Genmab A/S (GMAB) Earnings Call Transcript & Summary

Yes. So you just hit the nail on the head. We -- when we assessed the time advantage of filing frontrunner for second line vis-a-vis OS, there was minimal or no time advantage. So there was no reason to have 2 filings 1 month apart. So we decided to allocate all the alpha to OS and have a study that can support full approval in a global manner rather than do 2 cuts to gain 3 weeks didn't make any difference. And of course, the huge unmet medical need and the larger opportunity is the first line. The second line commercially is a much earliest opportunity. Still we could benefit patients and the data is strong. But we -- the data from the Phase II of peto-pembro could transform -- the landscape of head and neck treatment.

Got it. Very helpful. Maybe just in terms of how are we going to see this data? And how should we be thinking about the top line readout for the first line, more importantly, but also the second line? Should we expect any patient subpopulation information? Or is it more going to be like, oh, the study is positive primary endpoint and that's that?

So we will operate according to standard in industry, which is we will have the data we will share with -- because it's material top line data, we will engage with health authorities. And in parallel, we will plan for a full disclosure at a medical congress. And this is pretty standard.

Got it. Should we be expecting the full disclosure before the overall survival?

We haven't guided yet on when overall survival could come because we don't have these projections firm enough to communicate. So as soon as we have this, we will communicate. So I cannot say because we don't have a firm projections.

Got it. Maybe just touching upon the locally advanced opportunity. I mean, how do you see that opportunity for peto in head and neck? And how does it compare given competitive landscape?

In head and neck?

Head and neck.

So we think that PO will have not only time advantage in being first in line for the first line, but has the opportunity will be best-in-class as well. So based on, again, cross-study comparison are never very clean. But when we see the data of peto-pembro versus ami-pembro or Fizera-pembro in terms of efficacy, overall survival, safety, convenience, we see as a very, very attractive value proposition potentially for first-line patients with head and neck.

Got it. Maybe just touching upon the competitive landscape. Does the potential approval of amivantamab in later-stage head and neck impact your strategy for peto at all?

On the contrary, I think that -- so we know that J&J filed and will get priority review, but this will be accelerated approval on the second line plus second, third line, whether the Phase III for the first line will provide the approval on the first line. So it's something will strengthen the hypothesis of EGFR bispecifics, but they are not in direct competition. And we have a very important time advantage vis-a-vis OrigAMI-5, which could potentially will lead to the approval of Ami in first line. In addition, it's a separate strategy. We chose to go with a chemo-free because of the depth of response and the superiority of this combination vis-a-vis chemo or chemo pembro. So it's different, and we will be like 2 years ahead, which is massive.

Got it. And maybe just based on your diligence with physicians, what percentage of patients get treated with -- right now in first line with like pembro alone versus pembro and chemo? Is there any specific patient population that benefits?

Yes. It's a great question. So we -- there is a Flatiron real-world evidence published around 3 years ago, and this is after KEYNOTE-048, both arms were approved 6 years ago that showed 2:1 pembro alone to pembro versus pembro chemo. Of course, this is published 3 years ago based on the U.S. Flatiron data. But when we talk to sites or investigators, it's very individualized based on CPS, frailty or comorbidities of the patients, tumor size or speed of tumor growth. And for example, if the patient is CPS above 20, more likely pembro alone than pembro chemo. If the patient is frail or elderly, more likely, many patients are tobacco consumers or alcohol that have more comorbidities. So for those patients, same thing, more likely, they won't get exposed to chemo, although if the patient is young and has rapidly proliferative, we will take pembro chemo, but it's a very individualized patient and physician decision.

Got it. Do you feel like the due diligence give similar data or provide similar data in the U.S. versus the EU in this sense?

For -- I think I haven't seen the data for the EU. But when we talk with sites, they all say the same is individualized. And just remember, the chemo in combination with pembro is Carbo/5FU. 5FU is IV weekly, it's not very friendly on patients. So there is -- yes, it's an individualized patient by patient. But as per published data is 2: 1 pembro single agent versus pembro chemo.

Got it. Very helpful. Maybe just moving on to CRC. We're going to see some data at ESMO, and you presented also some data towards the end of last year. Can you just remind us what's peto's opportunity there and how you're thinking about the development strategy given that amivantamab is ahead?

Yes. So we think it's the data that showed in the EORTC-NCI meeting is very strong with an ORR of 80% in first line, independent validating by an ORR of 62% in the second line, which is unprecedented and doubles everything published and with a very solid biological foundation. peto was discovered through a library of colorectal organoids and shown in every preclinical model to overcome -- to be superior than cetuximab. So very strong data. Amivantamab is earlier, but we will present more data at ESMO that position the peto combination as potentially best-in-class, not just in terms of efficacy, but also safety.

Got it. And you just initiated the Phase III.

Two Phase III.

Two Phase IIIs. Can you just remind us which patient populations are you targeting?

So for the first line, we are combining with FOLFOX or FOLFIRI in the KRAS, BRAF wild left side patients. And for second line, same thing, KRAS, BRAF wild, both sites in combination with FOLFOX and FOLFIRI. But the comparator will be bevacizumab plus FOLFOX or FOLFIRI or cetuximab plus FOLFOX or FOLFIRI.

Got it. And in terms of the LGR5 part of peto, I guess like what's the rationale in CRC? I mean this is where, as you mentioned, the molecule was discovered, right, for this indication. What gets you confident that this is not only like a cetuximab molecule?

No. I mean -- so if you look at this paper from Eduard Batlle, it's clear that LGR5 plays a central role. So mechanistically, I mean, 2 very important things. First, the binding to LGR promotes internalization and degradation of EGFR. And in addition, in the context of treatment with peto, LGR is overexpressed and the binding of the bispecifics on LGR strengthens the ADCC and ADCP properties. And so beautifully demonstrated on those paper where in organoids, when they treat the organoids, patient-derived organoids from colorectal cancer with peto, more organoids are stopped because so the LGR is related to stem cells like. So it stopped growth and metastasis. So very strong preclinical and biological foundation that LGR is key for the activity of peto. Now the problem with LGR is that it's the plasticity. So only a few labs can measure it accurately, but it's no question that LGR and peto was discovered among 500 other bispecifics that were tested same organoids panel of colorectal cancer versus normal cells and peto was the winner, killing 100 more times tumor cells than normal cells, 100. So it's clear that LGR is the one to drive. Again, the problem with LGR is that not every lab can measure because of the plasticity of the cells.

Got it. Maybe just last question on CRC. How are you thinking about the commercial opportunity relative to head and neck?

It's much more bigger. So in terms of population, and I don't know on the top of my head, but I would say it's at least double the commercial opportunity than head and neck.

Got it. Okay. That makes sense. Maybe just with the last few minutes, just switching gears to your folate receptor alpha ADC, Rina-S. I mean you are going to read out the Phase III in the fourth quarter. I guess maybe to start, just -- we've seen a little bit of data in the Phase II, not a lot in terms of follow-up. I mean how should we be thinking -- are we just going to get the Phase III, also the Phase II? How are we going to see this readout? And how much information are we going to get?

Yes. So what we message is that we will have both Arm C, which is the Phase II with around 100 patients and the Phase III in Q4 this year. So a lot of data sets coming like pump and pump. But again, we are very confident on the data that Dr. Lee presented in terms of ORR duration, safety, convenience. So we are looking forward and very enthusiastic about the potential of Rina and PROC. And there is a time advantage because potentially Rina-S will become the first second-generation ADC to show positive data for patients with PROC.

Got it. And maybe just touching upon the study design. I mean, based on our calculations, it seems like the -- like the study is well powered to detect like around 1.5 months and PFS. If we assume control arm around 4 months, that would put it on par with ELAHERE. However, in your view, how much better than ELAHERE would Rina-S need to be?

So when you design a study or your powered, you establish your hazard ratio based on the control. Now it doesn't mean that the data will behave that way, but you need to power to be statistically positive. We know based on the data from Dr. Lee by 12 months, a single patient progress that we expect to be much more better than the minimal assumptions. But again, statistically and the clinical -- the actual data we expect that we will be -- the data will be better than ELAHERE in terms of PFS, duration of response, differentiation on safety with no ocular toxicity or the burden on patients to have this visual test and potentially the double indication in the future for endometrial and nonselective for folate receptor. So we expect to be really differentiated and superior.

Got it. And in terms of like the folate receptor high versus low patients, based on the data we have so far, are there any signs of difference in efficacy?

So what we showed is that in the 20 patients for ovarian in the high, the response rate was 5 out of 6 versus 5 out of 10 in the low. But still, 50% is very good with consistent durability across the board. So this is why we don't believe there is a need to enrich or to have a test that both another burden on patients. So the strategy is in all comers because the efficacy that support it.

Got it. And given that ELAHERE is approaching blockbuster status, how should we be thinking about Rina-S' commercial opportunity given we've seen so much better efficacy in the Phase II?

So thank you, Eva, for the question. So today, our estimate for Rina-S is 2 billion peak sales and the $2 billion include all the [indiscernible] Opportunities, PROC, PSOC and endometrial. So -- but we expect to serve a very -- so today, it's like 27,000 patients in the U.S. with PROC. But again, and this is the number that we estimate for now.

Got it. And based on the early data you have in endometrial and what we've seen for other -- for the receptor alpha ADC in PSOC, like how should we be thinking about indication expansion and Rina-S' progression once we get the PROC?

Yes. So I think that the breadth of the clinical development plan is -- so we started with PROC and endometrial 03, which is after PD-1 and chemo failure. We expanded to PSOC in second-line maintenance and replacement, and we plan to expand even further in both indications, ovarian and endometrial to cover every setting where Rina can help and to position as the ADC of choice.

Excellent. Well, this was incredibly helpful. Thanks so much for joining us today.

Thank you, Eva. Thank you.