Good morning, everybody. My name is Corey Kasimov, one of the senior biotech analysts here at Evercore ISI, and it's my pleasure to host this next discussion with Summit Therapeutics. You can see we have quite the team here. We've got several members here, a few down in the front row as well, and so, you know, we got Bob Duggan. Bob, I'm going to turn it over to you in a second to introduce the rest of the team. It's been obviously an absolutely remarkable year for Summit. So why don't I hand it over to you to introduce the team and maybe set the stage for kind of where things stand right now as we start to look towards 2025?
The best way to do that is to turn it over to Maky. More than that, we started years ago with the decision to bring in the best team we had access to and having completed successfully a pharmaceutical transaction for $21 billion. We left with an A team, and then we brought them back. Some said, well, you don't even know if you have a drug yet, and you're overspending.
The truth is, without this team, we would not have come upon Akeso. Akeso had had a partnership with Merck, so they were not a non-existent company. But it's clear now that we picked the gem of gems in bispecific tetravalent drugs, and they got off to an early start. We're very pleased with the way it's continuing. Our team is growing. We're over, I think, 130 people now and just accelerating.
We're handling most of the world outside of China. We're extremely excited. The drug is performing better than we expected, by, I'd say, at least 100% improvement, as we have been able to direct ourselves outside of non-small cell lung cancer. And the opportunity there is outstanding. But the details of all of that are the power. Dave Gancarz is here. Allen is the genius of bispecifics, of course. And you all know Manmeet Soni, who tends to attract buyers when he's working for a company. But this is not a company for sale, so we'll park that ability. And just a tremendous financial officer. And Maky was appointed about four or five weeks ago. I was talking with Jensen Huang and introduced Maky to him. And I said, she's one of the top 10 biotech executives in Northern California.
He looked at me, and he looked over at her, and he said, she's number one. I said, okay, thank you. I let our executive committee the next day to know that Jensen Huang at $83 billion had nominated her as number one, and we have no reason not to believe that ourselves. That's a bit of an introduction. This team is very capable of, during the conference here and today, answering any and all questions that you might have.
All right, that's great. So first one I want to get into, because this still comes up a lot in investor conversations, and probably for you, Allen, what are the attributes of ivonescimab and the bispecific design that it has that enables you to improve in such a dramatic way upon what people tried for so long to do, just in terms of combining PD-1s with VEGFs in the past?
Yeah, so that's like a two-day conversation.
Yeah, we have 16 minutes.
Let me give it 30 seconds. You know, it targets two known and validated targets in oncology, PD-1 and VEGF, right? You know, those targets are validated, which make the development program easier. Of course, they've been proven to be synergistic in individual monoclonal antibodies. I think what people underappreciate is that the way that Akeso engineered this molecule is that there's cooperativity. By cooperativity, and pardon the terminology, there's something called allosteric cooperativity, where the binding of one ligand or one epitope increases the binding of the other epitope, and that increases the affinity. Then the binding to VEGF, because it's a dimer, causes daisy chaining of ivonescimab, which actually increases the number of high affinity binding sites, and that increases something called avidity. I think that specific engineering is unique to ivonescimab, as far as I know.
Okay, and before we get into some specific questions on the HARMONi-2 study that kind of sent shockwaves through the industry this year, can you talk a little bit strategically about the HARMONi development program, what's ongoing, and how you plan to really kind of cast a very wide net here?
Yeah, so do you want to take it?
Sure.
Yeah, so, you know, I think we've been very public about the HARMONi study in terms of global development, which is our first fast-to-market strategy in EGFR, second line after osimertinib. You know, the results of that and the study design are based on the HARMONi-A study, which also contributes patients to the HARMONi. So we believe that will be the first study to read out. That's our first entry into non-small cell lung cancer. I would also add that both Pembro and Nivo have failed in that space, so we're very excited about the opportunity. Our second study is HARMONi-3 , which is in a combination with chemo, which was initially with squamous non-small cell cancer, sort of a minority, about a third of non-small cell lung cancer, but very important.
We've recently amended that study for executional reasons to expand it to include non-squamous, so include both squamous and non-squamous, which is about two times bigger. That is in combination with chemo. Then the HARMONi-2 results came out from Akeso, which showed monotherapy ivonescimab beat monotherapy pembrolizumab. That gave us confidence to amend HARMONi-3 . We had been thinking about that for a while, but it also gives us confidence to feed into HARMONi-7 , which is our monotherapy study, which will be a global study.
Okay. And then, you know, HARMONi-2 obviously had some groundbreaking data. And now the key outstanding questions around overall survival. How close do you have to, when you think about survival here, can you talk about what's going to matter at the end of the day? Is it just being statistically significant and you're good? Is there a hazard ratio? Is there a bogey out there that you would like to hit given the dramatic improvement you saw in PFS?
Yeah, so let's go back up a little bit for HARMONi-2 , the way it was designed. It was designed for the Chinese market, so included PD-L1 positive patients, so PD-L1 1% or greater. 1%-49% is not considered standard care in Western countries. The other thing, the primary endpoint for that study was only PFS. And so it was designed to meet that endpoint and register the drug in China.
We're designing the HARMONi-7 study to be both dual primaries, PFS and OS. I think the question of what is the clinical value, I think as long as you improve PFS significantly and you don't harm OS, you have significant value there. You know, telling a patient they won't start their next treatment for six months with this product is very valuable to patients. Now, if you have a big trend in OS and a positive OS, of course, that's going to be game-changing.
Okay. Are you publicly saying how close you might be to that OS readout in terms of gathering events?
No. So, remember, the HARMONi-2 study hit its primary PFS endpoint early in the first interim analysis. We were shocked at how quickly it met its primary endpoint. So if you look back at things like KEYNOTE-024, KEYNOTE-042, the PFS readout was significantly more advanced than the OS readout. It took three or four times longer. So it will take some time. I don't know how much we're communicating to them.
No, I think that's, you know, there was a limited number of months follow-up, a little over eight months when the PFS readout that hit on its first interim analysis. So it will take additional time. I think the important point, though, is like a lot of this comes down to what does this mean for you at Summit, right? I think, you know, strategically, we've made that decision. We are imminently initiating the HARMONi-7 study, the monotherapy and the PD-L1 high setting that Allen mentioned. So that's really our go-forward approach at this point.
Okay, and Allen, you mentioned with HARMONi-3 , the recent decision to include the non-squamous as well. Can you elaborate a little bit into sort of the key rationale behind it and how this might impact the overall trial in terms of accrual and timelines?
Yeah, so I think when we chose squamous, the original HARMONi-3 design, that was low-hanging fruit. We didn't have the HARMONi-2 data at the time. We knew that bevacizumab wasn't developed in squamous because of concerns for safety around bleeding events. Once we saw the HARMONi-2 data, it gave us confidence that the efficacy was both in the squamous and non-squamous setting. So it was really an operational decision.
How can you move both indications faster, noting that the non-squamous indication is larger and will help us with enrollment as well? So that was the decision around that. Remember, we're trying to do a lot, right? We're doing the monotherapy. We're doing a combination with chemotherapy. We have the EGFR, non-small cell lung cancer population. There are other key populations we want to think about. We want to think about consolidation after radiation, the perioperative setting. Those are the things that we're going to be on our checklist for non-small cell lung cancer.
Okay. When you think about combination therapy and you think about putting chemotherapy on top of these profound results you've seen so far with monotherapy, do you think combination like chemo will sort of narrow the benefit you see with Ivo? Do you think it just shifts the curves to the right?
Probably the latter. I mean, clearly, you know, when you look at that benefit, it may shrink a little bit. But if the magnitude of benefit, remember, Pembro had it a little bit easier. It went against chemotherapy, right? So in our indications, we're going to have to go against Pembro. But we're confident that we're going to be able to beat Pembro given the data from the HARMONi-2 study.
Okay.
No, I think that's right. I think the other thing I would say is we also have that phase two data that continues to mature. You know, it was last released at the ASCO prior to last and then the ELCC conference in the beginning of 2024, right? So there's multiple evidence support, if you will, for that benefit that ivonescimab plus chemotherapy looks to show in its potential up against Pembro plus chemo.
Okay. Are there other combinations you would explore as well? You plan to explore beyond chemo?
Yeah, certainly, right? So I mean, if you think about it, right, like our development plan currently is Ivo plus chemo or Ivo monotherapy in the case of the HARMONi-7 study, right? But if you look at solid tumors as a whole, right, especially in the frontline setting, many of those, if not nearly all of them, are combinations in some way, whether with chemotherapy, whether with another antibody, whether with a small molecule, or whether with an ADC now, right?
And so we're very well aware in terms of and encouraged by the safety profile of ivonescimab that's been demonstrated thus far. We're very encouraged about that and its potential. So we're very aware in terms of the landscape and where we'll need to take ivonescimab in order to fully maximize its potential. And in some ways, our obligation to bring it to as many patients as possible. So we're very confident in terms of its ability to combine. And that's very much on our roadmap. We haven't gone in terms of details on how exactly that'll take place just yet, but it's very much in our roadmap.
Okay. So that's a good segue into the next question I wanted to ask beyond lung cancer. What are some of the indications, the tumor types you're most excited about exploring or you think this has the greatest potential?
Yeah, I think if you go back to ESMO last year, right, or I'm already in 2025. I think at this point, so maybe it was a couple of months ago, in ESMO 2024, you know, there were four indications that were shown there, three plus one that was shown at ASCO, right. What we haven't done is necessarily publicly stated what the step plan will be there. But what we have shown is that there are multiple indications outside of lung cancer, biliary tract, colorectal, head and neck, triple-negative breast, where there's early phase two data has shown very high potential for ivonescimab, right. We've laid that groundwork in terms of this is not a lung cancer drug.
So as Bob was alluding to in the beginning, you know, when we did the deal, there was a core focus that this has real opportunity in non-small cell lung cancer. And we believe that there's opportunity given the targets and some very preliminary data that this had an opportunity beyond lung cancer. You know, now we've kind of shown in multiple settings that this has potential outside of lung cancer. So we've begun to lay that groundwork with ESMO and we'll continue through our IST program, through our work with our partners at Akeso in China to continue to expand on them.
Okay.
Yeah, and I would add that we've actually mapped out what we want to do. You know, the joke about a day in the library is worth six months in the lab or $1 million of consulting. So it's pretty easy. We know where Keytruda went. We know where Avastin went. I think we're looking at all those indications very carefully. It's really about unmet need and timing. But the thing that's really exciting is that Ivo is proving to be a little bit different. If you look at the activity and the data across some of those publications that they've mentioned, you know, colorectal cancer and microsatellite stable is very interesting. Triple-negative breast that has a lower CPS is also very interesting. It sort of suggests that Ivo is not just Keytruda and VEGF, right? It's something different.
Right, right. This is clearly a very competitive field and your data is like attracting more and more players into it. How much do you know about the other PD-1 VEGF assets out there or PD-L1 VEGF as it might be, like in terms of the IP that they have relative to what you have and how clinically, preclinically they may or may not compare with Ivo?
Yeah, we're tracking them and we're very well aware. I'm not going to comment explicitly on any one individually because I don't think that makes a lot of sense. But we very much know from patent filings, you know, what's in the actual inherent IP. We see very much through our competitive intelligence work where we each stand, where each is positioned, what differentiates in theory. What I would say though is, you know, through all of that work, you know, as we look at the structure, we look at what's being said about each one. When we worked through the deal with Akeso, one of the things that we were most bullish on was the specific engineering of ivonescimab.
I can really say with confidence to date, there is each of the specific engineering modifications that were made to ivonescimab were intentional and were done with a specific purpose and an explicit intent from a clinical benefit perspective in terms of these two existing targets. There still isn't anything to date that we've seen that, you know, looking back, we would say, oh, you know, we like that more than ivonescimab. Each thing that modifies, in theory, detracts from what the initial intent was with ivonescimab in terms of its specifically engineered structure. So we like where we sit.
Okay. And can you remind us of the key aspects of the Akeso deal in terms of relative responsibilities of each company and then the economic rights to ivonescimab down the road?
Yeah. I mean, so at a high level and somewhat simplistically, right, we have the rights to North America, South America, Europe, the Middle East, Africa, and Japan, right? And so basically we control the development through commercialization. And our territory is, you know, Akeso in the remainder, which is largely China and Australia and a few other Asian countries, right? We paid the upfront back in 2023 for $500 million. There's $4.5 billion of potential milestones. It's divided between basically $1 billion in regulatory, which are full approval regulatory milestones that are so no conditional approvals, no accelerated approvals.
And those are across a number of different indications across a number of different territories, right? So those are significantly broken down. And then there's commercial milestones that make up the remainder of that, which are based on annual sales amounts. So effectively, the milestones become self-funded in that sense. And so we would be very excited to effectively pay each of those milestones. And then there's a low double-digit flat royalty.
Okay, so I think we've gotten across, and I think everybody realizes the opportunity ahead for you guys is enormous, but it's also clearly competitive and it's going to be expensive. How do you strategically think about your balance sheet and in terms of balancing the opportunity with the spend?
Sure. I'll hand that over to our CFO and COO.
Yeah, we currently have $487 million in the bank. We recently raised, you know, through private financing, $235 million in September and earlier in June, $200 million. We have been opportunistic and, you know, raising cash, but we have been very efficient in our capital allocation. As we, if you see our run rate, we have been operating cash flow is like burn less than $35 million a quarter.
Though now we have intentions and plans to initiate HARMONi-7 and expand HARMONi-3 so that could expand. But certainly we have enough cash and there are so many key milestones which are coming up in the next six months to 12 months, right? There is more data expected. Obviously, HARMONi, if you recall, we enrolled it pretty quickly, you know, and ahead of our scheduled plan. So that data should come sometime in mid-2025.
So there are multiple opportunities for us to finance as those data comes. And as we said, there are other indications where more phase two, more mature data would be coming up in 2025. So those will give us a lot of opportunity to raise cash at appropriate times.
Okay. Perfect. And I think that leads into a question to end this as we have to wrap here in a minute. But we've already talked about the pending overall survival readout for HARMONi-2 . As we look ahead to 2025, what are the other key readouts people should have on their radar to make sure they're keeping close tabs on?
Yeah, first and foremost is the HARMONi readout, right? So that's the randomized phase 3 and second line EGFR post the TKI. But that'll include Western patients now, right? And so that's where randomized phase 3, it's our opportunity now to show the global data of ivonescimab. And then in addition, Manmeet kind of laid it out nicely there, which is additional phase 2 data that will continue to mature, different indications, you know, more maturing on previously announced. So we have a number of different places. We haven't kind of laid out publicly what explicitly that will be, but there's certainly additional information, you know, to come in 2025.
That HARMONi date is mid-next year, right?
Mid-2025.
Perfect. All right. Well, that's it. All the time we have. Thank you guys very much and best of luck.
Appreciate it, Corey. Thanks very much.