Biomea Fusion
Biomea Fusion presentation delivered at the 40th Annual J.P. Morgan Healthcare Conference on Wednesday, January 12, 2022 at 3:00 PM
Gavin Scott:  Good afternoon. Welcome to day three of the 40th Annual J.P. Morgan Healthcare Conference. My name is Gavin Scott. I'm a Biotech Analyst here at the firm.

It's my pleasure today to introduce Biomea Fusion, and CEO Thomas Butler. Please note that we will be going straight to the Q&A session following the presentation. Please feel free to use the ask-a-question button on your screen or email me directly. With that, I'll leave it to Mr. Butler.

Thomas Butler:  Thank you very much, Gavin. Thank you for having us. Despite a very challenging backdrop last year, it was really a breakout year for Biomea. We started the year with seven employees, having just completed a series A, raised about $50 million really in the middle of our key toxicology studies to support an IND.

Fast forward through the year we went through the IPO process with Mike Connor. Raised $150 million that allowed us to build out the infrastructure of not only our R&D engine, but to fully explore 219, which we'll talk about later in the in the discussion.

Going through and writing a 5,700-page IND, submitting it to the FDA, which was cleared rapidly. Then putting ourselves in position on a CMC perspective to generate all the material required for our first in-human and get our first site activated to end the year at MD Anderson. At the end of the day, all the while hiring 45 employees to get to 52.

We also did a custom design and build of our research facility, our Innovation Center in San Carlos. A really foundational year for the company. This year, at the end of the day -- I'm on slide 3 -- we have an experienced and very successful management team.

We've worked together for a very long time. We know the strengths and weaknesses of each other, and we're here to improve and sharpen everyone's skill set. We have a very efficient platform which I'll cover later in the talk and a very productive clinical asset, BMF-219, which we're really excited about.

Then, of course, an expanding pipeline that will start and kick off in the first half of this year when we announce our second program. Our mission, which you see on the right-hand side, our tenant inside these walls is we aim to cure.

We're doing what we do to not only improve but to extend lives for our patients. That's really what we're all about. When you see the pathways that we select, the targets that we select, to design our covalent irreversible inhibitors, all of the work that we do to go into the IND and execute our clinical trials is really just with that in mind.

Turning now to slide four, BMF-219 is a novel, irreversible, covalent inhibitor. We think of it as a pipeline in a pill. It's because we believe that single-agent activity will have a dramatic impact in multiple indications. It's through strong pathway control, multiple shots on goal in indications consistent on-target effect, and a very wide safety margin.

Turn to slide five. Our team, 10-plus years of success together, made up of myself, my cofounder and partner, Ramses Erdtmann, President and COO of the company. Franco, CFO, Naomi, Heow, Steve Morris, with Alex really taking control of all of our clinical science work. Thorsten I was lucky enough to work with at Gilead on the Hepatitis C Cure program.

Of course, Jim Palmer, our VP of Drug Discovery and really the leader behind the creation and discovery of Ibrutinib.

Switching now to slide 6, the tenet for what we do. We're extremely patient-focused and, of course, aiming to cure. Our vision is about creating a novel suite of covalent inhibitors. Selecting the right biology, the right pathway, to target with a covalent inhibitor is essential. There are certain attributes that you have to look at and validate when you pick your target.

We do custom synthesis at a target basis. That leads to what we believe is really breakthrough chemistry for our covalent irreversibles. What we do is we combine these all together with menin as the centerpiece.

We want to bring in and build proprietary combinations. From our experience at Gilead, shutting down multiple pathways for viruses. Cancer is also typically led by multiple pathways. We want to change the paradigm of treating patients with one pathway at a time to multiple pathways at once and give our best shot at these fast-growing tumors.

There's a lot of examples in history of successful covalent inhibitors, of course. We typically remind folks that covalent inhibitors have been out there for a very long time. They've been very, very successful. It's through this notion of binding to your target permanently and shutting it down. This gives you the best chance for your pharmacodynamic effect.

I'm on slide seven and there's, of course, the medicine cabinet -- pills of aspirin and penicillin that we're all very familiar with. We have some oncology examples, Tagrisso and Imbruvica, of course have...These oncology covalent inhibitors. Most people don't realize that the antivirals Vyriad and Sovaldi are also covalent inhibitors, all showing significant improvement in the lives of patients.

On slide eight, there are several important attributes and really the driving force behind selecting covalent inhibitors. Why go after these? Why specifically focus on them? We think they give you the best chance for success and not only success in the clinical setting, but also success in the commercial setting.

The high selectivity really is imparted through a two-step process where you do the same understanding of the target; the same structural design of your molecule to that target, trying to leverage non-covalent engagement but you add in a second step which the target, a specific single amino acid within the pocket.

You can imagine you have to modify the angle of your molecule where the warhead is attached to and also vary the distance. The combination of distance and angle gives you that efficient covalent binding, and drives what we see in the middle as a deep target of activation. You got to get that bond formation to happen. As soon as you do, you'll have significant control on that target.

The greater therapeutic window comes in by balancing the two. You have to have the balance of the high specificity-selectivity with the deep target of activation. That combination we think is second to none.

Flipping to slide nine, this is a great profile or great example of what a covalent inhibitor can do. This is a PK/PD curve of ibrutinib. Essentially, what we're showing you here is, look, if you understand the kinetics and the dynamic of your target and of your covalent inhibitor, you can shut down the protein.

Even though you only have four hours of exposure, the control on that target lasts for 24-hour period. That distance between the green line and the blue line is that benefit because you don't need to maintain exposure.

You don't need to constantly expose tissues and plasma to your drug to shut down the site. That just gives you more flexibility and tolerability and keep patients on your drug. Passing on to slide 10, our technology platform.

Really, at the end of the day, traditional small molecule drug design goes through target exploration like we do when we go through our validation step, but the initial hit is through library screening.

Library screening is you're screening not just thousands of molecules, but usually tens of thousands and sometimes hundreds of thousands of molecules to see where you find a scaffold that fits or hits your target.

You then have to go through painstakingly optimizing your molecule and the problem tends to happen where you lead to selectivity-specificity issues because that scaffold was actually designed for something else. It wasn't designed particularly for your target.

That's very different than what we do. We do custom design so we don't spend a lot of time having to tinker with specificity of the target. We really spend most of our time during lead optimization with the PK properties of the molecule.

That's why we're able to get from target to hit to now preclinical validation and IND selection within a three-year period, where typically it takes four, five, six years to get there.

Turning to page 11, our pipeline. For 219, we're pursuing up to seven tumor types. We'll be enrolling up to seven tumor types this year in 2022. Because of all the work that we've done from a translational perspective and validation of menin with a covalent inhibitor has really afforded the capability of doing this.

We're also announcing that we'll be taking BMF-219 into diabetes this year. What's so exciting is, again, menin as I've explained in earlier presentations that menin is this toggle switch. Whether it's in the on position or the off position, 219 does a great job of resetting the toggle switch into the neutral position.

For our second program or target number two, again, this is a target that was selected based on our increasing understanding of menin. We select and understand the biology and we want complementary pathways. This is what lends to this idea of proprietary combination. We want to shut down multiple pathways with menin as the centerpiece.

Program two and three will, of course, sit on their own two feet, and they will be able to go and have a dramatic impact with single-agent activity, and they'll have single-agent success. We just think that the future and long-term benefit will be with combination.

We'll announce the second program in the first half of this year. What you'll get with that announcement is, of course, the target, you'll get the molecule, the IND candidate, and all the preclinical data that supported the selection of the candidate. Program three is right behind program two. We made quite a productive effort in 2021 there.

On slide 12, what we're highlighting here is all the different tumor types that we're exploring with 219. We're exploring multiple tumor types again this year. From an initial understanding of menin when we first started this program, menin was very much focused in the acute leukemic area.

There's a lot of literature out there that suggests otherwise, like prostate cancer, endometrial cancer. Then, of course, if you go into other literature, there's support that I'll talk about later, but initially, the focus was really about the acute leukemias because of the understanding of MLL.

Menin-MLL is a very important protein complex that drives these aggressive leukemias. We just learned with 219 that we disrupt not only that complex, we just disrupt other protein complexes with menin as the centerpiece, and that lends to these other liquid and solid tumors.

Strong pathway control, and this takes us to slide 14. If you look at the complex with MLL, and this is an important piece, just to highlight the mechanism of action and why we went after covalent inhibitors.

MLL and the translocation, you look on Figure A on the top, the fusion mutation happens at the tail end of MLL, not the business end where it engages with menin. That site is completely conserved across all species.

What we thought was so novel is there's over 100 different fusion partners that have been elucidated. Technically, you can have different binding affinity of menin to MLL, depending on what fusion partner do you have, AF9 versus AF4 versus AF10.

You can certainly try to dose up to create an umbrella effect, but we decided to create a co-inhibitor that actually goes after the target, menin, and its ability to disrupt menin is really independent of MLL. That really allowed us flexibility of going into these other tumor types.

DMF-219, and on slide 15, when you look at these key oncogenes that are driving the acute leukemia, we looked, of course, at the target gene MEN1, which creates our protein menin. MEIS1, HOXA9 and DMT3 are all very supportive gene signatures of this pathway. What's great to see is just consistency.

At the 24-hour time point, we do a great job in not only shutting down the key gene signatures but shutting down the target chain.

On slide 16, what we're highlighting here is some of the other genes that gave us a clue in what 219 is doing that's unique to 219, to this covalent inhibitor, and what potential there is outside of acute leukemia.

If you look on the chart on the left, we highlight BCL2, we highlight MYC and HOXA9 Again, you look at HOXA9 and BCL2, it's actually equally matched with MYC, showing you greater than 90 percent. Conversely, reversibles tend to give you about 50 to 60 percent reduction. We believe that that nuance creates an opportunity to go into other tumor types like DLBCL and MM.

As you flip now to page 18, what you see on the left-hand side is the menin complex. As I mentioned before, menin is in multiple protein complexes. Menin-MLL is just one of them. We're showing you another menin and MYC with the chaperone protein MPM1. The protein complex that menin is engaged with just dictates the particular tumor type.

On the right, if MLL and MPM1 are engaged, you get acute leukemias, ILL and AML with MLL rearrangement, as well as MPM1 mutant. With MYC, however, it's a completely different tumor setting, where you have double hit, triple hit, double expressor, and DLBCL. You have various multiple myeloma genotypes, as well as really RAS/RAF but KRAS-activated tumors like colorectal, lung, and pancreatic.

On slide 19, this is some of the initial research work that we did that gave us a clue on menin dependency. Much to our surprise, acute leukemia actually ranked number three, not number one as initially proposed.

DLBCL ranks number one in terms of the proportion of tumors that are at or to the left of minus one, which represents a penny central or a critical menin dependency for that particular cancer.

Multiple myeloma ranks number two, acute leukemia number three, and then the solid that's where we get the KRAS-activated tumors. This serves as our initial roadmap to explore these other tumor types.

For 20, slide 20, I know this is a complex slide, but basically what it says is in a very unbiased manner, what we did was look at what 219 does from a transcription factor basis. We can get into this a little bit in the Q&A, but what it's showing you is that we're really disrupting MYC.

MYC is number two on this list, as well as if you look down the list, you see the other bad actors like KMT2A, which is MOL, UC, JUNB, and others, and really gives you a highlight of this disruption that's quite broad for 219.

Then on slide 21, this notion of menin and MYC and KRAS-addicted tumors continues to unwind. Greater than 80 percent of these engagements is really derived with menin engaged with MYC. MYK target genes are activated and driving significant aggressive growth in over 70 percent of human cancers.

On slide 23, what we wanted to look at was how does 219 exert cell killing, because at the end of the day, in order to drive a response, differentiation is great, but it's got to be backed up with cell killing. That's what's going to give you your response and that's what's going to drive, hopefully, survival in these patients.

What we looked at was for 219 the story is very consistent, whether it's MV4-11, whether it's Mom13 or OCI-AML3, at 560 nanomolar, or half a micromolar we see 90-plus percent killing capabilities. That's just a different profile than what you would observe with the clinical reversible as in terms of the ability to be effective in half-cell killing, which is in the 12 to 15 percent.

Transitioning to slide 24, we're highlighting just the consistency. That's the important takeaway is whether it's MV4-11, which is a biphenotypic cell line, the Mom13, which is the traditional MOL-B range cell line, or the FLT3-ITD NPM1 [inaudible] 3.

At about a half a micromolar you have near complete control of tumor growth. That's very different than what we have observed with our own reversible inhibitors, and MI-503 is a nice example of that.

On slide 25, we've now extended to outside of acute leukemia, exploring multiple myeloma and KRAS pancreatic cancer. This is MIA-PaCa-2 same concentration, and just displaying same consistency.

We get nice pathway control and, particularly in the KRAS world, we don't have a plateau effect. We don't have a problem getting to IC90, IC95, because we're not targeting KRAS. The KRAS on, KRAS off cycling doesn't really influence us. We're targeting menin here.

On slide 26, what we're highlighting here is the patient samples that we got, to really explore what are the concentration dependencies now if we took patient samples. It's really important from an ex vivo perspective to look at, is there variability?

We took a couple samples that were treatment-naive NPM1 AML. We also took some MLL-rearranged AML samples that are also treatment naive. Again, the key here is the percent of growth inhibition or control, as well as the consistency we see across the board.

At one micromolar we do an incredible job of shutting down this growth inhibition. Conversely, with MI-503 you see, even though it's a nanomolar potent molecule, you have less than 5 percent growth inhibition at one micromolar. Again, this inconsistency. You do see about 35 percent in the gray patient.

On slide 27, what we're highlighting here is now to double hit diffuse large B-cell cell lines, DB and Toledo. Again, the story is the same, because of the control on MYC that we observe with BMF-219, we see nice potency in both cell lines.

Conversely, for clinical reversibles, this is really predicated what we think is based on the ability to disrupt MYC. The green doesn't have great control on MYC. The red shows somewhat moderate control on MYC, and you see it coming out in the cell line data in terms of potency.

On slide 29 we did a very thorough job to make sure that 219 was our key candidate. We start with glutathione reactivity. This is something that you do as a covalent drug developer. What you're trying to test is, if you just take glutathione, which is basically a naked cysteine, how fast you form [inaudible] formation? If you have a very reactive warhead, you form it very quickly.

What we did was take some of the commercial drugs out there and compare it to our covalent sister molecules, 13 and 14, and then compared it to 219. What's nice to see is, out of the pack, that 219 performs just as well as ibrutinib, and much better than neratinib, from a [inaudible] formation perspective.

We also do a nice kinase paneling. We do SafetyScreen44, and really look at the specificity but also selectivity on-target/off-target effects.

On slide 30, now transitioning to in vivo works, one of the first models that we ran was using a disseminated model. Thus actually pushes the tumor into the bone marrow of the animal. It's the best way to replicate leukemia, because leukemia is residing in your bone marrow, AML and ALL.

What's important to note is, even just after two weeks of dosing we get considerable anti-tumor effect without implicating the body weight, and really showing a durable response, was our main goal here.

If you transition to slide 31, what we're telling you here is now this profile for 219, not only do we get nanomolar potency in several tumor types that are menin dependent, the hERG inhibition that we observe is 5 percent at 10 micromolar. Then we have consistent control across the key gene sets that we're looking for which are HOXA9, MEN1 the target gene, as well as MIC.

Throughout our toxicity studies, whether it was non-GOP or GOP, we had no histopath findings. 219 came out without delivering any of these typical signals that you would find for an oncology drug, which was an impressive feat for 219. Then on the right-hand side, our target efficacious AUC is 2,000 just to speak to the nature of 219.

On slide 32, 219, it should be considered a next generation menin inhibitor. It's very different than the ones in the clinic. It has different properties in the way it disrupts menin. It has very different properties in the way it can target other tumor types.

For us and back to this aim to cure, we're after extending life, improving overall survival. That aligns well with everyone here watching this presentation. In order to do that, the surrogate is typically PFS -- progression-free survival. For AML, the response rate has been used as a surrogate. We all know from our experience at that response rate does a terrible job of predicting overall survival.

The best thing you can do is look at complete response at six months so you have a durable CR. That's the initial hurdle one should look at when you're executing in the clinic against these diseases types. We're very excited about 219's opportunity within the acute leukemias and beyond.

Our trial designed on slide 33 highlights what we're doing in the phase 1 for ALL and AML. It's split into two arms, non-SIP and SIP, that just allows us to go through the dose escalation much more efficient and understand the drug. Then once we get to our optimal biological dose, what we believe to be the optimal biological dose, we'll expand into the key patient populations.

On slide 34 we're highlighting here our plans to get into the other tumor types. The trial's initiated and it's screening patients for acute leukemias, which is very exciting. We'll be enrolling, DLBCL and multiple myeloma sometime in the first half.

Then the solid tumor KRAS activated tumors, lung, pancreatic, and colorectal, we'll file the IND and get our trial up and running in the second half of this year.

Then, for the first time, we're announcing that we'll be developing 219 in diabetes. We'll be announcing preclinical data this year, then filing the IND and getting our site up and running in the second half of this year.

Just to touch upon diabetes, and I know it even surprised us, we initially set out just to do pathway validation to see what menin could do and menin inhibition could do for these diabetes models. To our surprise, our BMF-219 did a spectacular job. We touched upon that a little bit in the press release.

At the end of the day, GLP-1 has been described as the gas for Beta-cells, and menin has been described as the brakes. When I explain that menin is a toggle switch, you can think of the tumor or the cancers leveraging menin in the on position, and the Beta-cells leveraging menin in the off position.

If we take menin out and we inhibit it with a molecule like BMF-219, what we're doing is allowing the Beta-cells to turn over. Our goal is to re-establish a healthy pool of Beta-cells. If you can do that successfully in animals and do that successfully in humans, what you're doing is resetting the clock for their disease.

Diabetes forms over many years, over decades of hyperglycemia. What we're after is creating a finite treatment and understanding how long we need to dose with a menin inhibitor, and really reset the clock for these diabetes patients.

This slide on 35 shows you an STZ model where you physically destroy either partially or fully the pancreas. You form or you create a very hyperglycemic state, and that's the control on the right hand side.

The MEN1 excised never creates a hyperglycemic state, because the brakes are on to stop preventing the beta cells from turning over. The beta cells turn over, you repopulate the pool of beta cells in this animal quickly. That's what we're after here.

Then on slide 36, what we looked at was at the end of the day not only did 219 show significant reduction of glucose levels in animals with hyperglycemia with type 2 diabetes, we saw a very durable effect, an effect without needing constant exposure. That gets us very excited.

We used two models, the Zucker diabetic fatty rat, as well as the STZ model. These are the gold standards for exploring diabetes. We used the STZ model in the type 2 setting.

We'd love to also explore type 1, because depending on the biology, if there is still a remaining pool of beta cells, we should be able to repopulate, and that's really what we're after. We want 219 to be an oral, long-lasting treatment for diabetes.

We're excited we'll be engaging with the FDA this quarter to hone in on the IND package and the clinical trial design, and we're looking forward to filing our IND and kicking this off this year. We'll be, of course, submitting the data for presentation, and we're very excited to share these data with the rest of the community.

At Biomea Fusion, we have a technology platform that's been very, very efficient, very, very productive. We have a number of programs that are coming online, and we're very excited to announce Program #2, with Program #3 coming behind it. Lead molecule, we're after best-in-class, with a safety profile that allows patients to stay on and have a durable impact on their disease.

We're going to initiate studies in up to seven tumor types -- both liquid and solid -- this year and address the significant unmet need for patients at large. All the IND-enabling work is currently being done for diabetes, and we're well on track to get our study up and running this year. From a capitalization perspective, we're well capitalized into 2024.

On slide 38, we highlight some of these key milestones. You should think about 219 in two ways. We'll continue to validate 219, get all the translational work and paperwork done to support all these IND filings and, of course, enroll these patients.

Enrolling acute leukemia, enrolling DLBCL and MM in the near-term, and then looking to enroll the solid tumors in the second half of this year, as well as getting our study up and running in the second half for diabetes, and then, of course, the second pipeline product announced in the first half of this year.

Big year for 2022. Thank you very much, and we'll open it up for Q&A.

Gavin:  Thanks, Thomas. For a reminder for those listening, to submit a question, just go to the ask question button in your portal, and we'll try to address those. I see a few popping up as we speak.

Thomas:  I'll bring in Ramses, and Alex, and Priyanka, and Franco just to help address any questions.

Gavin:  Great. There's definitely been a lot of progress since your IPO last year. We can start with some of the more recent developments, particularly data presented at ASH demonstrating broad utilization of menin inhibition. You've mentioned some of that in your slides.

Thomas:  Yes, we did, absolutely. If we can go to slide, I believe, slide 20. Priyanka, do you want to talk about this slide 20 and the impact of MYC and what we showed at ASH?

Priyanka Somanath:  Right. I'd be happy to give more detail on this. What these analysis have actually shown us is that the set of transcription factors that regulate these gene expression changes that we observe, that are caused by BMF-219 are more broad than what is restricted to just the menin-MLL interaction.

This dataset highlighted MYC and its binding partner, MAX as top transcription factors that regulate these changes that we see in gene expression. In addition to that, we also saw known interactors of menin, such as GEN-D and CBTA, as well as KMT2A or MLL-1, which is what we expect to see with menin inhibition.

Gavin:  One from the queue, do you expect to see any resistance develop to BMF-219?

Thomas:  That's a great question. We're trying to force it. We're trying to force those through assay development. At the end of the day, from our experience with BTK is, obviously, you do get cysteine-to-serine mutations in very low percentile. Those are some of the things that we'll be looking for with menin. Do you get a cysteine-to-serine mutation?

Based on all the work that we have done to date with our assay work, we haven't seen any resistance pop up. Typically, you have to incubate these cells over very long periods of time to try to force it. We're working on it.

Gavin:  Thanks. A few on the safety side also in the portal. What are the theoretical safety concerns for irreversible inhibition or any on-target, off-tumor risks?

Thomas:  That's a very good question. Typically, the initial concern comes in. This is done through validation work when you select your molecule, is what you want to understand is, are there other proteins that 219 is binding to? You do these proteomic pull-down assays. What's nice to see is when we did that work, the specificity for 219 is incredibly high.

From an addict formation risk, we don't see it for 219. From an off-target perspective, keep in mind that in order to get into diabetes, you have to execute a lot of the non-oncology toxicity studies.

Most oncology molecules, I can tell you, would not pass these studies. You have to do neurology, you have to do cardiovascular, you have to do respiratory, as well as Ames and micronucleus. The good news is 219 is passing these studies with flying colors. It just speaks to the profile of 219.

If you think about it, this is a molecule that you can dose diabetes patients. Think about the flip side, what that means for cancer patients. What a molecule this could be.

Gavin:  There's a few competitors in the space, and they're clearly taking a different approach with reversible inhibition. What are your overarching views on the competitive data that we've seen so far in the clinic?

Thomas:  At the end of the day we don't have a ton of information other than what's published. Clearly, Syndax has had success in their PK/PD effort. The SIP inhibition has done well for them in terms of getting to the right concentration and be able to deliver complete responses.

What that does for us is provide an incredible proof of concept. That if you can get to the concentration needed for your molecule, which means that you're now able to have control on menin, you get these responses that you need for acute leukemia patients. For us, what's nice is that we believe that 219 is very efficient.

You don't need as high of an exposure to drive these responses. 219 does a great job of not only disrupting menin MLL, which reversible inhibitors do. We hit menin quite hard. That's what gives us this broad therapeutic potential. It's really just because of its way it disrupts menin. It's quite different.

Gavin:  Now that you're in the clinic, presumably we could maybe get clinical data later this year -- not that you're guiding to that now. As that data mature, are there any things that you look to to signal potential differentiation from those reversible inhibitors that do have clinical data, whether it's on the safety side or PK/PD data, etc.?

Thomas:  What we look at, Gavin, is the exposure that's required to drive the response. Typically, if you're able to keep that below a certain threshold, that just gives you more flexibility at keeping the patient on the right dose. This isn't something that the reversible menin inhibitors have a challenge with. Really, any molecule has a challenge with that.

It really has to do with what else your molecule is bumping into that's preventing you from dosing at the optimal dose. We think 219 affords you that flexibility and capability to get to the efficacious dose and stay on it.

This is a key attribute that we learned at Pharmacyclics -- Ramses is sitting here next to me -- patience. It seems quite obvious. It only comes out when you really think about it that patients can only benefit from your medicine if they're on it.

At the end of the day, we're trying to push forward a molecule that allows patients to stay off therapy.

Gavin:  We have a few minutes here. Wanted to get to the opportunity in DLBCL and multiple myeloma. The question is, is menin enough of a driver to use as a monotherapy as it is in AML? Or will the drug have to be used in combination for those indications?

Thomas:  That's a fantastic question. It has to do with the addiction to NIK. If the tumor type is a subtype of DLBCL or MM is addicted to menin, we believe it should lend to a single-agent activity. Again, we have to prove that biology out in patients. We should be able to see significant activity single agent.

Where single agent is enough. then we've been looking at what other combinations can be done to take care of what's missing.

Gavin:  Great. With that, I think we're just out of time. I want to thank you, Thomas, and the rest of the team for joining us today. Hope everyone has a great rest-of-the-day.

Thomas:  Thank you, guys, very much.