OPKO Health, Inc. (OPK) Earnings Call Transcript & Summary

Good afternoon. This is Yvonne Briggs with LHA. Thank you all for joining us today for OPKO Health's R&D Day highlighting ModeX Therapeutics multi-specific technology platforms. Following management's prepared remarks, we will host a question-and-answer session. [Operator's Instructions] Please note, this event is being recorded, and a replay will be available on OPKO Health's website. I'd like to remind you that any statements made during this call by management other than statements of historical fact, will be considered forward-looking and as such, will be subject to risks and uncertainties that could materially affect the company's expected results. Those forward-looking statements include, without limitation, the various risks described in the company's SEC filings, including the annual report on Form 10-K for the year ended December 31, 2022 and its subsequently filed SEC reports. The contents from the webcast contain time-sensitive information that is accurate only as of the date of the live broadcast today, March 20, 2023. Except as required by law, OPKO undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call. Now I'd like to turn the call over to Dr. Gary Nabel, Chief Innovation Officer.

Thank you, Yvonne. I'm Gary Nabel, President and CEO of ModeX Therapeutics and Chief Innovation Officer at OPKO. I'm delighted to welcome you to the first Research and Development Day for ModeX Therapeutics. Elias Zerhouni and I cofounded ModeX in November of 2020, and we've been working since then to bring innovative medicines to benefit patients facing serious medical challenges in cancer and viral infection. In May 2022, we merged with OPKO Health, where we now operate as an independent subsidiary of OPKO. Together, the efforts of OPKO and ModeX have been synergistic, building on the experience and infrastructure of OPKO to accelerate our therapeutics program and to provide a new story of growth for OPKO, outlined in this slide. Now I would like to introduce you to the President, CEO and Board Chair of OPKO, Dr. Phillip Frost, who will provide his perspective in his opening remarks. After his comments and Elias' overview, I'll be back to guide you through the program that describes the assets and capabilities of our team. Phil?

Hi, everyone. Thanks for joining us for our first R&D day. It's a real pleasure of talking about the innovative work of the ModeX team and the opportunities we see for the ModeX pipeline portfolio, platform technologies to treat infectious diseases in cancer. Since OPKO's acquisition of ModeX mid last year, the ModeX team has made really great progress. Two weeks ago, we announced ModeX' first collaboration with Merck or an Epstein-Barr virus vaccine program using ModeX' [indiscernible] platform. This was an extraordinary public review for the team's scientific programs, and we'll be talking more about that deal later. And we've seen with OPKO's collaboration with Pfizer for NGENLA, we have a track record of working with great global partners to realize the potential of our technologies. We expect ModeX pipeline provide even more opportunities to continue [indiscernible]. Evaluating ModeX as an addition to our gross portfolio of companies, we saw a truly differentiated therapeutic developer with next-generation technologies, focused on major global health needs. As you'll see today, the leadership is exceptional and the integration has been a great success. I want to take a moment to welcome ModeX' CEO, Gary Nabel, and the Chief Scientific Officer, John Mascola. Dr. Nabel was founding director of the Vaccine Research Center at the National Institutes of Health and as a leader in NIH for many years before as Chief Scientific Officer at Sanofi, where he led the breakthrough development laboratory. Dr. Mascola was also a Director of the NIH Vaccine Research Center, where he was seeing a wide range of research and vaccines and antibody therapeutics for a range of diseases. Between them, they have advanced some of the world's most important medical research and are now focused on driving a uniquely promising story at ModeX. Today, Gary and John are joined by Vijay Chhajlani, ModeX Chief Technology Officer; and Ronnie Wei, head of Biologics, Discovery and Development, all scientific leaders, who will [ provide with ] the development of ModeX platform technologies. As we think about the broader OPKO business, we built a diversified base that's allowed us to meet an important challenge for patients and society during the COVID-19 pandemic. Looking ahead to the next phase for OPKO, we see ModeX as an important engine for innovation that will increasingly replace therapeutics at the center of [ low ] value creation, with people, technologies, culture and focus of ModeX, a rare combination that places us in an incredibly strong position to build a larger and more diversified pipeline to help grow into the future. The work you'll hear about today reflects industry-leading expertise in the development of next-generation antibodies and vaccines. These bring the power of multiple medicines to bear in a single molecule. Many of the most significant infectious diseases and most cancers are notable for their complexity, which presents major challenges for [indiscernible]. The core with ModeX facility is realizing that potential in truly multi-specific codes that go far beyond current efforts in the market. We're incredibly enthusiastic about the opportunities we're creating together and the way ModeX is complementing OPKO's legacy of healthcare innovation. I invite you to take part of the Q&A at the end of today's session to [ learn ] more about our work and our vision for the future. Now, I'd like to pass over to Elias Zerhouni, our President and Co-Founder of ModeX, to give us a brief overview of the company's focus and what to listen for today.

Well, thank you, Dr. Frost, and thank you, everybody, for attending our R&D Day. What I'd like to do is really give you a perspective about the history of ModeX, how did we come together and why did we come together? So the first thing I would like to tell you is that ModeX is not a completely new company. Actually, Dr. Nabel and myself worked together at the NIH. And then when I went to Sanofi, Dr. Nabel joined me, and we decided to create a breakthrough lab, which was led by Dr. Nabel at Sanofi. And the idea was to generate transformational technologies based on multi-specific antibodies and multivalent nanoparticle vaccine platforms. We decided to focus on immuno-oncology, on viral diseases and vaccines. Our track record actually since 2012, when we created the breakthrough lab, was pretty good. We have 3 multi-specific antibodies in ongoing Phase I trials and -- proving, in fact, that the strategy can work in the clinic. We established a very strong IP foundation. As of today, we have 28 patents, applications filed. And really, what brought us together was the vision of Dr. Frost at OPKO to bring top-notch leading-edge R&D to OPKO. For us at ModeX, it also brought us a very experienced organization with all of the things that we would have had to recreate to be an independent company. By merging the two, we really combine our forces to create novel biotherapeutics. And the portfolio that we have is eliciting strong interest from strategic partners, as you will hear from Gary Nabel about our first major partnership with Merck. So the question that I always get is this one. What is the fundamental scientific driver of ModeX Therapeutics? And so let me share with you the fundamental scientific concept that is really driving us. And that is the fact that we have learned over the past decades that no disease depends on a single target. That's why you have many, many therapies that are a combination of therapies to achieve success. In fact, if you look at this network of molecules that I drew here on the slide, you can imagine that a certain disease can have multiple pathways leading to the disease. And the molecules that are in pathway 1 or pathway 2 or pathway 3 sometimes correct each other. And if you only act on one, the other two may actually persist in creating the disease symptoms. And so our idea was, can we come up with what we call dream molecules? One drug that can attack multiple targets, affect multiple biological functions and in diverse diseases. So this is based on the deep understanding of validated molecular networks and pathways. But the thing that is really interesting to appreciate here is that many, many of the targets have been validated in single-target, single-therapy drugs that have one target. And the scientific evidence indicates that many diseases now require a combination to achieve success, and we can see it. You can see it in humans with chemotherapy, with antibiotics, even in immunotherapy. We developed a drug called DUPIXENT, which attacks two targets, IL-4 and IL-13, for a disease pathway called the Th2 pathway, which is responsible for atopic dermatitis, asthma, esophagitis and other diseases. And what we realized is that by combining the two, the advantage is: number one, you are affecting two targets; number two, and more importantly, because you're affecting two targets, you don't have to really have high doses. And therefore, you can decrease side effects. The same is true in vaccines, and you'll hear about our platform, which can really combine multiple antigens to create stronger vaccines. And so that is the central concept, really. We are aiming to have synergistic targeting of what we know biologically are disease drivers in unique combinations that will actually bring the ability to develop a single drug over a single time period of development that will attack multiple targets, and it will be multifunctional. And this is really what we're based on. And I'll now turn it over to Dr. Nabel to go over the first illustration and then the rest of the portfolio on the -- of ModeX Therapeutics. Thank you very much. Gary, back to you.

Thank you, Elias. It's a pleasure to introduce you today to ModeX Therapeutics. We're excited to tell you about the pillars of ModeX. The 4 Ps, our people, platforms, products and the promise of our growing company. I'll provide a high-level view of the people, platforms and products of the company in this presentation, after which I'll describe our EBV vaccine program, the basis of the work and IP that was recently licensed and partnered with Merck. You will then hear about the platforms from Dr. Ronnie Wei, the Head of Biologics, our pipeline portfolio from our CSO, John Mascola and the CMC manufacturing programs from our Chief Technical Officer, Vijay Chhajlani. The first P of our pillars are people. We value medical experience, scientific excellence, creativity, pragmatism and collaboration. And our leadership team exemplifies those values. You've heard from Elias already. He and I are joined in the leadership of ModeX by Elizabeth Nabel, my wife, who's the Executive VP for Strategy; Ji Zhang, who is the Chief Operating Officer, formerly at Sanofi and Flagship Pioneering, our consultants in oncology, Edward [ Garmey ]; our outstanding Chief Scientific Officer, John Mascola; our extremely proficient Chief Technical Officer -- Technology Officer, Vijay Chhajlani, and our Head of Biologics, Discovery and Development, Ronnie Wei that you'll be hearing from later as well. Other heads of our department are CJ Wei and [ Xian ] Yang, who are heading our basic research programs. All have extensive experience in academia and government and industry, and it's really quite an impressive team and really an exciting work environment, where we can all come together. The promise of next-generation antibody technology is really what we're trying to deliver at ModeX Therapeutics, and we're trying to deliver that by creating multispecific antibody technology that allows for synergistic targeting in terms of disease targets, streamline manufacturing, rapid translation into the clinic and efficient delivery either by protein or gene-based vectors, all in a single product. ModeX also builds on known pathways to generate its effective new medicines. We use information about known immune mechanism, T cell signaling, B cell signaling, MK signaling and validated targets that have worked in the clinic, based on established biology, particularly clinical biologies, to develop our new medicines. And by using molecular engineering, structure-based design and digital design and machine learning, our candidates can stimulate biologic responses with novel combinations of antibodies and immune activators, all in one molecule to generate first-class candidates with best-in-class potential. And that's what you'll be hearing more details about in the upcoming presentations. The multi-specific technology is newer in terms of antibody modalities, the initial antibody modality that we're all very familiar with, [ they're ] monoclonal antibodies. You'll also see some of the data on bispecifics that represents the next generation. But there has been an increasing interest and movement from a number of companies to take advantage of even greater flexibility in attacking targets through trispecific antibodies and now even beyond trispecific antibodies to test in clinical trials. And the good news is that multiple clinical trials have now been performed, and they help to validate the promise of this platform. When we were at Sanofi, we developed an HIV trispecific antibody for both the treatment and prevention of HIV. That's now been in Phase I study, you'll hear more about that from John Mascola. And there were two cancer products that have gone to the clinic by using tri-specific antibodies, with arms directed to CD3 and CD28, in addition to the tumor. In these trials, they have shown the ability to manufacture at scale to bring these products to patients. No major adverse events have been observed, and there have been minimal degrees of the antidrug antibodies, providing a good starting point for derisking the new technology, and we'll say a little bit more about that later in Ronnie Wei's talk. The important new technology that we've developed at ModeX is called the MSTAR platform. This is the ModeX platform that allows synergistic targeting of antigens and receptors. And the way this is done is essentially by increasing the valency of our antibodies. A standard antibody is composed of a single-variable region, and it allows us to basically target our antigens by using the single-variable regions to interact with them. In the MSTAR platform, we're able to put these variable regions together in different combinations so that they can give rise to new molecules that can interact with different targets all at once. These new modules are complementary and self-assembling. So in addition to the ability to create new combinations, it also has benefits with regard to manufacturing because it eliminates mispairing that reduces the yield of product that we can make during CMC. We've also been able to engineer them so that they have simplified configurations, single chains for each arm that enable gene delivery that could accelerate clinical development. And this is all supported by intellectual property applications. We have 28 patent applications that have been filed today. In this animation, you can see the rationale for how we create multispecific antibodies. The blocks on the top of the slide represent the variable regions of heavy and light chains that we've made as single molecules, and they can be assembled in different combinations on top of the constant regions. We can put 4 copies of 1 type of variable region. We can put 4 different types of variable regions where we can, for example, make up to 6 different variable regions. And by putting them together in different degrees and in different orientations, it allows us to select the molecules that are best suited for the treatments that we're trying to develop. I should mention also that at the bottom of the slide, you noticed the constant region of the immunoglobulin is preserved. The constant region itself carries many important immune functions. It regulates the half-life of proteins, it also interacts with other cells of the immune system. So by having the capability of recognizing different targets, for example, on tumor cells or viruses or bringing together immune cells based on what we know about their activation pathways, whether it be T cells, B cells, natural killer cells, we now have the ability to selectively both activate and sustain those cells at the sites of the disease. The second technology that has been part of our efforts relates to ferritin nanoparticle vaccines. In this particular case, we're showing an example of the Epstein-Barr virus vaccine, where we can take components derived from Epstein-Barr, we can take different molecules from the surface of the virus, we can then extract them out and make genetic forms that we can fuse to specific sites on the ferritin molecule. Ferritin is a molecule found in a wide variety of species. They carry iron. We actually used a bacterial form of ferritin so there is no cross reactivity with any human ferritin proteins. And it is a multi-unit particle with 24 sub units that self-assemble. So by putting it at the right position on the outer surface of ferritin, we can get a self-assembling nanoparticle. In this case that has been attached to the gp350, which is a viral entry protein for B-cell entering. Or alternatively, we can take other viral proteins like the gH, gL, gp42 trimer that mediates entry of the virus into epithelial cells, and we can again expose up to 24 copies to the immune system in an effort to stimulate antibodies that will neutralize the virus. So now I'd like to switch and tell you a little bit about the EBV vaccine program. We have partnered this program with Merck. There was an announcement on March 8, just 1.5 weeks ago, where OPKO Health entered into an exclusive worldwide license and collaboration agreement to develop this vaccine. It was widely reported in the biotech and biopharma world. This is an important milestone for our infectious disease program. It is an exclusive worldwide licensing agreement and a collaboration agreement for MDX-2201, this is the program at ModeX that delivers these 2 vaccine components. We will be working jointly with Merck to advance these candidates to the stage of IND. After reaching IND, Merck will assume responsibility for all for their clinical development. The terms of the agreement included a $50 million upfront payment, with the potential for additional payments of up to $872.5 million in milestones, and there will be additional tiered royalties. Importantly, this is a validation of our platform capacity. I think most importantly, what we're most excited about with this collaboration and this license agreement is that we really feel that there's a very important unmet medical need globally. And both Merck and ModeX are quite closely aligned and share a very similar vision for how to bring this vaccine forward so that it can really make a profound effect on human health. My experience in the field of EBV vaccines actually dates back to my time at the NIH, where I was the Director of the Vaccine Research Center. And we published an article together with Jeff Cohen, Tony Fauci, Harold Varmus on the need for an EBV vaccine. After working on this project, largely with Jeff and at Sanofi with others, we've now, at 12 years later, created some very encouraging vaccine candidates that we think are ready for further clinical assessment. As you know, Epstein-Barr virus causes infectious mononucleosis in adolescents and young adults. Probably more significantly to human health, EBV was the first human cancer virus to be identified. That was over 150 years ago -- I'm sorry, over 50 years ago. And it's been linked to more than 200,000 cases and 150,000 deaths each year. It's been implicated in Hodgkin's disease, Burkitt's lymphoma, gastric, nasopharyngeal cancer and also with post-transplant lymphomas. It's also been associated with autoimmune diseases, including multiple sclerosis. And importantly, there are no licensed vaccines or treatments for this disease. There is substantial cost to the medical system and dealing with EBV infection. It's thought that infectious mononucleosis alone accounts for about $2 billion in healthcare costs yearly. You can also see the rising incidence of EBV-associated malignancies with age. You can see here the rise of the lymphomas that occurred starting in the '20s and peak in the '50s. Importantly, gastric cancer is also a very frequent malignancy associated with EBV infection. In terms of the clinical and commercial potential of such a product, there have been analyses done for infectious mononucleosis. Infectious mononucleosis would carry a projected peak sales of about $400 million. Our great interest goes beyond infectious mononucleosis, though, to cancer prevention. And we think that there is potential for an EBV vaccine to do for these malignancies, the EBV-related malignancies, what Gardasil did for HPV. As you know, Merck led the way with Gardasil. And that's another reason why we're so excited to be working with Merck because they carry that expertise with them to these studies. It's a very nice collaboration, where we build on the scientific and the medical understanding that ModeX carries to this disease with the development and the real-world experience in developing a cancer vaccine for Merck. Obviously, for Gardasil, the commercial impact is well known. Last year, $5.7 billion in sales. And then after addressing the cancer prevention indication, there are others that will be explored, including multiple sclerosis and perhaps other immune disorders. The reason that we are -- we pursued the approach that we did for EBV, a bivalent vaccine, is that there have been previous studies where investigators have looked at gp350, which prevents the entry of virus into B cells. B cells are the cells that make immunoglobulins. In those studies, particularly a study that was published by GSK in 2008, the vaccine did reduce the incidence of infectious mono, which was very encouraging, but it didn't prevent viremia or didn't create a sterilizing virus environment in the body. And the reason for that gets back to the fundamental biology, which is that B cells are not the only cells that the virus infects, they also infect epithelial cells. And the entry of virus into epithelial cells comes through the gH, gL, gp42 [ hydro ] trimer that I described earlier in the presentation. So our rationale was if we can make a bivalent vaccine that both targeted the gp350 pathway and the gH, gL, gp42 pathway that, that would give us a chance to create the kind of protective immunity that would prevent replication of the virus. So our vaccine is a two-component vaccine, both the gp350, it's a truncated form of gp350 that gets fused to the ferritin nanoparticle, as well as a single chain form. We've reengineered gH, gL, gp42 so that it's made as a single molecule. This allows for greater consistency and homogeneity and scalability of the product. And we now have this two-component vaccine. We think that it's scalable. It should be cost effective. And there's actually been a Phase I human cell of -- just human trial, just the gp350 component, providing some derisking of the technology in humans as well. This work done by Jeff Cohen at NIH. The rationale for the vaccine has been published, and I would direct you to the paper that's been published last year in Science Translational Medicine from our team and from Jeff Cohen at the NIH. In it, you can see that there are very high titers of antibodies, neutralize the antibodies generated by our vaccines that will neutralize infection to both B cells and epithelial cells. Most importantly, in our best in-vivo models, if we vaccinate in humanized mice and if we take serum from immune animals and transfer those to humanized mice and then challenge with infection, you can see that the control animals give rise to over 10 logs of viremia by 9 weeks after the infection, whereas the immune animals have a literally undetectable replication. And that's been published. So if you have questions, you may want to look further at those papers. So that's where the project stands. It is in terms of our pipeline and our products, which will be the next subject of this presentation, it is the MDX-2201 program. And as I mentioned, we will be working with Merck to advance this to IND and for them to then take it beyond that step. And what you're going to hear about now in the remainder of the presentations today, first, you'll hear about the platform from Dr. Ronnie Wei. She will describe some of our tetra-specific technologies. She'll describe what we call a laser approach, which is the approach where we can simultaneously activate multiple pathways and lymphocytes and prolong their survival. And then you'll hear about our solid-tumor leukemia programs as well as some of our multi-specific immune modulation programs from John Mascola. He also will tell you about our antiviral programs. And so I look forward to sharing more of our technology. You've heard about the people. You'll next hear, in depth, about the platforms, followed by the pipeline and manufacturing. Then I'll come back at the very end with a few brief closing remarks before we turn to the question-and-answer session. So I thank you for your time. And now what I would like to do is introduce you to Dr. Ronnie Wei, our Head of Biologics, Discovery and Development. And she'll tell you more about the details of the ModeX platform technology. Thank you. Ronnie?

Thanks, Gary, for introducing the MSTAR platform. Next, I will give you an in-depth look of ModeX technologies, their advantages and potential applications. MSTAR is an agile multi-specific, multivalent platform, built upon lessons learned from nature, variable domains containing the VH-VL pair from monoclonal antibodies, like the one on the left, become building blocks for MSTAR. They are mounted on the constant regions like Lego pieces in a variety of configurations. MSTAR technology can incorporate up to 6 specificities in a single molecule, such as mono-specific tetravalent, bispecific tetravalent and tetra-specific to name a few. We are building a true plug-and-play system where we can fine-tune the specificity, valency and geometry to optimize biological functions. Using the bispecific tetravalent MSTAR as an example, we have built these different permutations to find the most desirable configurations for the targets and applications. The modular design enables us to rapidly test numerous combinations of antigen-binding building blocks and identify [ these ] in about 6 months. Assessment of many combinations allows us to augment specificity and avidity, minimize off-target effects and improve therapeutic efficacy. We leverage in cynical rational design and are building up deep learning digital biology capabilities to interrogate structure activity relationships and further accelerate the candidate selection process. With a quality-by-design mindset, we view the MSTAR technology, emphasizing both functionality and developability. By optimizing the MSTAR architecture, we overcome long-standing challenges in multi-specific antibody design, such as light chain mispairing and interference on binding modules so we can ensure full functionality. The Fc region [ contains ] can be tuned to modulate immune functions and half-life, giving a similar pharmacodynamic behaviors as monoclonal antibodies. It has favorable biophysical attributes and can be manufactured using standard cell lines and processes. Our Chief Technology Officer, Vijay Chhajlani, will further delve into the manufacturability of MSTAR molecules later in the presentation. When we engineer a novel antibody platform, we are very much mindful of potential immunogenicity risks. We took learnings and insights gained from multi-specific molecules that had been exposed to hundreds of human subjects in previous and ongoing clinical trials. We designed MSTAR binding domains to be structurally superposable to human antibodies and linkers to be non-immunogenic to minimize such concerns. We also developed a MSTAR-compatible STEALTH molecule that has the potential to improve therapeutic index for cancer treatments. In this environment, a tetra-specific STEALTH molecule can target tumors through 2 tumor antigens while the anti-CD3 is masked. Monovalent anti-CD28 combine and recruit T cells without activating them. Once the STEALTH molecule reaches tumor, anti-CD3 is uncloaked by proteases enriched in the tumor microenvironment. Consequently, recruited T cells are activated by anti-CD3 and anti-CD28. This localized activation of T cells mediate potent tumor kidney with minimal systemic toxicity that has improved the therapeutic window. This next slide shows a proof-of-concept anti-CD3 unmasking experiment. The masked STEALTH molecule has minimal CD3 activity, shown in the black binding curve. This activity is restored, showing the blue curve upon protease treatment. The MSTAR platform is also well suited for other immuno modulatory applications. For the next few minutes, I will give you two examples of such approaches, multi-targeting payload delivery and chimeric antigen receptor design. MSTAR can be easily modified to enable multi-target delivery of payloads such as cytotoxic drugs, radionuclides or immune stimulators. They have the potential to bind 2 or 3 targets to maximize specificity and minimize mutational escape. This is exemplified in this slide. Prostate tumor cells are targeted by conjugated bispecific MSTAR molecules, showing the cell surface binding experiment. When one binding site is knocked out, in other words, if one tumor antigen is [ done ] regulated, there is still effective binding, demonstrating that this approach can potentially mitigate tumor resistance through antigen escape. The next slide shows an example of a trispecific for a TriStar antibody, with all 3 active binding sites for their respective targets. The MSTAR cassette can be readily built into an all-in-one multi-specific CAR construct for adoptive cell therapies, where a single gene can cause up to 3 specificities, and delivers stimulatory signals simultaneously. In this proof-of-concept experiment, while using luminescent signals as T cell activation results, CAR-T cells carrying correct receptors for the tumor cells can be activated by matching targets. As shown in the middle red box, while receptor mismatched CAR-T cells, in purple dotted box, do not respond to tumor binding. In summary, I hope, through these examples, I gave you a flavor of MSTAR as a multivalent and multi-specific platform with flexibility, adaptability and diverse potential applications. We have filed 28 patent applications in the past 2 years, surrounding ModeX technologies. Next, John Mascola, our CSO, will show you specific programs utilizing MSTAR platform. Thank you.

Thank you, Ronnie, for introducing our platform multi-specific antibody technology. Next, I will give an overview of several of our product development programs, starting with multi-specific antibodies for immuno-oncology. And as you can see on our pipeline slide, I'll be talking about a multi-specific antibody for the treatment of solid tumors and a multi-specific antibody for the treatment of leukemia and lymphoma. Here, I'm highlighting the growing value proposition and success of multi-specific antibodies specifically bispecific T cell-engager antibodies called BiTEs, show clinical efficacy for B cell malignancies. BiTEs are also being developed for solid tumors, with encouraging clinical data. However, BiTEs are limited to 2 targets total, 1 tumor antigen and 1 T cell antigen. Tetra-specific antibodies can engage 2 T cell antigens and 2 tumor antigens, providing the potential for expanded mechanisms of action and clinical indications. Here, I'm showing that we're going beyond bispecifics with ModeX tetra-specific antibodies and I'll say more about the details of this antibody in a moment. Existing bispecific T cell engager antibodies harness the immune system by directing T cells to kill cancer cells. ModeX is developing the next generation of multi-specific antibodies, with greater power to recognize tumor antigens and enhance T cell killing. So here, I'm showing you a diagram of a tetra-specific antibody molecule. I'll start with the diagram. You can see the antibody on top of the cancer cell and that the antibody engages CD3 to activate the T cell and then CD28 in orange to enhance T cell survival, while also being able to engage a tumor antigen in purple and a second tumor antigen in blue, directing killing of the cancer cell. So we call these antibodies lymphocyte activation and survival enhancement receptor antibodies or [ LASERs ]. These are next-generation multi-specific antibodies, activating T-cells using Signal 1 CD3, enhancing survival by CD8 -- signal through CD28 to optimize sustained tumor killing. The dual tumor targeting increases the specificity of tumor recognition and mitigate escape resistance that can occur through the loss of a single tumor antigen. These are some data, making the point that I was just explaining. These data were published by the ModeX team in nature earlier this year. The middle graph highlights the upregulation of a CD4 cell survival signal called Bcl-xL. And what the graph shows is that we only see upregulation of that survival signal when the cells see both CD3 and CD28, as highlighted in red. Likewise, on the right panel, we see the optimal level of T cell proliferation when the T cells are stimulated by both CD3 or CD28. So in summary here, CD3/CD28 co-signaling activates Bcl-xL, a protein that promotes T cell survival, providing the potential for long-lasting activity against cancer cells. Here, I'm highlighting the medical need and clinical potential of solid tumor multispecific antibodies. There are limitations of standard-of-care treatments. For many solid tumors, existing treatments do not induce complete and sustained remission. For example, long-term survival rate for lung cancer is less than 30%, even with immune modulated therapy. Immunotherapy with antibodies has shown promise for some solid tumors, but relapse and development of resistance remains common, often due to the loss of expression of tumor antigens. ModeX tetra-specific antibodies have activity against the most common and deadly solid tumors, with the potential to be active against relapsed disease after chemotherapy and immunotherapy, including CAR-T cell treatment. Here, I'm showing you a tetra-specific [ LASER ] antibody for solid tumors, MDX-2001. Our lead candidate has been selected and is in the IND-enabling phase. As I just explained, this antibody signal activates through CD3, enhance its survival through CD28, optimizing potent and sustained T cell killing. It binds to 2 tumor antigens that are undisclosed, but that are highly expressed on diverse solid tumors, and it minimizes the potential for resistance to a loss of a single antigen. MDX-2001 targets tumor antigens that are found on the 4 most common solid tumors, which are listed on the table below, breast, prostate, lung and colon cancers, which, in the U.S., are estimated to account for over 900,000 new cases of cancer per year and over 250,000 deaths. So the antigens targeted by this antibody are able to bind to tumor antigens on those 4 common [ solid ] tumor cells. Here again, we're highlighting the foremost common solid tumors worldwide with regard to medical value. The global oncology drug market forecast for 2026 is $328 billion. And the total proportion of cancer is accounted for by the top 4 are generally high in the 40% to 50% range, indicating a total addressable global market for the top 4 solid tumors, as shown there in red on the right. We use several functional criteria for the lead selection of our antibody. I'm going to show you an example of two types of data, antitumor efficacy in vivo and antitumor efficacy in vitro. This is an example of our antibody that mediating antitumor efficacy in vivo, where we can see tumor regression in a xenograft breast cancer mouse model by MDX-2001 in black and not by the control antibody in red. Importantly, using in-vitro cell killing assays, we can show the advantage of the tetra-specific antibody targeting 2 tumor antigens Here, we use cell lines expressing prostate cancer antigens, gastric cancer or breast canter antigens. And what one can see is that the MDX-2001 tetra-specific antibody is able to kill those 3 cells and others that we have tested. This is the projected timeline and pathway to the clinic for the MDX-2001 antibody program. We start tox studies in quarter 3 this year. We are projecting GMP drug product release early in 2024, IND submission in quarter 2, at the end of quarter 1, 2024, and first dose, first patient in the middle of 2024. Importantly, we have met with key opinion leaders. We are evaluating optimal clinical study designs based on major unmet medical needs and market potential. Next, I'll talk about our tetra-specific antibody for the treatment of leukemia and lymphoma. So a little bit about B-cell cancer multi-specifics and the medical need. B-cell leukemia and non-Hodgkin's lymphomas account for greater than 140,000 new cases and 43,000 deaths per year in the U.S. alone. The overall 5-year survival rate for B-cell malignancies varies widely by disease type. Unfortunately, relapses comment for more aggressive types, and complete remission rates for relapsed disease is often less than 50%. Antibody immunotherapies, including bispecific T-cell engagers, can be effective but are often limited by incomplete responses and loss of expression of key tumor antigens. The total global addressable market for leukemias and non-Hodgkin's lymphomas is estimated at over $22 billion. This is our tetra-specific [ LASER ] antibody for B-cell malignancies, MDX-2003. The lead candidate is an IND-enabling phase currently, and I won't review the attributes shown on the slide, which are similar to our other antibody for solid tumors with regard to the ability to stimulate T cells and bind 2 tumor antigens. Here's an example of in-vivo data, showing antitumor efficacy in a mouse model. So the histogram here, the bar graphs show tumor regression in a disseminated B-cell lymphoma mouse model, again showing that 3 different doses of the MDX-2003 antibody are able to mediate tumor regression compared to a control. This is an important slide showing the advantage of dual targeting of tumor antigens and the ability of such an antibody to overcome antigen loss that confers tumor resistance. So on the left is a schematic of a cancer cell. It expresses 2 tumor antigens, purple and green, tumor antigen 1 and 2. And the green line shows cell killing by the antibody. If a tumor molecule -- if a tumor cell only expresses one of those antigens, it's still killed, if. It expresses only the second antigen, it is still killed. Of course, it is not killed if it is [ neither ], doesn't express either antigen. So this is an advantage of being able to target 2 tumor antigens with 1 antibody. This is the projected timeline and pathway to the clinic. We project starting toxicity studies in 2024, GMP drug release at the end of 2024, submitting an IND and aiming for first patient -- first dose first patient either at the very end of 2024 or the beginning of 2025. So in summary, for this program for leukemias and lymphomas, ModeX tetra-specific antibodies are potential therapies against B-cell leukemias and non-Hodgkin's lymphomas, including relapsed disease after bispecific T-cell engager in CAR-T cell treatments, multi-specifics addressing from downregulation of single-target antigens, for example, the downregulation of CD19 causing resistance after CAR-T cell treatment. These antibodies offer a potential off-the-shelf alternative to individualized CAR-T cell treatment, and our IND is planned for late 2024. So in the next section, I will review our programs for multi-specific antibodies for infectious diseases. Here, I'm going to present two programs in our antiviral program in antibody for our HIV and a multi-specific antibody for COVID. I'm going to highlight first the medical need and global impact of HIV infection, both worldwide and the United States. Globally, there are an estimated 38 million HIV-infected people, 1.5 million new infections per year and 650 deaths per year. Global HIV drug sales are estimated to be greater than $28 billion annually. In the U.S. there are an estimated 1.2 million people who are HIV infected, and it would require lifelong antiretroviral therapy, and 37,800 new estimated HIV infections per year. There are some limitations to current HIV therapy, despite the fact that current therapy is highly effective. These include drug toxicity due to lifelong treatment, for example, renal, metabolic, neurologic and other toxicities; drug resistance that can impact efficacy of viral suppression, the need for daily drug therapy, the need for lifelong therapy and the fact that there are no vaccine or antibodies that can provide long-acting protection to prevent infection. So here, I'm showing a schematic of the potential of multi-specific antibodies for both HIV treatment and prevention. So for example, in an HIV-infected individual who does -- who has suboptimal antiretroviral drug therapy, for example, due to resistant strains, one could add on an HIV multi-specific antibody to their therapy, or in the middle, a person who is on successful maintenance therapy, who may need better long-term therapy options in what's the shift from daily antiretroviral drugs to long-acting options, which include antiretroviral drugs or adding on an HIV multi-specific antibody that can also be given in a several month regimen for long-acting maintenance therapy. And then lastly, at the bottom, for those who are uninfected but at high risk for acquiring HIV, they can take advantage of the HIV multi-specific antibody to provide long-acting protection. So with regard to HIV multi-specific drug development, we are guided by detailed structural knowledge of the virus. I won't explain the less schematic in detail, except to say that we understand the vulnerable regions on the virus where antibodies can attack. So our goal then is to develop a potent HIV multi-specific antibody that can attack and neutralize diverse strains of HIV worldwide by targeting independent sites, more than one site on the virus, be dosed simply and effectively as a single antibody and be used for both treatment and prevention of HIV infection. Here are some of the in-vitro data by our team that were published some years ago, in this case, using a trispecific antibody on a platform called CODD. What this schematic graph on the right shows is that for HIV, the concept of the percent of virus strains neutralized is very important because of the diversity of the virus worldwide. So we aim to get a neutralization level that's close to 100% of viruses. One can see the curves for the individual antibodies, and we can see that one can attain close to 100% neutralization with the curve shifted to the left for the trispecific antibody. So when one builds all 3 antibodies into one, the trispecific antibody has greater potency and coverage of HIV diversity than any single parental antibody. This antibody is now in a Phase I first-in-human study by this antibody at the time made by Sanofi, and it is being conducted by investigators at the AIDS Clinical Trials Group, which is an NIH-funded clinical trials organization. The antibody has been dose escalated in 3 cohorts up to a dose of 30 milligrams per kilogram, which we think is a therapeutic dose, and it's also been given as multiple doses. So far in the Phase I study, the antibody is safe and well tolerated at both single and multiple doses, and additional data are expected in the middle of 2023. So I'll also mention that we are working on even a next generation of multi-specific antibodies for HIV. We already have in the laboratory antibodies with tenfold improved potency and breadth than the product that's in the clinic. This is a collaboration between ModeX scientists, scientists at the Vaccine Research Center, NIH, at Scripps Research Institute and at the International AIDS Vaccine Initiative, taking advantage of some of the best scientists in the world studying HIV antibodies. We have several preclinical pre-IND candidates under development, including a second-generation COD trispecific and a third-generation multi-specific using our new MSTAR format. Lastly, I'll review our COVID multi-specific antibody program. So I highlight here the ongoing medical need even in the post-pandemic era of COVID. The left graphic shows the weekly number of COVID deaths in the U.S. reported to the CDC. And one can see a persistent high level of deaths in excess of 2,000 deaths per week, even ongoing now in March with about 15,000 deaths per week, highlighted in the red text, equaling about 78,000 lives loss per year to COVID-19. Even as we speak, greater than 100,000 cases per week and 5 million cases annually. The medically vulnerable, including those with immune suppression, pre-existing conditions, cancer and transplantation, remain at risk for severe disease and death from COVID-19. With COVID-19, we have the problem of viral diversity with the global emergence of resistant strains. So on the left, we show the strength that people have heard about, alpha, beta, delta, now Omicron. Important to note that antibodies have proven effective for the treatment of acute COVID, with greater than 80% efficacy in preventing progression to severe disease. Antibodies are also highly effective for passive immunization to protect medically vulnerable patients for acquiring COVID. However, new Omicron variants have rendered prior antibodies ineffective, highlighting the need for new antibodies that are broadly active against all circulating variants. Annual 2002 sales of COVID antibodies were in excess of $7 billion, but no antibody treatments are currently effective against Omicron, highlighting the need for new therapeutics. Here I'm indicating the clinical indications for a multi-specific antibody for COVID, which include treatment of acute COVID in high-risk patients, passive immunization with a long-acting antibody to infection and potentially as a treatment for long COVID, while that would require clinical studies. The MSTAR advantage for addressing SARS-CoV-2 diversity is, again, our knowledge of the SARS spike protein shown on the left and the regions of the virus that the antibody can attack to neutralize it, which are shown schematically with the colored overlays. So our MSTAR multi-specific antibodies are modular, which allows rational selection of antibodies to optimize potency against current and future strains. The antibodies allow the potential for synergistic neutralization, leading to improved potency and lower therapeutic dose. It provides simultaneous immune pressure to prevent viral escape and a multi-specific antibody potently neutralizes all current variants of concern, including the predominant XBB strain currently dominant in the world. I'm going to show you one example of synergistic neutralization by the multi-specific antibody. So this is a graph showing the percent neutralization, and we want the curve to be shifted to the left, indicating we can see high neutralization percentages at low antibody concentration. So what we're showing here in the red curve [ combination ] of 2 regular antibodies that can neutralize well. But when we build those 2 into a single tetravalent bispecific antibody, either as the blue line or the green line, we can see a greater than twentyfold more potent neutralization shift then a combination of the 2 parental antibodies at the same concentration. This indicates synergistic mutualization. This is a graph which I, again, won't describe in great detail, but I'll explain the key point, which is the multi-specific antibodies can preempt viral escape, and this is something that's not seen with a single antibody. So in the purplish graph -- purplish slide on the graph, which we can see that, that line is flat. So the trispecific antibody but not the single antibodies prevent viral escape during serial passage. If one looks at the red of the blue lines, the virus has grown and escaped after selective rounds of replication because new mutations have arisen that allow it to escape from one antibody, but not from 3 antibodies at the same time in one molecule. Here on showing data with a tetravalent trispecific antibody for COVID, MDX-2022 -- or 2202, which shows potent neutralization of all circulating variants. In the schematic, we showed the various variants listed, including the XBB strains now prevalent. These very low IC50 numbers show potent neutralization against all these strains at the nanomolar level. So we have selected a lead candidate, and developability assessments have successfully concluded that a lead candidate meets manufacturing criteria. I want to just highlight one or two other points. An important point is what is the circulating half-life of our MSTAR antibodies. Here, we use the humanized mouse model. We have also done non-primate models. We can show in the red or burgundy line an MSTAR tetravalent bispecific antibody, and we're showing right underneath that in -- a human HIV antibody that has been in the clinic and has a serum half-life of greater than 70 days. And you can see that our MSTAR tetra-specific antibody is somewhat above that in this mouse model, which is often predictive relatively of the circulating half-life in humans. So we expect good pharmacokinetics. Finally, I'll mention that the MSTAR platform is amenable to attacking other viral diseases and pandemic diseases. In this case, I'll mention that we have an early discovery program in influenza, targeting both seasonal influenza and pandemic influenza strains. We again take advantage of our knowledge of the proteins on influenza, here showing [ hemagglutinin ] neuraminidase. And we can devise antibody -- multivalent antibodies and multi-specific antibodies that build the right combination of antibodies to mediate broad and potent neutralization of influenza for the potential to protect and passively transfer protection in those who need protection against influenza. Finally, let me highlight some of the advantages of the MSTAR or multi-specific antibodies over standard antibodies for viral infections. So on the left in green, the MSTAR multi-specific antibodies on the right would be a standard antibody targeting one epitope on the virus. So multi-specific antibodies target different sites on a viral protein, have the potential for synergistic neutralization, can cross-cover antigenic variance, have the potential to minimize viral escape and are likely to remain active despite viral evolution in contrast to an antibody that targets on site. And similarly to regular antibodies, we can mediate Fc effector functions to optimize cell killing, we can use mutations to extend serum half-life, and we use standard manufacturing technology like regular antibodies. So next, I'm going to turn over to the next sections to our Chief Technology Officer, Vijay Chhajlani. Thank you.

Thank you, John and Ronnie for presenting on our programs and on the MSTAR technology platform. I'm happy to present on the manufacturability of these MSTAR molecules. Based on the information we have gathered so far on multiple MSTAR molecules for virology and immuno-oncology indications, we can say that MSTAR multi-specific antibodies for this developability and manufacturability attributes similar to that of monoclonal IgGs. In a tetra-specific MSTAR molecule, 4 distinct [ binders ] can coexist and maintain their potency. These molecules can be produced just as monoclonals can be, and they are stable, both biochemical as well as in serum, and display half-life comparable to monoclonal IgGs. As a visual example of developability data, you see that multi-specifics, a tetravalent bispecific and 2 tetravalent trispecifics, as shown on this slide. When subjected to thermal and pH stresses and analyzed by capillary electrophoresis, remain stable over a length of time, confirming the developability of these MSTAR molecules. ModeX lead IO candidates, both MDX-2001 and -2003, demonstrate manufacturability across a range of assessments, when expressed for production to assemble predominantly incorrect format as heterodimers. These molecules also pass the criteria for stresses such as freeze, [ thaw ], exposure to heat, light and extreme pH conditions. In addition, they demonstrate excellent stability in human serum and do not bind to predominant blood cells, such as neutrophils, platelets and RBCs. Based on all these developability and manufacturability data commonly applied to monoclonal IgGs assessments, we can say that both lead IO candidates passed the manufacturability criteria. As an example of data shown here are the binding potency curves of 4 binders upon incubation in serum. All 4 specific binders in the IO lead candidate MDX-2001 maintain their potency for binding to targets, two tumor antigens on the top as well as CD3 and CD28. And this binding potency maintains over a period of 14 days in human serum, confirming the stability of MDX-2001 in natural metrics. We are at the cusp of GMP manufacturing for the lead IO candidates. Cell line development is nearing completion, and we have clones with productivity with 1 gas per liter for MDX-2001. More importantly, these clones produce high percentage of correctly assembled heterodimer, eliminating the need for extensive process development. The process for the purification itself resembles that of a monoclonal IgG, and we have already completed a 50-liter bioreactor manufacturing unsuccessfully. Our GMP manufacturing for MDX-2001 is scheduled for July of this year, and we have high confidence of success as MSTAR molecule MDX-2001 demonstrate compatibility with platform monoclonal antibody manufacturing process. With this, I would like to hand over to Gary Nabel, our CEO.

Thank you, Vijay, for this great summary of our productive CMC efforts. And thanks also to Ronnie and John for your excellent explanations of our platform and pipeline. To summarize what you've heard today, I'd like to leave you with both an understanding of the expected timeline on the delivery of our products and key takeaways about ModeX as an evolving biotechnology company. As you've heard today, we have an exciting pipeline that addresses substantial unmet needs in cancer and infection, diseases that inflect untold human suffering and impose significant costs to our medical system and economy. Regarding the delivery of the ModeX pipeline, we expect to deliver our 2 lead oncology products for solid tumors and lymphoma leukemia in 2024, the first probably earlier in 2024 and the latter at the latter part of the year. We also have plans to deliver additional products in the infection and infectious disease arena, either in late 2024, '25 for the COVID antibodies or 2025 for the HIV multi-specifics. And we will be working hard together with Merck to advance the EBV nanoparticle as rapidly as possible. And you'll hear more about that as we make progress in that collaboration. Finally, I'd like to give you the key takeaways about our presentation today related to the promise of people, platforms and the pipeline of ModeX. We have a world-class scientific team that's developed at least 3 novel platforms and multiple products that are advancing to the clinic, with a proven track record of manufacturing. Those products have been derisked in part by previous trials of analogous products. More importantly, the company has really developed a mastery of the multi-specific and the nanoparticle platforms by building on structure-based design, by building on our learnings through the digital world and in particular, through machine learning and artificial intelligence, that is really only beginning. We're able to deliver products either as protein or by gene delivery, mRNA or DNA, and that will considerably accelerate our path to the clinic. We have a strong foundational intellectual property base with 28 patents that have been filed. And the important item to remember after this presentation is that our platforms really allow the company to generate its own products and bring them to the clinic and bring them to patients. But at the same time, to also pursue partnerships by -- that are independent of our own product pipeline, that will, in some, maximize the value of the ModeX technologies. We've already begun this process of partnering with external organizations. Some are in the public domain, like NIH and DARPA, others in the private -- in the academic world like Duke and then in the biopharma sector, as demonstrated by the license and collaboration agreement that was recently completed with Merck. So to summarize, our people, platforms and products have driven a promising ModeX pipeline of innovative medicines for diseases with significant unmet need and substantial commercial potential. I'd like now to turn over the proceedings to my colleague, Elias Zerhouni, who will moderate the question-and-answer session. Elias?

Thank you everybody for a terrific presentation. I know it's very dense. There are lots of information. The sessions will be available on our website, if anybody wants to review. But it's clear that we've had a lot of interest as I see the questions that I'm going to moderate now and aside. So the first question is from Maury Raycroft, Jefferies. The question is as follows: "With MDX-2001 and -2003, the CD3 and CD28 combo activation can be very potent. What's the threshold for background or low expression, obviously, not -- no, on non-tumor cells for the two separate tumor antigens you will be targeting? Or how do you think about that?" "In other words, the target-to-background ratio, what is your expectation? What target are you going to go after that do not present a safety risk because it will have off-target effects, if you will, because of the CD3, CD28 combo?" Gary, I think you've the most experience in that domain, and perhaps you can begin to answer and anyone else who wants to participate.

Yes. Great, Elias. Thank you for that really thoughtful question. As you can imagine, this is a topic that we've been looking at and considering from the very beginnings of our programs. And in fact, I would refer you to our paper in Nature Cancer that was published in 2020 that actually gives some background information on toxicities in nonhuman primates actually related to that combination. The first thing to recognize is that the toxicities of this combination, we would expect to be probably less than what you see with typical T-cell engagers, in part because we -- rather than having 2 copies of CD3 or 2 arms engaging CD3 or 2 arms engaging CD28, we have only one arm. And what we're doing is looking at the cross-linking between the 2 components to engage the T cell. And so in our development assays, we are able to actually measure and compare the kinds of signals that we're inducing in the -- with the CD3/CD28 combination compared to previous molecules that have gone into the clinic. So we feel that the side effects, the immune side effects can be fine-tuned. We haven't seen any that are -- ones that are beyond what has been observed previously. And some of those molecules have already been started in the clinic. And at least thus far, we're not seeing any adverse events that are creating concern. At the same time, your question is a really important one, it's all about achieving therapeutic index. And so what we're trying to do and what we have done by fine-tuning the ability of these to work on these targets in various combinations, we're really trying to minimize any type of adverse response and maximize the signaling that we can see from them. The only other point I would make, and maybe Ronnie wants to comment on this, is that with the MSTAR platform, there's another screening assay that we've incorporated into our product development research. And what we now do is any time we develop a molecule, we look at the ability of that molecule to activate T cells in the presence or the absence of tumors. And what we now can do is to look at and select molecules that have minimal activity in the absence of tumor and maximal activity in the presence of tumor. And maybe Ronnie or John, please feel free to amplify on that because those are part of the screening that we've done to advance those products.

Thanks, Gary. Maybe two points to add. So the CD3 is a relatively low-affinity CD3 to mediate the toxicity concerns. The second point Gary mentioned, when we screen one of the standard the differential -- the activity differential between that -- against tumor cells versus normal tissue cells.

Can I, Gary, maybe detail -- point of detail. The fact that you choose two targets, two separate targets rather than one, also plays in your favor because it is unlikely that normal cells would have these two targets on the same cell. And that's chosen in that way in many ways. Is that a factor also that plays in your favor -- in our favor?

Yes, absolutely, Elias, especially on the tumor targeting side, right? Because -- for example, let's pretend that we're looking at a tumor that expresses 2 antigens, we'll call them A and B, and we can have the antibody to A and B on our therapeutic. On normal tissues, you'll only see A alone or B alone. And so by having them both together on the therapeutic and on the tumor target, it allows us to get better honing to the tumor specifically. So absolutely, that plays in our favor there.

We have a lot of questions. So I'm going to go to the next one from Yale Jen at Laidlaw. One is for the EBV vaccine, what adjuvants might be used? Number two, if you have 4 -- more than 4 to 5 molecular targets, will specificity be impacted versus fewer targets? And three, given current treatment of HIV are mainly oral, how can an IV drug best compete? So I'll start with the first one with you, Gary. What adjuvants might be used for the EBV vaccine that we licensed to Merck, do we know or are we going to explore that?

That will be an important part of the Phase I and I should say, nonhuman primate preclinical development plan. As you might imagine, we will start and look at some adjuvants that have been well known and well used in medical practice of adjuvants like Alum, for example. MF59 is another one that's had relatively wide usage in clinical trials. We will also be looking at proprietary adjuvants that are available to Merck. So we will be doing comparisons and asking questions about the potency and longevity of the immune response. And then we will downselect among those different candidates and pick one, possibly two in the early stages to move forward.

Question two, a reminder, and this is probably a question for you, John. If more than 4 or 5 molecular targets, if there are more than -- would the specificity be impacted versus fewer targets?

So Elias, if I understand the question correctly, we're talking about targets, whether they could be viral targets or cancer targets?

It's not specified, I guess. Yale did not say one way or the other. Essentially, he's trying to talk about constructive or destructive interference. As you have more targets, do you have a risk of disruptive interference and multiple collisions? And maybe Ronnie also can comment on that. But that's my understanding of the question.

I think Gary got this particular question in part when he gave his answer with regard to the ability to have more selective binding when 1 targets 2 antigens of interest that are present on a cell and therefore maximizes the potential for that antibody to bind the cells of interest rather than off-target interactions. So I think that's the intent there.

Running any comment on the issue of design at 4, 5, 6 and interference or noninterference relative to specificity versus fewer targets.

Yes. That's an excellent question because the interference oftentimes cost both potentially by the geometry of the molecule as well as the epitope on line agent. This is how we iterate, build up this high-throughput screening platform as well as taking advantage of machine learning knowledge to quickly screen out the potential binders that could interfere with each other.

And the third question, given -- and John, probably you can answer that, given current treatment of HIV are mainly oral drugs, how can an IV drug best compete? What is displaced?

Yes. I'm glad this question came up. So there's quite a bit of experience in administering antibodies, either intramuscularly or subcutaneously. And we would certainly aim to go in that direction. And I think even recent experience with licensed antibodies that are self-administered and the advantages here are that one can administer an antibody with a long serum circulating time long half-life that potentially could have a therapeutic activity over several months. So there is a strong interest in HIV therapeutic of moving towards something that might offer a better quality of life. Certainly, the daily pills work, there's no doubt about that, but there could be an option to do just as well with something that could be self-administered on a several month basis. So I think there is a strong potential for such therapeutics.

What is your estimate of the proportion of patients that would benefit from the 3 fields of applications of antibodies to HIV?

Therapeutically, I think potentially anybody who is benefiting from antiretroviral drug therapy could benefit from an improved regimen. So it's essentially all individuals, at least potentially. And then for those people who might be failing a drug regimen which is less common now but still occurs. It gives an option there for treatment. The patient population who are at risk is very large. And really, there -- it's more about the opportunity for access, depending on where in developing world and less developed regions, many, many tens of thousands of individuals remain at risk.

Thank you, John. Another question came from Michael Zuk, a shareholder, "Have any patents been granted to date out of the 28 patents we mentioned?" Maybe Ronnie and Gary, you can pair on this one because I know some have been because they are earlier and some have been filed and some are provisional. Maybe you can give an indication of that, although it's an evolving situation given the fact that we've applied not only in the U.S. but internationally. Any comments? Ronnie, John?

So there are 2 parts. The ModeX proprietary IPs, they have been filed in the past 2 years. So we have non-provisional IPs filed both in the U.S. and in foreign countries. But their current status is pending, but we also in-licensed exclusive license from Sanofi that are granted.

That's right. Gary, any addition to that question?

I think Ronnie answered it well, and I think that at least 2 of those have been issued. So yes, it's early days for the ModeX ones, but we're working hard on those and stay tuned.

Thank you. So a question from Yi Chen from Wainwright. "Does the company plan to produce the initial proof of concept preclinical data and then find a strategic partner for each of these programs?" I think that goes to you, Gary.

Yes. Well, again, another great question. We really don't have anything that's fixed in stone. I think we're very flexible. And that we're -- there are some that would be natural for us to bring at least to a human proof of concept and then partner them. And there are others that we would be perfectly open to partnering at an earlier stage. So I don't -- I think it's not a 1 size fits all. We're very adaptable depending on the development costs, depending on the complexity and the cost to get to a human proof of concept. I would say in all cases, our strategy would be to get to human proof-of-concept study, whether it be with a partner or on our own as quickly and efficiently and as cost effectively as possible.

Now a question directly from shareholder about maybe a shorter-term outlook, how will you go about creating shareholder value in Q2? That's quite a direct question. And the timeframe is a little -- maybe I'll give it a try since I received the entire units and then maybe Dr. Frost, you can complete. I think that's a very good question. We've been working very hard actually over this year to transition to a posture where we can create value. First example is in Q2, we will receive the $50 million from Merck which are a license, which we basically fund ModeX for quite a bit of time. And in addition to that, maybe something that Gary did not mention is that any work we do, which we will, will be reimbursed fully by Merck. So this is, I think, a contribution to shareholder value. The second is we've worked diligently to provide information and data, reanalysis for somatrogon, which is ongoing FDA review, and we're hoping that something will come in the second quarter, maybe, can't promise because it's in the hands of the FDA, but we did work to create value that way. The third one is BioReference Laboratories, I'm spending quite a bit of my time to really transition BRL from COVID to a post-COVID world and bring it into balance financially within Q2, maybe Q3, but bringing us closer to that goal. Those are the 3 things I see. In addition, we're working for our other products, RAYALDEE and scyllo-Inositol and others to look at different options to create value, if you will, in those programs or greater value because they're already there. And so those are the ways I see creating shareholder value from the R&D and development point of view. But I'll turn it over to Dr. Frost for a more general perhaps vision and view on how to create shareholder value.

I think you handled the question rather well and completely, but I'm glad that there are small parts and small assets that have been in OPKO for some time now that we have kept them on the back burner. But now that we have more talent in the company and the ability to address some of these, they're project's that have a potentially great value, and I hope you'll be hearing about them in the near future. So stay tuned. But otherwise, I think Gary has covered the major projects that are going to contribute to the value of each of the assets and the value of the company as a whole.

Thank you, Phil. Another question from Neil Penny, a stockholder. "Are they competing technologies in development? What competing technologies are in development that compete with us. I don't know who we want to take that question. Ronnie, you might know, technologies in the trispecific, quadra-specific world or John, in the Ferritin based platforms. Could you comment, maybe?

So Ronnie, why don't you start?

What competing technologies do we know about, Ronnie, that may be competing with us at this time?

Yes. So because this isn't really an area with active research activities, so different companies are developing different type of technologies to also going into multi-targeting approaches. I think one of our advantage where one of highlight is our approach even though they are more specific, but they are really as regular IgG or regular monoclonal antibody like as possible so that we can ensure higher safety profiles and less [Technical Difficulty].

Elias, I don't know what happened with Ronnie, but I would just add one part to her answer there, and Gary may want to comment, which is that if one certainly area of bispecific antibodies has been very active and there are many under development. But you see this kind of pyramid when one gets to trispecific, there are very many fewer and when one gets to tetra-specific, we really are in a territory where there is much less competition. So I think we really are on the cutting edge of multi-specificity with our platform.

I would definitely add that there is a huge amount of interest in going that way. It's been hampered by manufacturing issues, mispairing issues, quality issues, but it's progressing to the point where, as an example, there was a company that was going into the multi-specific field, Teneobio, which has been acquired by Amgen giving you the validation that even the large companies are really exploring this as the next wave of revolutionary therapeutics. I think you can see that also at Xencor, for example, if you want to look at a comparable. So I think there is an interest in competing technologies. However, there's no one out there that I know of that has a trispecific in the clinic and a quadrispecific and the preclinical pre-IND stage. So that's what we think about our competing field. The technologies, I think maybe I'll ask Vijay to address the question that I think relates to that in terms of how we -- how competitive are we in this technology. It is a question from Maury Raycroft, again from Jefferies. Can you talk more about how you minimize light chain mispairing and binding site interference? And I think Dr. Wei mentioned capabilities and focus on making the linkers and multi-specifics less immunogenic. Can you talk about the technology here, too? So Vijay, you can talk about the manufacturing, the mispairing, and maybe I'll have Ronnie talk about this binding site interference because it's a structural designer issue. So Vijay, how do you find the quality of the product in terms of mispairing of light chains.

So first, let me say, as Ronnie was describing, just to remind everyone that the way our molecules, the multispecifics are designed that we don't have a separate lightchain hanging out there, which can mispair from one site to the other site. So our molecules are designed in such a way that they are -- if they are tri-specific, there are 2 chain molecules, and they are designed in such a way that the heavy and the light components fall within the chain. So we don't have that problem of lightchain mispairing.

If I may, Vijay, this is actually the secret sauce, if you will. We don't have any pairs to mispair in the design that was designed by ModeX over the past 18 months and with Ronnie's help and Gary and Dr. Yang. So I think the question is we minimize it by not having a pair that can mispair. And please, I'm sorry to have interrupted you.

There is one point. And if there is a half antibody and things like that, that can be very effectively removed during the downstream purification of the molecule. As I was saying before as well when I was presenting that, the cells clones, when we select the clones, we also select the clones which kind of produce most of it as in heterodimer or as a correctly folded antibody. So we put in the methods in place. First of all, the molecules are designed in such a way that we avoid those mispairings or we don't have those mispairings, then second, we selling the clones, which produce a correct molecule or correctly folded molecule. Third, our downstream purification is such that those half antibodies can be very easily removed. So that's why I would say that our downstream purification for our MDX2001 looks like a classical monoclonal antibody, a protein capture and followed by a couple of ionic exchange or mixed-mode resins column to do the purification. Ronnie can add more to it in terms of the binding hindrance and so on.

So Ronnie, the question -- I know you were not connected when that happened, but let me read it to you. Can you talk more about how you minimize lightchain pairing, which Vijay just addressed, but also binding site interference and there was a mention of what you said, Ronnie, the capability and focus on making the linkers and the multispecifics less immunogenic. Tell us how you do control binding interferes and immunogenicity, if you may.

So the binding interference part, it's really two constructs, the configuration of the difference of these binding domains to be specially relatively opposite from each other, so they are not for example, on top of each other or facing the same direction because obviously, we are not disclosing the exact details yet. But hopefully, we can tell you more in the future scientific conferences and publications. In terms of immunogenicity, so we understand some of the risk from immunogenicity is MHC binding, and there are structure and sequence features that can promote MHC recognition and binding, which will lead to potential immunogenicity. So when we design the linker, we're very careful about not introducing that type of structure and sequence features.

Elias, I might add one thing as well to the part about recognition to really expand on the point that Ronnie just made, I would refer any interested person to our science paper from 2017 because we have in that paper, the structure of the trispecific antibody. And you can actually see in that structure what Ronnie just was talking about, that the 2 variable regions are actually almost cocked at angles, almost at right angles to one another. So they're not put in a way that they can interfere and so it's in the way in which you assemble those 3 regions so that they avoid that clash with their target antigen. And that's really one of the important ways that we can maximize multi-contact binding.

Can you -- next question from Ed Tenthoff, Piper Sandler. "Can you provide examples where multivalency can be used to increase avidity against specific targets?" John, I think you provided us. Maybe you can just highlight that they were illustrated. And perhaps on the cancer side, you can do that as well.

I can start it and Gary may want to also comment. So for our antiviral multispecific antibodies, we've actually shown that a specific point. We can show that the increased avidity from the multivalency leads to the synergistic neutralization. And we showed that, for example, in the setting of the spike protein for COVID, and that's actually in a preprint that's publicly available that I cited on the website. We carefully choose the configuration of our molecules through our preclinical screening process. So not every single binding arm that we put on there in every configuration gives us the optimal avidity. But one of the beauty of the process in the platform is its modularity. We can look at hundreds of options and screen through those to give us that avidity and synergy.

Thank you. And another question from Yale Jen again from Laidlaw. "Other than T cells, would you consider targeting other immune cells, such as NK cells or others?"

Sure. Yes, I can answer that. Elias, yes, of course, that's the whole point of the technology. This is a modular plug-and-play technology. If we want, we can swap out the CD3/CD28 for an NK cell binder, an NK cell activator. It doesn't have to stop there. We can look at macrophage activators. So yes, those are on the table. We don't currently have candidates in our pipeline with those features, but we certainly are investigating the possibility of including them in the future.

Can you talk -- I mean, for Maury Raycroft, Jefferies. "Can you talk more about partnership strategy? And what are the key criteria that drive a decision to partner or keep in-house?" I'll have you, Gary, answer that, and maybe I'll supplement as well, as well as Dr. Frost. Why don't you start?

Elias, my general approach to collaboration, whether it be with partners on a product or even a scientific collaboration is always, you want to pick partners where you both have something to gain by working together and where you couldn't do it by yourself alone. And I think that with the product development pipeline that very much applies. I think the best example is really the one we did with Merck. I think with the example where there are capabilities and experience that Merck has on the downstream development side that simply just are not available at ModeX, but at the same time, there was scientific expertise and knowledge and even early manufacturing expertise at ModeX that Merck didn't have. There were resources that Merck could bring to the table that ModeX didn't have. So -- but most important to me at the end of the day is that there be alignment on the vision of what you want to do and how you want to get there. I think there's nothing that is more important than that. And then structuring the details of the collaboration agreement so that you incentivize both parties to create that alignment and that mutual benefit and sharing, I think that's really key to any collaboration agreement. So that's where I would leave it.

Yes. I think there are -- definitely, this is a great question, and we've thought a lot about it. And really, the decision is multifactorial, the scope of the development costs the time of the development costs. And then if you want to think about timing, timing is important, being a partner prior to IND, at IND or Phase I, you need to think about the inflection points that are likely to be achieved by the molecule that you're developing. And as we've done in many developments, I mean, I have been in-charge of 31 developments, there are points where you have to consider partnering or going alone. Now you can imagine that when we talk about a vaccine that requires several thousand patients before the end of Phase II, this is something that you obviously would not be able to do alone. When you consider a cancer asset, we know that we can get to a proof-of-concept to a basket trial relatively quickly with reasonable funding. And so we would tend to rank our portfolio as to its partnership needs or ability in addition to what Gary is saying, sometimes you have to be opportunistic. There is a partner that comes and that has exactly the culture that we want and that has the resources to carry this program much faster than we would be able to. So it's a multifactorial, but what drives it is opportunity cost of not doing a partnership and the second is the ability to create inflection points of value within the time frame that's affordable and doable within OPKO via ModeX. I hope this is clear. Can I just -- maybe -- I mean I don't know Dr. Frost, you want add about, you have a lot of experience in partnering and keeping assets. I mean what is your thought here.

I think, you and Gary again, comes a [indiscernible] that it also depends on the type of product and the target. For example, if we're dealing with a rare disease, which will be prescribed by a relatively small number of physicians, even a small company might consider taking it all the way, particularly with their American [ thesis ] it's more likely to get a -- have a shorter development and approval time versus a drug to treat say hypertension or even one of the more kind of a cancer. So it all depends on the product. Traditionally, of course, it's always been a small company, licensing it to a bigger company, primarily for economic reasons but all the other reasons that you cited are valid too, speed of and open to market. And of course, having a great fit. In our case, I'm really happy that our team there that you've seen today has the capability to add technical know-how above and beyond the discovery as a product is developed and I think that will lead to bigger and better partnerships.

Well, we have exhausted questions that I have here on the screen. There were a couple of others that showed up and then disappeared, which related to other issues that don't have to do with ModeX Therapeutics and its role within OPKO. Let me say as a moderator, it's been a pleasure to really see these great questions from the attendance, the attendees. And finally, I just want to thank you all. I mean this was an outstanding R&D presentation, very thorough, very thoughtful, very detailed. I think that anyone that is versed in the art of biotech would really appreciate what you've done. As a colleague, as President of OPKO, as Co-Founder with Gary, as working with Dr. Frost has been the privilege to MC this Q&A session, and I want to essentially turn it over to Gary and Dr. Frost for closing comments.

Gary?

Well, Elias, I think you said it well. And I think we've had a long exposure to a fairly complicated topic. So I'll really just end by thanking everybody. I think what we're really most excited about here at ModeX is really advancing new technology innovative therapies that can really make a difference to patients. That's what it's all about. We think the EBV vaccine is one example is one that could change the way that medicine is practiced in the future. We'd like our cancer drugs to do the same thing. So we appreciate the support from OPKO. We appreciate the support from our investors, we appreciate the hard work of our team at ModeX, and we hope to have more sessions like this in the future to share our progress. So I'll just thank you and hand it over to you, Phil, for the last.

Again, I want to thank everybody. I particularly enjoyed listening to the presentations and the answers to the questions. I think it is what represents sort of a coming out party for not only ModeX, but for what I consider to be the new OPKO with a strong emphasis on technology and new products that will be considered breakthrough and significant around the world. So again, thank you, and we look forward to this being the first of many others to follow as the developments come along. Bye bye now.

Thank you, Dr. Frost, and this ends our R&D. And if you have any other questions, you can send them to the website. However, if you want to review some of the presentation, it will be available on the website. Good evening, everybody. Take care.