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spk02: Good afternoon and welcome to day one of Barclays global health care conference, my name is Carter ruled covering analyst here in the US biopharma space. We are pleased to welcome summit therapeutics to the stage got a full house of leadership here, but before we start Dr Dr marki marki is going to make some opening opening presentation and then we'll we'll go from there.
spk03: Thank you very much, thank you very much for inviting us for the presentation. I'm sure you are very familiar with all of the forward-looking statements, but let me talk a little bit about our company. Our company is a mission-focused company led by Bob Duggan and myself as the co-CEOs. Bob invested in a company in December 2019, and I joined Bob around November 2020. As a reminder, the company at this time was exclusively an anti-infective company. Over the past three years, our leadership team joined us. It's a high-speed execution team with an unmatched proven track record. In 2022, we decided to fully transform from an anti-infective company to an oncology-focused company. We look at more than 100 companies and drug candidates. And finally, we decided to partner with Ekeso and develop our Ivonecimab. Our lead compound is the only phase III PD-1 VEGF by specific antibody in Summit license territory, which is United States, Europe, Canada, and Japan. Our headquarter office is in Miami, but we have other offices in California, in Menlo Park, as well as UK in Oxford. We have over 110 employees. As of today, I can say our market cap should be around 3.1 billion. Our cash position as of end of last year was 186 million. We have a solid capital foundation to support the company expansion as well as Ivonecima development. Our focus in 2024 will be execution of our two main phase three clinical program for Ivonecima. Let me talk a little bit about our partner, Ekeso. Ekeso is a leading biopharmaceutical company in China with a valuation of approximately five billion, led by Dr. Michelle Shaw, who is a co-founder, chairwoman, CEO and the president. And they have over two thousand eight hundred employees with an end to end in-house capability. They are a source of incredible innovations. having more than 30 compound-enhanced 120 clinical trials across over 120 clinical trials. Three of their drug got a regulatory approval in China. They discovered six bispecific antibody. Their first one, which is catalimumab, which is a PD-1 CTL-4 bispecific, got approval in China. It's the world's first approval for a bispecific. Avonitumab was discovered using the same discovery platform as Kadalimab. As you can see, 1,600 patients have been treated with Avonitumab across 19 clinical trials. That foundation from AKSO has allowed us to immediately start two Phase III trials in our licensed territory in non-small cell lung cancer, which is Harmony and Harmony III. We are treated to have a case as our partner. What we did last year, let me talk a little bit about our achievement of last year. As soon as we finalize our partnership agreement with in January 2023, we accelerate our clinical development program with. We held multiple FTA meetings to discuss the design of multiple potential phase three clinical trials. For Ivonecimab, in addition, we interact with EMA in Europe, as well as PMDA in Japan. We raised 500 million in the first quarter of 2023, 1,500 individual participated in the offering, and the cost was approximately 500,000 US dollars. We launched our first phase three clinical trials, Harmony, in a record time. from the day that we signed the agreement till the first patient enrolled was just four months. Details of phase two of Ivonisimab has been presented in different scientific events, ASCO, CITI, as well as all of our mechanism of action in multiple events has been presented or multiple articles. We started our enroll our second phase three can call program harmony tree in fourth quarter, twenty, twenty three. And in both of our clinical trials, we are working together with a to enroll patient in our license territory. In addition to China, allowing us to collapse time, increase patient diversity and set up for global success. Beside of the lung cancer, we are trying, we are working on going outside of the lung cancer for different therapeutic area. We received different proposal from our investigator for ISD program, and we are giving a little bit update during this year. Let me talk a little bit about the mechanism of action, and after during the Q&A, Dr. Alan Young, our CMO, will discuss further and more in details our mechanism of action. Avonisimab is the first in-class PD-1 VEGF bispecific antibody that was intentionally designed to improve the safety and efficacy standard of these two well-established targets in oncology. The question is, why is Avonisimab unique? Why not simply administer the two targets sequentially? Avonisimab is designed to be greater than the sum of its parts And the answer is because of cooperative binding. This cooperative binding increases the binding strength of each target in the presence of the other target in vitro. In other words, cooperative binding allows for strong simultaneously blocking of both PD-1 and VGEF, which are present at their highest concentration in and around the tumor. Because Ibanesimab binding strength or affinity to each target is highest in the presence of both targets, and both PD-1 VGEF are in their highest concentration in and around the tumor, it is believed that Ivonisimab is effectively activated in the tumor microenvironment, where Ivonisimab is designed to be and can drive its anti-tumor activity. In addition, concentrating in the tumor microenvironment is believed to reduce certain adverse events, which may occur from binding to PD-1 or VGEF outside of the tumor microenvironment, including bleeding risk. associated with some VEGF antibodies. Ivonisimab goes where it is intended to, optimizing its anti-tumor activity and safety profile. Let me explain a little bit our cooperative binding and the basis for the mechanism of action of Ivonisimab. You can see from the image here, Ivonisimab not only performs the function of both an anti-PD-1 agent and an anti-VEGF antibody, but it optimizes the activity of both in such a unique way. It is intended to be greater than the sum of its individual parts. The presence of VGEV increases abonissimab affinity to PD-1 by over 18-fold, and the presence of PD-1 increases abonissimab-binding affinity to VGEV by 4-fold. With PD-1 and VGEV highly concentrated in many tumor types, abonissimab-binding trait is then activated in the tumor microenvironment. By concentrating in the tumor microenvironment, it enhances the activity of T cells. Both elements of Ivonisimab work together to stimulate the immune system. Because VGEF is often found as a dimer, and Ivonisimab has the ability to bind to multiple VGEF protein through its tetravalent structure, it cannot only concentrate in the tumor microenvironment, but also cluster or daisy chain together as illustrated here. further enhancing the PD-1 inhibition of the checkpoint on the T cells and allowing the immune system to further destroy tumor cells. This is a critical component of the bio-specific design. This is something that we believe cannot be replicated by co-administrating an anti-PD-1 and anti-VGF separately. If you look at our pipeline in combined with, as mentioned, we are, we enrolled over one thousand six hundred patients and we are in the nineteen clinical trials for phase three trials, thirteen phase two and two phase one in seven different indication outside the non small cell lung cancer in gynecology cancer, breast cancer, colorectal cancer, several other GI cancer, as well as head and neck squamous cell carcinoma. With over 1,600 patients treated with Ivonisimab, we are quite quickly generating the proper path to advance Ivonisimab in late-stage trials through the help and collaborations with our partners at ECSO. As data continue to mature from this study, we are planning to expand our current portfolio of clinical trials by initiating additional late-stage studies. This is a key differentiator and value driver to our partnership. I would like to highlight that is being studied in four phase three clinical trials in non small cell lung cancer. The first phase three trials is, if you look at it, the first two, actually, we are in combinations with a case. So we are doing this two clinical trials. The first one is an EGFR mutation who have progressed after a TKI. AKSO has completed the enrollment in China territory and submitted their analysis to the Chinese regulatory authority CDE. Their primary endpoint is PFS. They have created a multi-regional study in this population, which we call the Harmony Study. In this trial, we will take most of the patients from AKSO China specific study, about 270 of their 320 patients. plan, and we plan to enroll additional approximately 150 patients from North America and Europe and evaluate this multi regional population using co-primary endpoint, which is PFS and OS. The second phase three trial indicated on the second star, the green one, is the frontline metastatic squamous non-small cell lung cancer, which we call it Harmony 3. This multi-regional study is evaluating the combination of Ivanesimab with chemo versus Pembro with plus chemo. This multi-regional study is being enrolled by both Summit and ECASO. The third phase three trial is a sister study to Harmony 3. It's a Chinese-specific study in which ECASO is comparing Ivanesimab plus chemo to Tazalimab plus chemo in the frontline squamous non-small cell lung cancer study. setting in order to compare against a PD-1 that was originally developed in China as well. The fourth phase three, which is the most important one, is the monotherapy of ivanesimab versus PEMBRO in frontline non-small cell lung cancer patients with PD-L1 positive tumor, a TPS score of one or greater. Let me give you a little bit update about ivanesimab clinical trials that presented at ASCO last year by Ekeso, is based in part of the Phase 2 data generated by our partner, AKESO, and because of that, we initiated our multiple Phase 3 clinical trials. Here, I will go into more details on the data from the AK112-201 Phase 2 clinical trial. We will present on two of the cohorts from the trial that support our Phase 3 clinical trials, Harmony and Harmony 3. The first trial is a frontline advanced metastatic for almost non-small cell lung cancer. If you look at it at the waterfall plot on the left, only two patients saw a minimal increase in tumor burden. The remaining patients saw a reduction of the tumor burden, often significant. Overall response rate is 67%. The PFS is over 11 months. In the 63-patient single-arm phase 2 trial, exceed historical benchmark data. For the standard of care, both in the phase three trial, you see on the global setting as well as a phase three extension study conducted in China of keynote for seven. The is around eight, eight months or eight point three months. I would like to give you an update on the overall survival. Both 12 months and 24 months overall survivor rate of patient look very promising in this setting. Over 85% of patients in this study were alive after one year, which would exceed what has been seen by the standard of care historically. While median OS has not yet been reached after a median follow-up time of 21 months, you can start to see with a lower bound of the 95% confidence interval of 22.5 months that we believe that there is a significant opportunity here. We're evaluating avonisimab in frontline metastatic non-small cell lung cancer in order to demonstrate its efficacy safety profile using OS in our primary endpoint in our Harmony 3, Phase 3 trial. From a safety perspective, avonisimab plus chemo was generally well tolerated, highlighted by the fact that there were no treatment-related adverse events leading to death in the Phase 2 trial. What makes this so critical is that certain prior anti-VGF antibodies such as Avastin were not able to be developed the squamous non-small cell lung cancer because of the risk of severe bleeding. The fact that Ivonizumab across 63 patients specifically in the squamous cell carcinoma setting has not seen the same issues that previously observed when an anti-VGF agent was administered further amplify the notion that Ivonizumab mechanism is unique from previous compound or combinations. Taking a look at the phase two trial data supporting patients on the second line EGFR TKI progressor, such as azimertinib. This is data that support in part our Harmony phase three clinical trial. Again, the setting we are seeing response rate and durable result that exceed historical experience with the standard of care in this setting. Patient in this trial experience and media on at eight point five months and we have included data related to in a phase two setting as well as recently released data from try that read out in twenty, twenty three in the city. Note that the chemotherapy arm, which is on the last column showed twenty seven point three percent overall response rate and around five point five months of. On the overall survival, a median OS of 22.5 months was observed in this study after a median follow-up time of about 25.8 months. Again, the control arm of our Harmony study is placebo plus chemo, where recent observed benchmark in overall survival for chemo in this space have ranged 14.7 to 15.9 months. From a safety perspective, Avonizumab plus chemo was generally well tolerated in this setting. For additional safety program, if you look at the data treatment related events, even leading to the discontinuation of occurred in 11% of the frontline squamous patients and 0% on patients progressing after the result is quite encouraging. I want to sum up opportunity as we mentioned, we are in the nineteen clinical trials. Fifty indication is already approved dark by P. D. one. We just therapy, according to T. D. coin estimated P. D. one cells worldwide will exceed sixty four billion in by twenty, twenty seven long cancer to present based on T. D. coin, twenty billion for P. D. one alone here. These provide a greater opportunity for based on the mechanism of action. the non-small cell lung cancer patients, approximately 600,000 patients, and you can see 40,000 of them is potential for Harmony and 80,000 of them in Harmony 3. To just give you what's expected in the 2024 key catalyst for this coming year, this year, as we discussed, we have a data of AK112301, a large majority of which represent the Chinese patient population of Harmony study, was submitted to Chinese authority and we are expecting to get data sometimes in the second quarter 2024. As well, the results will be presented in around the same time. We plan to complete our enrollment of Harmony study in the second half of 2024. An interim analysis, a plan for this year for upcoming trials, which is a Pembroke versus, which is very, very important for us to continue our development of globally. And for sure, we are working on an investigation program for other indications, which we are going to tell you more about it with that. I have six minutes to let my team answer all of the questions. Thank you.
spk02: Great. Thank you, Makai. A number of places to go first, but maybe let's dig into that cooperative binding, you know, a mechanism here. And maybe just help, you know, when we think about bispecifics, there's that dual binding aspect, but it seems like you're referencing something above and beyond that here. Can you maybe just dig into that a little bit and exactly how you kind of frame that for folks?
spk01: Yeah, Carter, thanks for the question. So I've been working on bispecifics for quite some time, about 20 years, actually. What people don't appreciate about Ivanessimab is the targets are well validated, but the way they're arranged in the molecule, there's cooperativity. And there's two types of cooperativity. There's an intramolecular and an intermolecular. The correct terminology is actually allosteric cooperativity and associative cooperativity. Let me go through that real quick. Allosteric cooperativity means when one ligand binds, there's a conformational change so that the other ligand binds tighter. So when PD-1 binds, VEGF binding increases by fourfold. When VEGF binds, PD-1 binding increases by greater than 18-fold. And so we get the optimal binding is going to be in the tumor microenvironment where both ligands are expressed. The other thing that's underappreciated is something called associative cooperativity. Because there's four binding sites and VEGF is a dimer, that Jeff can actually cross-link Ivonessimab to another Ivonessimab molecule. And then you have a VEGF cross linking that to another. So you have this daisy chaining of Ivonessimab and VEGF. This is well described with the Bevacizumab literature, which is sort of the parent molecule for Ivonessimab. And that leads to multiple high target PD-1 sites being sort of presented by this daisy chained Ivonessimab VEGF binding to PD-1 on lymphocytes. And that leads to sort of an associative cooperativity. So intramolecular cooperativity.
spk02: Okay, and when we think about that, what that then means in terms of efficacy, does that, because you have this sort of heterogeneity of binding, does that potentially complicate things, or maybe that doesn't play out?
spk01: Yeah, so there's a number of ways that can be effective, right? So you're going to get most of the binding in the tumor microenvironment. That could lead to both efficacy and safety benefit, right? You're also going to lead to a clustering or the daisy-chaining of these molecules to in specific places, which is the tumor microenvironment, right? So you can imagine that collection occurring there, and then that will lead to better safety and efficacy. And then finally, you know, when you have these daisy chaining and you have this associative cooperativity where you have multiple PD-1 sites, you actually enrich for binding to lymphocytes that have high PD-1 expression, which are known to be the most active in the tumor.
spk02: So we think about the Harmony data that's going to essentially decision that's already coming out of going to come out of China. I'm sure when you acquire this asset, you had we know you had interactions with the agency thereafter and just how the agency is going to look at that data relative to the data that's coming from, you know, U.S. and Western Europe. And, you know, we've seen, you know, the agency take a stance on past Chinese data.
spk01: Yes, Carter. So I think you're asking, like, for our fast to market strategy, which is the Harmony study in the EGFR refractory, that's our easiest study, right? So that's Ivan SMA chemo versus chemotherapy, right? The other studies we have are against PD-1. So let's be clear on that. So I think what the agency is looking for is not only a positive study, but consistency between the Chinese data and the Western data. So, you know, ACASO had already started conducting their version of the study, right? at the time of the deal. So the fact that Summit was able to sort of acquire or sort of agree with the agency to add on to that study created significant value after the closure of the deal, right? But we're going to add a bunch of Western patients the analysis will be the aggregate analysis between both populations the chinese and the western population but i'm sure the agency is going to want to look for directional consistency between the chinese and western data okay and but specifically you have buy-in from the agency in terms of the num the numbers percentage yes that's all been agreed to okay great uh maybe to to jump in uh the harmony 3 study is a uh potentially pretty transformational if you do uh be pembro uh that's a very big swing can you talk about you know taking that taking that risk taking that swing and you know maybe that maybe that's what drew you to the to the opportunity here whoever wants to yeah take a stab at that i'll take that one so so it's our first first line indication it's a big indication squamous non-small cell lung cancer makes up about 40 of the market depending on you know the stage it could be a little bit less than that but 40 of non-small cell lung cancer And I don't think it's a big risk, right? So let's be clear here. If you look at previous data from Roche, the Empower study showed that there's a benefit of VEGF in non-small cell lung cancer, but it was never fully developed in squamous because there were certain safety concerns that we're not seeing, right? We know that it will add value, the VEGF here. And so I think for a lot of reasons, we're pretty comfortable and confident around that study, aside from the data that's That is already generated in this space. We're pretty comfortable with the other data out there that this is going to be a successful study.
spk02: Okay. Maybe, maybe just last question between Bob and me, there is the element of sort of getting the band back together here. Maybe, you know, what specifically drove you to this opportunity with an SMM so much?
spk00: Well, we have a real love for helping this healthcare industry. The 1st, 4 letters of health are all healthy individuals have to be healed from time to time and through our work from robotics into to patient friendly oncology therapy. We just became very attracted to it. So now we sell, we got a bonus of money. We looked around at other things. We're much more experience. We have more access to money. We have more convenient power, more regulatory power. And we saw this opportunity with Keso. It's a Chinese company, but three of them are American citizens. They speak fluent English. They love what we're doing, how we're doing it. We do things that they haven't. And so this partnership really, really fit together. And we could go out to a major opportunity and make a significant difference for the better. And we think it's the right risk for us to take.
spk02: All right, perfect. Well, we're out of time. We'll have to leave it there. But thank you very much for joining us today.
spk00: Okay. Happy to be here. Thank you.
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