Good afternoon and welcome to day one of the Barclays Global Healthcare Conference. My name is Carter Gould, covering analyst here in the U.S. biopharma space. We are pleased to welcome Summit Therapeutics to the stage. We've got a full house of leadership here. But before we start, Dr. Maky Zanganeh is gonna make some opening presentation, and then we'll go from there.
Thank you very much. Thank you very much for inviting us for the presentations. 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 Maky, Bob Duggan and myself as the Co-CEOs. Bob invested in the company in December 2019, and I joined with Bob around November 2020. As a reminder, the company at this time wasn't 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 looked at more than 100 companies and drug candidates. Finally, we decided to partner with Akeso and develop our ivonescimab.
Our ivonescimab is our lead compound, it's the only phase III PD-1/VEGF bispecific antibody in Summit's licensed territory, which is United States, Europe, Canada, and Japan. Our headquarters office is in Miami, but we have other offices in California, in Menlo Park, as well as U.K. 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 ivonescimab development. Our focus in 2024 will be execution of our two main phase III clinical programs for ivonescimab. Let me talk a little bit about our partner, Akeso. Akeso is a leading biopharmaceutical company in China with a valuation of approximately $5 billion.
Led by Dr. Michelle Xia, who is a co-founder, chairwoman, CEO, and president. They have over 2,800 employees with an end-to-end in-house capability. They are a source of incredible innovations, having more than 30 compounds in-house, 120 clinical trials, across over 120 clinical trials. Three of their drugs got regulatory approval in China. They discovered six bispecific antibodies. Their first one, which is cadonilimab, which is a PD-1/CTLA-4 bispecific, got approval in China. It's the world's first approval for a bispecific. Ivonescimab was discovered using the same discovery platform as cadonilimab. As you can see, it's 1,600 patients has been treated with ivonescimab across 19 clinical trials. That foundation from Akeso has allowed us to immediately start two phase III trials in our licensed territory in non-small cell lung cancer, which is HARMONi and HARMONi-3. We are thrilled to have Akeso as our partner.
What we did last year. Let me talk a little bit about our achievement of last year. As soon as we finalized our partnership agreement with Akeso in January 2023, we accelerated our clinical development program with ivonescimab. We held multiple FDA meetings to discuss the design of multiple potential phase III clinical trials for ivonescimab. 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 individuals participated in the offering, and the cost was approximately $500,000. We launched our first phase III clinical trials, HARMONi, in a record time from the day that we signed the agreement till the first patient enrolled was just four months.
Details of phase II of ivonescimab have been presented in different scientific conferences, ASCO, as well as all of our mechanism of action in multiple events has been presented in multiple articles. We started enrollment of our second phase III clinical program, HARMONi-3, in fourth quarter 2023. In both of our clinical trials, we are working together with Akeso to enroll patients in our licensed territory in addition to China, allowing us to collapse time, increase patient diversity, and set up ivonescimab for global success. Besides the lung cancer, we are working on going outside of the lung cancer for different therapeutic areas. We received different proposals from our investigators for IST program, and we are giving a little bit updates during this year. Let me talk a little bit about the mechanism of action.
After, during the Q&A, Dr. Allen Yang, our CMO, will discuss further and more in details our mechanism of action. Ivonescimab 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 Ivonescimab unique? Why not simply administer the two targets sequentially? Ivonescimab 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 simultaneous blocking of both PD-1 and VEGF, which are present at their highest concentration in and around the tumor.
Because ivonescimab binding strength or affinity to each target is highest in the presence of both targets and both PD-1 receptors are in their highest concentration in and around the tumor, it is believed that ivonescimab is effectively activated in the tumor microenvironment, where ivonescimab 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 VEGF outside of the tumor microenvironment, including bleeding risk associated with some VEGF inhibitors, antibodies. Ivonescimab 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 ivonescimab of mechanism of action of ivonescimab.
You can see from the image here, ivonescimab 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 VEGF increases ivonescimab affinity to PD-1 by over 18-fold, and the presence of PD-1 increases ivonescimab binding affinity to VEGF by 4-fold. With PD-1 and VEGF highly concentrated in many tumor types, ivonescimab binding strength is then activated in the tumor microenvironment. By concentrating in the tumor microenvironment, it enhances the activity of T cells. Both elements of ivonescimab work together to stimulate the immune system.
Because VEGF is often found as a dimer, and ivonescimab has the ability to bind to multiple VEGF proteins 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 bispecific design. This is something that we believe cannot be replicated by co-administrating an anti-PD-1 and anti-VEGF separately. If you look at our pipeline in combination with Akeso, as mentioned, we enroll over 1,600 patients.
We are in the 19 clinical trials, four phase III trials, 13 phase II, and two phase I in seven different indications outside the non-small cell lung cancer, in gynecology cancer, breast cancer, colorectal cancer, several other GI cancers, as well as head and neck squamous cell carcinoma. With over 1,600 patients treated with ivonescimab, we are quite quickly generating the proper path to advance ivonescimab in late-stage trials through the help and collaborations with our partners at Akeso. 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 ivonescimab is being studied in four phase III clinical trials in non-small cell lung cancer. The first phase III trials is, if you look at it, the first two.
Actually, we are in combinations with Akeso. We are doing these three two clinical trials. The first one is an EGFR mutation that progressed after a TKI. Akeso has completed the enrollment in China territory and submitted their analysis to the Chinese Regulatory Authority, CDE. Their primary endpoint is PFS. We have created a multi-regional study in this population, which we call the HARMONi study. In this trial, we will take most of the patients from Akeso China specific study, about 270 of their 320 patients, 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 III trial indicated on the second star, the green one, is the frontline metastatic squamous non-small cell lung cancer, which we call it HARMNi-3 .
This multi-regional study is evaluating the combination of ivonescimab with chemo versus pembro plus chemo. This multi-regional study is being enrolled by both Summit and Akeso. The third phase III trial, which is a sister study to HARMONi-3, is a Chinese-specific study in which Akeso is comparing ivonescimab plus chemo to tislelizumab plus chemo in the frontline squamous non-small cell lung cancer setting in order to compare against a PD-1 that was originally developed in China as well. The fourth phase III, which is the most important one, is the monotherapy of ivonescimab 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 ivonescimab clinical trials that presented at ASCO last year by Akeso.
It's based in part on the phase II data generated by our partner at Akeso. Because of that, we initiated our multiple phase III clinical trials. Here, I will go into more details on the data from the AK112-201 phase II clinical trial. We will present on two of the cohorts from the trial that support our phase III clinical trials, HARMONi and HARMONi-3. The first trial is a frontline advanced metastatic squamous non-small cell lung cancer. If you look at the waterfall plot on the left, only two patients saw minimal increase in tumor burden. The remaining patients saw a reduction of the tumor burden, often significant. Overall response rate is, say, 67%. The PFS is over 11 months. In the 63-patient single-arm phase II trial, it exceeds historical benchmark data for the standard of care.
Both in the phase III trial you see on the global setting, as well as the phase III extension study conducted in China of KEYNOTE-407, the PFS is around eight, eight months or 8.3 months. I would like to give you an update on the overall survival. Both 12 months and 24 months overall survival rate of patients 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 are evaluating ivonescimab in frontline metastatic squamous cell non-small cell lung cancer in order to demonstrate its efficacy safety profile using OS in our primary endpoint in our HARMONi-3 phase III trial. From a safety perspective, ivonescimab plus chemo was generally well tolerated, highlighted by the fact that there were no treatment-related adverse events leading to death in the phase II trial. What makes this so critical is that certain prior anti-VEGF antibodies, such as Avastin, were not able to be developed in the squamous non-small cell lung cancer because of the risk of severe bleeding. The fact that ivonescimab across 63 patients, specifically in the squamous cell carcinoma setting, has not seen the same issues that were previously observed when an anti-VEGF agent was administered further amplifies the notion that ivonescimab mechanism is unique from previous compound or combinations.
Taking a look at the phase II trial data supporting patients on the second-line EGFR TKI progressor, such as Osimertinib, this is data that supports, in part, our HARMONi phase III clinical trial. Again, in this setting, we are seeing response rate and durable results that exceed historical experience with the standard of care in this setting. Patients in this trial experienced a median PFS at 8.5 months. We have included data related to ivonescimab in a phase II setting, as well as recently released data from trials that read out in 2023 in this setting. Note that the chemotherapy arm, which is on the last column, showed 27.3% overall response rate and around 5.5 months of PFS. 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 HARMONi study is placebo plus chemo, where recent observed benchmarks in overall survival for chemo in this space have ranged 14.7 to 15.9 months. From a safety perspective, ivonescimab plus chemo was generally well tolerated in this setting. For additional safety data, if you look at the data, treatment-related adverse events leading to the discontinuation of ivonescimab occurred in 11% of the frontline squamous patients and 0% of EGFR-positive patients progressing after TKI. The result is quite encouraging. Ivonescimab opportunity, as we mentioned, we are in the 19 clinical trials. 50 indications are already approved drugs by PD-1 based therapy. According to TD Cowen, estimated PD-1 sales worldwide will exceed $64 billion by 2027. Lung cancer represents, based on TD Cowen, $20 billion for PD-1 and PD-L1 alone here. This provides a greater opportunity for ivonescimab based on the mechanism of action.
The non-small cell lung cancer patients, approximately 600,000 patients. You can see 40,000 of them are potential for HARMONi and 80,000 of them in HARMONi-3. To just give you what's expected in the 2024 key catalyst, for this coming year, this year, as we discussed, we have data of AK112-301, a large majority of which represents the Chinese patient population of HARMONi study, was submitted to Chinese authority. We are expecting to get data sometime in second half 2020 the second quarter 2024, as well as the results will be presented in around the same time. We plan to complete our enrollment of HARMONi study in the second half of 2024. An interim analysis is planned for this year for upcoming trials, which is pembro versus ivonescimab, which is very, very important for us to continue our development of ivonescimab globally.
And for sure, we are working on an investigational IST program for other indications, which we are going to tell you more about. With that, I have six minutes to let my team answer all of the questions. Thank you.
Great. Thank you, Maky. A number of places to go first. But maybe let's dig into that cooperative binding, you know, 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?
Yeah. Carter, thanks for the question. So I've been working on bispecifics for quite some time, for about 20 years, actually. What people don't appreciate about ivonescimab 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, VEGF can actually cross-link ivonescimab to another ivonescimab molecule. And then you have a VEGF cross-linking that to another. So you have this daisy chaining of ivonescimab and VEGF.
This is well described with the bevacizumab literature, which is sort of the parent molecule for ivonescimab. And that leads to multiple high-target PD-1 sites being sort of presented by this daisy-chained ivonescimab-VEGF binding to, to PD-1 on lymphocytes. And that leads to sort of an associative cooperativity, so intramolecular cooperativity.
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, of binding, does that potentially complicate things? Or maybe that doesn't play out quite as well?
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. And 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, 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.
Okay. So when we think about the HARMONi data that's going to, or essentially decisions that's already coming out of, going to come out of China, I'm sure when you, you know, acquire this asset, you had, you know, you had interactions with the agency thereafter.
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 tough stance on past Chinese data.
Yeah. So Carter, so I think you're asking, like, for our fast-to-market strategy, which is the HARMONi study in the EGFR refractory, that's our easiest study, right? So that's ivonescimab 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, Akeso 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 onto 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 numbers, percentages, etc.?
Yes. Okay. That's all been agreed to.
Okay. Great. Maybe to jump in, the HARMONi-3 study is potentially pretty transformational if you do beat pembro. That's a very big swing.
Can you talk about, you know, taking that risk, taking that swing, and, you know, maybe that's what drew you to the opportunity here, whoever wants to take a stab at that?
Yeah. I'll take that one. So, it's our 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. 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 IMpower 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 to 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 Akeso is already generating in this space, we're pretty comfortable with the other data out there that this is going to be a successful study.
Okay. Maybe, maybe just last question between Bob, Maky, Manmeet. There is the element of sort of getting the band back together here. Maybe, you know, what specifically drove you to this opportunity with ivonescimab so much?
Well, we have a real love for helping the healthcare industry. The first four letters of health are H-E-A-L. All healthy individuals have to be healed from time to time. Through our work from robotics into patient-friendly oncology therapy, we just became very attracted to it.
So now we sell. We got a bolus of money. We looked around at other things. We're much more experienced. We have more access to money. We have more convenience power, more regulatory power. And we saw this opportunity with Akeso. These are, it's a Chinese company. But they are, 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 now we could, we could go after a major opportunity and make a significant difference for the better. And we think it's, it's, it's the right risk for us to take.
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.
Okay. Thanks .
Thank you. Happy to be here. Thank you.