levels in 60% of cases and effectively reversed the disease in 89% of mice treated at early stage. Diabetic reversion was also seen with AG019 as a single component, while treatment effects were generally stronger when combined with anti-CD3. Increased levels of antigen-specific regulatory T cells were observed and were essential to the induction and maintenance of active immune tolerance. I would now like to turn the call over to Dr. Kevan Herold, one of our lead investigators for the trial. Kevan?

Next slide. Thank you, Pieter, and thank you for giving me this opportunity to give you an update on this trial that's in progress. Through oral administration of AG019, the genetically modified Lactococcus lactis bacteria is introduced into the subject's gastrointestinal tract. During the residency in the GI tract, the engineered bacteria produce and deliver therapeutic concentrations of human proinsulin and human Interleukin-10 locally at the gut-associated lymphoid tissue, which is also abbreviated GALT, G-A-L-T, which is the largest immune organ in our body. The goal of this approach is to induce proinsulin-specific regulatory T cells that migrate to the inflamed pancreas to block tissue destruction and stabilize insulin production. AG019 is currently being evaluated in a Phase Ib/IIa clinical trial in patients with early onset type 1 diabetes. The trial is enrolling patients in clinical sites in the United States and Belgium and is evaluating AG019 as a monotherapy and in combination with teplizumab, which is currently under investigation in the PROTECT Phase III study for the treatment of newly diagnosed type 1 diabetes. Next slide, please. This Phase Ib/IIa multicenter study consists of 2 concurrent phases. The Phase Ib portion is the open-label part of the study designed to investigate the safety and tolerability of different doses of AG019 in patients 12 to 17 years of age and adults 18 to 40 years of age. Patients are treated twice daily with AG019 for 1 treatment cycle of 8 weeks at either a low dose, which is 2 capsules per day or a high dose, which is 6 capsules per day. The Phase IIa portion is the randomized, double-blind part of the study designed to investigate the safety and tolerability of AG019 in combination with teplizumab in the same 2 age groups in comparison to placebo. Patients are treated twice daily with AG019 or placebo for 8 weeks at a high dose 6 capsules per day. In addition, patients received daily intravenous infusions of teplizumab or placebo for the first 12 days of the 8-week AG019 or placebo treatment period. The primary objective of this study is to assess the safety and tolerability of AG019-alone monotherapy as well as AG019 in combination with teplizumab. The secondary objectives of this study are to obtain pharmacodynamic data of AG019 alone as well as in combination with teplizumab and to determine the potential presence of AG019 in systemic circulation and the presence of Lactococcus lactis bacteria in fecal excretion. All patients are followed for a total of 12 months after treatment start. Enrollment and treatment in the Phase Ib portion and Phase IIa portion -- adult portion of the study is complete. An interim analysis was conducted in September 2020, and all available data for all Phase Ib patients up to 12 months after treatment start as well as all available data for the Phase IIa adult patients up to 6 months after treatment start were analyzed. The Phase IIa adolescent portion of the trial continues to enroll. Next slide, please. As I've said, the safety and tolerability up to 6 months after treatment initiation is the primary objective of the ongoing Phase Ib/IIa study. Here, we list the main conclusions related to the safety and tolerability based on the analysis conducted thus far. AG019 treatment was generally safe and well tolerated when administered as a single low or high dose and as a repeated low or high daily dose for 8 weeks as monotherapy or in combination with teplizumab. No AG019 treatment discontinuation occurred due to treatment-emergent adverse events, or TEAEs, either in the Phase Ib portion nor in the Phase IIa patients treated thus far. To date, there has been no evidence of dose-related adverse events nor of a different safety profile in adolescents compared to adults. Finally, no serious TEAEs were reported in any of the patients. The combination of AG019 and teplizumab was safe and well tolerated. The TEAEs reported in the AG019 teplizumab combination cohorts are in line with the safety profile reported for teplizumab alone in its investigator brochure and no unexpected TEAEs were identified. Furthermore, pharmacokinetic analysis showed that there was no evidence for systemic exposure of AG019 in the circulation, reaffirming our understanding of the safety profile of AG019 both as a monotherapy and in combination is good. Overall, we confirm the safety and tolerability of the AG019 mono and combination therapy up to 12 months and up to 6 months after treatment start respectively. The primary objective of the study was met for the dose-completed cohorts and is pending for the adolescent combination cohort. Next slide. Encouraging data were observed in the Phase Ib AG019 monotherapy adult cohorts for the mean AUC, the area under the curve of C-peptide, which is a marker conventionally used to determine the functionality of pancreatic beta cells. At 6 months after treatment initiation, 58% or 7 of the 12 of the patients of 17 years and older receiving the AG019 monotherapy were able to maintain their baseline C-peptide levels, which is designated here as responders. The degree of AG019-induced stabilization at 6 months is similar to what has been demonstrated in other clinical trials using a 14-day daily infusion of teplizumab anti-CD3 antibody. At 12 months, C-peptide levels in the AG019-treated patients were higher than placebo-treated patients, as prolonged C-peptide stabilization may be achieved by repeating the AG019 treatment cycle, which could be examined in subsequent clinical trials. In addition, in a mechanistic analysis performed by The Immune Tolerance Network, a leading independent research group, AG019 monotherapy showed an increase in the frequency of different types of antigen-specific regulatory T cells, a potential mechanistic indicator of therapeutic activity in the circulation of adult patients 3 months after treatment initiation. Type 1 regulatory cells with reactivity against pre-proinsulin, which forms the major part of the auto antigen proinsulin, delivered by AG019 to the mucosal lining of the gastrointestinal tissues. But also activated T regulatory cells with reactivity against other islet antigens such as GAD65 and IGRP, indicating induction of disease-specific bystander suppression. This induction of bystander suppression is an important property by which antigen-specific treatments modulate different autoreactive pathogenic T cells. It would allow treatment of autoimmune and hypersensitivity responses where not all of the initiating auto-antigens are known. In conjunction with the induction of antigen-specific tolerance, AG019 monotherapy shows a significant reduction in the frequency of circulating antigen-specific CD8-positive T cells. This significant reduction in this disease-specific T cell response has been demonstrated mainly at 3 months after treatment initiation. Next slide, please. Also, in the adult combination group, encouraging data were observed for the interim analysis of the mean AUC of C-peptide. At 6 months after treatment initiation, 70% of adult patients or 7 out of 10 receiving AG019 in combination with teplizumab were able to maintain their baseline C-peptide level, their designated responders. The percent change from baseline of the mean C-peptide response area under the curve at 6 months was an increase of 10% in the combination group, the [ n=10 ], as compared to a decline of 27% in the adult placebo group, [ n=2 ]. Both of them are designated as nonresponders. As compared to the stabilization at baseline that was demonstrated in clinical trials using a 14-day infusion with anti-CD3 teplizumab, the levels of C-peptide in patients treated with the combination AG019 with teplizumab at 6 months appears to be similar, if not, higher. Similar to the immunologic effects seen in the AG019 monotherapy patients, pre-proinsulin specific in islet-specific regulatory T cells increased in the circulation of the combination the AG019 plus teplizumab-treated patients, confirming tolerance induction towards proinsulin and towards other autoantigens, the bystander suppression. In these combination therapy patients, there is also a significant reduction in the proinsulin specific CD8-positive T cells similar to a degree as what was measured in the monotherapy-treated patients. Since the extent of these antigen-specific modulatory effects in the combination therapy patients is similar to what was seen in the monotherapy patients, this effect may be attributed to the single 8-week treatment cycle of the oral AG019. Next slide, please. So in terms of our overall conclusions, the oral AG019 monotherapy has been safe and well tolerated, and I believe this could provide an opportunity for chronic treatment in different age groups and different stages of type 1 diabetes. In addition, the fact that we have seen it stabilizes C-peptide in the first 6 months following 1 treatment cycle of the ingested AG019 may provide an opportunity to prolong treatment effect by repeating the treatment cycles. It has potential to be effective in preserving insulin production in early onset type 1 diabetes through its capacity to induce antigen-specific immune modulation. And finally, the ease of treatment due to oral dosing and disease-modifying potential differentiates AG019 from competing therapies. To date, AG019 in combination therapy has been safe and well tolerated and has potential to boost or prolong teplizumab-induced metabolic effects for reduction of antigen-specific immune modulation. And there is opportunity to explore combinations with other systemic inducers in addition to teplizumab, therefore, this study is validating the ActoBiotics platform for antigen-specific immune therapy. The ease of administration and emerging safety profile could enable treating a wide range of chronic immune-mediated diseases and gives us the ability to establish antigen-specific immune modulation by inducing disease-specific immune modulation and reducing disease-specific effector T cell responses. I look forward to the opportunity to broaden this therapeutic application towards the many other autoimmune diseases in humans. With that, I would now like to turn the call back to Helen for concluding remarks. Helen?

Thank you, Kevan. As you can see, we are very excited about the portfolio that we have brought forward in number of indication and the field. And as we started this journey in January of 2020 at JPMorgan and we put forward our goals for this year, we have done a tremendous amount of work and the teams and PIs for our clinical trial as well as our preclinical. And as you can see in this slide, everything that we had put as goal for our organization, we have met. We have met the initial data released for IP arms. We have now given a transparent look to our manufacturing and establishment of our UltraCAR platform and expansion to Phase Ib for both PRGN-3005 and 6. We showed the interim data released from Phase II of AG013, the interim data from Phase Ib and IIa of AG019 as you just heard, which is quite exciting. We have finished our 4001 heart failure program, the 12-month observation, and we'll be reporting on that. And finally, we have initiated our very, very exciting AdenoVerse platform PRGN-2009 in collaboration at NCI and have dosed the patients, and we will be reporting on that in the first half of 2021. So with that, I'd like to thank you for all joining us for our update call. As you can see, we continue to advance our existing programs. Both our teams and our PIs, we are looking forward to 2021 to be discussing our programs at various conferences and events. And I would like to, on behalf of the Precigen, wishing you and your families a safe and healthy holidays. And we'll turn the call now for question-and-answer to Steven and our operator.

Thank you, Helen. Go ahead, Chuck. Thank you.

[Operator Instructions] And our first question will come from Jason Butler with JMP Securities.

For Jason. I guess I'll start with questions for Dr. Disis and PRGN-3005. Can you put into context how encouraging the signals you are seeing with PRGN-3005 in ovarian cancer, how predictive you think the data can be for clinical responses in subsequent cohorts and trials, especially in light of the low doses and heavily pretreated patient population? And then as far as the manufacturing process, can you give us some practical perspective, any experience you have with the UltraPorator and the ability to treat without lymphodepletion? And then has any of this been relevant particularly during the COVID pandemic?

Sure. The first is about the clinical responses. I do have to say, of every clinical trial I've ever run in ovarian cancer, these patients were the most heavily pretreated. I mean they're in their eighth or ninth line of therapy, and these were truly patients where the next step for them was nothing. So I've never really had patients at that stage previously. So I think seeing anything in terms of target lesion responses was unexpected for me. How these would predict responses in a Phase II clinical trial, it's impossible to say because the Phase II patients are not going to be as sick as these patients were. So all I can say is that the responses that we saw were unexpected, and they were mixed. Concerning the manufacture of the cells, I'm at the University of Washington, Fred Hutchinson Cancer Center, so we do a lot of CAR-T cell therapy here. This was a very streamlined manufacture that we were able to do easily in our academic GMP facility. We had absolutely no problems with the protocol as it existed. And the interesting thing about our patients is that several of them came in really lymphopenic from their previous chemotherapy because the chemotherapy of these patients in particular really does have an effect on the lymphocyte. So we had patients who were really on the cusp of not qualifying and going back. They had low lymphocyte counts. We still were able to get enough cells to be able to infuse the patients. So I think that considering this as a point-of-care therapy, it worked very well in our center as being just that, a point-of-care therapy. And we were mostly able to continue the clinical trial during COVID because we could get the patients in and out. And once we had COVID testing where we would test the patients before they -- in the 72 hours before they came in, we were able to keep the clinical trial moving. There was a period where we had to shut due to the fact that it was a new CAR-T cell therapy protocol and people were used to CAR-T cell therapy patients going into ICU. But now even though we're in a surge, because the trial has been so nontoxic out of all the trials going on at our institution, they're letting ours continue because we haven't been able -- we haven't had any use of the ICU or any indication that the patients were going to have severe toxicities.

Okay. Great. And then if I can ask one follow-up. I guess given the ease of manufacturing, how do you think about retreatment with this candidate?

Oh, definitely. We've discussed retreatment. We've -- I think we've retreated one patient, but definitely in the Phase II or the Phase Ib component, we're planning on revising to do retreatment.

Our next question will come from Swayampakula Ramakanth with H.C. Wainwright.

So this is a question for the doctor. So when you are looking at the data at this point, considering that these patients certainly are heavily pretreated, but at the same time, I believe these are patients with mixed ovarian cancer [ in ] the fallopian tube or in the peritoneum. Do you see any difference between the regions at all? And do you think you can tease out anything in terms of which lesion within the ovary this therapy could be effective? Or is it universal between the 2?

In terms of what the histology is, primary peritoneal or clear cell or serous, is that what you mean?

Yes.

Yes. We definitely have primary peritoneal tumors. And I think that that's very important because there really is no good therapy for those patients, and they have the tendency not to respond so well to the chemotherapy. But there are so few patients in the Phase I study at this point. We can't really tell whether one histology responds better than another. We just don't have enough histologies enrolled in the study at this point.

If I can ask an additional question, this is on AG019. So if we look at the stabilization of C-peptides at 6-month data, it seems like the combination therapy with teplizumab does not seem to do much to AG019. Do you have any commentary on this observation? And how do you plan to take this program forward? That is -- would you consider this as a monotherapy or a combination therapy?

I think it's a little early to say, in a relatively small number of individuals, what the final effect on C-peptide is going to be. And the other part of this is, remember, a lot of the data that you're looking at is in adults. And the adults tend to decline slower than children, so there may be an even bigger effect in children. We don't know. So in terms of sort of taking it forward, I think that the beauty here is that this is a therapy that can be readministered. It's safe that it seems to be specific in its activity. And so I think the next steps would be designing a more fully powered study to look at the longer-term efficacy on C-peptides, something along the lines of at least a year and then probably out to 2 years.

Our next question will come from Eric Joseph with JPMorgan.

I have a couple. First, if you could clarify the level of overall anti-tumor activity you're seeing with PRGN-3005 at non-lymph node lesions. And secondly, do you have a sense of how well the UltraCAR cells are trafficking outside of the lymphatic system? And would you expect a different expansion or trafficking dynamic with IV administration?

Definitely, the lymph nodes are the most responsive place where we're seeing like the complete remissions, although we have seen responses in metastases and organs. So it's such a small number of patients. I can't say that there is a trend. I mean the data was presented that we saw them at both, but that's something that we're definitely going to look at as we go into the Ib expansion, really get a handle on whether some lesions are more responsive than others. Like, classically, you don't see responses in liver lesions for example. We saw response in a bladder lesion for example. So too few patients to be able to say a trend. Now the second part of your question was what? Can you repeat that?

Expectations around cell expansion with IV administration versus intraperitoneal administration.

Right. So as you saw in the intraperitoneal administration, we were getting expansion in the vascular space because we were taking blood and looking for expansion. So we saw expansion both in the blood as well as in the peritoneal cavity in that one patient. We are finishing up the final dose for the IP expansion, and we're rolling over into the Ib expansion study for that. And simultaneously, we're starting an IV study now that will mirror this IP study. So it has been very easy to enroll this study because many patients, when they get to the end of the road, they feel like doing at least one more thing. So we hope that we'll have data on at least 2 of the IV arms by the time ASCO comes along.

Great. That's helpful. And maybe just one more if I could. You provided some thoughts about the ease of manufacturing the cells at your center, which is highly experienced. Do you have a sense of -- or what are your impressions of how well the manufacturing process might be integrated at less CAR-T experienced hospitals if the company were to move forward with a noncentralized manufacturing scheme at commercialization?

In my opinion, and I've done a lot of even adoptive T cell therapies where we were doing autologous T cell expansions ourselves in our GMP facility. I think that this could easily be translated to a blood bank, easily. In terms of how difficult it is to do this manufacture, it's pretty straightforward. I think the thing that keeps CAR-T cell therapy from going out into the community is not necessarily the manufacturing because now you can get GMP in a box and put it in your investigative drug pharmacy. I mean T-VEC and agents like that have really pushed the envelope of what can be done at local hospitals. What has prevented CAR-T cells from going out into the community has been the toxicity, which is stunning and local practitioners are scared of it. It's like bone marrow transplantation. So they always send people to the academic medical center. I think that, that is the benefit of this approach. It doesn't appear to have those toxicities, even though you can detect the cells and the cells appear to be active. So that is the big hurdle that I think has been overcome that will allow this to go into primary care oncology practices.

I'd like to raise a few questions that have come in to our website. This one's for Pieter on the ActoBio platform. Pieter, the question is since you've developed the microbial platform with oral dosing, can you comment on the possibility of redosing opportunities.

Sure, Steve. Thanks for the question. So indeed what have -- what we learned from this first-in-a-man study is that whether 1 treatment cycle of 8 weeks is safe. And that's one thing that's clearly coming out from the primary objectives. So it's a safe platform and product to be applied to patients via the old route. So that's one thing. What we already learned from the C-peptide data but also from the mechanistic assessment is that we already, with the one treatment cycle, can [ have ] immune system and move it into the direction of immune tolerance induction, which is obviously the goal of an antigen-specific immunotherapy and which the value results in the mono CAR-T and stabilization of C-peptides the first 6 months, which gives us the impression that we already have an impact. But since it is safe, we -- and that is what we're currently planning to do in the next study as Kevan already discussed, is to repeat the treatment cycles so that we have the option to prolong the treatment effect that we can see on C-peptides. And the same from the mechanistic assessment, we already could demonstrate that we induce antigen-specific T cell subsets in the circulation and at the same time, reduce the disease-specific CD8, which we see that mainly is happening 3 months follow-up. So a booster treatment makes sense to prolong the effect, and especially the safety profile makes that feasible.

Thank you, Pieter. Chuck, any other questions in the queue? I think I see one.

Yes, sir. We have a follow-up question from Jason Butler with JMP Securities.

We just had a follow-up on AG019. Just how does the patient population that you're studying compare to that risk population that was study for teplizumab?

So the at-risk population that was used in the TrialNet TN10 trial, those patients do not have diabetes yet. They are at high risk, but they do not -- they have not fulfilled the diagnostic criteria that the ADA has established. These patients -- and I would point out again in response to the previous question about the efficacy, these patients had been diagnosed with diabetes. And some of them have had diabetes for a couple of months. And so I think -- so the answer to your question is that in the teplizumab prevention trial, those patients were at risk. They had not yet been diagnosed. These patients had diabetes, and they were further along. And the reason I wanted to raise that question about timing is that the available data would suggest that the intervention very soon after the onset or even just before the onset but certainly very soon after the onset, is likely to yield a better efficacy of immune therapies. And so I think all things considered then, you would have to say that these results are pretty reasonable considering it was a tough population. And if anything, you would expect that now if a new trial is done with those most likely to respond, the efficacy might even be better.

We have another question that came in through the website for Dr. Disis. Do you see an opportunity to position this treatment earlier than the 6 to 8 rounds of previous treatments patients have had?

Oh, absolutely. Obviously, because of the previous track record of toxicity, we had to go into a population where there was a risk/benefit ratio. But you could almost see this being part of adjunct therapy in anyone with primary ovarian cancer. Most patients are diagnosed at advanced stage, and most patients, 75% of them end up relapsing. This is a type of therapy that could be easily integrated into the adjuvant setting as kind of a consolidation therapy after the initial chemotherapy. So I think that it could be a universal treatment for ovarian cancer and maybe lead to an overall survival benefit. That's where I would see this placed as primary therapy.

Dr. Disis, there's a follow-up to that. Could you just comment on the possible economics of allogeneic versus off the shelf in this?

Yes. Maybe I can...

Or Helen, please.

Yes, maybe I can take that. Obviously, in regard to the allogeneic CAR-T, they still have to manufacture these for, as you know, in cases of Allogene and others, that you're basically manufacturing for upwards of 100 patients. This is a heavy manufacturing, which can be quite expensive. And on top of that, what off-the-shelf allogeneic has required, it has been tremendous lymphodepletion, which has led to high toxicity. As Dr. Disis referred to, this is one of the major issues that the physicians are basically shying away. And clearly in our settings, we have first of all, testing all of the non lymphodepletion, and we are showing that our manufacturing is capable to do that and also to see some of the clinical indications on the non-lymphodepleted patients both in hematological as well as the centers. And the one other aspect of this is we basically by overnight manufacturing, we have turned this to off the shelf but even faster. As people are aware in allogeneic, it takes between 5 to 12 days of transfer. And again, for every 100 patients, you have to go and manufacture these things, which is costly, time-consuming and not practical. As what we have seen for instance in the cases of Novartis and Kite, Gilead that the number of the patients that are being really treated per year is very limited because of the manufacturing cost. This is something that obviously we feel the UltraCAR platform has the advantage.

And then one final question for Helen. This person asked do you have any plans to expand to other indications that also express MUC16 for the trial that you have with ovarian cancer.

As we mentioned, clearly the MUC16 expression is seen in number of other indication including pancreatic, lung as well as the endometrial. And we are very excited about the possibility of this UltraCAR being applied to other indication. And next year, I will invite and we'll be in communicating with our base, actually the approach that we will be taking on an UltraCAR and UltraCAR platform in regard to number of other indications and in general to the whole platform, which we are very excited about.

This concludes our question-and-answer session. I would like to turn the conference back over to Dr. Helen Sabzevari for any closing remarks. Please go ahead, ma'am.

Thank you so much. First of all, I want to thank all of our listeners and everyone that has dialed in. We are extremely excited about our portfolio and programs. And I also would like to thank all of our PIs and KOLs. We are eternally grateful to them for treating our patients and advancing the treatment. With that, I wish all the best holidays and new year. Thank you.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.