Medivir AB (publ) (MVIR) Earnings Call Transcript & Summary

Welcome to Medivir's Quarter 2 Report 2022. [Operator Instructions] Today, I'm pleased to present CEO, Jens Lindberg; and CFO, Magnus Christensen; and CSO, Fredrik Öberg. Please begin your meeting.

Thank you, operator. And we can immediately move to Slide 2, just for some further sort of color on who we are. So on the call, myself, and I have been CEO since January this year. And then Magnus, our CFO; and Fredrik, our CSO, will be sharing the presentations, and we'll be sort of sharing the Q&A session at the end of the call as well. So with that, we can move to Slide 3, please. Important slide, you please access the slides on our website and you can read it there in a bit more detail and we'll jump forward. And we can jump ahead to Slide #5, please, operator, in terms of highlights during last quarter, and we'll divide things into sort of 2 categories: one, focused on our lead asset, fostrox, and the other with regards to the other portfolio development. Fostrox for liver cancer is our lead asset and where we focus our efforts. During the last quarter, we are now up and running across our different sort of study sites in U.K., Spain and South Korea. There's been a lot of focus on getting and activating sites, getting them up and running. Now that we have it up and running, we're also looking to add additional sites and investigators, especially in Korea, where we see as good movement. As we've communicated in our report, we did see during the last quarter, a slower-than-planned study recruitment rate in the European countries. So we have launched a set of initiatives to overcome that and we've sort of set up conditions that will increase the recruitment rate during the second half of 2022. And we've seen also sort of good movements over summer. But we'll touch on that in a little bit sort of slightly later. Perhaps not the biggest news, we've had our INN name approved previously and now we also have it approved as a drug named by USAN. So, good to have the same drug name approved. The final element with regards to fostrox in liver cancer is that we, maybe a bit weird to put a negative outcome of another study as a highlight, but I think that we have seen a press release from Merck and Eisai where they communicated that the LEAP-002 study read out negatively, and we'll touch a little bit more on that. But the important element for us is that it further highlights the need for alternative combination therapies with different mechanisms of action in the HCC space. With regards to our other portfolio, a couple of movements or progressions during the quarter. The birinapant compound that we have out-licensed to IGM Biosciences, they continue to study the combination with their own IGM-8444 in solid tumors. And they have communicated that they've cleared the third of 4 planned dose escalation cohorts with no DLTs. The other element is that a previously out-licensed program, MBLi program or metallo beta-lactamase inhibitor, which was out-licensed to a company called AMR Center, which is today named Infex Therapeutics. They have presented additional preclinical data in '22 and also communicated that they are moving the program into Phase I sort of 2022, '23 time frame. And we'll touch a little bit more on that as well. So if we move forward one slide, go to Slide 6. This is just our pipeline overview and the only thing to sort of mention here is that, sort of for those of you who have seen it before, we have added back sort of the MBLi program now that it has progressed and moved and we're seeing kind of movement towards clinic, we added it in. So it's here as well. From a financial viewpoint, we have -- there's a revenue share potential. So whenever Infex would sort of further sort of partner with someone or out-license or sell it, then any revenue as part of that agreement will be shared with us. Then let's start with our lead program, fostroxacitabine bralpamide, so we can go to Slide 8, please. And as mentioned, we did -- we had -- during quarter 2, we have seen sort of a slower-than-planned recruitment rate in our European centers. So that's been analyzed, and we've looked at, okay, what can we do to overcome that and speed things up? And we have taken on initiatives in 3 buckets. One, we have amended the protocol, where we have simplified the inclusion criteria somewhat. But most importantly, we have broadened the criteria. So now we sort of allow for inclusion of second line as well as third-line patients, third-line patients who are into sort of with liver disease. But sort of third-line patients are now eligible as well to be included. And we have also -- we're also sort of adding additional investigator sites in existing countries, primarily focused on Korea, where we see sort of further potential to further drive recruitment rate up. And we're also exploring additional countries to go into and looking at feasibilities across a few countries. And when we have honed in on selection, then we'll communicate a bit sort of further detail. And the third part, we are seeing sort of increased competition, sort of more studies have started in the wake of COVID-19. So in order to ensure engagement, et cetera, we have sort of further increased our presence and our activity at the activated trial sites to sort of engage sites to continue to recruit to the study. So -- and as I mentioned previously, sort of these are initiatives that we, to some extent, have launched, and we have seen sort of -- we're seeing sort of positive movement. But there are sort of further benefits to come from this. So for example, the protocol amendment, they have just this week been approved in both Korea and in the U.K., so that will further fuel sort of uptake in recruitment speed. So looking good with regards to sort of creating a change with that respect and so we feel positive about the future. With regards then to other elements, we can go -- if you move to Slide 9, I did comment a bit on the LEAP-002 study. And for those of you who may not be as familiar with the study, it is a first-line study in unresectable HCC, which is comparing PD-1 KEYTRUDA plus TKI LENVIMA, comparing it with LENVIMA monotherapy treatment to progressive disease, and they've had a study with dual primary endpoints. And a couple of things to note here. They've just announced that it did not meet its dual primary endpoint in OS and PFS. It is -- since they've only shared a press release so far, it's too early to speculate on the reasons for the negative outcome and we need to see the data in more detail to sort of further analyze. That data will be presented at an upcoming medical conference. We don't know yet, but there is a sort of a high likelihood that it will be presented at ESMO in Paris in a couple of weeks. But reason for mentioning it here is that sort of the HCC space is an evolving space. And it's clear that sort of these patients are difficult to treat. And in order to get best possible patient benefit sort of combination therapies will be needed. And what LEAP-002 study is highlighting is that then there will be a need for alternative combinations with compounds that have a different mechanism of action and come from a different class of drugs than the ones that are either used or in development today across HCC. And this is where we believe that there is a great opportunity for fostrox. So I will stop there, and I will hand over to Fredrik, who can go through some of the rationale as to why we believe that we fit nicely into that space in terms of alternative combination therapies. So Fredrik, and then operator, you can go to Slide 10.

Thank you, Jens. So as you may know, the current HCC therapy space is heavily dominated by 2 classes of drugs. So either stimulating the immune system with so-called immune checkpoint inhibitors, either anti-PD-1 or anti-PD-L1, but also anti-CTLA4, which are usually then combined with either anti-PD-1 or anti-PD-L1 antibodies. So that's one part of this space. The other one is inhibiting angiogenesis, blocking the blood supply to the tumor, either by antibodies such as Avastin anti-VEGF or by multi-kinase inhibitors. And so these types -- these classes of drugs have been combined. For instance, the KEYTRUDA plus LENVIMA that Jens just mentioned, and this has been a dominating combination therapy. So with that in mind, what does fostrox bring to the table? If we move to Slide 11, it briefly describes what fostrox is. So it's a slow drug of a nucleoside analog, but it delivers an activated -- already activated nucleoside and nucleotide with a mechanism that allows it to generate high concentrations in the liver while, at the same time, minimizing systemic exposure. So it's orally administered, it's rapidly converted in the liver to the active metabolite. This active metabolite induces DNA damage and cell death of the tumor cells. And we have in the Phase I part of our study studied monotherapy of fostrox. And we have shown both that by our analysis that we deliver fostrox to the liver cells and the tumor cells. But we've also shown proof of concept in terms of generating DNA damage or inducing DNA damage, specifically in tumor cells. So with biopsies from patients show clearly that in tumor cells, we induced DNA damage, whereas in surrounding normal liver tissue, we don't observe that. So we have shown proof of concept with the monotherapy. But as Jens pointed out, of course, in the space and with the difficulty in treating HCC, combinations are required. So if we move to Slide #12, there's good rationale for why a combination of fostrox with either checkpoint inhibitors or multikinase inhibitors should work. We know that fostrox induces DNA damage and tumor cell death and thereby potentially it increases tumor antigen presentation and increase immune response, and we have preclinical data supporting this. The other combination with tyrosine kinase inhibitors, for that there is also a very good scientific rationale, and that is that blocking the tumor angiogenesis or blood supply will lead to hypoxia, lack of oxygen. This in turn leads to upregulation of enzymes that generate the active metabolite, which means that the combination generates more active fostrox in the tumor when there is lack of oxygen. And we have data from patient biopsies showing that we do induce DNA damage in hypoxic areas from the Phase I part of the study. These regions are usually quite hard to reach with drugs. So we're sort of very satisfied that we know that we can induce DNA damage in these regions and there's a good rationale for actually having increased effect in combination with these multi-kinase inhibitors. So if we move to Slide 13, this describes then the current phase that we're in. So combining fostrox with either the TKI LENVIMA or fostrox with the checkpoint inhibitor, the anti-PD-1 antibody KEYTRUDA. So we're starting this now and are in the phase of escalating the dose right now. These are those cohorts of 3 patients. And the aim of this part is, of course, to examine safety and tolerability. Whereas we don't think that there will be any interactions since the mechanisms of action and the toxicity profiles are very different for these, we do need to escalate the dose until we reach a dose where we can say that this is the recommended Phase II dose. And this is going on in parallel for both the combination with LENVIMA and with KEYTRUDA. Once we have completed those cohorts and reached a dose that we think is the maximum dose, and it will be the recommended Phase II dose, we move into the second part, which is an expansion phase, to generate more data on the correct dose, to also be able to see some signals of efficacy and also to build a better understanding of the safety and tolerability. And as Jens mentioned, we are doing this across the world really, both with [indiscernible] in Europe, in U.K. and Spain currently and also in South Korea. So we're capturing different geographies, which I think is really important. So with that, I will hand over to Jens to continue.

We can stay on this slide for a couple of seconds because, one, I just sort of -- I realized that considering the latest changes in Korea and U.K. with regards to protocol, this slide should say patient population second and third line advanced inoperable HCC, so just pointing out that error. The other element is that sort of as you also see from a patient population, which has turned out to be quite important, that patients who have progressed on sort of standard of care therapy, i.e., including atezo-bev patients are included, which is an important element as atezo-bev is today has become sort of clearly the standard of care as a first-line treatment. And we've said sort of all along and that we continue to do, we will sort of -- in terms of communication with regards to where we are and how things are progressing, we said that we will communicate when we have selected or when we finalized that first sort of dose escalation and we've selected the Phase II dose and with the decision to move into the expansion phase, that's when we will sort of communicate. It might be that sort of there are different time lines for either of the arms. But that's when we are planning to sort of make further communication and can provide a bit more color as well on sort of what we've seen in the different dose cohorts. We can move to the next slide, Slide 14, which is a relatively busy slide. And I just wanted to keep it here just to say that under 2022, we have said and we continue to say that selecting sort of combo dose and decision to move into dose expansion, that's sort of the ambition to do that in 2022, and that ambition remains the same in terms of next steps. Another element to highlight, and we can move to Slide 15, please. I think I mentioned previously that we're seeing a changing HCC landscape to some extent, if nothing else highlighted by the LEAP 2 study. And a couple of things to highlight there on the treatment algorithm. And it used to be that systemic therapies like Atezo-Bev or for fostrox or other drugs were primarily used in that advanced stage (c). What we're seeing here is that more and more patients in the intermediate stage, rather than being treated with TACE or chemoembolization, et cetera, rather than being treated that way, they are given sort of first-line systemic therapy. So we've heard quite clearly from KOLs as of late that, that's a movement that is very consistent. So more and more patients flow into the systemic therapy, i.e., more and more patients are receiving first line, which also has a downstream impact of more patients will then be eligible or able to receive second-line systemic therapy for 2 reasons. One, because more are receiving first time, but also, two, with better and better treatment options in first-line, patients will be sort of healthier coming out of that first line and will be eligible to a larger degree for second line, which also has a downstream impact on third line. So good news for patients in terms of better treatments allow patients to also receive multiple lines of treatment, i.e., growing that sort of initial target population in second and third line which -- where we are planning to enter. So that's a bit of a movement in the HCC landscape. We can sort of round things off with Slide 16. So this we've said before and we will continue to say that we believe that fostrox is a unique and first-in-class potential treatment for liver cancer. There's clearly unmet need, as if nothing else evidenced by LEAP-002. And we do believe that sort of we are more complementing than replacing existing therapies. We bring a different mechanism and a unique combination partner to the other classes. And being also sort of a liver-targeted drug, then hopefully we can bypass the resistance mechanisms that chemotherapy has seen sort of in exploratory research. And the other thing that we do know is that sort of inducing DNA damage and cell death through a cytotoxic is, one, well established in cancer, but, two, also has a strong potential for attractive combinations. We know from other tumor areas that sort of the combination of PD-1 plus chemo, for example, is a very, very good combination. So we believe that with fostrox, we are able to bring those types of combination to a tumor type, i.e. liver cancer, where that wasn't possible before. So we'll stop there with regards to fostrox at this stage and just a couple of notes on the other sort of program highlights of the remainder of the portfolio. And if you -- operator, if you go to Slide 18 and then Fredrik will take us through the movements that we've seen in the last quarter.

Okay. Thank you. So it's worthwhile spending a few minutes on the progress of the birinapant program. So as you know, it was out-licensed to IGM. So therefore, it also has an IGM number, IGM-9427 as well as birinapant. It studied in Phase I in combination with their IGM molecule, IGM-8444, which is an agonist of the Death Receptor 5. And there's a very good scientific rationale for combining these inducing cell death at the same time as removing the anti-apoptotic molecules in the cell. This study was initiated in 2021, but it was, of course, preceded by a lot of preclinical work by IGM. I mean one of those studies is highlighted on the right-hand side, a negative breast cancer model in which combinations of IGM-8444, the death DR5 agonist, with birinapant shows a very large synergy in eradicating the tumor. And you find more examples on IGM's homepage. Really spectacular synergies observed in the preclinical model. And now they're moving this rapidly through their early clinical phases. They have concluded the third of the 4 planned birinapant combination dose escalation cohorts. And importantly, this was cleared with no DLTs, but also, in particular, no clinically significant liver toxicity, which historically has been an issue with IGG-mediated agonist DR5. So that's very encouraging. And for us, this means that we're moving along. The agreement allows for development, regulatory and eventually sales milestone payments plus the royalties on the sales eventually. And we're very happy with this collaboration with very professional and dedicated teams at IGM. So that's clearly something we're very happy with. If we move to Slide 19, another program out-licensed in 2017 within the anti-infective space has made some interesting progress by INFEX. So one resistance mechanist in multi-resistant bacteria is beta-lactamase, which essentially degrade many of the used antibiotics. And in this collaboration with this licensing, an inhibitor program for metallo beta-lactamases has been licensed. And INFEX has progressed, showing very nice data preclinically in sensitizing again bacteria which are resistant to antibiotics. And we know that in this type of diseases, these type of indications, there's really a very good translation of the efficacy from preclinical models into the clinic. As long as safety and tolerability is okay, efficacy is very translated from these early models. So, I think that's really, really great and probably really great for all patients who are going to be exposed to multi-resistant bacteria. And as Jens highlighted, there's a revenue share agreement. So when INFEX earns money, we get a share of that. But although the need for this type of drugs, new antibiotics or ways of making old antibiotics effective again, there's a critical need for this. It has been very challenging to develop or to find commercial models that really work. So I'll leave that to Jens to comment on.

Yes. The interesting part is because as Fredrik said, this has been an area where there's been almost a resistance to developing new compounds because of the difficulty of kind of commercializing them. But what has made the INFEX team sort of excited and thus ourselves as well is that there has been some quite interesting recent development in financing solutions for novel antibiotics. There is a NICE in the U.K. launched a sort of almost like a prescription Netflix model. And if you also do a bit of googling on the PASTEUR Act in the U.S., there's quite a bit of movement towards finding financing solutions where the financing isn't tied to sales volume but rather sort of a prescription or availability. So basically, you get paid for developing the compound, whether it's used or not, because you don't -- the hospital doesn't want to overuse it. So quite interesting financing solutions potentially around the corner on this topic. So with that, and as I said, sort of they've communicated on intention to move into clinic towards the end of this year or beginning of next year. With that, financial highlights, and we can move to Slide 21. Magnus.

Thank you, Jens. Yes, please see Slide #21, where you can see the financial summary for the quarter 2 accumulated for quarter 1 and quarter 2 of this year, which I will briefly comment on. And all numbers are in million SEK. The turnover for quarter 2 amounts to SEK 0.5 million, which relates to royalty income from Xerclear accumulated [indiscernible] to SEK 1 million which is lower compared to last year. But then last year, we included the upfront payment for the birinapant outlicense to IGM Biosciences that Fredrik just mentioned. Other external expenses are higher compared to last year, both in the quarter and accumulated, and relates foremost to high clinical costs for the ongoing fostrox combination study. Personnel cost is higher as well, that's due to more FTE than last year. The operating loss for quarter 2 is around minus SEK 22 million and higher than last year and also due to the higher chemical costs with the fostrox combination study. The cash flow from operating activities for this quarter amounted to SEK -18 million, which is lower compared to Q1 and more or less in line with the plan that we have for the year. And the cash position at the end of quarter 2, it's SEK 163 million. And according to the current plan, the cash run rate is well into the next year. And with this, I will hand back over to Jens.

And we'll round things off with -- if you move to Slide 22, quite a busy slide, so I'll not go through all of it, you can access the slides on our website as well. Fredrik talked about the movement we've seen on the bottom with regards to birinapant, INFEX, et cetera. The other sort of what I just want to emphasize from a fostrox perspective, sort of as I said before, we're now up and running sort of across our study sites. We're seeing sort of really good recruitment movement in Korea, and we want to sort of put fuel on the fire, which is also why we're then aiming in the progress of adding additional sites and investigators in South Korea to fuel that recruitment data even further. And where we mentioned sort of where we're seeing sort of slower-than-planned rate in Europe, we do have initiatives in place, including the protocol amendment that have just now gone into effect. And we've seen also sort of signals already sort of over summer of progression with regards to recruitment rate, which -- and with the protocol amendment, we are seeing sort of further signals. So in terms of making sure that we then, from a future perspective, as I mentioned, our ambition is to select a combination or combination doses and make a decision on moving into Phase II during 2022, that ambition sort of still remains. So with that, I think we stop there. We can move to Slide 23 for the sake of the argument. And open up for Q&A if there are any questions on the line.

[Operator Instructions] And our first question comes from Joe Pantginis from Wainwright.

Gentlemen, so a couple if you don't mind. So first, glad to hear that you're doing these enrollment initiatives. And beyond Korea, first wanted to ask where else you might be seeing initial movement as a result of your efforts.

I think that's sort of one of the things that we have seen or am I -- can you hear me, Joe?

I can.

Yes. Sorry, I wasn't sure whether I was muted or not. I think primarily, the summer is always a difficult period and especially so we have 3 countries where we do. We have U.K., Spain and Korea. Spain is more of a sort of summer challenge where we are anticipating to see a bit more movement in September now with the change of the protocol amendment. So where we've seen primarily is that a really good sort of pace in Korea and also a bit of movement in the U.K. And we're getting sort of quite good feedback on sort of adjusting the protocols to include third-line patients. Because we've gotten feedback that sort of we've been a bit too strict in that sort of second line population because there are actually quite a few third-line patients who are doing quite well and they're quite sort of healthy, sort of if you want to call it that way, that we've sort of -- they've been unnecessarily excluded. And there, we've seen sort of kind of patients who are eligible and potentially waiting to be included as we sort of adjust the protocol.

Got it. And actually, that's a very good segue to the second part of my question. So regarding the third-line patients then, it does sound like you might have sort of, I mean, how would we call it, a strict window to be able to get a patient enrolled in time before they advance rapidly.

No. I mean, sort of we're including third-line patients, and we have the same sort of -- what's the word I'm looking for, sort of all the other elements with regards to how healthy they need to be and their liver disease, they all remain the same. So they still need to be sort of reasonably healthy from a liver disease perspective in order to be included in that third line setting. But no other specific restrictions regarding to the third line population. But we've had that discussion with the of the investigators and the safety review committee, and it was felt to be unnecessary basically in terms of the population that they are seeing. What we have done, and I think that could be worth noting, is that we do have in the protocol the possibility of restricting the third-line patient population in terms of numbers, especially for the expansion phase in IIa. So we want to make sure that we don't have a too big of a third-line population for the reason that you are sort of a little bit alluding to, they might be sort of progressing too fast. So we want to make sure that we have a good balance. And we've made sure that in the protocol, we have the opportunity then to sort of restrict that third-line population. But for now, I think it's important to get -- establish the combination dose with a focus on safety element. So I think we might be a bit more liberal in that sort of balance between second and third line in the dose escalation cohort, which is actually quite normal in the dose escalation phase. Makes sense?

Got it. It does. That's very helpful. And then just lastly, I guess, a logistical question, depending on what you're willing to share, maybe for Magnus, too. But what your next anticipated milestone payment might be from IGM and potential size?

Magnus, do you want to take that one?

Yes. Thank you. And I think that's -- thank you for the question, Joe. And as I think that Fredrik mentioned is that IGM is really driving all this clinical study. But as Fredrik said, they're recruiting patients now to go plan for cohort in the dose escalation phase. So hopefully, it will not be that long, but we don't know that. IGM is in the driving seat for that study. But so far, so good as we see it.

So maybe it would just be like an enrollment-based milestone that would be the next trigger?

Triggers could be a next phase. I would say the next phase will be a trigger milestone in the developed phase. So -- and we don't know when that phase will come.

And our next question comes from Richard Ramanius from Redeye.

Guys, I also have some questions. Maybe I can continue on the same line as before with the third-line patients. So I was just wondering what kind of treatments will the third line patients have had before? What first line, what second line will they have had?

I think one of the things that we have seen, and I didn't touch on that before, but one of the things that we have seen, which is also a little bit of a trigger is that there's been a change in the HCC landscape, i.e., atezo-bev has come in as sort of clearly the standard of care. And -- but it's equally then we've seen that sort of the -- there has been and still are patients who were not able to receive atezo-bev in their first-line setting maybe because sort of atezo-bev wasn't eligible when they started or due to reimbursement, et cetera. So one of the things that we've seen is that the new patient may have received a TKI mono in that first-line setting. And then in order to ensure that they receive atezo-bev, they get atezo-bev in second line. So that's a flow that we have seen, has been of interest to make sure that while just because they moved that way, they're not excluded from being included in our study. Because those patients are many times can be quite sort of healthy, if you want to call it that way, as they come out of that second line.

Okay. It makes sense. But do you think all patients that will be part of your [indiscernible] have received [indiscernible]?

I think it's quite likely that set of patients -- they may not have gone sort of exactly that sort of stepwise route with sort of first maybe a single TKI and then atezo-bev in the second line. But with regards to -- and sort of there is -- we do believe that sort of most patients who enter our study, they will have received the atezo-bev combination either as a first line or maybe as a second line. I think that seems relatively clear these days. Maybe there are pockets in the world where that combination isn't yet reimbursed. And therefore, there might be -- there might be a challenge. But most patients will have received the atezo-bev combination either in first or in second line.

Okay. Yes, that makes sense. So I was thinking about to make comparisons logical about -- with the benchmarks, if it might affect that if you have 2 different combinations of second line and third line, if you want to compare your results with a benchmark.

And I think that's something that we're going to need to watch for. And I think that's why sort of, if I go back to my previous comment, we've been quite sort of, in those discussions in terms of expanding into third line, there have been many -- or allowing third-line patients to be included as well, that's why we've been quite conscious in the discussions with the investigators and looking ahead to make sure that we are able to sort of restrict that sort of third line percentage or cohort as we move into the expansion phase. I think at this stage, when we're looking at safety, just establishing the combination dose, et cetera, then it's not as important to put it that way. It's more about the safety. How are the combinations? How are they working? What dose is not kind of providing DLTs, et cetera. So I think in this phase, less relevant or less important if I want to call it that way, where is in that expansion phase? Yes, that is an element that could be of relevance. But then that's why we also put into the protocol the ability to sort of restrict that population to ensure that we don't land with a challenge with regards to comparison.

Yes, that absolutely makes sense. And I was thinking about another thing concerning the design of this study. Will you distinguish between first line responders or nonresponders and then progress because I was thinking if someone -- if a patient responds to checkpoint inhibitor and then relapses, maybe that's -- maybe they'll respond to another type of checkpoint inhibitor that might influence results.

Yes. And that could be the case as well. But I think in terms of this -- in this -- that's a bit difficult for us to -- how should I put it? Since we are allowing sort of physicians to choose ARM, i.e. sort of they sit with the decision as to whether a patient should go into the Lenvima-fostrox arm or the pembro plus fostrox arm, i.e., they will draw, okay, what have the patient been on before and then they treat it accordingly. So I mean, what we have seen is that it's not -- how should I put this now? It's relatively logical to a patient that comes out of an atezo-bev combination, it's relatively logical to put that patient on Lenvima-fostrox for sort of mechanistic reasons, et cetera. Similarly, if you come out of a TKI-based treatment, then it would be logical to put that patient on a sort of pembro-fostrox solution. So -- and that's a decision that lies with the investigator. Does that make sense?

Yes.

I mean as we go forward and we start to go into expansion phase, et cetera, then you get to a point where maybe you can start to explore, okay, what are there different sort of patient types coming out of first line that might respond differently, et cetera. But at this stage, the important thing is establish a dose and then move to expansion phase just to make sure that we see the signals that are needed. And then in IIb, then we can start to explore sort of those types of details, I would argue.

Concerning this Phase IIb, is that the IND that you will submit in 2023? Is that the Phase IIb trial?

Yes, the U.S. plans for an IND are there to not to include U.S. sites in the current study, but to sort of make sure that the U.S. sites are eligible to participate in the IIb, yes.

And that will not be a potentially pivotal trial, I guess?

Well, sort of we are planning -- we have to plan for success. And we are planning for an outcome where we have overall -- we see an overall response rate in that sort of IIa expansion phase that could potentially signal and then warrant sort of the IIB to be sort of a potential for accelerated approval study. So and that -- so in that IIb study, we would then sort of -- maybe sort of hopefully instead of show overall sort of overall response rates in the IIb study, that will be good enough for an accelerated approval in the U.S. or conditional approval in the EU. That's our aim, and I mean it depends a little bit on how the world is moving. But again, going back to LEAP-002, we're not seeing a wealth of combinations or other data sets that are sort of making the unmet need lower, on contrary sort of. So if there's an opportunity to show, let's say, overall response rates of 25%, 30% in that second-line space with a combo, that's quite an attractive ORR. And that ORR in the IIb study, unless something happens between now and then of significance, I would argue that, that would enable a potential accelerated approval. So that is still our aim.

Yes. Sounds like a good plan. And I guess that would probably -- surely be much smaller studies than the KEYTRUDA LENVIMA first line that failed if you could do it in groups with even higher unmet need in later lines.

Yes, I think we can. That we can speculate on, and we can sort of clearly sort of hope for it from an accelerated approval. Usually, those studies are a bit smaller, yes. But there's also -- I think that in terms of study design and the size of study is dependent on sort of assumptions you make regarding sort of what effect size will you see and power do you need. And we will need to see a set of -- we need to see the IIa data before we may draw any sort of conclusions on size of population in that. I don't know, Fredrik, if you have any further sort of you would like to add on that note. I think it's too early to say. It would be my general comment. But anything else, Fredrik?