Good morning, evening, and welcome everyone to Antengene's first ever R&D Day. Today, we will take a deep dive into Antengene's broad, deep, and truly differentiated pipeline, our organization and R&D infrastructure, and our strategy for commercializing our first product. We have made tremendous progress since our four years of operation, and we believe this is just the beginning of Antengene's journey. As a reminder, during today's call, Antengene will be making certain forward-looking statements, including our business plans and objectives and timings of success of our clinical trials, registration applications, and commercial launches. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect.
I refer you to our Hong Kong Stock Exchange filings for a discussion of risk factors that could cause our actual results to differ materially from those discussed today. I will now introduce our speakers. Today's presentation will be led by Dr. Jay Mei, Antengene's Founder, Chairman, and Chief Executive Officer. Together presenting, we have Dr. Kevin Lynch, Chief Medical O fficer. Dr. Bo Shan, Chief Scientific Officer. Mr. John Chin, Chief Business Officer. Dr. Bing Hou, Executive Director, Drug Discovery. Dr. Aihua Wang, Executive Director, Clinical Development, and Dr. Godfrey Guo, Executive Director, Medical. Here is our agenda for the day. With all the materials we have to cover, our event will take about three and a half hours. Jay will begin by introducing and giving an overview of our company. After that, Kevin will share with you our R&D philosophy, strategy, and capabilities.
Following Kevin's part from 9:20AM all the way to 11:20AM, Bo, Bing, Aihua, and Godfrey will present to you our discovery and early development programs, as well as our clinical programs in hematology and oncology. John will follow by presenting XPOVIO or selinexor's commercial readiness. This is our first asset entering the commercial stage. Lastly, Jay will conclude the event for us. We have reserved time for a total of four Q&A sessions interspersed throughout the program. Hopefully, we can address all your questions and feedback. We will handle the Q&A session by reading out the questions that we receive in the Q&A box. Without further ado, it is my pleasure to turn the event over to Antengene's Founder, Chairman, and Chief Executive Officer, Dr. Jay Mei. Jay, please.
Thank you, Donald, our Chief Financial Officer. Hello, everyone. Thank you so much for joining us today at our first ever Research and Development Day. I would like to thank all our investors for your continued interest and support. Just to recap for everyone, at Antengene, our vision is to develop innovative cancer medicines to treat patients beyond borders worldwide. Our mission is to build an extraordinary research-driven global biotech company to boldly deliver transformational medicines for cancer and other life-threatening diseases. We believe disease and patients do not have borders, and neither should we. True to our vision of treating patients beyond borders, we strive to be a truly global company, conducting clinical trials and bringing therapies to patients around the world. We have abundant content that we would like to share with you today.
Before I pass the time to our clinical and drug discovery team to go through our achievements and outlook for pipeline, I shall start with a brief introduction on our strategy and strategic positioning on where Antengene is today and where we would like to be in five years. Treating patients beyond borders worldwide has always been the core of our company. We are built with an international management team with a presence across different regions of the world to develop therapies for cancer and life-threatening diseases. Our management team, despite being located in different parts of the world, has worked closely over the past decades at multiple points of our careers, allowing seamless collaboration. The same also applies to our operations. We take advantage of the efficiency and talent pool, wherever it may be, to allow us to execute swiftly in the innovation fast lane.
We are an R&D driven company, and we innovate and source innovations from around the world. In other words, we follow where the science goes. We believe our drug candidates, if successfully developed, will ultimately be marketed and benefiting patients globally. We run clinical trials simultaneously in the United States, in Australia, and in China. Lastly, we are laser-focused on the unmet medical needs in each of the specific markets that we operate in, recognizing that unmet medical needs differ across regions. We aim to bring treatment to patients where there are the greatest unmet medical needs, and that is the philosophy behind our highly differentiated pipeline. The remarkable progress we have made over the past four years is a testament to our execution capabilities. Antengene began operations in 2017 as a biotech company.
We did our IPO in 2020 and we are now a publicly listed company in Hong Kong. This year marks an important year when we officially transform from a clinical-stage biotech into a commercial-stage biopharmaceutical company. We are now equipped with core capabilities in drug discovery, clinical development, and manufacturing. Currently, we have a rich pipeline of 15 assets, 10 of them are wholly owned with global rights. Our journey does not stop here. We are not waiting. We are bringing forth to the world disruptive products that will bring transformative therapeutic benefits to patients, and at the same time, to bring value to our investors in a relatively short period of time. In the next four years, we envision ourselves to grow into a truly global biopharmaceutical company.
In 2025, we aim to have a portfolio of two to three assets approved and commercialized globally, have business operations expanded to other parts of the world, and be able to present the world continually with the breakthrough molecules that rescue patients and prolong their lives. This slide will be run through in greater details by Dr. Kevin Lynch, our Chief Medical Officer. I would like to make two points. First, this is a growing pipeline. Today, we are unveiling two additional targets which will be exciting additions to this portfolio. Dr. Bo Shan, our Chief Scientific Officer, will go through this in detail. Second, it is the philosophy for us in selecting future targets, whether through BD partnerships or our in-house discovery efforts.
We will continue to be very focused on combinatory synergies among assets in this pipeline, creating and further enhancing a portfolio that allows unique novel combinations in-house. The value and opportunity in this pipeline go far beyond the individual assets themselves. We believe in hiring the best talents, and each person on this team has extremely impressive track records. Many of them are industry veterans and leaders with established careers already, working on some of the biggest blockbuster drugs in the world. More importantly, many of our business leaders have worked closely together in the past, despite being located in different locations, and have built deep levels of trust at the different times of our careers, allowing us to empower them to help build Antengene's business and operations quickly across functions and across the world.
We are in a unique environment right now, where innovation and opportunities are thriving in China and around the world. With this world-class management team, combined with local insights, we can build Antengene into truly international and extraordinary biopharma. With 15 assets in our pipeline, Antengene will be delivering a steady stream of catalysts in 2022 and beyond. I highlight here five of our assets that will each be able to deliver meaningful upside for our investors on their own upon the next development milestone. ATG-101 is our anti-PD-L1/4-1BB bispecific antibody. We will spend more time on the science on why we are so excited about this molecule.
We think it has the potential to treat a large homogeneous cancer population exposed and resistant or refractory to a conventional anti-PD-1 or PD-L1 therapies, which as we all know, is growing rapidly as a new unmet medical need globally. With conventional checkpoint inhibitors becoming more and more accessible and moving into earlier lines. On the same logic, ATG-037, our highly differentiated CD73 oral small molecule inhibitor, has high potential to be an ideal combo partner with various immuno-oncology therapies, which again, is a large market where the immuno-oncology therapies themselves are entering a stage where price is beginning to be lowered.
ATG-017, our ERK1/2 inhibitor, can be a potential anchor of combo with immune oncology therapies or MAP kinase pathway inhibitors, which similar to immune oncology therapies, will be a growing and huge unmet medical need as we see resistance already been developed for different MAP kinase pathway inhibitors. We believe ERK1/2 is the last and important target along this pathway to overcome the resistance. The next one is ATG-010 selinexor, our first generation XPO1 inhibitor. This is our first de-risked commercial stage asset. I think the commercial potential of ATG-010 is way underestimated. We are only seeing the tip of the iceberg. We have 10 clinical trials ongoing for selinexor in China alone. That will expand many more indications for this unique, only-in-class asset in Asia-Pacific.
We also have the second and third generation XPO1 inhibitors in development. The fifth is ATG-008, our dual mTORC1/2 small molecule inhibitor. We are very happy with ATG-008, as we are getting very clear signals in clinic while using this drug in combination with anti-PD-1 in our clinical trials. In addition to these five assets, we also have the next wave of assets coming up, and many of them being highly novel with true first-in-class potential, which will fill the next stage of Antengene's growth. The execution by our team has been swift and remarkable, with 19 INDs obtained today, and we will run through these trials in detail with you. Before we dive deeper, allow me to provide some highlights without spoiling the rest of the presentations too much.
For selinexor, as I mentioned, we have 10 clinical trials in total ongoing in mainland China, three of which are global registration studies with our partner, Karyopharm. While the remaining seven studies are all unique studies conducted by Antengene in mainland China to further expand differentiated indications in Asia-Pacific markets. We will walk through data from the MARCH trial for multiple myeloma and TOUCH trial for T-cell, NK/T cell lymphoma, a disease that is endemic in Asia but underserved by current therapies. Aihua and Godfrey will go through the rationale for the other eight studies, which provide meaningful upside beyond the current understanding of selinexor's potential in Asia. The second highlight will be from ATG-008, onatasertib. We have obtained robust clinical signal for this asset in our TORCH-2 trial, where four out of five cervical cancer patients reached partial response or complete response.
Godfrey will share more with you. Third is from ATG-101, our anti-PD-L1 4-1BB bispecific antibody. We have just presented the preclinical data for this clinical stage asset at SITC conference in Washington, D.C., that show high differentiation and best-in-class potential. Bo and Bing will run through in greater detail. On ATG-017, our ERK1/2 small molecule inhibitor. Godfrey will provide updates on our phase I dose escalation study in Australia, as well as discussing the preclinical data announced at the same SITC conference in Washington, D.C., that supports further combination strategies for this molecule. Regarding our early development and discovery programs, Bo and Bing will walk through our two newly announced targets and walk through the differentiated data so far for ATG-037, ATG-022, ATG-018, and ATG-012.
Thank you.
Thank you, Jay. May I now invite Dr. Kevin Lynch, our Chief Medical Officer, to go through his section on R&D philosophy, strategy, and capabilities. Dr. Lynch, please.
Thank you, Donald, and good morning, everyone. And thank you for this opportunity to lead you through our thinking with regards to the building and advancement of a cancer pipeline. In the next 30 minutes, I'd like to discuss the context of our pipeline development, the specific products in our portfolio, which diseases we are focusing on and why. In this era of immune oncology therapies, how can we address checkpoint inhibitor resistance and incorporate those concepts into our development programs. It's always a little bit sobering to take note of the sheer scale of the challenge that we all face and the huge negative impact cancer continues to have on our societies for the millions of patients affected by this disease. There is much to be done and an ongoing need for more effective and better-tolerated therapies.
This representation of improvements in U.S. five-year survival rates in the past generation gives us cause for optimism. However, it also illustrates very clearly that there are many diseases where outcomes remain poor and others where our improvements have really had little impact. This gives us some clues as to where so many opportunities remain for novel treatments for a company like Antengene. We should also note that these improved outcomes and outcomes more broadly are not geographically consistent. While this chart illustrates the differences in five-year survival rates between the U.S. and China, this can be applied in other geographies and tells us that our clinical development strategy needs to be one that is globally aware while allowing for different focus in different geographies.
For example, you can see the major differences in outcomes in hematological malignancies in China, suggesting a particular need in that country for lymphoma, leukemia, or multiple myeloma. As well as the broader improvements in outcomes in some diseases, the change in the oncology drug market shows a very clear trend towards a dominance to two classes, immunotherapy drugs and targeted drugs, that by 2030 are expected to represent the large majority of the global oncology drug market. It's clear that those companies transforming oncology treatment will be those with a portfolio embracing novel targeted and immuno-oncology therapies.
With this background, we begin to see how a rationally composed portfolio of novel anticancer agents can be put together, addressing diseases where remains great need, recognizing geographic diversity and opportunity, focusing on agents that either fit into those buckets of targeted agents and immunotherapies or potentially enhance their activity through rational combinations. You can see the evolution of the Antengene pipeline represented in this cartoon across extracellular, membrane, and intracellular domains. If we start at the top left, ATG-101, bispecific antibody targeting PD-L1 and 4-1BB that via differential affinity for those antigens ensures a PD-L1 binding-dependent activity of 4-1BB, thereby avoiding the systemic toxicity that's characteristic of 4-1BB agonism. Next, ATG-027 will be IND-ready within the next 12 months or so, targeting PD-L1 and B7H3. My colleague, Dr. Bo Shan, will describe in more detail in the next talk.
ATG-037, within the tumor microenvironment, a small molecule inhibitor of CD73 that can reverse adenosine-driven immunosuppression that may have activity as monotherapy but is positioned extremely well for combination use. To the right of the screen, we remain highly interested in the potential to modulate macrophage behavior via novel signaling pathways with our lead compound, the CD24-directed antibody, ATG-031, will be IND-ready next year and will be discussed shortly by Bo Shan and Bing Hou. There remain cell membrane targets that are relatively unexplored, one of which is Claudin 18.2 seen in the center of this diagram. Highly relevant malignancies of the upper GI tract for which ATG-022, an ADC, will be IND-ready in 2022. If we move to the intracellular domain, we can see ATG-019. This is the PAK4/NAMPT inhibitor and a regulator of cancer cell metabolism.
A range of pathway inhibitors, including ATG-008 is the dual mTORC inhibitor, ATG-012, KRAS G12C inhibitor, and ATG-017, the dual ERK inhibitor. Moving into the cell itself, we can see potential nuclear targets, including ATG-018, a differentiated small molecule inhibitor of ATR. Then the SINE compounds, selinexor as mentioned by Jay as lead, but next-generation compounds like ATG-016, where we have an interest in myeloid malignancy, and ATG-527, where we're focusing on the antiviral properties of these compounds, where there are broad developmental opportunities with all of those. Each of these products will be discussed in more detail in the coming talks. This broader portfolio lends itself very nicely to our combinatory approaches, not only with the multiple compounds in this slide, but also a range of standard-of-care therapies that can be added to our platform of assets and development.
We also need to match products in development with appropriate target diseases. If we reflect back to our earlier slides, we can again bring some focus to our development plan by implementing programs in cancers where there are the greatest need or diseases in which we have particular opportunity in this geography or where the biological rationale is particularly strong. Thus, we have ongoing or planned trials in lung cancer with ATG-008 and ATG-101, in pancreatic cancer with ATG-017 and ATG-101, upper GI malignancy with ATG-101 and ATG-037, or gynecological malignancy with ATG-010, ATG-008, and ATG-101, and various hematological malignancies with ATG-010, ATG-101, ATG-016, and ATG-017.
There are particular areas of disease focus we are pursuing in the Asia-Pacific region, hepatocellular carcinoma with ATG-008, or nasopharyngeal carcinoma with ATG-008 and ATG-101, or head and neck squamous cell carcinoma with ATG-101 and ATG-037, upper GI with ATG-101 and ATG-037, melanoma with ATG-017 and ATG-101, and extranodal NKT cell lymphoma with ATG-010. We're also very interested to embrace the sometimes more challenging development programs that are based on biological rationale, with programs targeting specific mutations relevant to ERK or mTORC or XPO1, or viral premalignant disease with ATG-527, or myelofibrosis with ATG-010. In the context of our broader development program, it's important to appreciate that successes in immuno-oncology have transformed thinking in the past decade. Current drug development demands consideration of the role of immuno-oncology drugs, especially checkpoint inhibitors. However, 70% of patients remain as non-responders or progress after initial response.
We need to consider the many patients who fail and what are the mechanisms of drug resistance, whether that's primary, adaptive, or acquired, and what options we have to address those. This gives rise to great opportunities to improve outcomes with checkpoint inhibitors or move beyond existing checkpoint inhibitors, especially when we see the explosion in awareness of potential immuno-oncological targets. In this broader picture, some key questions arise for us that can help guide drug discovery and development strategies. How do cancer cells hide? What additional immune regulators can be modulated? Can we modify the tertiary immune microenvironment, that is the balance of different immune cells around the cancer? What genetic changes are driving resistance, and are they targetable? What additional cell surface targets or signaling pathways can we address? Are there critical metabolic changes within the tumor microenvironment that can contribute to immunosuppression?
If we refer back to our pipeline, you begin to see where we are headed in trying to answer these questions at multiple levels, as well as building the case for rational in-house combination approaches. I should emphasize at this point that while we have great internal expertise and capabilities, we are extremely aware that we cannot answer these questions alone. Building relationships and partnerships with key institutions around the world is a critical success factor for us and an area of great emphasis. Our intent is to establish multidisciplinary partnerships with these institutions, including collaborations across preclinical, clinical, and translational research disciplines. This slide illustrates this plan in action. In the last few years, we've established R&D programs and collaborations across more than 100 leading institutions in the Asia-Pacific region, and we are already benefiting from their tremendous expertise, input, and guidance.
Just in the last few months, we've begun the same process in the U.S. as we roll out our phase I plans with ATG-101, ATG-037, and ATG-017, and Europe will be on our agenda later in 2022. Now that availability of checkpoint inhibitors is so broad, we can work with these sites to better understand the mechanisms of resistance to current therapies and approaches to try and address that resistance. Within the tumor microenvironment, we are aware of metabolic changes that render the environment immunosuppressive and that provide a metabolic switch that favors cancer survival. More conventionally, we can try to identify genetic alterations that are potentially targetable, including signaling pathway activation, additional mutations, and epigenetic silencing.
In respect to functional changes in immune capacity, we start to think about T-cell exhaustion, changes in the structure and function of other immune cells, including the "don't eat me" messaging to tumor-associated macrophages, and alternate pathways for immune checkpoint activation in the presence of inhibitory cytokines. All of these considerations can be applied in the pursuit of rendering a currently cold tumor hot or changing the immune structural environment into one that is less favorable to cancer growth. We're thinking of these options in the context of our antigen portfolio. Our CD73 inhibitor, our PAK4 NAMPT inhibitor, and our dual mTORC inhibitor can all work to reverse the metabolic changes that favor tumor growth. We have a cluster of agents that may address the many genetic alterations driving checkpoint inhibitor resistance.
Our SINE compounds ATG-010 and ATG-016, our inhibitors of the Ras/MAPK kinase pathway in ATG-017 and ATG-012, tumors that are driven by specific TORC-dependent mutations with ATG-018, or reversal of ATR-mediated DNA damage response with ATG-018, and cell surface targets such as Claudin 18.2 with ATG-022. Finally, of course, we're extremely committed to seeking novel immuno-oncological approaches that may re-engage checkpoint inhibitor sensitivity, either by employing bispecific targeting, as in ATG-101 and ATG-027, or by reversing the tumor-supportive behavior of tumor-associated macrophages via a range of macrophage behavioral modifiers with ATG-031, ATG-032, and ATG-041. With this rich pipeline, we are also looking very carefully at how best to explore rational combinations with existing and future immuno-oncological therapies. Even agents that are not considered immuno-oncological can have indirect effects that can enhance the efficacy of IO treatments.
We appreciate that conventional cytotoxics can induce lymphodepletion and bystander immune stimulation. Pathway inhibitors can reverse immunosuppressive environmental signaling, and metabolic controllers can similarly reverse an immunosuppressive tumor microenvironment. Cancer cell disruption by ADCs or monoclonal antibodies or oncolytic viruses can render a tumor highly antigenic and make a cold tumor hot. Of course, we can look at other immuno-oncological agents that may provide a break to cancer-driven checkpoints or an accelerator to immune response and stimulation. I want to give you three specific examples from our pipeline that we are particularly excited about, and this relates to work with ATG-101, ATG-017, and ATG-037. I show this slide again highlighting where these three molecules are acting, ATG-101 as a T-cell activator and checkpoint inhibitor, ATG-037 as a tumor microenvironment regulator, and ATG-017 as the Ras/MAPK kinase pathway inhibitor.
We're currently exploring ATG-017 in a dose escalation phase of a phase I study called ERASER. However, we're also very aware that checkpoint inhibitors may enhance tumor growth via activation of AKT and ERK in the absence of adaptive immunity and therefore can contribute to hyperprogressive disease induced by anti-PD-1s. There's also several lines of preclinical data suggesting ERK activation contributes to tumor-associated macrophage infiltration and the M2 macrophage phenotype that accentuates the immunosuppressive tumor microenvironment and reduces the efficacy of checkpoint inhibitors. These dual mechanisms create a strong biological rationale for the exploration of ATG-017 in combination with checkpoint inhibitor, either in secondary checkpoint inhibitor resistance or indeed in tumors that are primarily refractory to checkpoint inhibitors. We're due to commence the combination module of our ERASER study with ATG-017 in the next few months.
A second example that we're very keen to pursue is with the bispecific antibody ATG-101. I think we're all familiar with the efficacy of the PD-1s, PD-L1s. We're also aware of the great potential of 4-1BB T-cell co-stimulation. However, we appreciate that this promise has yet to be realized in the clinic, primarily as a consequence of significant toxicities, particularly dose-limiting hepatotoxicity. The particular appeal of this highly novel molecule is the differential binding for PD-L1, coupled with the conditional activation of 4-1BB, such that 4-1BB agonism only occurs when cross-linked in the presence of PD-L1 positive tumor cells. This delivers a highly localized 4-1BB signaling in the presence of potent checkpoint inhibitor with a reduced risk of systemic toxicity.
This positions the drug very strongly to enhance activity in checkpoint inhibitor-sensitive disease, and perhaps more provocatively, to have activity in checkpoint inhibitor-resistant disease. The third example of great promise is ATG-037. The adenosine axis plays a critical role in suppression of the immune response. Adenosine generation is in turn heavily dependent on the enzymatic action of CD73 and has a number of downstream effects, including impaired NK and T-cell function and cytotoxicity, and reduced dendritic cell, macrophage, and T-cell interactions, with an overall significant enhancement of tumoral immunosuppression. Effective reversal of CD73-mediated adenosine generation can restore a more favorable tumor microenvironment and presents a very attractive combination partner for existing and novel immuno-oncological therapies.
These three exciting assets are in clinical stage now, and I should note that the compounds for which Antengene has worldwide rights, and all have best-in-class potential as illustrated in this slide. As mentioned, ERK has remained a target of interest, but it's been very difficult to identify a compound that can be delivered at biologically effective concentrations while limiting characteristic toxicities. ATG-017 has a number of key areas of differentiation to previous agents. Its greater potency and specificity allows a potentially lower efficacious dose with a broader therapeutic window. We are currently close to the end of our dose escalation phase and hope to identify a recommended phase II dose within the next few months. We will then be able to firstly commence expansion cohorts in solid tumors with relevant mutations.
Secondly, commence the hematology cohorts, and then on this point, I should note that Ras/MAPK is an important pathway in a number of hematological malignancies, including myeloma, lymphoma, and myeloid leukemia, myeloid malignancy. Finally, we will be ready to commence combination modules, initially with a checkpoint inhibitor. 2022 will be a very interesting period for this drug. In the middle of the slide, we can see ATG-101. I've discussed some of the unique features of this drug that we will believe will give the drug mechanistic advantages over combinations of separate antibodies. The preclinical efficacy data are very impressive, including in checkpoint inhibitor-resistant disease and will be described in more detail by Bo Shan. Critically, GLP toxicity confirms that the agent is largely devoid of significant organ toxicity, and in particular, does not demonstrate hepatotoxicity.
The phase I clinical trial is approved and ready to start in Australia, and we have just last month received IND clearance from the U.S. FDA. Our intent is to explore the drug initially as a monotherapy to assess its potential to resensitize prior checkpoint inhibitor responders and its efficacy in disease where checkpoint inhibitor activity has previously been limited. Importantly, we also see a very broad range of combination opportunities with this drug. The third of these exciting assets is ATG-037, as described previously. This small molecule avoids the hook effect of monoclonals and allows full tissue penetrance that is not possible with biologics. You'll see more data on the preclinical and combination activity of the drug in Bing's presentation, including strong data suggesting monotherapy activity.
This is quite important as up until now, there's been a presumption that CD73-targeted agents will only be of use as a combination partner, yet we were very interested to assess the single agent activity of this drug. We are currently preparing the full protocol for submission in Australia to scientific and ethics review, into which we will explore the drug as a monotherapy and then in combination with a checkpoint inhibitor. We do expect that this drug is particularly well-suited as a combination partner, especially in light of its truly excellent tolerability profile in GLP tox studies. We don't wish to exclude the possibility of substantial monotherapy activity based on the encouraging preclinical profile. The next slide, we have a look at the range of in-house discovered molecules that are coming through very rapidly behind.
You can see five listed here, which we expect to be IND-ready within the next six to 18 months. The first of these is ATG-018. This is a small molecule targeting ATR, which plays a critical role in regulating DNA damage response and replication stress. We believe that this drug has better in vivo efficacy compared with benchmarks. It's a small molecule with an excellent preclinical profile and IND planned for Q1 2022. ATG-022 is an antibody drug conjugate targeted towards Claudin 18.2. The claudin family are a range of membrane protein. It's expressed in multiple cancers. Claudin 18.2 in particular is abundant in gastrointestinal cancers. This molecule brings a targeted payload to the membrane antigen.
Our molecule will be therefore differentiated, particularly because of its high affinity for Claudin 18.2 and the fact that it's an antibody conjugate. IND for this drug is planned for Q2 2022. ATG-012 in the middle of the screen is a small molecule-targeted inhibitor of KRAS G12C mutation. This mutation is relevant particularly in lung cancers, and we've seen the recent approval with the Amgen compound, sotorasib, that has been given an accelerated approval for the treatment of KRAS G12C mutated non-small cell lung cancer. Our preclinical data indicate that this molecule has a better therapeutic index and more impressive in vivo efficacy and therefore has best-in-class potential. IND is planned for Q3 2022. ATG-031 is the CD24 targeted monoclonal antibody mentioned before.
I think many of you will be familiar with the CD47 target as the typical don't-eat-me signal that can inhibit macrophage phagocytosis of cancer cells. Unfortunately, targeting CD47 has proved difficult because of the broad expression of CD47 causing pharmacological challenges as well as characterizing red cell toxicity. CD24 has an advantage over CD47 in relation to its tumor-specific expression, and this is a true first-in-class target without existing competition. We have impressive in vivo efficacy confirmed as a monotherapy but also have great interest as a combination partner to other monoclonals, to checkpoint inhibitors, and to chemotherapy. This has very broad potential. Again, we'll be ready in 2022 around Q4. Finally on this page, ATG-027. This is the other bispecific that combines targeting of PD-L1 with B7H3.
B7H3 is expressed aberrantly in many cancers and correlates with progression and aggressive cancer phenotype. There are monoclonals in development directed to B7H3, and we understand the proof of principle to that approach. This is, however, the first bispecific bringing together B7H3 and PD-L1 targeting. Again, we have in vivo proof of concept completed, and IND will be in Q1 2023. As a summary, these are all exciting best or first-in-class assets, and we'll discuss this, a number of them in more detail in the discovery presentation to follow. This next slide shows our Asia Pacific rights portfolio in the clinic. In 2021, everything has moved along as we had hoped on the broad range of clinical activities that we have ongoing with selinexor, onatasertib, the mTORC inhibitor, eltanexor, verdinexor, and the PAK4/NAMPT dual inhibitor, ATG-019.
For selinexor, in addition to the three bridging studies that we're conducting in China for the three U.S.-approved indications, in 2021, we've also started three trials in China that are part of Karyopharm's global clinical studies, the pivotal phase III for selinexor as a monotherapy for maintenance of endometrial cancer. Should note here the study itself passed futility analysis without problem, so we're very encouraged and potentially this may represent another indication for selinexor. By including Chinese patients in this study, we aim to avoid a bridging study in China. Similarly, we're starting up trials in myelofibrosis and in combination with the chemotherapy R-GDP for diffuse large B-cell lymphoma. The TOUCH study, this is the selinexor in combination with ICE or GemOx chemotherapy in T-cell and NK/T-cell lymphoma.
We've seen encouraging activity, particularly with the GemOx combination, resulting in extension of that study and that may potentially trigger regulatory discussions regarding a subsequent pivotal study in this disease. This is coupled with some impressive, intriguing case reports from our main patient program of selinexor combined with a checkpoint inhibitor in extranodal NK/T-cell lymphoma, suggesting we may also have a potential regulatory path for selinexor in this disease. Some of these interesting data were presented to you by Aihua Wang. With ATG-008, our dual mTORC inhibitor, multiple trials are ongoing as monotherapy and combination. We're also seeing clinical responses in several diseases in our TORCH-2 study, particularly cervical cancer and in combination with a checkpoint inhibitor that may trigger plans for regulatory discussions regarding subsequent trials later this year. Again, you'll see more of these data in Godfrey Guo's presentation shortly.
This slide shows an increasingly impressive list of global rights drug candidates that are in transition to the clinic, which I've discussed a little earlier. The first of these, ATG-017, our dual ERK inhibitor, is the most advanced and is moving smoothly through a phase I dose escalation. We believe we're close to identifying the recommended phase II dose. ATG-101 has moved a few months ahead of schedule. After a smooth passage through scientific and ethics review in Australia and is on track now to dose our first patients imminently. Coming right behind these two molecules, we anticipate protocol finalization and protocol submissions of ATG-037 later this year, and then ATG-018 should be ready early in 2022 for submissions.
With ATG-022 into 2022 through 2022, and ATG-031 and ATG-027 into 2023. You can see a very busy and exciting time with our early portfolio. This series of INDs and first-in-human studies also translates into an exciting series of data readouts running from early in 2022 through to 2024. We should be seeing some interesting developments on more or less a quarterly basis, at least with this portfolio. In 2022, we also expect early data on safety, PK, and PD with ATG-101 and ATG-037. All of this activity also demands efficient execution. I'm happy to say that we're on track with pretty much all of our clinical development goals for 2021. Specifically, our bridging studies are proceeding as planned.
We have NDA submissions under review across Asia Pacific. We're starting to generate clinical data from these studies with selinexor in myeloma and non-Hodgkin's lymphoma, solid data with ATG-008, and we're progressing smoothly through the dose escalation with ATG-017 and ATG-019. We've commenced the ATG-016 phase II program, defined a signal-seeking exploratory program with ATG-527, and we're beginning our build-out of our clinical program in the United States. As mentioned, ATG-101 has Australian Health Research and Ethics Committee approval, and recently, U.S. IND approval to start that dose escalation study. Our final goals for 2021 are to define a recommended phase II dose for ATG-008 and agree a potential registration path for that drug.
We also aim to complete dose escalations for ATG-017 and ATG-019 and commence combination study planning. Finally, completing our Australian scientific and ethics submissions for ATG-037 by year-end, and begin that process with ATG-018 with an intent to submit early in 2022. I wanted to finish with a five-year aspiration of where we believe we are headed in our clinical development program. We believe we can achieve at least another two regulatory successes with new products or new indications in that time. We wish to move from one late-stage asset to two and then four and complement that with a rich early program of six to eight early products. We will target three INDs each year that can feed into that portfolio, and we'll expand our activities sequentially to the U.S., then Europe, then Japan.
We will couple these internal developments with planning for two new partnerships or in-licensed assets each year. Of course, this also means we need to remain highly focused on an ongoing review that we invest our time and resource in the most promising assets, and also potentially needing to make some tougher decisions along the way. I'd like to thank you all for your time and attention. Hope that gives you a bit of a flavor of the excitement we have around the strategic direction we're taking with this rich development pipeline. I will hand over to Dr. Bo Shan and thank you all very much.
Thank you. Thank you, Dr. Lynch. May I now invite Dr. Bo Shan, our Chief Scientific Officer, and Dr. Bing Hou, our Executive Director of Drug Discovery, to go through their section on discovery and early development program. Dr. Shan, please.
Thank you. Good evening, good morning, all. Thank you very much for joining the Antengene R&D Day. My name's Bo Shan. I'm the CSO at Antengene. In the following slides, Dr. Bing Hou, our Head of Biology, and I will take you through the drug discovery capability and projects. There are two topics we will cover today. I will introduce the Antengene drug discovery overall capability, and Bing will present the detailed scientific data for our products that will proceed into clinical development in the next three to 10 months. Antengene's primary discovery focus is in hematology and oncology. Our broad pipeline covers most cancer indications. Some of these products have truly first-in-class or best-in-class potentials. For example, we're starting from top left, the ATG-101. It is a PD-L1 and 4-1BB. ATG-027, the B7H3 and PD-L1.
Both are bispecific antibodies targeting T-cell activation. In the middle- left box is a focus on macrophage regulation, because we do believe macrophages will be the next immuno-oncology wonderland in the near future. ATG-031 and ATG-032 are products targeting CD24 and LILRB proteins respectively. The bottom left is the small molecule inhibitors blocking the classic tumor pathway. Those drugs will be a perfect combination targets, either with our existing pipeline or with standard care treatments. In the bottom right is ATG-022 an ADC targeting tumor-specific antigen, CLDN18.2. Recently, Antengene announced a collaboration with LegoChem to develop the next generation novel payload and linkers with site-specific conjugation technology. This collaboration will accelerate Antengene's internal efforts to develop safer and better ADC products.
To regulate the tumor microenvironment in the mid right, ATG-037 is entering the clinic as one of the very few CD73 bioavailable small molecule drugs, as most competitors are antibodies. Last but not least, the top right is our most advanced XPO1 inhibitors, ATG-010, also called selinexor. Following its recent approval in South Korea on July 29, 2021, ATG-010 expected to be approved in China and other major APAC regions in the next few months. Today, we would like to take today's opportunity to disclose two new targets. ATG-041, the AXL and MER dual inhibitor. ATG-041 is dual targeting AXL and MER enzymes. It is designed with dual functioning with both tumor-specific killing as well as modulation of immune microenvironment. ATG-032 is an antibody targeting LILRB proteins.
We will discover these products in great detail today. As combination treatments become more common for cancers, we are systematically seeking potential synergism within Antengene's existing pipeline, as well as other standard of care in specific indications. As examples, combination experiments in in vitro cell line studies indicated a synergistic effect of ATG-008, the mTORC1 and mTORC2 dual inhibitor with ATG-010, the XPO1 inhibitor. This finding was then further confirmed in several in vivo animal models and resulted in a MATCH clinical trial for relapsed and refractory DLBCL. The China IND for this study was cleared just a few days ago. In terms of modality, we believe the science itself will play a more important role than the drug formulation. Based on the nature of targets, our products cover small molecules for their well-established development pathway and efficient manufacturing cost.
We also develop antibodies that are more tumor-specific, better PK profile in human, and able to enhance the immune function. The ADC products were designed to demonstrate advantages in direct killing of tumor cells and improve safety when the novel payload and the linker technology were applied. Antengene's discovery capability has expanded rapidly since the company was first established in 2017. Currently, we have scientists based in Shanghai, China, and Pennsylvania, United States, with 80% having a post-graduate degree. The small molecule and biologics research and development capability has already been established with a track record to deliver drug candidates for clinical development in the past two years. Looking forward, we will reach 200-300 scientists in the next three to five years and bring in new platforms and technologies such as novel ADC, AI discovery, multi-specific antibody configuration, and potentially cell therapy products.
Antengene scientists based in China and United States will work on more than 50 research projects simultaneously, with a significant portion of these projects have first-in-class potentials. Now, please allow me to provide more detail about the Antengene and LegoChem's collaboration. Antengene's in-house antibody discovery platform has delivered a wide range of novel antibodies targeting multiple tumor-associated antigens. We already disclosed the CLDN18.2, B7H3, and the CD24 as perfect examples. Some of the antibody sequences demonstrate good internalization to the tumor cells, which can be a perfect candidate for ADC antibody. LegoChem has its novel ADC platform called ConjuAll. It is a next-generation ADC technology utilizing novel linker chemistry combined with site-specific conjugation.
It provides solutions for high purity ADCs with defined drug to antibody ratio, plasma stability, and the tumor selective payload release, which has been now clinically validated. This collaboration will accelerate the discovery and development of innovative ADC products by antigen. As we mentioned earlier, we believe the macrophage will be the next focus in immune oncology. Our toolbox includes antibodies as well as small molecules, which can target a series of macrophage- expressing antigens to re-educate the M2-like TAM polarization towards an antitumor M1 subtype. This eventually activates the macrophage-related immune response to kill tumors. We disclosed two new assets, ATG-041 and ATG-032. Both fall into this space. ATG-041, the dual AXL and MER inhibitors, targets macrophage polarization and regulates the tumor microenvironment. ATG-032 is an antibody targeting a series of LILRB protein with macrophage regulation as one of the key MOAs.
We believe small molecule drugs still have their own advantages. Nearly half of the Antengene new projects will be small molecule. We will apply new technologies to improve R&D efficiency. Most of the in-house small molecule discovery projects are aided by AI technology. The calculation algorithm was applied to optimize the ADME properties to predict the target ligand binding, as well as to generate the novel structures. We do not only invest heavily in early discovery. Antengene will have two manufacturing facilities to support our near-term commercial launch. Our small molecule manufacturing facility is located in Shaoxing in the Zhejiang Province. It has been completed and expects to obtain the packaging GMP certificate in 2022. The biologics R&D and manufacturing center will be located at Hangzhou City. The construction will commence next year and expected to be completed in two years' time.
In summary, our internal capabilities allow for identification of high-quality targets by data mining and phenotype screening. We can increase drug discovery efficiency by AI learning. With all this new technology and capabilities, the antigen discovery team has full confidence to deliver two to three R&Ds every year to further expand the company's pipeline. Now, I will pass it on to Dr. Bing Hou, our head of biology. He will take us through the detailed data. Thank you very much.
Thank you very much, Paul, and good evening, good morning. My name is Bing Hou, Head of Biology. I will cover some of the in-house development assets in more detail in the following slides. As Paul mentioned, ATG-101 is a PD-L1/4-1BB bispecific antibody currently being evaluated in a phase I trial. As we know, PD-L1 and PD-1 blockade therapy has revolutionized the cancer treatment landscape. However, only a minority of patients are anticipated to experience a deep and durable response due to primary or acquired drug resistance. In addition, successful therapeutic agonism of 4-1BB, a promising costimulatory immunological target, has been limited by major safety concerns with liver toxicity. ATG-101 was designed to activate 4-1BB positive T-cells in a PD-L1 cross-linking dependent manner and to effectively treat tumors without on-target off-tumor liver toxicity.
It was developed by introducing low affinity 4-1BB scFv into a human IgG1 PD-L1 monoclonal antibody. Higher affinity of PD-L1 binding versus 4-1BB ensures tumor microenvironment distribution of ATG-101. The binding capacity of ATG-101 to FcRn prevents the degradation of IgG in vivo, while the deficiency of other Fc gamma receptors binding ensures that ATG-101 shows 4-1BB agonist activity only when cross-linked by PD-L1 positive cells. ATG-101 activates T-cells and exhausted T-cells upon PD-L1 cross-linking, blocks PD-1 PD-L1 interaction, and renders cold tumor hot. It shows potent in vivo efficacy in multiple syngeneic tumor models, including those resistant to anti-PD-1 or PD-L1 therapies. ATG-101 is well-tolerated in GLP tox studies in cynomolgus monkeys with dose up to 100 mg/kg. As we know, T-cell exhaustion is one of the reasons for checkpoint inhibitor resistance.
To test if ATG-101 could reactivate exhausted T-cells, we induced exhausted T-cells in vitro by co-culturing human CD3 positive T-cells with anti-CD3/CD28 beads for 6 days. The exhausted T-cells expressed PD-1 and TIM-3 as surface markers, as shown here. In the presence of PD-L1 positive cells, ATG-101 induced the IL-2 and interferon gamma secretion by exhausted T-cells, while the IgG control showed no effect. This data suggests ATG-101 is able to reactivate exhausted T-cells. As you know, there are several mouse syngeneic models reported to display a cold tumor phenotype and are resistant to anti-PD-1 or PD-L1 treatment, such as melanoma model B16-F10 and lymphoma model EL4. We can see anti-PD-L1 antibody, atezolizumab, did not show anti-tumor efficacy in B16-F10 model. However, ATG-101 significantly inhibit tumor growth, with the tumor growth inhibition higher than 50%.
ATG-101 also inhibited tumor growth in EL4 model with 50% tumor growth inhibition. EL4 and B16-F10 are tumor models with primary resistance to checkpoint inhibitors. It is also very interesting to know if ATG-101 could treat tumors with acquired resistance to anti-PD-1 or PD-L1 therapy in animal models. To evaluate ATG-101 efficacy in tumors progressing after anti-PD-1 or PD-L1 treatment, 30 mice bearing MC38 tumors were treated with anti-PD-L1 initially to achieve tumor growth inhibition. Half of the mice switched to ATG-101 upon disease progression, while the other mice continued with anti-PD-L1 treatment.
Panel A shows a representative MC38 tumor growth curve for individual mice treated with PBS, which is marked in black, 10 mg / kg atezolizumab only, which is marked in red, or mice initially treated with 10 mg / kg atezolizumab and switched to ATG-101 upon disease progression, which is marked red to green. As we can see, switching to ATG-101 therapy induced potent tumor growth inhibition and tumor regression in most mice bearing anti-PD-L1 progressed tumors and prolonged their survival. We also analyzed the tumor-infiltrating lymphocytes in samples collected from the animal tumor models just mentioned in previous slides using multiplex IHC staining and flow cytometry analysis compared with control of the atezolizumab-treated group.
ATG-101 significantly increased the infiltration, proliferation, and activation of CD8+ T cells, the infiltration of NKT cells, and the CD8 T-cell/Treg ratio in the tumor microenvironment, suggesting a function in turning cold tumors hot and increasing anti-tumor immunity, which might be the underlying mechanism of ATG-101's activity in treating checkpoint inhibitor-resistant tumors. As you may know, liver toxicity is the most significant on-target toxicity of 4-1BB agonists, which has hampered the successful development of 4-1BB targeted therapy in the clinic. The safety of ATG-101 was evaluated in a four-week repeated dose toxicity study in cynomolgus monkeys, followed by a four-week recovery period. Up to 100 mg/kg ATG-101 was well-tolerated, with no obvious liver toxicity observed. No AST or ALT elevation was observed during the study, as shown in panel A and panel B. Therefore, ATG-101 has an excellent safety profile.
Furthermore, ATG-101 maintains a long-term full receptor occupancy, as shown in panel C, suggesting potential for prolonged therapeutic effect in the clinic. As a tetravalent bispecific antibody, ATG-101 could bind with PD-L1 positive tumor cells and 4-1BB positive T-cells concurrently to generate a T-cell drug tumor cell trimer. The trimers are assumed to drive the pharmacological activity of the bispecific antibody. Antengene collaborated with Applied BioMath to complete a quantitative and systems pharmacology modeling of ATG-101. Based on this QSP model, we believe that the avidity of each arm of ATG-101 hits the so-called sweet spot that allows an optimal dose level, 2 mg / kg, at which the drug could induce maximum trimer formation, over 90% of PD-L1 receptor occupancy with no 4-1BB on-target toxicity.
Tetravalent PD-L1 4-1BB bispecific antibodies with higher 4-1BB affinity, such as INBRX-105, may induce on-target liver toxicity at low doses without reaching full PD-L1 receptor occupancy. Bivalent PD-L1 4-1BB antibodies, such as GEN1046, on the other hand, might cause a hook effect in the trimer formation. At the doses with the maximum trimer formation, GEN1046 has not reached full PD-L1 receptor occupancy, which may limit clinical efficacy. In summary, we believe ATG-101 is a highly differentiated product with potent anti-tumor activity and excellent safety profile. A phase I multi-center dose escalation clinical trial evaluating ATG-101 in patients with solid tumors and hematological malignancies is ongoing. ATG-037 is an orally available, highly potent, and selective small molecule inhibitor of CD73. CD73 is a cell surface enzyme which is overexpressed in the tumor microenvironment and promotes tumor growth by limiting antitumor immunity via the adenosine receptor pathway.
Degradation of AMP into adenosine by CD73 results in the generation of an immunosuppressive tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 has resulted in favorable antitumor effects in preclinical models and in the clinic. The combination treatment of CD73 blockade with other immunomodulating agents, such as checkpoint inhibitors, are particularly attractive therapeutic option. The overexpression of CD73 in a series of tumor types suggests the broad applicability. ATG-037 has demonstrated the preclinical monotherapy potential and synergism with Antengene's existing pipeline. Currently, the preclinical study of ATG-037 has been completed, and we will complete the IND submission by the end of this year. As you know, there are several anti-CD73 antibodies being evaluated in clinic, showing early signals of antitumor efficacy. However, we think there are advantages to a small molecule CD73 inhibitor or antibodies.
Firstly, CD73 is an extracellular enzyme, making it an excellent target for small molecule inhibitors. Some of the clinical antibodies, such as MEDI9447, may not completely inhibit CD73 activity due to the so-called hook effect. ATG-037 showed complete CD73 inhibition and improved in vivo efficacy compared with MEDI9447. As we know, the key MOA, mechanism of action, of CD73 inhibitors is to restore the normal function of effector T cells from adenosine inhibitor. To compare ATG-037 with clinical stage CD73 antibodies, human CD8 positive T cells were treated with a high concentration of AMP, which is 100 micromolar. ATG-037 completely restored the cytotoxicity, activation, and proliferation of human CD8 positive T cells, while neither clinical stage antibodies could rescue T cell function at 100 micromolar AMP levels.
The most advanced clinical stage small molecule CD73 inhibitor is AB680, which showed promising clinical efficacy in combination with checkpoint inhibitor and chemotherapy. AB680 needs to be administered via IV infusion. Compared with AB680, ATG-037 is already available with higher usage flexibility. Also, ATG-037 is more potent than AB680. In human plasma, ATG-037 demonstrated 50-fold higher activity compared with AB680. Although most clinical stage CD73 antibodies or small molecule inhibitors are evaluated for combination therapies, and ATG-037 showed strong synergism with checkpoint inhibitor and chemotherapies, we do believe there is a monotherapy potential for ATG-037. Firstly, it has been reported that single gene systemic CD73 knockout could inhibit tumor growth in vivo. Also, due to the high potency of ATG-037, it has demonstrated good single agent in vivo antitumor efficacy in syngeneic mouse models.
Therefore, both monotherapy and combination therapy of ATG-037 will be evaluated in the clinic. ATG-037 also demonstrates an excellent safety profile. There is limited on-target toxicity expected with ATG-037, as CD73 knockout mice are viable with no overt phenotype. CD73 deficiency in humans has only a mild phenotype in adulthood, and anti-CD73 antibodies are well-tolerated in patients to date. In the GLP tox study, no ATG-037-related toxicity was identified. It is also highly selective with no inhibition of CD39 and other related targets and no cytotoxicity of syngeneic mouse cell lines. Beyond ATG-101 and ATG-037, Antengene has several other in-house development assets at IND-enabling stage. ATG-022 is an antibody-drug conjugate targeting Claudin 18.2 with high potency and homogeneity. Claudin 18.2 is a tumor-associated antigen overexpressed in gastric, esophageal, and pancreatic cancers.
The high affinity of ATG-022 allows targeting of patients with low expression of Claudin 18.2. As you can see in the PDX model with low Claudin 18.2 expression on the right-hand side, ATG-022 showed much better in vivo efficacy compared with the benchmark ADC. ATG-022 demonstrated a good safety profile in non-human primates, and the IND submission for ATG-022 is planned for early 2022. ATG-018 is an orally available small molecule ATR inhibitor. There are two major pathways for DNA damage repair mediated by ATM and ATR respectively. Many cancer patients carry ATM or downstream P53 pathway deficiency, making ATR inhibition a promising synthetically selective strategy for treating such tumors. By targeting ATR, ATG-018 inhibits DNA damage repair, releasing tumor cells from cell cycle arrest and inducing tumor cell death.
ATG-018 demonstrates superior in vivo efficacy compared with clinical benchmarks, and the IND submission for ATG-018 is planned for early 2022. ATG-012 is a KRAS G12C inhibitor with potent single-agent in vivo efficacy and high combination potential. As we know, antitumor therapies targeting the KRAS G12C mutation have demonstrated a profound ORR, but with relatively short PFS in the clinic. The potential reasons for the short PFS and drug resistance are MAP kinase pathway reactivation through wild type RAS and activation of the PI3K-mTOR pathway, which leads to the bypass and acquired resistance to KRAS G12C inhibitors. The clinical combination of KRAS G12C inhibitor with mTOR inhibitor or ERK1/2 inhibitor might overcome the drug resistance and prolong PFS. ATG-012 is a potent KRAS G12C inhibitor with better in vivo efficacy, time-dependent drug-drug interaction, and hERG profile compared with clinical benchmark.
ATG-012 also showed in vivo synergy with ATG-017, ERK1/2 inhibitor, and ATG-008, a mTORC1 inhibitor. The IND submission for ATG-012 is planned for 2022. As you know, blocking don't eat me pathway has been proven to be a successful strategy for treating cancer. CD24 is a newly discovered don't eat me target. Compared with a well-known don't eat me target, CD47, CD24 has no red blood cell distribution and higher tumor expression, which potentially allows for a wider therapeutic index in the clinic. It is also a tumor-associated antigen for multiple solid tumors and B-cell malignancies, as well as a marker for cancer stem cells. ATG-031 is a first-in-class CD24 antibody at IND-enabling stage. It showed potent single-agent in vivo efficacy and synergy with chemotherapy or checkpoint inhibitors. We also developed a companion diagnostic antibody in-house for patient selection.
The IND submission for ATG-031 is also planned for 2022. ATG-027 is a bispecific antibody targeting PD-L1 and B7H3. B7H3 is highly expressed in multiple tumor types and inhibits T-cell function. ATG-027 is designed to inhibit the interaction of PD-L1 and B7H3 with their receptors, respectively, to induce antitumor immunity. The functional FC region enables tumor killing by ADCC and CDC effects. The B7H3 parental antibody is highly differentiated from the clinical benchmark antibody. ATG-027 demonstrated potent in vivo efficacy and immunological memory. The IND submission for ATG-027 is planned for early 2023. With this brief summary of Antengene's in-house discovered assets, we hope that we have been able to give you a glimpse into the exciting and robust pipeline that is continuing to build at Antengene. Thank you very much.
Thank you very much, Dr. Shan and Dr. Hou. We will now move on to a Q&A session until ten o'clock. If you have any questions, feel free to key them into the Q&A box on the webcast link. Feel free to identify yourselves as well if you wish to be identified on the call when you ask the question, so we can view the questions live. We have the first question. Congratulations to the Antengene team on all the achievements. With your internal developed pipeline progressing into the clinic now, how do you think about BD and any directions on future BD? Will you continue to be focused on Asia rights assets for BD? I'll invite Jay to address this question. Jay?
Well, thank you. This is a great question. BD remains one of the core business functions at Antengene. As a matter of fact, we have further expanded our business development effort and from clinical stage or commercial stage assets and now also with a drug discovery partnership. As illustrated by our CSO, Dr. Bo Shan, the recent announced partnership with LegoChem Biosciences to develop novel ADCs. As a matter of fact, we continue to seek opportunities with novel agents, with first-in-class potentials, and particularly focusing on hematological malignancies, myeloma, lymphomas of all kinds, and leukemias. These diseases, as we heard from our CMO and Dr. Kevin Lynch earlier, remains at a greater gap.
Between our markets in Asia Pacific and the developed countries in the United States and Europe, for example. Our focus will continue to be broad, but also that to try to capture the potential synergy with our regulatory and clinical development expertise in hematological malignancies as well as our expanding commercial capabilities, not only on mainland China, but also in other APAC markets. Actually, in the following presentations, we're going to hear from Dr. Aihua Wang, our therapeutic area head on hematology, and also Mr. John Chin, our CBO, on our commercial readiness. Our BD effort will continue to expand.
In the next year or two, we envision that we may seek a partnership for co-development or co-commercialization of 10 of the wholly owned assets for which Antengene has global rights and potentially for development or commercialization in other parts of the world. Thank you.
Thank you, Jay. Again, if you have any questions, feel free to enter the question into the Q&A box on the webcast link, and we can see the questions live. The second question, you have a very rich pipeline of 15 assets, 10 of which you have global rights. How are you going to undertake developing such a large pipeline with the resources that you have? How do you think about, first, collaboration or partnering out these assets in the future, and secondly, prioritizing these assets at some stage? I'll invite Kevin Lynch, our CMO, to address this question first and, Jay, if he's got anything else to add.
Yeah. Thank you, Donald. I think in terms of partnering, we're very open to flexible or different models. I think clearly where we have the capability and expertise, we are likely to pursue opportunities ourselves. However, where we see strength and capability in a potential partner, especially where we feel there is a cultural fit, then I think we would be open to such discussions. I think on the prioritization question, that's a really important one, and there obviously will be a need for prioritization in the future with such a deep pipeline. We are starting to think about that very carefully.
As seen in the presentations, we are focusing our selinexor development efforts in areas where we think there is a strong need or where there is a regulatory need, or where we think there's a high probability of success in a target indication. I think for our early development platform, you've seen the great interest we have with ATG-017, ATG-101, and ATG-037. They clearly deserve priority. Concurrent with this, I think, and I know that Jay is a great believer in this, we really need to continue to build our talent pipeline. You know, so we're interviewing continuously in China, the USA, Australia, and we are open geographically to where we might find that talent. I think something that COVID has demonstrated to all of us very clearly, that our business can be managed effectively without being constrained by geography.
I think, you know, I alluded to in my presentation as well, there will be a time when we need to make some tougher decisions in the future where we see a compound that's looking less promising. We need to make those decisions as early as possible.
I would like to just add on to what Kevin just said. As Kevin mentioned, we actually are very keen in recruiting or inviting the best talents to join us wherever they are. Please, as an advertisement, please refer any of your friends or colleagues or classmates to consider Antengene. It can be anywhere. It can be Asia Pacific, or it can be in the United States, North America. Pretty soon, we'll be in Europe. On partnership, as we discussed earlier, we have multiple clinical stage or commercial stage assets. Selinexor is one good example. The other assets through partnership, where Antengene takes on the responsibilities to develop in Asia Pacific markets and for registration to commercialization.
With the ever-expanding wholly owned global assets, we remain very interested and to seek a partnership. As a matter of fact, we wish to announce, hopefully, in the next month or two, a clinical partnership as an example of part of that effort. We think that the partnership and collaboration are key to efficiency and also effective innovation around the world. Thank you.
Thank you, Kevin and Jay. We've received a few questions on ATG-101, our PD-L1/4-1BB bispecific, so I'll probably group them together. First, very impressive were the agents that appeared to de-exhaust T-cells. Have you considered management of chronic hepatitis B? There's another question: Hi, is there any monkey data regarding the PD-L1/4-1BB bispecific antibody to test if there is any liver toxicity? You've touched on some of the key features of ATG-101, your PD-L1/4-1BB bispecific and potential advantages versus benchmark molecules. At the same time, there are also a few other companies working on this bispecific MOA. How do you compare ATG-101 to other molecules? Scientifically, what has advanced that allows ATG-101 to be better designed to overcome some of the issues seen in previous molecules? I'll invite Dr.
Bo Shan and Dr. Bing Hou to address these questions.
Thank you, Donald. These are all very interesting and good questions, so I will answer them one by one. The first one is how we consider to use ATG-101 to treat HBV. That's a very interesting suggestion because we know that PD-1 antibody has shown some preliminary efficacy in clinic in treating HBV. So far, we haven't considered to use ATG-101 for HBV. That's a good suggestion. We'll take that into consideration in our future clinical development planning. The second question is how we test ATG-101 in monkey to see if there is a liver toxicity or not.
As shown in the slides, we have complete GLP tox study in cynomolgus monkeys with a dose up to 100 mg / kg. We did not observe any liver toxicity, so it is a very safe antibody preclinically. The third question is a comparison of ATG-101 with clinical benchmark antibodies. Yes, you're right that there are several other PD-L1/4-1BB bispecific antibodies in clinic. They are either tetravalent just like our ATG-101 or bivalent like GEN-1046. Instead of comparing ATG-101 to them one by one, maybe we can look at the fundamental parameters of the antibodies, which has a binding affinity and avidity to the target proteins.
Bivalent bispecific antibodies like GEN-1046 and Merus MCLA-145 due to monovalent binding to each target, a lack of avidity. According to our QSP simulation, this kind of one plus one bispecific antibody will demonstrate hook effect in the tumor formation as higher doses are explored. Genmab interestingly, Genmab published similar findings in the SITC conference last week that are consistent with these simulations. Compared with other tetravalent bispecific antibodies, as I mentioned during the presentation, we think the affinity of each arm of ATG-101 hits a sweet spot. Higher 4-1BB activity may induce 4-1BB related liver toxicity as shown in Inhibrx INBRX-105. ABL503, I think, from a Korean company, has a tenfold lower PD-L1 affinity compared with ATG-101.
We think this might affect the tumor-specific localization and the efficacy mediated by the checkpoint blockade of the antibody. Overall, the bispecific are not all the same, but we believe that ATG-101 has a profile that appears to have advantages over others.
Yeah. I would like to add a further comment for the ATG-101. We haven't touched upon the CMC manufacturing site. What we can disclose is, thanks for our great help from the CDMO. We'll be able to develop a process which is robust and with higher yield and tighter. This process will be able to deliver a large quantity of clinical trial material at a relatively lower cost. Thank you.
Thank you, Dr. Shan and Dr. Hou. We're at 10:00, so we'll start the next session. But, feel free to keep sending in your questions. We can address them in the next Q&A session. I'll now invite Dr. Aihua Wang to go through clinical program on hematology. Dr. Wang, please.
Thanks, Donald. Good morning. Good morning and good evening. I am Aihua Wang, head of clinical development at Antengene. Now, Antengene is exploring various indications in hematological malignancies, including multiple myeloma, diffuse large B-cell lymphoma, indolent lymphoma, T-cell lymphoma, AML, MDS, and myelofibrosis. XPO1 is overexpressed in most cancer cells. Overexpression of XPO1 is associated with poor prognosis and treatment resistance. ATG-010 or selinexor is a potent oral selective inhibitor of nuclear export, which reversibly binds to a critical cysteine residue in the nuclear export sequence binding groove of XPO1 and prevents the transport of over 200 cargo protein from the nuclear to the cytoplasm. Inhibition of XPO1 retains tumor suppressor protein such as P53 in the nuclear, leading to their activation and prevent the nuclear export of mRNA coding for oncoprotein such as Myc, Bcl-xL, and Cyclin D1.
These effects are lethal to cancer cells at concentrations that are not toxic to normal cells. This is a summary of ATG-010 ongoing studies in various indications. The first indication is multiple myeloma, and there are two pivotal studies. MARCH is a phase II bridging study in China for patients with relapsed and refractory multiple myeloma refractory to both proteasome inhibitor and immunomodulatory drugs. BENCH is a phase III randomized study for second-line relapsed and refractory multiple myeloma. The second indication is lymphoma. There are also two pivotal studies for diffuse large B-cell lymphoma. SEARCH is a phase II bridging study in China for third-line diffuse large B-cell lymphoma. XPORT-DLBCL-030
XPORT-DLBCL-030 is a global phase III randomized study for second-line DLBCL. Other pilot studies include MATCH and SWATCH for DLBCL and indolent lymphoma, and TOUCH for peripheral T-cell and NK/T-cell lymphoma. The last indication is primary myelofibrosis. There is a global phase II randomized study for ruxolitinib-failure myelofibrosis. The studies highlighted in blue are sponsored by Antengene and the study highlighted in orange is co-sponsored by Antengene and Karyopharm. As we know, multiple myeloma is the second most common hematological malignancies, not only in western countries, but also in China. Incidence of multiple myeloma is highly variable among countries. It was reported that among the regions, the highest increase in incidence cases from 1919 to 2016 were seen in East Asia, including China, with a rise of 262%.
Despite the development of novel therapies, multiple myeloma remains incurable and almost all patients will eventually relapse and become refractory to all available therapies. There is a high unmet medical need for therapies with new mechanism of action. MATCH is a phase II single arm study to evaluate selinexor plus low-dose dexamethasone in relapsed and refractory multiple myeloma. This is a China bridging study for STORM, which enrolled patients refractory to both proteasome inhibitor and IMiDs, and refractory or intolerant to the last line of therapy. The selinexor and dexamethasone were given twice weekly, and the primary endpoint was ORR by IRC. Selinexor plus dexamethasone obtained ORR of 29.3% in Chinese multiple myeloma patients, and the primary endpoint is met. Consistent responses were observed across various subgroups, including high-risk disease. The MATCH study enrolled heavily pre-treated patients with high-risk factors.
The median prior regimen number was 5, and 74% of patients had disease with high-risk cytogenetic abnormalities, and 22% of patients had impaired renal function. Twenty-four percent of patients were refractory to prior anti-CD38 monoclonal antibody, and which were categorized as triple-class refractory population. Ten patients had received prior CAR-T therapy. The ORR was 25% in the triple-class refractory population. All patients with high-risk cytogenetic abnormality, impaired renal function, and prior CAR-T therapy demonstrate benefit from the SD regimen. Notably, patients post CAR-T failure obtained an ORR of 50%. The safety profile was as expected, with no new safety signal identified. In general, the efficacy and safety data from the MATCH study was consistent with STORM.
An NDA package was submitted in January 2021, and priority review was granted, and the regulatory approval is expected in China very soon. The BENCH study is a phase III randomized study to evaluate SVD versus VD in relapsed and refractory multiple myeloma patients with 1 to 3 prior therapies. It is also a bridging study in China for the BOSTON trial, and it is also a confirmatory study for CDE. The primary endpoint is PFS. The first patient was dosed in July 2021, and the recruitment is expected to be completed in Q4 2022. DLBCL is the most common subtype of non-Hodgkin lymphoma, accounting for 40% of NHL. The outcomes for patients with relapsed and refractory DLBCL are poor, especially in high-risk subgroups such as double hit, triple hit, and transformed lymphoma.
There is no standard of care for relapsed and refractory disease, and in recent years, only one CD19 CAR-T is kind of have been approved in China. SEARCH is a phase II single arm study to evaluate selinexor monotherapy in patients with relapsed and refractory DLBCL with 2-5 prior regimen. This is the China bridging study for SADAL, and the primary endpoint is ORR by IRC. This study is currently recruiting patients, and the results are expected to be reported in Q3 2022. XPORT-DLBCL-030 is a phase II/III confirmatory study evaluating selinexor combined with R-GDP in patients with relapsed and refractory DLBCL with 1-2 prior regimen. The phase II part is a dose-finding study, and the primary endpoint is ORR. The phase III part is a randomized study with a primary endpoint of PFS.
This is a global confirmatory study co-sponsored by Antengene and Karyopharm. Antengene will contribute at least 15% of the total population per registration request, and the first patient is expected to be dosed in the next few weeks. In addition to the above two pivotal studies, there are other selinexor combination regimens currently under investigation in B-cell non-Hodgkin lymphoma. The first combination is selinexor with ATG-008. ATG-008 is a second-generation mTOR kinase inhibitor targeting both mTORC1 and mTORC2. Preclinical research showed selinexor combined with ATG-008 had a synergistic effect in triple-hit DLBCL cell line and animal model. The phase I MATCH study will evaluate selinexor combined with ATG-008 in relapsed and refractory DLBCL, with special attention to patients with double-hit, triple-hit lymphoma.
An IND has been approved for MATCH study in October 2021. The SWATCH is a phase I study to evaluate selinexor combined with rituximab and lenalidomide in relapsed and refractory DLBCL, as well as indolent lymphoma. R-squared is a standard of care for indolent lymphoma and has demonstrated activity in diffuse large B-cell lymphoma. We will evaluate the activity of this chemo-free regimen in patients with relapse, relapsed and refractory DLBCL who are not candidate for transplantation and explore if selinexor combined with R-squared has potential value in indolent lymphoma. SWATCH is expected to obtain IND approval in next several days. Antengene will further explore other new combination, especially combination with Antengene's own pipeline. Our investigations will also focus on high-risk population such as double hit, triple hit, and transformed lymphoma.
T and NK cell lymphoma is an endemic disease in Asia, and PTCL, NOS, and extranodal NK/T cell lymphoma are the most common subtype of T non-Hodgkin lymphoma in China. There is still no clear consensus on primary therapy for newly diagnosed or relapsed or refractory setting. The response rate of approved therapy in the relapsed and refractory disease is only about 30%, and the duration of the response is short. The survival outcome of patients who relapse after first-line treatment is extremely poor, as reported in previous retrospective studies, only about six months, with little improvement achieved in the past decades. Antengene is conducting a phase I-B study named TOUCH to evaluate selinexor combined with ICE or GEMOX in relapsed and refractory T and NK cell lymphoma, and the chemotherapy regimen is investigator's choice.
The ICE cohort was terminated following discussion between investigator and Antengene due to the safety and tolerability consideration. In a preliminary analysis, the ORR in the selinexor plus GemOx arm was 52.9% with 60% in NK/T cell lymphoma subgroup and 62.5% in PTCL NOS subgroup. Updated data for more patients will be presented at the upcoming ASH meeting. Considering the median number of prior regimen was 2.5 and 50% of patients had received more than two prior regimens, including GemOx, the ORR data was impressive in such a heavily pretreated and highly refractory patient population. Our next plan is a sample size expansion for efficacy and safety validation. Antengene is also investigating another promising combination for T/ NK cell lymphoma, ATG-010 plus PD-1 inhibitor.
The preclinical research demonstrated that selinexor combined with a checkpoint inhibitor increase anti-tumor activity in multiple solid tumor models, including melanoma, colorectal cancer, and renal cell carcinoma. Then we also received several impressive case reports of patients who were treated with this combination. There were several relapsed and refractory NK/T cell patients, some with central nervous system involvement and were heavily pretreated with three to four prior regimen. All these patients had been pretreated with a PD-1 inhibitor for several cycles and were PD-1 inhibitor refractory. After treated with selinexor plus PD-1 inhibitor, these patients obtained good response. Most were CR with EBV virus clearance. It was encouraging to see that the response was durable, with the longest duration of response reaching more than 8 months.
We present here the imaging from two patients at baseline and following treatment, and both patients obtained a CR after two to four cycles of therapy. XPORT-MF-035 is a phase II randomized study designed to evaluate selinexor versus investigator's choice in patients with myelofibrosis, that is relapsed, refractory, or intolerant to a JAK inhibitor. This is a global study co-sponsored by Karyopharm and Antengene. There is also another myelofibrosis study under discussion, XPORT-MF-034 of selinexor combined with ruxolitinib in patients with untreated myelofibrosis. The selinexor has other clinical opportunity worth first exploration. For multiple myeloma, we are interested in investigating various combination with other multiple myeloma backbone therapy. For example, SPD, SCD, STD, STCD, and SVRD. We remain focused on high-risk population. For example, the patient with high- risk cytogenetic abnormality and extramedullary plasmacytoma.
Second, T and NK cell lymphoma, a disease in which Antengene has significant interest, considering the most common subtype of non-Hodgkin lymphoma in APAC and promising data obtained from ongoing study and case reports. The selinexor can cross the blood-brain barrier and has demonstrated activity in central nervous system disease. We remain interested in investigating the clinical value of selinexor in central nervous system disease. Finally, acute myeloid leukemia is another indication which we'll be taking into consideration next year. The ATG-016 eltanexor, this is a second-generation SINE compound with reduced brain penetration and improved tolerability in animal models compared to selinexor. The preliminary anti-tumor activity in solid tumor and hematological malignancies was observed in a phase I study. Among all the disease investigated, the higher risk of MDS is the most promising. Antengene is conducting a study named the HEDGE.
This is a phase I dose escalation and extension study to evaluate ATG-016 in high-risk MDS after HMA treatment failure. For now, dose 1 enrollment has been completed with no DLT, and dose level 2 is currently enrolling. Later, we also plan to explore ATG-016 combined with HMA in the treatment of untreated MDS. ATG-019 is a first-in-class PAK4 and NAMPT dual inhibitor. Inhibition of these two targets leads to synergistic effect through DNA repair inhibition, cell cycle arrest, and apoptosis. There is a phase I study to evaluate ATG-019 in advanced solid tumors. Considering the activity observed in drugs with diffuse large B-cell lymphoma, Antengene will aim to recruit more lymphoma patients in Antengene-sponsored TEACH study. TEACH is a phase I study to evaluate ATG-019 in advanced solid tumors and non-Hodgkin lymphoma.
The study is conducted both in Taiwan and Mainland China, and the study is currently in dose escalation phase. Once we obtain clinically meaningful data from this monotherapy study, we will further explore the combination of ATG-019 with a PD-1 inhibitor. The preclinical data suggests that lack of response of PD-1 inhibitor was associated with increased PAK4 expression. An inhibition of PAK4 improved anti-tumor activity by PD-L1 inhibitors. It is viable to explore this combination, especially in patients that have failed PD-L1 inhibitors therapy. That's all for this section. Thanks for your attention.
Thank you, Dr. Wang. We will now move on to our second Q&A session. Again, if you have any questions, feel free to send them through the Q&A box on the webcast link. Feel free to identify yourselves if you wish to be identified on the call. We have a question right now. How do you decide on opening these additional Antengene-sponsored trials in China, apart from the bridging studies and the global studies that you are participating in? What advantages does Antengene have in conducting these new trials in China versus your partner? I'll invite Aihua Dr. Wang and Kevin to supplement on this question.
Thanks for your question. There are several factors to consider when opening Antengene-sponsored trials in China. The first, the endemic disease in APAC with a huge medical need is considered. For example, T/ NK cell lymphoma is an endemic disease with the highest incidence rate in East Asia, including China. However, survival outcome is still very poor with available therapy. Secondly, the study is initiated based on promising preclinical data and efficacy signal from IIT study and case reports. For example, MATCH study is initiated due to preclinical results, and a study of selinexor plus PD-1 inhibitor is under development due to impressive efficacy signal from an IIT case. Third, we start a trial to generate some China-specific data for Chinese investigators and Chinese patients.
Finally, we pay attention to the indication not being under the Karyopharm's clinical development plan, where we think there is a strong rationale and limited data. For example, the SWATCH study in the indolent non-Hodgkin lymphoma. Regarding the advantage of Antengene, it is reflected in the following three aspects. First, Antengene's team has superior clinical development experience and a track record across multiple hematological malignancies areas in China. Secondly, Antengene's team has extensive experience of conducting clinical study in China. Now, we are doing clinical trials in about 50 medical centers across China and with good enrollment progress. Finally, Antengene has established a professional relationship with KOL in China. All above aspects make it possible for Antengene to conduct a clinical trial in an efficient and high-quality way. Thanks.
Thank you, Dr. Wang. Again, if you have any questions, feel free to enter them into the Q&A box on the webcast link. We have a second question. Great to see that you're expanding indications in addition to what your partner is doing and the encouraging data seen in TOUCH trial for T and NK lymphoma and the case reports in combination with PD-1. What are next steps, and what do you envision to be the regulatory pathway for this in China? Again, I'll invite Dr. Aihua Wang and Kevin Lynch to supplement on this question.
Thanks. This is a great question. For now, we are collecting more data with chemotherapy combination data in TOUCH study, and then we'll discuss with CDE later. In terms of the PD-1 combination, there is preclinical evidence supporting this combo regimen, and the case reports describe the demonstrate very rapid disease control as well as EBV clearance. We need to validate this and try to better understand the mechanics of such response. We are planning a phase I dose escalation study to determine the RP2D for this combo first, then a phase II study to collect more efficacy and the safety data. If the data continue to be this strong in this phase I/II program, we will very interested to talk with CDE about an accelerated registration strategy. Thanks.
Thank you. I see there's a question on commercialization of selinexor. We have a section on commercial opportunity for selinexor later in the program, so I'll leave that question for later on. At the moment, that's all the questions that we've got. We will move on to the next section on clinical program for oncology. I invite Dr. Godfrey Guo, our Executive Director of Medical , to go through a section on clinical program on oncology. Godfrey, please.
Thanks, Donald. Good morning, good evening. This is Godfrey. On behalf of Antengene Solid Tumor Clinical Development Team, I will present our solid tumor oncology clinical programs. Actually, our investigations have encompassed a wide range of solid tumor types, such as gynecological tumors, digestive tract cancers, central nervous system carcinomas, et cetera. For sure, we will strive to explore more disease areas to treat patients beyond borders. Here is a summary of Antengene solid tumor clinical portfolio. Our clinical program contain a diverse portfolio of assets, including small molecules, bispecific antibodies, antibody-drug conjugate, and monoclonal antibodies. Thereinto, some compounds are the most advanced assets with great potential to change the paradigm of cancer treatment in the near future.
Currently, we have one ongoing pivotal phase III endometrial cancer maintenance therapy study ongoing and a phase III study in previously treated non-small cell lung cancer is under discussion. In the following slides, I will illustrate our ongoing clinical programs from early stage to late stage. The first of this is ATG-017, which is a highly potent selective ERK1/2 molecule inhibitor. ERK belongs to the Ras/MAPK pathway. The dysfunction of this pathway was found to be a major trigger for the development of many cancer types. ERK is the final common target in the pathway, but is yet to have a successful drug candidate approved. We believe that ATG-017 has the potential as a monotherapy in Ras/MAPK mutant cancers, and there are potential synergies with the checkpoint inhibitors as well as the pathway inhibitors upstream of ERK.
This creates opportunities with other established agents in this space, and indeed combinations with our own KRAS G12C inhibitor and the PD-L1/4-1BB bispecific antibody. The clinical trial we are performing is the ARIAS trial, targeting advanced solid tumor and hematological malignancies characterized by Ras/MAPK mutations. We have progressed very smoothly. To date, we have expanded cohort at 20 mg BID with potential escalation to 30 mg BID. Then this study will be open to enroll patients with hematological malignancies after MTD of solid tumor group reached. For the other ERK inhibitors, they were in the large part unsuccessful because of off-target toxicity. The high selectivity of ATG-017 would overcome that. In addition, ATG-017 is more potent in vitro, and it is more flexible regarding dose regimen.
We believe that ATG-017 has the best-in-class potential. The next asset is ATG-008, our second-generation mTORC1, mTORC2 dual inhibitor. Comparing the first generation of mTOR kinase inhibitors besides mTORC2 and mTORC1 inhibition, ATG-008 demonstrates comprehensive mTOR kinase inhibition, which could minimize development of resistance due to mTORC2 upregulation. As you know, the increase of mTORC2 activity generates a surplus of activated AKT, which despite mTORC1 inhibition, inhibits apoptosis and promotes cell proliferation via alternative pathways. TORCH study is the very first Antengene clinical program investigating recurrent hepatocellular carcinoma. It was noted that HBx protein can upregulate PI3K/mTOR signal, which increases pro-cell proliferation and VEGF production. Compelling preclinical and clinical data supports the exploration in HBV-positive HCC population, especially in the Asian territories.
Currently, TORCH study is proceeding well, and we are currently recruiting subjects in the 45 mg cohort. A planned analysis will be conducted after the enrollment of all 4 planned dose cohorts. The PK profile was analyzed across the dose cohorts. The key conclusions are that ATG-008 PK profile is linear from 15 mg QD to 45 mg QD in the Asian patient population. There is no significant exposure accumulation after multiple dosing. Not surprisingly, ATG-008 treatment seems associated with the increased adverse events at higher dose. Therefore, we have selected lower doses in the subsequent clinical programs. Beyond monotherapy, ATG-008-based combination therapy is definitely worth exploring.
There is an abundance of preclinical data confirming that blocking both mTOR and PD-L1 demonstrate a synergistic antitumor immunity through the enhancement of antigen-specific CD8 positive T cells. We believe that ATG-008 in combination with anti-PD-1 or anti-PD-L1 antibody could generate a synergistic antitumor effect across tumor types. With an unsolicited request from West China Hospital, we supported a TORCH-2 study collaborating with Junshi Biosciences in advanced solid tumors. Currently, the TORCH-2 study is well on track. The dose expansion phase commenced at the beginning of this year. Most importantly, we have identified promising signals in certain tumor types using ATG-008 in combination with toripalimab.
As of October 31, 20 patients were efficacy evaluable with a 30% overall response rate and a 75% disease control rate observed in this heavily treated population. The safety profile is quite good, with no DLT found across the cohorts. Six responders were four cervical cancer patients, one nasopharyngeal carcinoma patient, and one ovarian cancer patient. It is worth noting that robust and durable responses were observed in cervical cancer patient population using this combination. Four out of patients reached PR or CR, and all responses are still ongoing. It's actually the CR patient has benefited from this combination for more than 500 days. Here is a summary of cervical cancer cases thus far. All the five patients are stage four diseases with remote metastasis. The response rate seems quite impressive in the evaluable cervical cancer population, regardless the status of PD-L1 expression.
Although the sample size is relatively small, this extremely promising signal warrants us to conduct further development. Considering that current checkpoint inhibitors generate only about 15%-30% overall response rate, even in a PD-L1 positive setting. From the CT scan images, we can see the involvement of the target lesions from para-aortic lymph nodes to lung lesion. All the target lesions of the responders with cervical cancer regressed dramatically and had durable responses. Next, we will recruit more cervical cancer patients and nasopharyngeal carcinoma patients to further validate the signal. In parallel, we will move very rapidly to expand that with an aim of potential accelerated regulatory path. Biomarker-guided clinical development is another strategy we are following.
Some mTOR pathway-related driver gene present in 5-15 across tumor types, such as NFE2L2 mutation, STK11 mutation, RET amplification, et cetera. Based on the preclinical and clinical data, we initiated the ATG-008 BUNCH study to identify potential targeted therapy for patients with some mTOR-related rare mutations. BUNCH is an Antengene-sponsored study. We took the opportunity to develop this biomarker-defined population, firstly in China. This program achieved first patient in Q2 this year. We are keen to see the results of this study in the near future. Moving on to SINE compounds. As you know, we have the first-in-class SINE compound, selinexor, and this next generation compound, ATG-016. Both are under investigation in solid tumors. Additionally, investigation of ATG-527 in various viral conditions is planned.
Tumor suppressor protein activation, oncoprotein level reduction, and NF-κB signaling inhibition are the primary antitumor mechanism of SINE compounds. XPO1 inhibition is a novel and a promising anti-cancer strategy with broad applicability across tumor types. There is no doubt that selinexor, the first-in-class SINE compound, is a highly specific inhibitor of XPO1. Increasing preclinical and clinical evidences have proven that it is a novel and safe therapy with antitumor activity demonstrated across solid tumor types. Gynecologic Oncology published the phase II SINE study result last year, which demonstrated single-agent selinexor activity and a disease control in patients with heavily treated ovarian and endometrial cancers. The first selinexor phase III study in solid tumors, the SEAL study, successfully met the primary endpoint last year.
We believe that with more data read out, selinexor will become a mainstream clinical tool for treatment of solid tumors. SIENDO study is co-sponsored by Antengene and Karyopharm. The top-line result of this phase III selinexor maintenance therapy in advanced or recurrent endometrial cancer is expected at the beginning of next year. This is a setting which has no current standard of care. We hope to establish selinexor maintenance therapy as a new approach for endometrial cancer patients. The next generation SINE compound, ATG-016, has a better pharmacological profile, resulting in better tolerability and ultimately leading to sustained disease control. Preclinical data demonstrated that XPO1 inhibition could inhibit viral replication directly, and ATG-016 demonstrate inhibition, effect on viral cancer cells. Hence, we believe that ATG-016 could augment the value of SINE compounds by targeting viral cancers.
ATG-016 RICH study is an Antengene-led phase I-B, phase II study focusing on virus-associated tumor types. In the dose expansion phase, EBV-positive nasopharyngeal carcinoma patients would be included, which is a unique population in China. First patient in a RICH study is expected in the end of this month. Actually, there is a patient under screening right now. For ATG-527, we differentiated the development strategy from the other two SINE compounds to investigate viral diseases and other non-malignant disorders. Antengene is planning to support a phase II basket trial evaluating the antiviral effect of ATG-527 in multiple virus diseases. In addition to SINE monotherapy, we have identified several strategic combination directions to make SINE molecule-based combinations as a concrete treatment option for patients. The first one is KRAS mutant solid tumors.
Although sotorasib was FDA-approved to treat KRAS G12C mutant non-small cell lung cancer this year, a huge unmet medical need are still there. Antengene is planning to initiate a trial combining selinexor with checkpoint inhibitor to treat refractory KRAS-mutant non-small cell lung cancer and colorectal carcinoma patients. The second direction is immune-inflamed carcinoma. XPO1 inhibition can regulate immune function and potentially reverse the resistance of checkpoint inhibitor treatment. Preliminary clinical data suggests that combining selinexor could significantly improve the response rate of pembrolizumab in frontline melanoma patients. Another direction is chemo-dominant cancers like pancreatic cancer and glioblastoma. We intend to combine with standard chemo regimens to magnify the benefit to these patients. The optimal direction is viral-related cancers. If the RICH study generates positive signals, we would then proceed with combination development approaches.
From a long-term perspective is to combine antigens or assets and other novel agents like PD-L1/4-1BB antibody and ERK inhibitor, et cetera. This is my last slide. Look forward to sharing in the next Antengene R&D Day. Thanks for your attention.
Thank you very much, Dr. Godfrey Guo. Again, we have a Q&A session right now, and feel free to enter your questions into the Q&A box on the webcast link. We've been receiving a few questions on ATG-008. I'll group them together. First, "Hi. May I ask why ATG-008 is particularly effective in cervical cancer?" There's another question on ATG-008. Exciting data on ATG-008 TORCH-2. What is next steps, and what do you think will be the regulatory path for this asset in China? I'll invite Godfrey and Kevin to answer these questions. Maybe Godfrey can start first.
Thanks for the question. They are great questions too. The first question regarding the cervical cancer patient type benefited from TORCH-2 study. Actually, we identified that cervical cancer patients are harboring mTOR pathway alterations. So maybe this can explain why this population can benefit from the mTOR inhibition combined with PD-L1 population. You have monotherapy combination. The second question is, TORCH-2 study looks very encouraging with around 75 achieving clinical benefit and confirmed responses now in three diseases, particularly in cervical cancer population. However, this data remain a little early, and we need more patients to further validate this promising signal.
In parallel, we will come up with a proposal and then, exchange it with CDE intensively to get their endorsement regarding the accelerated regulatory path. This is my short answer. Maybe Kevin can add more comments.
Yeah. I mean, Godfrey, I think that's a very, very clear answer. I mean, perhaps just add that there are some recent data suggesting that the activation of the PI3 kinase, AKT, and TOR pathway seems to play a key role in the viral crosstalk and cancer progression in cervical cancer, which does seem to have an underlying viral origin. And that activation of the mTOR pathway may make that particular disease, you know, a particularly, you know, suitable target for this combination. I think your comment in terms of the regulatory pathway is also correct. You know, these are really interesting, encouraging data, but we need to collect more. We will be attempting to expedite that with a focus on cervical cancer.
I think, you know, the responses we've seen in nasopharyngeal and ovarian cancer, you know, are worth further exploration as well. And then once we have a little bit more validation, we can enter that discussion with the CDE as to what is an appropriate regulatory path. Thank you.
Thank you, Kevin and Godfrey. Again, if you have any questions, please feel free to enter them into the Q&A box on the webcast link. We have another question on ATG-017, a ERK1/2 inhibitor. Can you please outline some of the possible combo opportunities for ATG-017? I'll invite again Kevin and Godfrey to comment on this question.
Okay, thanks again. I think the most obvious combination to start with is with checkpoint inhibitor. This will explore the potential synergy of this combination in terms of its direct antitumor efficacy but also explore the really interesting hypothesis that ERK blockade can reverse the hyperprogressive disease that can complicate this checkpoint inhibitor treatment. That we can remove the ERK-driven immune-suppressed tumor microenvironment. I'd like to stop here and hand over to Dr. Lynch to add more comments.
No.
Yeah.
No, thanks, Godfrey. I agree that the preclinical data is very exciting, and we're well advanced in that discussion and plan to implement the PD-1 antibody combination once we're comfortable with the dose of ATG-017. You know, beyond that, there is actually a very strong rationale to combine ATG-017 with multiple other agents. I think you mentioned in your own presentation the upstream combinatorial possibilities in terms of inhibition of MEK or RAF, or indeed our own KRAS G12C inhibitor. But there's also the potential to look at parallel pathway inhibition with PI3 kinase and TORC. You know, so down the track, that might be an opportunity as well. There's preclinical data suggesting potential synergy with some more conventional agents.
We know that chemotherapy, for example, there is ERK-mediated chemoresistance and indeed ERK-mediated p-glycoprotein overexpression, so the rationale to combine with conventional chemotherapies. We know that ERK activation protects cells from the cytotoxic effects of radiation, so there are opportunities in combination with radiotherapy. Just finally, I'd also want to stress that, you know, this is the first time that we may have an active ERK inhibitor deliverable at doses in the clinic. This gives rise to real opportunities in hematological malignancies where we see activation of the RAS MAP kinase pathway. This is an area that's not really been explored to date. We have that written into our ERASER study as soon as we have a phase II dose identified, and we're pretty close, we think.
After that, we can open up a broad range of the hematological explorations, and that opens up a broad range of other combination possibilities as well. I think you can see our enthusiasm that, you know, the range and breadth of opportunity with this compound is really, really very substantial. Thanks.
Thank you, Kevin and Godfrey. Again, if you have any questions, feel free to send them through the Q&A box as we go through the presentations. Let's move on to the next presentation. I'll invite John Chin, our Chief Business Officer, to go through his section on XPOVIO selinexor ATG commercial opportunity. John, please.
Thank you, Donald. Now, I'm very pleased to provide an overview of our strategic commercial approach and our readiness to launch XPOVIO across the Antengene markets. With 17 markets in our region, our strategic approach to the launch of XPOVIO focuses on six core markets based on three parameters for success. These parameters are, one, that there is a high unmet medical need in these markets. Two, there is a high GDP per capita in the market. And three, that these markets have a structured reimbursement system in place that supports rapid access to innovative therapies. Today, we've established commercial and medical affairs teams in China, Australia, South Korea, Taiwan, Singapore, and Hong Kong. And we continue to build our teams as we prepare for the launch of XPOVIO. In fact, we're launching XPOVIO this week in South Korea as I speak.
As we build momentum with our XPOVIO launch in these six core markets, we tend to expand the launch of XPOVIO across the ASEAN markets in the future, where we do find large population centers with the same unmet need. Now, as we move to slide 3, I want to take a step back and highlight the unmet medical needs that remain across many cancers in the Asia-Pacific region, especially in China, and the opportunity to impact survival for these cancer patients. When you compare the five-year survival rates for the selected cancer types in China versus the U.S., you can see that there's a substantial difference in five-year survival rates, especially for hematologic cancers like multiple myeloma and non-Hodgkin's lymphoma. One of the main reasons in the difference in five-year survival is the number of available innovative therapies in the U.S. versus China to treat relapsed refractory disease.
We see a great opportunity to make an impact in the lives of myeloma and DLBCL cancer patients with the approval and launch of XPOVIO in the near future. As I just highlighted the difference in five-year survival rates amongst cancer patients diagnosed with myeloma and NHL, this slide highlights the significant opportunity for new innovative therapies for these patients. As you can see, the incidence rates of myeloma and DLBCL are much greater in China and the APAC region versus the U.S., with the median survival being lower in these markets. This again is highlighting a significant opportunity and high potential for growth to introduce XPOVIO as a new innovative treatment with a novel mechanism of action to treat these patients after they have relapsed from initial treatments and to extend their survival.
As stated earlier, we believe we have a significant and differentiated opportunity for the successful launch of XPOVIO and its growth across our core markets. With limited innovative therapies and regimens available in China and across the APAC markets compared to the U.S. for both relapsed refractory myeloma and DLBCL, and from the results of our market research, treating physicians are highly motivated to provide patients with new mechanisms of actions and novel treatment regimens. As triplet combination regimens become further ingrained as standard of care for relapsed refractory myeloma, we see a differentiated opportunity for our XVD regimen to be used in earlier relapsed patients relative to the U.S. Also, relapsed refractory DLBCL has been characterized by a lack of novel therapies in Asia as well.
Thus, XPOVIO now offers a new mechanism of action that is combinable with other existing therapies to provide patients another opportunity to extend their survival. Asian physicians have recognized the need for XPOVIO due to its novel MOA in treating myeloma. Results from our market research report that physicians are enthusiastic about a medicine that has a new MOA and that provides them another option for patients that have failed previous treatments. It is our belief that XPOVIO's MOA is a major differentiator compared to other medicines, but it's not the only primary reason to prescribe. Physicians recognize that XPOVIO delivers robust clinical outcomes in key patient segments and coupled with the convenience of oral therapy for patients is what will influence the prescribing of XPOVIO after failure prior therapies.
Our initial key messages will focus on high-risk genetics, a convenient regimen with fewer clinic visits, efficacy for patients regardless of age, as well as how to manage the expected side effect profile of XPOVIO, and having a new MOA so as not having to recycle previous classes. Our commercial team is in place across our core markets and are ready to launch XPOVIO once approved by each market. This is a team that has strong track record and experience in launching some of the most successful hematology oncology brands in China and the APAC region. Both Thomas Karalis, our leader of the APAC region, and Lixin Yu , our commercial leaders for China, have over 30 years of experience across many commercial functions and launching global brands.
Our strong leaders in each of our core markets have a proven track record and have laid the groundwork for a successful launch of XPOVIO. XPOVIO's launch momentum is building. As I noted earlier, we received regulatory approval for XPOVIO for relapsed refractory myeloma and relapsed refractory DLBCL in South Korea, and the team is launching this week. We expect approvals in the other core markets in early to mid-2022, and have submitted reimbursement dossiers in both South Korea and Australia. With the commitment of our experienced leadership teams, we are leveraging our disease market and physician insights to lay the path to a successful launch and will continue to build the commercial teams, engage our KOLs, and pull through XPOVIO usage as we gain reimbursement approvals in the future.
As we launch XPOVIO across our markets, we will commercialize at a time compared to when it was launched in the U.S., where we will have more clinical data across myeloma, DLBCL, and other cancers. The brand is now also recognized by the NCCN and CSCO treatment guidelines, as well as there is a depth of clinical experience with XPOVIO and strong relationships with our key opinion leaders across all major markets. Our team is well prepared for the launch of XPOVIO across our key markets. A number of pre-launch activities have been ongoing. As mentioned earlier, our commercial and medical affairs teams are in place. Numerous stakeholder physician and market access engagements are occurring. Importantly, physicians are getting hands-on experience treating patients with XPOVIO through our early access programs, laying the path for a successful launch.
Our confidence in a successful launch stems from the strength of the foundation we have laid in the past two to three years. As of today, we have more than 700 patients that have been treated with XPOVIO through our early access programs, with greater than 250 physicians gaining experience with the brand and greater than 500 engagements through ad boards, meetings, and symposia presentations. With one regulatory approval in South Korea, we are looking forward to the commercial launch of XPOVIO in the first half of the year in the other five markets.
Lastly, as the clinical team just reviewed the ongoing development of XPOVIO in relapsed refractory T-cell and NKT cell lymphoma, myelofibrosis, and endometrial cancers, where the incidence rates of these cancers are much higher in Asia than in the U.S., we believe there's tremendous opportunity for growth of XPOVIO in China and the APAC region, and most importantly, access to this novel innovative medicine to treat these patients in the future. Thank you for your attention, and I'll pass it over back to Donald.
Thank you, John. We now have another Q&A session. Again, feel free to key in your questions into the Q&A box. Feel free to ask questions on their previous sections as well, other than just immediately preceding section. We've got one question. Selinexor sales is starting to recover in the U.S., but has had a few quarters of challenging sales. What have you learned from the experience from the U.S., and how will you be launching differently in China or Asia? I'll invite both John and Jay to comment on this question.
Sure. Thank you, Donald. John, you want to go ahead, please?
Yeah, yeah. Thanks for the question. First of all, I think we have a great relationship, working relationship with our partners at Karyopharm. I think when you have to consider when selinexor was launched in the U.S., there was greater than 15 medications to treat myeloma. A lot of competition. Physicians had numerous choices of medicines and combination regimens that they could choose from to treat their patients. In addition, there was not a lot of experience with selinexor on how to manage toxicities and dose reductions, especially in the penta-refractory setting, where these patients, as we know, have been heavily beat up from earlier lines of therapy and of their underlying disease.
I think one of the key learnings for us is, as we launch XPOVIO in our markets, we will be spending time to educate our physicians on the expected side effect profile of XPOVIO, and more importantly, how and when to dose reduce the patients in order to keep, to continue to keep them on therapy so that they are benefiting from this innovative medicine. I think when you look at the data from Dr. Sundar Jagannath, a clinical site that was actually on the BOSTON trial, they learned how to manage the side effects and dose reductions, which resulted in higher response rates, longer duration of treatment, and longer PFS. It'll be interesting data that will be presented here at the upcoming ASH, so please look for the data.
I would like just to add on to what John just discussed. We have a very close partnership with Karyopharm. As a matter of fact, we have a weekly if not daily multi-functional team and discussion, including and commercial and medical affairs teams. Of course, we have learned a lot from colleagues at Karyopharm over the past little more than two years since the commercial launch of XPOVIO in July 2019 in the United States. We actually have had the benefits that, for example, XPOVIO has since been included in with multiple regimens and across myeloma and DLBCL in the NCCN guideline as well as the Chinese CSCO guideline.
Since December last year, XPOVIO has also been included as a second-line treatment option in the U.S. Whereas we have multiple trials, not only in the triple class refractory, the MARCH study and Dr. Aihua Wang described the data, also the BENCH trial in the second-line setting, and then the third-line and SEARCH study in the diffuse large B-cell lymphoma and second-line in combination with R-GDP. All these clinical activities and the clinical practice and guidelines around the world have benefited, to be very frank, and engaged tremendously.
Our physicians in our territory are much more aware of this drug with novel mechanism of action, with convenience of use, with the benefits to be able to adjust the dose and very easily, and so across different regimens. These are the benefits that were not available, to be very frank, to our colleagues at Karyopharm two to three years ago. We actually have this advantage of a lot of lessons learned and then a lot of timely exchange of information.
As a matter of fact, we have also invited a large number of key opinion leaders from the United States and Europe to share their personal experience using XPOVIO either in clinical trial settings or their own practice, from physicians from the United States and Europe. Actually, before COVID and in 2019, many of them visited our study centers in China and participated in our advisory boards. Even during the COVID, over the past year and a half, we have hosted multiple symposiums and advisory boards, and many of the same U.S. myeloma and lymphoma KOLs have participated remotely.
These are the benefits actually and that we think will help us to have a very successful launch of XPOVIO in the Antengene end markets. Thank you.
Thank you, Jay and John. We have a question on the earlier parts of the program on the discovery side and early development. Have you tested the ATG-037 function in T-cell rescue experiment at higher AMP concentration? I'll invite Dr. Bing Hou and Dr. Bo Shan to supplement on this question.
Yeah. Thank you for the question. It's an interesting question. The simple answer is yes, we have tested the ATG-037 function in higher AMP concentration. It has been reported that in colorectal cancer patients, in the tumor microenvironment, the AMP concentration for most patients is around 20 micromolar. Only a few patients have higher concentration of AMP, with the highest concentration reached 1000 micromolar. We test the ATG-037 function in rescuing T-cell function in higher AMP, with AMP level up to 1000 micromolar. We found that ATG-037 still is still capable of completely rescue T-cell function at 1000 micromolar AMP level. On the other hand, if you remember, we showed that the monotherapy activity in two mouse models.
One is EL4, the other one is CT26. It has also been reported that in these two mouse models, the AMP concentration in the tumor microenvironment reached 1,000 micromolar. ATG-037 still have a very potent antitumor activity in vivo. Thank you.
Thank you, Dr. Hou. We have a question on the pricing environment in China and NRDL, and thoughts on pricing for selinexor in China and entrance into NRDL. I'll invite John and Jay to comment on this question.
I may start, and John, please, chime in.
Yeah, sure.
You wanna go ahead?
Yeah. Go ahead, Jay. You can start.
Thank you.
I can chime in.
Sure. Okay, good. As we just discussed that, we have multiple indications or line extensions for XPOVIO in China, including the triple class refractory as well as the second-line multiple myeloma in combination with bortezomib, for example, and then in the third-line DLBCL and the second-line DLBCL in combination with R-GDP. Potentially, as we discussed, we're going to have a data readout on the SIENDO study, the endometrial cancer maintenance study, the first of its kind in that setting. We have, as you can see here, multiple indications and expansions in our market. We are basically planning very strategically on when to apply for NRDL.
The answer is that for sure, we will be applying for NRDL for reimbursement on made in China. That is basically a matter of time and given that we have multiple indications to be approved in the next month to next couple years. Yes, the NRDL has been challenging and that admission to NRDL, but we think that XPOVIO has an advantage as not only the first-in-class, but as a matter of fact, is only-in-class in the molecule. It's oral agent, and then there's no any other drugs in the same class. Has demonstrated a single agent activities across multiple tumor types.
It works very well synergistically and with the targeted therapies and with other backbone therapies for myeloma and lymphoma. We also heard with immune checkpoint inhibitors and with chemotherapy in, for example, the TOUCH study. I think we're in a unique position and to be admitted on to NRDL. Frankly speaking, I also think that as challenging as it has been, but also I think that NRDL has improved and progressively over the past four years since 2017. As we may recall and up to 2017, the reimbursement list on NRDL was not updated for almost eight to nine years. Now that list is being updated on yearly basis.
Prior to 2017, there were no novel therapies included on NRDL, and now there are numerous, a number of novel agents that end up being admitted and reimbursed through via NRDL. We are confident, we are optimistic, and XPOVIO will be listed on NRDL. But we are also thinking and planning strategically on when to apply, given that we have multiple indications and in the next, well, as I speak, as I mentioned, next couple months to the next couple years. These are, of course, constantly, and we are looking at these options. Thank you. John, please.
No, thank you, Jay. I mean, I think you covered many of the points that I was going to make, so I think that was a complete answer.
Great. The CEO can double as the CBO, I guess. Sorry.
There you go.
Thank you. I see no further questions right now. If there's no further questions, I'll hand it over to Jay for closing remarks. Jay, please.
After our event today, I hope you have gained a more comprehensive understanding of Antengene and are impressed with our current clinical trials as well as potential of our next generation assets. By continuing with our swift execution across regions, Antengene will be delivering a steady stream of catalysts that will continue to drive value for all our investors. Antengene's first commercial launch of the only first-in-class drug, selinexor, is imminent, and we are excited that we'll officially be generating substantial revenues starting next year. We started with two disease areas that we are most familiar with, multiple myeloma and diffuse large B-cell lymphoma. We are also expanding to multiple future indications that represent untapped and blue ocean opportunities in our regions.
In addition to selinexor, Antengene has a broad and deep pipeline of 10 global assets with wholly owned rights, with highly differentiated combinational and synergistic mechanism of action. We are progressing very rapidly with these assets. There will be a series of data readouts coming out soon for these assets. Antengene is also working relentlessly in business development. We are in continued BD discussions on new assets, on clinical collaborations, on various technologies that could synergistically expand our product portfolio, ultimately delivering transformational medicines for our patients all over the world. We have been generating a very high return on investment for our investors, utilizing cash, running trials, building teams in a highly efficient manner. As you can see here, with the cash reserves that we still have, we are confident in continuing to deliver value to our strong base of global shareholders.
Over the past four years, we are extremely grateful for your continuous support. This is just the beginning for Antengene, and I'm certain that we can achieve great things together. Once again, thank you very mucph for attending our first ever research and development day, and we look forward to continuing working with you to achieve our vision of treating patients beyond borders. Thank you.