Good evening or good morning. Welcome to mRNA Therapeutic Vaccine Program updates call of Everest Medicines. Please be advised that today's conference is being recorded. During the Q&A session, for participants who joined the call through PC or app, please click the red button at the bottom of the screen to queue for voice questions or text your questions as messages. For participants who dialed in, please press star one to queue for questions. And finally, I would like to hand the conference over to the speaker today, Ms. Leah Liu. Please go ahead.
Thank you, Operator. Good morning or good evening to everyone, and welcome to our call today to discuss the recent developments on our mRNA therapeutic vaccine programs. Joining us today are Mr. Rogers Luo, our Chief Executive Officer; Mr. Ian Woo, President and Chief Financial Officer; Dr. Jennifer Yang, our Chief Scientific Officer; and Sunny Zhu, our Chief Medical Officer. Before we get started today, I would like to remind you that the speakers on this conference call may make statements that constitute forward-looking statements, including descriptions regarding the intent, belief, or current expectations of the company or its officers with respect to the business operations and financial positions of the company, which can be identified by terminology such as will, expects, anticipates, future, intents, plans, beliefs, estimates, confidence, and similar statements. Such forward-looking statements are not guaranteed to fully perform or involve optimism.
Uncertainties and actual results may differ from those in the forward-looking statements as a result of various factors and assumptions. The company or any of its affiliates, directors, officers, advisors, or representatives have no obligation and does not undertake to revise forward-looking statements to reflect new information, future events, or circumstances after the date of this conference call, except as required by law. And now I will hand over the call to Ian to give you an introduction on our mRNA vaccine programs. Ian, over to you. Thank you.
Thank you, Leah, and good morning, everyone. Thank you all for joining us on this call. We're here, as you can see in the agenda, to discuss a future organic growth driver for Everest, which is our internally discovered pipeline of mRNA therapeutic vaccines. But I also wanted to take this opportunity to mention that we have already created a strong revenue base through our unique and growing commercial asset portfolio, which includes products such as Nefecon, Xerava, and Velsipity across Greater China, South Korea, and Singapore. Our commercial verticals of nephrology, immunology, and infectious disease have the potential to deliver 10 billion RMB, or approximately $1.5 billion, in peak sales over time, and we are now approaching corporate-level profitability.
To supplement the contribution from these products and grow shareholder value, we are now rapidly advancing a pipeline of attractive and differentiated mRNA therapeutic vaccines, including personalized cancer vaccines, tumor-associated antigen vaccines, and an in vivo CAR-T platform that could be used for both autoimmune and oncology diseases. We have been working on this platform and these programs for several years, and today we will discuss our progress on these important assets, which carry global rights that may facilitate partnerships and create a second powerful growth engine for Everest. I would now like to turn it over to Dr. Jennifer Yang to discuss our programs. Dr. Yang?
Thank you, Ian. At Everest, we have a fully integrated and clinically validated mRNA platform and established end-to-end capabilities across the value chain of this platform. Our proprietary mRNA antigen design algorithm can ensure high expression of target protein. Our proprietary LNP delivery system can lead to enhanced T-cell immunity suitable for cancer vaccine. Our CMC process development capability ensures robust DS and DP production. Last but not least, our self-owned manufacturing facility has successfully produced different batches of GMP material. The mRNA sequence design algorithm is enabled by AI modeling. The first-gen algorithm focused on optimization of codon usage and minimized sequence liabilities. Our second-gen algorithm further took into consideration RNA secondary structure. And the third-generation algorithm is an AI scoring model to co-optimize UTR and CDS to further increase mRNA stability.
As shown in the bottom graph, with the third-generation AI-assisted algorithm, we can achieve five-fold more protein expression as compared to that generated from the first-gen algorithm. Even for a commercial enzyme like EGFP, our third-generation algorithm can further enhance its expression. AI has also been used in our efforts for the high throughput lipid screening. It not only expands the diversity of the lipid library, but also increases the screening efficiency. As a result, we now have an in-house proprietary ionizable lipid library. Shown on the left side top panel, you can see in our library we have more lipids that can generate high immunogenicity as compared to the benchmark MC3 and SM-102 lipid. If you focus on the top middle panel, we tested our in-house Lipid A for three different antigens: antigen one, antigen two, and antigen three.
For all three antigens, you can see LNP with our own Lipid A can generate higher immunogenicity compared to that from MC3. And this does translate into better anti-tumor efficacy as depicted in the right side graph. To minimize potential toxicity liability of lipid, we want the ionizable lipid to be biodegradable. As shown in the bottom graph, this is a rat PK study. You can see our Lipid A has a faster clearance rate compared to SM-102 in both the plasma as well as in liver. This proprietary delivery system can also achieve tissue and cell-specific delivery via either passive or active targeting. As you probably know, classic LNP tends to enrich in liver. Very few of them will end up in spleen. With our own proprietary LNP, we can detarget liver and enrich the antigen expression in spleen.
By conjugating targeting moieties such as monoclonal antibodies on the surface of LNP, we can further achieve cell-type specific delivery. Shown as an example in the bottom graph, here we conjugated a T-cell targeting antibody, and you can see in mouse in vivo experiment, target antigen or protein expression is specific for T-cells. There is no expression in other immune cells such as B cell, NK cell, or monocyte. With this platform, we've established a pipeline of mRNA therapeutics. The most advanced one is our personalized cancer vaccine PCV program, EVM16, which has commenced an investigator-initiated trial in China. We are glad to announce that the first patient was dosed on March 4th. Our off-the-shelf TAA cancer vaccine program, EVM14, has successfully completed our IND- enabling studies, and US IND was submitted last month.
The in vivo CAR-T program has made significant progress last year and achieved preclinical proof of concept. And we recently also completed a non-human primate study, and this program continues to progress towards preclinical candidate selection. Now, in the next session, I will give updates on the progress made for all three programs. First is our personalized cancer vaccine program. As you probably know, personalized cancer vaccines utilize new antigens targeted for vaccine design. So what are new antigens? As you know, during the cancer progression, tumor cells accumulate a lot of somatic mutations, and these somatic mutations will generate new antigen that's only present in the tumor cells, not in normal cells. These new antigens can be processed and presented on the surface of tumor cells and can be recognized by immune cells like T-cells to launch immune response against cancer cells.
Neoantigens nowadays have been used in vaccines and other types of immunotherapy such as TCR-T, and they've been studied in the treatment of many types of cancer. Personalized neoantigen cancer vaccine has generated promising early clinical signals. They can significantly reduce recurrence and enhance immune response in multiple types of cancer. Shown here are two examples. The left side is a PCV from BioNTech. In their pancreatic cancer Phase 1 study, it was found that at 3.2 years follow-up, 75% of responders were recurrence-free, as depicted in the top left side figure as the red line. The non-responders had a median PFS of only 13.4 months. So this represents a reduction of 86% recurrence risk.
More interestingly, after a booster shot, it was found that neoantigen-specific CD8 T-cell clones have an average estimate lifespan of 7.7 years, and 20% of the clones have an estimate lifespan greater than 10 years, suggesting that PCV can elicit memory T-cells in patients, and these memory T-cells are long-lived, can combat cancer, and prevent recurrence. Right side is another example of a PCV from Moderna, mRNA-4157. In the melanoma trial, it was found that at three years follow-up, the recurrence risk was reduced by 49% compared to Keytruda monotherapy, and the death risk is also having an encouraging reducing trend, so we all know not all neoantigens are immunogenic, there are certain requirements that need to be met for inducing a robust neoantigen T-cell response and tumor killing.
For example, there needs to be presence of somatic mutations, and these mutations need to be expressed, and neoantigen needs to be presented, and the availability of neoantigen-specific or cross-reactive T-cells needs to be present to fight tumor cells. So to identify the most immunogenic neoantigens from hundreds or thousands of mutations is actually the key for success for PCV. At Everest, we developed a proprietary machine learning-based neoantigen prediction algorithm named EverNeo-1. This algorithm took into consideration many aspects of a strong immunogenic neoantigen, and we can rank these immunogenic neoantigens and design them into a vaccine. We first validated EverNeo-1 in human neoantigen immunogenicity data. We used two different data sets. One data set is from TIL reactive MHC Class I neoantigens in more than 7,000 mutations from 39 cancer patients.
We tested the ability of EverNeo-1 to capture immunogenic mutations and did a head-to-head comparison with an industry-leading neoantigen prediction algorithm, MSKCC algorithm. This algorithm was developed by Memorial Sloan Kettering Cancer Center. As you can see from the top table, if you took the top 20, top 30, or top 34 neoantigens, our EverNeo-1 algorithm performed superior to the MSKCC algorithm in that we can capture more immunogenic neoantigens. The second data set we used was a published PCV mRNA vaccine phase I study immunogenicity data. Again, we are glad to see EverNeo-1 performed very well in this data set. We can capture the majority of the high immunogenic neoantigens, especially for those CD8 neoantigens. Our capturing rate reached 84%. In addition to in silico validation, we also validated EverNeo-1 in preclinical animal models.
Here, we took mouse tumor and blood. After next-gen sequencing, we used EverNeo-1 to predict and select immunogenic neoantigens and assemble them into a vaccine called EVM5. In the mouse immunogenicity study, as shown in the middle panel, you can see that EVM5 vaccination elicited strong T-cell response, much higher than those elicited by a positive control vaccine. So the positive control vaccine, we used all literature-reported neoantigens and put them into this positive control vaccine. In the syngeneic mouse tumor model, you can also see that EVM5 treatment leads to greater anti-tumor efficacy. The tumor growth inhibition, TGI, reached 84%, whereas the positive control vaccine only has a TGI of 63%. We also show that PCV vaccine in combination with anti-PD-1 antibody showed a strong synergistic effect in T-cell activation.
In both the early treatment setting as well as the advanced disease setting, the combination group always elicited stronger T-cell activation, supporting the exploration of this combination in clinical studies. PCV vaccine can also stimulate potent and sustainable T-cell response in NHP in monkey in a dose-dependent manner. Interestingly, after a booster shot at day 161, you can see T-cell response can be further stimulated, and the T-cell response is sustained up to day 182. In preclinical toxicity studies, a personalized cancer vaccine showed a favorable safety profile. With that, we've launched an IIT study in two top cancer hospitals in China: Fudan University Shanghai Cancer Center and Beijing Cancer Hospital. In this phase I study, we are evaluating safety tolerability of EVM16 monotherapy as well as in combination with anti-PD-1 antibody to determine RP2D of EVM16.
We'll also be evaluating immunogenicity and other clinical aspects in this trial. And we are glad to announce that the first patient was dosed on March 4th. In the next year or two, there will be more multiple important milestones for PCV, including a phase III data readout of Moderna's PCV in adjuvant melanoma setting and a phase II data readout of BioNTech's PCV in adjuvant colorectal cancer. We hope that this new class of cancer vaccine can bring clinical benefit to cancer patients. Now, I'm going to introduce the second program, Tumor-Associated Antigen TAA Cancer Vaccine Program. So EVM14 is an off-the-shelf TAA vaccine. There are certain advantages of TAA cancer vaccine. First of all, this class of vaccine usually has good tumor specificity, as those TAAs are only expressed at high level in tumor tissues, very limited expression in normal tissue.
Second, because there are more T-cell epitopes in the TAA vaccine, therefore there is no HLA selection needed for patients. This is in contrast to the TCR-T type of therapy. Due to its off-the-shelf nature, this type of vaccine is well-suited for advanced disease setting. Compared to PCV, TAA vaccine has much reduced manufacturing cost, and it also has potential to be applicable for multiple cancer indications. TAA vaccine has shown promising early clinical signs. An example here is BioNTech's TAA vaccine, BNT111. This vaccine has four TAAs. In their phase I in relapsed melanoma trial, you can see that vaccine in combination with anti-PD-1 can give 35% ORR, suggesting that advanced stage cancer patients can have benefit from this type of vaccine. Our EVM14 is a bivalent vaccine designed to target five TAAs expressed in squamous non-small cell lung cancer as well as squamous head and neck cancer.
In vitro, we observed good expression of all five TAAs. In a mouse immunogenicity study, EVM14 elicited dose-dependent immunogenicity, and with the highest immunogenicity achieved at 10 microgram dose. If you focus on the left side graph, each of the colors indicates one TAA, and you can see a general trend of dose dependence in this mouse immunogenicity study, and this does also translate into quite impressive anti-tumor efficacy, as shown in the right side graph. The black line indicates mice treated with PBS. The green line is mice treated with control mRNA. For this control mRNA, there is no TAA present, and group three to five are mice treated with EVM14 at different doses. Again, 10 microgram dose gives the best anti-tumor efficacy. We also looked at the mechanism of action of EVM14 and found that two doses of EVM14 can significantly enhance T-cell infiltration into tumor cells.
Especially, increased cytotoxic T-cell activation was observed. As you can see from the right side top panel, group two are mice treated with EVM14. For the T-cell marker, as well as the cytotoxic T-cell marker, granzyme B and Interferon- gamma, you can see there's increase in group two. In the meanwhile, two doses of EVM14 can also significantly decrease tumor infiltration Treg cells and exhausted T-cells, as shown in the bottom two graphs, suggesting that vaccine treatment can have an impact on the tumor microenvironment to reduce the suppressive immune cells, which we believe contribute to the anti-tumor efficacy. More interestingly, we also found that TAA cancer vaccine can induce immune memory and prevent tumor recurrence. In this particular experiment, after vaccine treatment, the majority of the mice, 13 out of 15 mice, did not grow tumor. They were tumor-free.
We stopped treatment on day 25, and on day 46, and day 90, we reimplanted tumor cells to these mice. Impressively, these mice remained tumor-free. Basically, they rejected tumor cells, suggesting that vaccine treatment induced long-lived memory T-cells, and these memory T-cells can combat cancer cells. Basically, these mice are cured for tumor. Combination of EVM14 with immune checkpoint inhibitors, such as anti-PD-1 antibody or anti-CTLA-4 antibody, can significantly enhance anti-tumor activity, supporting further exploration of this combination regimen in clinic. As shown in both graphs, the combination group has highest anti-tumor efficacy. Last year, we have successfully completed overall IND enabling studies, and we successfully submitted U.S. IND last month, and CDE IND submission is in progress. Now, let me switch gears to introduce our mRNA in vivo CAR-T program.
Recent years, CAR-T therapy has expanded its application beyond liquid tumor into other disease settings, especially for the B-cell-mediated autoimmune disease. There is a great success of an anti-CD19 CAR-T therapy for refractory SLE patients. Key findings of this clinical study are that there is no relapse in long-term follow-up up to 17 months after CAR-T therapy, despite B-cell reconstitution around four months. This suggests that CAR-T therapy can reset the immune system. The reconstituted or recurrent B cells were mostly naive B. There are no plasma blasts, memory B, or activated memory B cells, or pathogenic B cells. CAR-T therapy in this particular setting also has a favorable safety profile. There is no or only very mild CRS observed. Importantly, there is no immune effector cell-associated neurotoxicity syndrome. Despite this exciting success, we understand that traditional CAR-T therapy has its own challenges.
The cost of production remains to be high, and patients need to do lymphodepletion, which potentially increases the safety risk. Patients also need to be hospitalized post-treatment. Because the traditional CAR-T is in vivo expansion, the PK and PD is uncontrollable. There are certain manufacturing challenges because there's variation in cell quality. We think in vivo CAR-T can address the majority of these challenges. First of all, in vivo CAR-T, like a traditional medicine, it is off the shelf, so it's easily scalable. There's no lymphodepletion needed, and hospitalization may not be needed for the patient. The PK/PD is more predictable, and quality is more controllable. There are two platforms to achieve in vivo CAR delivery. At Everest, we use the mRNA targeted LNP system to achieve in vivo CAR delivery. Let me explain how this in vivo mRNA CAR-T works.
We conjugate a T-cell antibody to the surface of mRNA LNP. Once in vivo, this LNP can bind to the surface of T-cells. After endocytosis, the CAR-encoding mRNA will be released in the cytoplasm of T-cells and translated into CAR protein and expressed on the surface of T-cells. So it turns regular T-cells into CAR-T cells. Last year, we've made significant progress for our mRNA in vivo CAR-T program, CAR-T program. We've developed a robust conjugation method to ensure consistent and high-efficiency conjugation. We've also identified appropriate targeting ligand that allows specific and high expression of CAR in T-cells. In humanized mouse tumor models, we've shown anti-tumor efficacy and target T-cell depletion. We've also done studies in non-human primate models and showed good T-cell transfection and high CAR expression. Moving forward, we will progress all these programs.
For EVM16, the personalized cancer vaccine program, we aim to complete phase I-A part of our study this year. For the EVM14 TAA cancer vaccine program, we anticipate to receive IND approval in the US and China to start phase I study. The in vivo CAR-T program, we anticipate to generate first preclinical candidates this year in preparation for moving this program to clinic. All of these programs do have great potential for global partnership. With that, I'll hand over to our CEO, Rogers, for closing remarks.
Thank you, Jennifer. As you can see, we have made remarkable progress in our mRNA platform as we just announced that the first patient has been dosed for our first personalized cancer vaccine, EVM16, in China this week. This is a great milestone for our in-house R&D program. We are expecting a catalyst to reach 2025 with a preliminary human data readout from the EVM16 later this year. In addition to EVM16, we have submitted our IND application to US FDA for EVM14 off-the-shelf TAA vaccine in February, and we plan to file IND applications to China's NMPA in the first half of this year. Those all would mark the company's first IND submissions and approvals of our first developed products. Our in vivo CAR-T program is also expected to achieve the first preclinical candidate milestones later this year.
As Everest holds global rights to all of these mRNA therapeutic vaccine programs and assets, we may seek global partnership or BD opportunities to all of our current mRNA therapeutic assets to benefit patients globally as soon as possible. This will be an organic driver for the future of Everest's growth. Thank you.
Hey, operator, can you see if we have any questions on the line, please?
Okay. We will now open for Q&A session. For participants who joined the call through PC or app, please click the raise hand button at the bottom of the screen to queue up for voice questions or text your questions as messages. For participants who dialed in, please press star one to queue up for questions.
We'll give everyone another minute or so. I think there's a lot of material to digest, and Jennifer was very thorough in her presentation, but we'll give the audience a couple more minutes.
For participants who joined the call through PC or app, please click the raise hand button at the bottom of the screen to queue up for voice questions or text your questions as messages. For participants who dialed in, please press star one to queue up for questions.
Okay. I think probably as we go on, we're happy to open for questions if you want to contact the IR team. And I think we'll end the call here. Thank you to all the speakers today, and thank you for all the participants who listened in. Please reach out to us if you have any follow-up questions or if you want additional information. Thank you very much.
Thank you.