Scholar Rock Holding Corporation (SRRK) Earnings Call Transcript & Summary

Good morning, and welcome to Scholar Rock's call this morning to discuss the SRK-181 data presented at ASCO yesterday. Before we begin, please be reminded that members of the Scholar Rock team will be making various statements about the company's expectations, plans and prospects that constitute forward-looking statements for the purpose of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Any forward-looking statements represent the company's views only as of today and should not be relied upon as representing views as of any future date. Please visit the Investors and Media section of Scholar Rock's website to find the most up-to-date SEC statements and filings. Now I would like to introduce Scholar Rock's Chief Executive Officer, Jay Backstrom. Jay, please go ahead.

Well, thank you, Officer -- operator, and good morning. Turning to Slide 3, it's such a pleasure to have you join us today. It's a very exciting time at Scholar Rock. As we shared last week at our investor event, the focus of today's call is to review the [indiscernible] data from our DRAGON study, evaluating SRK-181, our highly selective inhibitor of TGFß1 activation in combination with pembrolizumab, which we're being developed to overcome primary resistance to checkpoint inhibitor therapy in patients with advanced cancer. Moving on to Slide 4. I'm joined this morning by Jing Marantz, our Chief Medical Officer. And on Slide 5, we're very fortunate to have Dr. Toni Choueiri with us today. Dr. Choueiri is the Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, co-leader of the kidney cancer program at Dana-Farber Harvard Cancer Center and the Jerome and Nancy Colberg, Chair and Professor of Medicine at Harvard Medical School. Dr. Choueiri is an internationally recognized expert and researcher in renal cell carcinoma. Turning to Slide 6. For today's agenda, Jing will review the SRK-181 data that was presented yesterday as part of the oral session in Developmental Therapeutics immunotherapy at the Annual Meeting of the American Society of Clinical Oncology. Following Jing's presentation, we'll have a discussion of the data with Dr. Choueiri, then we'll open up the call for questions. I'll now turn the call over to Jing to provide a review of the updated data. Jing, please take over.

Thank you, Jay. It's my pleasure to share with you the updated results on 181. Now turning to Slide 8. As Jay mentioned, the updated results were presented yesterday afternoon by Dr. Alka [ Vahanian ] at an oral session of ASCO. So turning to Slide 9. A brief note about the mechanism of 181. It has been well established that TGF data signaling is involved in tumor immune escape and resistant to checkpoint inhibitors. 181 is designed to improve the therapeutic index in 2 specific ways. First, the selectivity specific to the beta 1 isoform is designed to avoid off-target toxicities seen with beta 2 or beta 3 signaling. Second, the contact independent actions allow 181 to address all of the compartments of the tumor microenvironment and therefore, maximizing efficacy potential. Now turning to Slide 10. Here, you can see the schematic of the Phase I study design. On the left of the screen, we have Part A dose escalation as a single agent on top left, and in combination with pembro on the bottom left. Part B, which is shown on the right is the dose expansion part of the study. The purpose is to confirm the tolerability of the recommended dose and also assess antitumor activities of the combination. Part B included 6 parallel cohorts of specific cancer types. To be eligible, patients must have locally advanced or metastatic cancer for which standard of care is either not available or has failed or is not tolerated. Patients must have had at least one prior anti-PD-1 therapy, for renal cell and head and neck cancer patients must have progressed on the most recent PD-1 therapy and the rest of the cohorts enrolled patients who are refractory to all the prior anti-PD-1 therapies. Now going to Slide 11, 181 is reasonably well tolerated with the recommended dose with Part B determined to be 1,500 milligram dose every 3 weeks or 1,000 milligram dose every 2 weeks. Some early signs of efficacy was seen as you can see on the right-hand side, we have 3 ovarian patients with stable disease greater than 6 months following the single agent 181. And we also saw additional 5 patients with stable disease lasting longer than 4 months with the combination of 181 in pembro. Now going to Slide 12, it summarizes the key baseline characteristics of the patients enrolled on the left and the disposition on the right. Overall, the median prior lines of therapy received for these patients was 3, all of the patients have already received a prior anti-PD-1 therapy as mentioned before, all but one patients were refractory to PD-1 therapy. With the exception of 2 melanoma patients, all the other patients had progressed on their most recent PD-1 therapy. A total of 78 patients were involved, 10 patients still on study of those who discontinued approximately 22% was due to AE, 12.8% was due to treatment related to AEs. Moving on to Slide 13. This is a detailed look at the specific treatment-emerging adverse events. Most of these adverse events as you see are dermatologic in nature, including rash and pruritus. And other AEs included fatigue and some low instance of GI side effect in liver enzyme elevations. Serious adverse events are primarily rash. There was one treatment-related grade 4 as exfolliative generalized dermatitis and 1 treatment-related pemphigoid that is considered immune related, which is mechanisms of the base, so it's not entirely surprising. Importantly, there's no treatment-related Grade 5 adverse events reported. Moving to Slide 14, which I will show you several slides on the efficacy in specific cohorts. Let's start with the clinical responses in melanoma cohort. On the left, we have the butterfly chart, to the left is the vertical access, you can see the purple bars represent duration of treatment on the prior most recent PD-1 therapy. The green bars represent the duration of treatment on the 181 pembro combination. It's quite clear that patients stayed on the 181 pembro much longer than they did on their prior most recent PD-1 therapy. Of the 11 enrolled melanoma patients, we saw 3 responders, including 1 complete responder with duration response approaching 5 months. Also notable in the middle is the -- that over 70% of the patients had stable disease or better, that's illustrated by the waterfall chart in the middle of this slide. The CT scan on the far right shows the tumor shrinkage of a metastatic lymph node highlighted by the yellow circle. Going to Slide 15. You can see the results in urothelial cancer. Of the 11 enrolled patients, we saw 1 partial response with impressive durability of 12.9 months. The waterfall chart in the middle shows that close to half of the patients had stable disease or better. The CT scan on the right -- far right shows an impressive tumor reduction of a metastatic long lesion. Moving to Slide 16. We see the results in head and neck cancer. The butterfly chart on the left shows 2 out of 11 participants had partial response with durability of response greater than 2 months to date. The waterfall chart in the middle shows approximately 1/3 of the patients had stable disease or better. And the CT scans on the far right shows the near complete shrinkage of a metastatic lung nodule. Going to Slide 17. You can see the results in clear cell renal cell carcinoma, where we have the most mature data. A total of 30 patients were involved. Seven responded with durability response to 7.7 months. The butterfly chart clearly shows that patients stayed on the 181 pembro much longer than they did on their most recent PD-1 therapies. The waterfall chart in the middle shows the slight majority of the patients had stable disease or better, 56.7% to be exact. And the CT scans on the far right shows tumor shrinkage of metastatic lymph node. Now moving to Slide 18. We started to show you the impressive biomarker data the team were able to gather. Paired biopsies pre and post treatment were collected and data from available samples were analyzed and presented here. The panel on the left shows that the combination therapy was associated with increased infiltration of CD8 plus T cells into the tumor compartment across multiple tumor types. With the amount of the CD8 infiltration before treatment shown in light blue bars, and the value after treatment in dark blue bars. The middle panel analyzed pair biopsies before and after treatment, and the results show that the CD plus T cells were activated in patients with partial response shown in orange and stable disease shown in gray, the patient with progressive disease was shown in black. The panel on the far right shows that the CD8 plus cell activation correlated with the degree of tumor shrinkage. Taken together, these results collectively suggest that 181 pembro combination creates a pro-inflammatory microenvironment. The next slide is Slide 19. You can see the biomarker results in the ccRCC cohort where we have the most mature data. The vertical access of the 2 spider plots represent the percentage of tumor reduction and the horizontal access is time expressed in months. The spider plot on the left looks at the baseline CD8 infiltration status. It's clear that the -- those patients we see an infiltration shown in green, have a higher level of tumor reduction. And the spider plot on the right looks at the baseline regulatory T cells or T reg, where a similar trend they've seen, those with elevated baseline T reg cells appear to have a higher level of tumor response. For the ccRCC, patients with CD8 T cell infiltration or elevated T reg levels, the response rate is nearly doubled from 23% to 40% to 50% and the durability of response also improved from 7.7 months to either 9.3 months or 9.8 months. So now to Slide 20. In summary, the 181 pembro combination has resulted in antitumor activity across multitude of cancer types with encouraging durability of response. The results are particularly promising in ccRCC where we have the most mature data. Biomarker results established a proof of mechanism for 181 with baseline CD8 infiltration and T reg value as potential basis for patient selection. So to conclude, on Slide 21, the level of antitumor activity in PD-1 resistant patients are promising, and the combination is generally well tolerated. These data were in further investigation in 181 and the biomarker results not only establish proof of mechanism, but also provides valuable information about potential patient selection strategy. And with that, I will now turn it to Jay to facilitate the next segment of the call.

Well, thank you, Jing, for such a nice overview. And now shifting to Slide 22. We're on the portion of the agenda, which I'm really looking forward to, which is a conversation with Dr. Choueiri to kind of give us his opinion on the data and to help us understand the role that SRK-181 could play in clear cell renal carcinoma. So now we're on Slide 23. So Dr. Choueiri, the design of the DRAGON study was intended to demonstrate a few things. It's a Phase I study, proof of mechanism. We wanted to demonstrate that through the biomarker strategy and to identify cohorts that we thought would generate a strong enough signal to allow us to advance. So maybe first with respect to the mechanism, the proof of mechanism data. What's your view of our CD8 T cell infiltration and do you believe that we demonstrated proof of mechanism with the DRAGON trial.

Well, in short, Jay, first, good morning, everyone, at least it's morning where I am. I think this data is compelling. I think in the subset that you have shown, there is a proof of concept in term of CD8 T cell infiltration. The data is very intriguing here. You're doing something to the tumor micro environment that is favorable in terms of CD8 T cell increase and this interaction between CD8 T cell and T reg. And that is your best responders overall. So I think this is spot on and all what you can do with data like this, that is the first I've seen in clear cell renal cell cancer.

Very nice. And then the other thing Dr. Choueiri, as we look at these data, it's a common question that we receive is we're seeing these response rates in the 20-some percent range, and actually, we doubled that -- we have a selection strategy. But how confident can we be that these data -- these results are driven by SRK-181 and not just related to continuation of pembro.

I mean that's a good question, it's a normal question. And I would say probably before a RCC specific randomized clinical trial, the question would be, I don't know what's reported was all over the place from retrospective studies or from other tumors. But not long time ago last year, we had a study where patients with clear cell RCC, who experienced at some point, disease progression on the checkpoint inhibitor being the last therapy were randomized to receive the TKI cabozantinib or cabozantinib and atezolizumab, which is not used as a first-line therapy. And that study was largely negative. When you look at the response rate, PFS, it only increased the risk of side effects. So this is the rechallenge paradigm where A plus PD-1, PD-L1 versus A has sailed. Now you could argue this was a PD-L1 inhibitor -- I don't know. I don't think this is true. We have a second study that is the same sister study with a different TKI cell mechanism B plus PD-1 versus [indiscernible] plus nivo [indiscernible] That study is called TiNivo-2 and will answer again this question.

So basically from these results then, if we were to go forward with the selection strategy that we saw that really looks like we could double the response, how compelling do you think those data would be in light of the current options for patients with second, third-line therapy?

I would think it will be very compelling. I think overall, I have to say that 20% -- would you see 20% with pembrolizumab alone, if your less immune checkpoint inhibitor, you did experience progression on most of the patients under spending from reviewing data we received nivolumab. Now I would say you do not have that such response rate because other therapies that are totally over like newer CKI like tivozanib or even [indiscernible] was approved in December of last year, had a response rate, 18% to 20%. So to see it with a drug, a class of agent that is quite similar that you've been on before an experienced disease conversion is very unlikely, especially in the light of contact free. Add to that a biomarker strategy and focus my career on biomarker, I think this will be quite attractive.

And then finally, as we're really kind of leaning in you saw across the cohorts, the signal with clear cell renal really seemed to raise its hand. I mean it was almost from the beginning as we saw this data. But maybe as you give us some sense of how do you manage these patients with clear cell renal who were first line, second line, what are the current options as we're thinking about a path forward for 181?

Well, that's good. I do love always for my patient to stay alive as long as possible with acceptable quality of life, so that one day, folks smarter than I come up with a cure. When I trained 2006, 2007 or even a bit before the median survival was the year from kidney cancer. We're talking metastatic. Now it's 5 years plus. And that's because although I would argue that very few therapies have achieved a complete response that is durable over 10%, 15%. This is -- the fact is that we had classes of agents that we sequence that work well. PD-1, CTLA-4, obviously, VEGF TKI and multiple, some more important than other. And most recently, in December, there was a [indiscernible], which is a [indiscernible] inhibitor, a study that show a response rate and progression-free survival, but not yet, I would say, or overall survival benefit. So this is important. So besides PD-1, CTLA-4 and [ HIF2 ] and the CTLA-4 is really restricted to first line with ipilimumab, not alone in combination with nivolumab. And HIF2, I would love to have like other like lung cancer, breast cancer and other target. So having a drug that is selective TGFß1 antagonist, where the development was based on a very thoughtful methodology. That incorporates I would say, not just the science but the backup plan, where if one size does not fit all, you have a selected biomarker studies, that's very, very attractive. And I think will be very attractive to patients. The other thing, if we're trying to say that the combination of 181 plus an immune checkpoint inhibitor will lead to responses, it's possible that the quality of those responses because this is immunotherapy is very, very good and durable because we achieved durable responses when we harness the immune system the most or at least in renal cell cancer. So that makes it really quite attractive to patients.

Yes. Very good. Again, the intent of DRAGON was to demonstrate proof of mechanism, TGFß1 plays such a strong role in creating that immune suppressive environment. We believe we hit it on target. And it sounds like being able to have this continue potentially to be part of a future therapeutic option for you would be appealing in light of the current therapies.

I do agree it will be appealing to move to a next stage and bring it to patients. We have to -- like everything, there is no guarantees. I'm also, I would say, somewhat relieved with the side effect profile. I'm not an expert at least yet in just TGFß1, in fact, [indiscernible] in what to do. But based on the pathway overall and based on trying to reset the immune system, especially in term of immune resistance, I think this is quite reasonable to go to the next level. And I hope Jay, that we continue getting more follow-up to look at additional responses, perhaps just simply because some of these responses, especially the immune system and [indiscernible] come late to look at durability and to look at potential side effects can emerge later. That's going to inform the next study.

Yes, very good. And for those on the call, if you didn't have a chance yesterday, the discussion too is reviewing the oral abstracts that Dr [ Brona ] did a very nice job of reviewing the history of TGFß1 and really highlighting again, with things that we've been saying repeatedly at Scholar Rock, selectivity matters and reviewed that prior efforts had bleeding events, had events on the [indiscernible] cardiac events because you're hitting TGFß2. So the selectivity has really translated it seems from our data to date, and we certainly will continue to follow up. All right. Excellent. Well, this has been good fun. Dr. Choueiri. We certainly will want to continue the dialogue with you. For those on the call, we're going to then proceed now. I'd like to open it up to question and answers.

[Operator Instructions] The first question comes from Allison Bratzel with Piper Sandler.

Congrats on the update. Two from me. First, could you update us on where things stand with FDA? I think you're planning to hold end of Phase I discussions with the agency to help determine next steps in development. So just wondering where that stands and how you plan to communicate that -- and then. Go ahead.

Go ahead, Ali. No, no, please.

Yes. I was hoping you could describe in more detail with derm-related AEs seen in the trial. I know this came up from the discussion yesterday, but hoping you could talk to kind of how this differs from PD-1-related derm AEs and just like potential mitigation measures you could employ going forward.

Yes. So first, with FDA, as we signaled even when we closed out the trial last year, I mean, we thought at the time that the data we're worthy of proceeding to an end of Phase I meeting with FDA but we're continuing to follow. And Ali, to the point, which I think we were absolutely delighted that we were selected for an oral presentation. That continued follow-up data further strengthens our conviction. So that's still planned. We're updating our safety data to be sure that we have a full briefing book in front of FDA, plan is to get in front of them sometime Q3 this year. So that's definitely on track, clearly, a plan for us to continue. It's very critical, as you know in next steps with making sure that we're aligned with FDA on our dose and really how we manage the next, what we'll anticipate to be a randomized study. And with respect to the skin toxicity, very interesting, right? The very first event that we saw was the exfoliative dermatitis. And that really caught our attention because, frankly, that's on mechanism. right? We're firing back up the immune system. And so you look at that, while it was extreme, and we certainly don't want to have it to that extent, it definitely got our attention early on that we thought we were on mechanism with this. What we've seen over time is that there are mitigation strategies to manage in the derm effects. We had very few patients actually drop. We did have, as you heard yesterday at the discussion at the oral abstract that we did have to interrupt dose to some extent. We're thinking very carefully about how we do that, and we may need to consider a little bit of modification on the dose as we go forward. But at the end, I think these are really well managed and have the opportunity to really progress nicely. But very interesting because we did think it was a bit on mechanism. Certainly, you have such events in checkpoint inhibitors. You've seen it in other IOI or combination CTLA-4, I think, most notably. But I think as we put those into context, the discontinuation rate is really quite low, all things considered. And so we believe that this is very manageable. And importantly, as I mentioned earlier, we're not seeing the effects that have historically plagued targeting this pathway. I think it's another validation that our selectivity really gets around the challenges with all the complex biology with TGF-beta biology and now we're really dealing with IO mechanistic basis which, again, in the end, that's the goal to really try to restore the immune system.

Please stand by for the next question. The next question comes from Michael Yee with Jefferies.

Thanks, Jay, for the review. Maybe 1 or 2 questions on the data. Question number 1 is do you believe or are you surprised about the results in renal cell as opposed to seeing more responses or more activity in some of the other cohorts you ran, which are also immunosensitive, why do you think you saw so many responses here? What do you think the hypothesis is going on there? And the second question is, Jay, you made a comment about prior TGF beta issue, but my understanding was that prior studies sort of just failed in randomized controlled studies. So is your point that you're just choosing a subgroup and you're actually going to implement that, and that would improve your probability of success?

Yes. So maybe, Michael, maybe I'll start with the latter point. I think there was 2 things that I think have plagued, I think, the TGF-beta field principally toxicity early days. And so that's the historic reference where I do think selectivity matters. I agree with your point. I think if you look at some of the prior approaches, they did -- were not as successful as one would have hoped. I think in part, though, as we look at it, our approach is different. Some of these were bispecifics. And when you look at the bispecifics, you're tethering the TGF beta to the PD-1, PD-L1 and so what we recognize is there's a geometry sort of the spatial difference within tumor that you're not having to tether, I think, having individual components to this, I think, matter. And I think we're seeing very nicely a very, very strong signal here, particularly with the durability of effect. Now when you go back to the cohorts, it's very interesting, right? When I joined in 2022, I took a look at the trial, and I thought, I think renal is likely to be a strong signal given what we know about renal. And we have Toni here who can give us a commentary around it. The one thing that's really interesting, right? The scientific rationale was that we thought that we could drive CD8 T cells into tumors and turn a cold tumor hot. We've seen that. We've shown that with melanoma. We've been able to do that. What Dr. Choueiri has advised us, early days and what the literature I think, has supported is that renal is more of an inflamed tumor background. You tend to have that. And what's interesting is, and I think this is where we were very intrigued by and very kind of optimistic around the selection strategy because it's on mechanism. You've got CD8 T cells in the tumor that are kind of in this immune suppressive environment. We blocked TGFß1 and we kind of restore it. And maybe Dr. Choueiri will give you to make a comment to that point.

No, absolutely. I think this is a very good question. I asked myself that like other immune-sensitive tumor, immune sensitive could be a lot of things like melanoma. And I would say renal cell is quite a different disease, perhaps at that time, the CD8 T cell and melanoma were completely saturated. I'm not talking numbers, but function. Where in renal cell cancer, this is the tumor, the solid tumor that is most by far CD8 T-cell infiltrated. But at the same time, the CD8 T cells don't work well. They're exhausted, maybe perhaps a small increase in CD8 T cells, coupled with CD8 T cells that are more active are doing the threat. I'm extremely intrigued by this interaction with T reg, which is the other spectrum of the immune response. And we're trying to see here if we can come up, perhaps with the ratio, T cell, T reg to interrogate to the next level. But that would be quite interesting. And the value when you do even smaller studies and can obtain biopsies pre and post.

One moment for our next question. The next question comes from Etzer Darout with BMO Capital Markets.

Great. Just a couple of questions, Jay, Jing. To what extent does the ccRCC biomarker data translate to maybe other tumor types that you evaluated? And then also, I guess, what's your expectations for patients, CD8 and T-reg biomarkers that baseline in pre-PD-1 setting in RCC? And could you envision a combination in the PD-1 sensitive population that could also maybe drive further responses in that setting.

Yes. Good question, Etzer. Maybe I'll start. It's really interesting. I think with my general sense of IO-IO combinations or just IO in general that one fares better, the earlier line of treatment you could proceed. And so clearly, it would be something that we'd envisioned going earlier. Now whether or not we would need a selection strategy at the beginning versus what we would need in the relapsed refractory setting. It's a really good question. And I think certainly, part of our plan is to further refine this biomarker strategy which we believe really could be very interesting. You saw a doubling of those responses, would be very interesting in this setting of having failed, right? Because it's identifying a different subset.

Correct. So what I want to add is, first, if we identify the biomarker it's obviously in tissue, we need a biopsy or we need tissue that is not too old. Should we do a CD8, T reg, a combination of both. We're looking at that. And what's the percentage of those patients. Actually, it's a substantial part. It's not like 5% of everyone. So that's one strategy. Then what do you do? And we have other outside renal -- these randomized studies where the primary endpoint where like 2 co-primary endpoint, if you want. One is the total population, one in biomarker because at the end of the day, you don't also want to miss -- especially if your biomarker is good and good enough, but not perfect. You don't want to deny other patients' therapy. And the third thing always I wish and I think we're looking into that or we have the blood, if there's something we could do in the serum or plasma that really reflects what happened in the tissue, that could be easier and easier. I think in the past, if you tell me 10 years ago, that's [indiscernible], let's get the tissue sometimes accrual, maybe slowed down, less so now. But imagine if you have also a blood test. So I'm personally from a scientific, I would say, interest, quite intrigued with this possibility if we -- if the company decides to move forward.

Yes. So good points. And then to kind of wrap back up. So we certainly have -- we are continuing, continuing to evaluate the baseline data and on study data to really understand how translatable this is across the cohorts. As you know, we were advantaged in clear cell renal because the signal was early, we have the most cohort we could really evaluate it. We're continuing, Etzer, to look to see whether it plays a role across. But it likely will. But at this point, premature, we're going to look into it. And then to add to Dr. Choueiri's commentary, clearly, as we go into -- the plan would be to socialize this. And of course, we're going to talk later, this is clearly a program we'd be the beneficiary of a partner as we go forward. But as I would envision, just drug development in general, the plan then would be to see whether or not we couldn't amplify this signal for the biomarker selection and to continue to see if, in fact, there isn't something other than tissue that we would need to do. Those are all planned in what we would consider and discuss with FDA on the next steps. But very, very exciting. I mean, from us, to be honest. I think this is -- you think about what Dr. Choueiri talked about, patients progressing, alternating between therapies, coming in here, failing and we're able to restore that. Moving that upfront, I think would result in far more durable responses potentially. The quality of that response that you talked about, Dr Choueiri, so that would be ultimately the goal. But one step at a time, and the first step is DRAGON, I think, delivered.

One also thing. One also thing is I'm asking always the company to get more and more data on biomarkers, et cetera. The one I want to mention, these are not the typical, these are activated CD8 T cells. So granzyme B positive, not the regular T cells that could be a bit in [indiscernible]. And that's the one that's associated with tumor shrinkage. I think next step is looking again, hopefully, with a bit more patient if they are to happen and their interaction with T reg and why it happened in renal. But just as a reminder, renal is a bit different disease. So that's why it's a different disease compared to other, for example, you take any tumor and you look at general CD8 T cells, and it predicts good prognosis, meaning disease-free survival, overall survival, better. In renal cell cancer, it's a bad prognosis. This is irrespective of therapy or anything just in general, throwing it. So it's a bit different. This is why how the drug works here, especially in renal cell could be based on how renal cell and immunology, the PD-1 inhibitors are active in renal cell. It's not a viral mechanism, it's not a TMB mechanism. It's not just the regular CD8 T cell. It's not PD-L1. It's different. Things are different. It's some signatures that we came up with and others, but it's different from others.

The next question comes from Gary Nachman with Raymond James.

For the various cancers, especially renal cell, what's the addressable market if you assume it's only used in those selected patients with high CD8 infiltration and high T reg levels, I think you said it's not small, but maybe just quantify that. So that's the first one.

Great question. So it's a bit hypothetical. So we have to start. Usually, we start the drug development unless it's a vaccine or something in refractory population, okay? The question is if we have activity in a randomized setting, then you move earlier and earlier. And I would say the number of patients, the percentage of patients with kidney cancer gets higher and higher. The other thing where I think this is reasonable in terms of percentage of patients is that the prior therapy, I quoted you initially median survival went 1 to 5 years. But even on PD-1 and VEGF and HIF2, our patient, unfortunately, their tumor experiences disease progression. It's not like here they're curable and fuel progress. No, this is different. So we need additional drugs that keep them alive for the longest period of time. So again, something works. And I think that's the strategy that I have in mind.

And then to your point, I think what we shared even in this relapsed refractory, I mean, median line 3 lines of therapy already progressed on checkpoint and TKI and this selection strategy, half of the patients we had samples on demonstrated that. So that's the other piece I think about and I think actually Dr. Choueiri mentioned, it's not 5%. We're talking half of this group. And then you would envision -- and this is kind of how I think about therapeutic strategies. And again, maybe not to say for Dr. Choueiri. But the point is, you have active effective therapies, how do you combine them, how do you sequence them? When do you initiate them. I think ultimately, if this mechanism is on mechanism, which we believe it is, and it contributes to the reason why patients progress through a checkpoint inhibitor, you can envision earlier lines of combination strategy that would certainly then expand, I think, the potential opportunity from a commercial perspective. But importantly, I think Dr. Choueiri, to your point, which is what drives us is how do we improve outcomes from patients.

And then one more. Just -- I know you're waiting for the data to mature more, but how much might you need to modify the dose in Phase II based on what you've seen so far with the derm tops -- any visibility on that? And how much that could potentially impact the efficacy if you need to do that?

Yes. With the current FDA view of Project Optimus, we certainly need to engage the agency. I think the one thing that I saw within the DRAGON study. We did a lot of dose exploration. We have a lot of PK/PD data, right? If you look at that monotherapy, I mean, that was really a lot of data escalating up. We escalated data on the combination. So we've got a rich data set. It may well be that in the next step we'll need to randomize to maybe another dose than the 1,500 that we went forward with. But if we take a look at that overlap of what we think is needed for efficacy, we don't think we're off for it at all. And in fact, quite honestly, I think as we continue to look at our data going forward, the chances are that this is really just a matter of mitigating a little bit of when you see the first sign of the toxicity, the classic means to manage that. Everybody gets "smarter" as you go forward, and you have more experience. So I think this is something we can easily manage. Again, I was very encouraged because this was the first study, we saw it, we adjusted, we responded. As you saw, that was a very early signal. We haven't seen quite that again. We've already shown within the trial that we're managing it more effectively. And I think as now we have that leaning into the next study, Gary, I think we'll be fine to manage. But -- but again, I think we'll have more insight after we have our meeting with the FDA.

The next question comes from Kripa Devarakonda with Truist.

This is Alex [ Sunakis ] on for Kripa. Congrats on the update. Really exciting. Couple of questions. One, for the Phase II, do you think that you would likely pursue the same inclusion criteria so we get the same line of therapy for patients? And also, can you clarify for the what you said about -- I think it was half the patients that you sampled would qualify for the biomarker. Is that either biomarker that you tested? Or is it a combined.

Yes. Jing, you want to take the biomarker question.

Yes. So we are -- first of all, I want to say the biomarker data are ongoing. We're continuing to gather data, continuing to analyze the data. So secondly, to answer your question directly, yes, approximately half or more than half the patients were enriched either for the CD8 infiltration or for the T-reg elevation. So if you look at the renal cell cohort, 10 out of the 14 patients, the samples actually has the presence of infiltration and 6 out of the 11 had a T-reg elevated level. So I do want to add one more thing. The question about the broad applicability of the biomarker data. While we have the most mature data in renal cell, the elevated infiltration, based on the treatment associated infiltration increase. We did see that across tumor types.

No, I want to add that when we say we have CD8 T cell infiltrated, T reg infiltrated, it's really not infiltrate as much, but that's the easier way to say it. It's a cutoff that we use and other have used knowing there is no strategies in a cutoff that is accepted like, let's say, all of us get hemoglobin and [indiscernible] more than, I don't know, 14 is high, less than 13. This is a cut off even there are thousands of hundreds of paper. This is a cutoff that we still -- so it's something like that. I'm more interested and I would say for the biomarker, it depends if we pick up CD8, T reg or a combo of both, okay? But it's certainly more than 50% of all patient, one. And second, what I would like to say, you may say, well, CD8, T-cell infiltrate, there are CD8 T cell there, et cetera, what's happening, well, these are also the CD8 T cell, perhaps even if they're there, they're not functional. And now this is not driving this mechanism of action in new CD8 T cells into the tumor as much as reinvigorate most T cell and make them already there, make them more active.

Yes. And it's really fascinating if we look at mechanistically, blocking TGFß1 should be able to do both. They should be able to reactivate that within the tumor, which is what we're seeing in the renal and we're also shown in the other samples that we can overcome immune exclusion. But the signal is very, very strong, at least we think, in the renal, which is beautiful. And then to your question, yes, as we engage whether -- I think it's really optimal to be able to move up to lines of therapy, and so we could potentially loosen the exclusion/inclusion criteria to move it a little closer. The specific trial design and the details around that will come forward. But certainly, I believe these data, considering the tolerability would warrant us being able to advance to a little bit earlier line of therapy. That will certainly be a point of discussion with the FDA.

One moment for the next question. The next question comes from Marc Frahm with TD Cowen.

Maybe first on the AEs, did you -- sometimes in IO, we're seeing [indiscernible] association, right, with the immune related AEs and actually efficacy? Is there any association between patients who are getting these skin reactions and the ones that are responding and having very long stable diseases. And then related to the -- in renal cell, we've seen attempts to have triple combos with TKIs, which have had some efficacy signals, but also some significant toxicity issues, but a lot of that seems to be toward CTLA-4 driven. Do you see this combo going forward potentially as the triple combo with the TKIs?

Well, why don't you talk -- I will have Jing speak to the adverse event profile?

Yes. So -- yes, for your first question, is there an association between the AEs and the response, so we're still analyzing the data in totality. So what it appears like that there is a little bit of association. So that's not surprising given the fact that Jay mentioned this, it's a mechanism-based adverse event that has been seen with PD-1 therapies before. So we do see a little bit of that. But the second point I want to make is that patients are -- like the clinician are learning to manage through that. As Jay mentioned earlier, and over the course, and we saw these early and then the team has been able to sort of dose hold or dose reduce and most patients are managing through them. So I think we're learning to manage them, these patients. For example, there is a renal cell cancer patients that had an AE. We dose held the patients that did well and the AE grade went down to Grade 1. So Dr. [indiscernible] actually spoke about that. So I'll let Jay answer the second question.

Well, the question, I think, and maybe I'll turn it to Dr. Choueiri, you think about where treatment is going with clear cell renal. Certainly, my experience in myeloma and others is you combine as many drugs as you can, providing they're tolerable. Right now, it's in checkpoint inhibitor in TKI, typically would you envision triplet therapy? And the tolerability that we've seen with the checkpoint inhibitor, I would not think it would preclude adding a TKI to it, but perhaps you can just give us your view on that.

I agree. It doesn't preclude future adding TKI to it. We have to see what TKI [indiscernible] those conduct the study. Many of the TKI have data to decrease the number and percentage of T reg. So that could be, that could lead to synergy with the mechanism of action here, we see at least in the responders. So this is something that could be interesting. The other thing I want to mention, talking about the toxicities, which the ones that are mentioned here, more serious than [ unmediated ] dermatitis [indiscernible] and generalized dermatitis. I think more and more physicians, oncologists and dermatologists are using IL-4 blocker, Dupixent directly rather than going, but let's see what's the -- that's biopsy, let's get some steroids, after steroids, let's do this. So they're using it and it worked very, very well. And in the one case, I'm familiar with when patients had [indiscernible] and rash in a clear cell RCC, subcutaneous Dupixent worked quickly and the patient was able, despite the dose reduction to be on the safe side to continue on therapy without recurrence. I think this would be a strategy because I think the dermatitis is on -- is real. I wouldn't say I prefer dermatitis over hepatitis or [indiscernible]. I don't want anything to happen. But I think here, writing protocol in a way, having a dermatology may be consultant, having subcutaneous Dupixent may be provided to work like that. Because when we go to a larger study, I don't think we have the quick access with dermatitis. I know I sometimes wait over a year to get enough pointers then I have to make a phone call. But that will be a very important strategy.

Yes. And that was the point I was raising earlier, right? We saw it initially. You learn as you go, clearly understand we believe we can mitigate on-mechanism effects, not many drops because of it, but also managing it so it doesn't get to the level of a grade 4. So I think we have -- it's visible. We understand it. It really allows us to manage it beautifully. And we'll certainly take all these things into consideration in the next study.

Okay. That's very helpful. And then -- maybe just as you meet with the FDA, I mean, you mentioned some objective trial phases, just randomized dose exploration to kind of satisfy Project Optimus. Are those trials you would be willing to do yourself or to some of your comments about this being best placed with a partner is all of that work really dependent on finding a partner.

Yes. I think to be clear, because I think we've been very front footed on this. We have taken a decision over the last year to really, really focus on our myostatin program. So DRAGON was initiated when I joined. We felt it was worthy to complete it, absolutely the right decision. I mean we have got something here in our hands that I believe can go forward. Next steps, I think, will help guide any subsequent thinking. Right now, I think our goal would be to just get and understand what that would mean. Certainly not going to redirect any capital to deploy beyond what we're doing currently. We're delighted that there are still patients receiving treatment on DRAGON. We are continuing to explore the biomarker. We're doing all that work that we can do. And then I think when we see what the next study looks like, we'll see where we are as a company, we'll see where we are at the partnering development discussions, I think we'll be very poised to continue to move this program forward. But right now, it's just an exercise of defining next steps, which I think then ultimately would define what would be the cost and time to get to really a definitive way to advance this such that Dr. Choueiri could then consider seriously having us to manage his patient.

The next question comes from Tess Romero with JPMorgan.

So just piggybacking a little bit on the last comment that you just made, Jay. Like just to put a finer point on it, strategically for the company, what is the ideal next step for this program and are there any specific outcomes from the end of Phase I meeting that you think a potential partner could be most interested in? And what do you think a potential partner would still like to see from the program, if anything.

All good questions, right? I think, again, early days when I joined the company, the question is what are we going to be? Are we going to be an immuno-oncology company? Are we going to be in SMA, right? And it's an interesting point because at the end of the day, we've got a platform targeting TGF-beta biology that is broad without question. And I think we've demonstrated, I believe now we're getting further and further evidence of the validity of the platform. So just to put that into context. But having said that, the way we think about it, Tess, is that in drug development, the next steps really define the scope of the trial, time lines, et cetera, what you would need to do next. I believe that we have within this study demonstrated proof of mechanism and I think we've heard that this morning from Dr. Choueiri, if you again listen to the discussion yesterday, Absolutely. She had 3 questions she posed, yesterday's discussion. Did we demonstrate proof of mechanism? The answer was yes, based on our biomarker data. How about safety, same conversation, tolerability, notwithstanding the skin, but that's easily manageable going forward? And the final question she posed, and I have to tell you I sat there yesterday because I didn't know what she was going to say, and a bit on the edge of my chair, did we demonstrate that we've overcome resistance to the checkpoint inhibitor. That was her question. And she said, unequivocally, yes. These data are impressive considering the background patients. So I think that's what we have in hand. I think now going forward for the next step with the FDA would be to say, okay, we have some ideas of what that next trial would look like. We have an understanding of what that would be towards ultimately getting the program registered. So understanding that, Tess, I think does put some context to whoever would want to partner to get their understanding in it. And I think that's kind of the direction we'll take. We been very clear. We've certainly had some interest in the program. We'll continue to explore that. But for today, and I feel obligated to take these next steps to meet with FDA, just to lay that path clear. But to go back to the finer point, right now as we spoke just last week at the investor event that we held, we are really focused on myostatin today, full stop, push those programs forward, but DRAGON is just worthy of continued compensation without question.

I show no further questions. At this time, I would now like to turn the call back over to Jay for closing remarks.

Well, listen, thank you again for your interest and for your time this morning. I say this at an exciting time at Scholar Rock. We spent a full almost half day last week at an investor event but yet couldn't resist having a conversation today. So thank you for joining. Thank you, Dr. Choueiri, for taking your time. He's a busy gentleman at ASCO, and we were fortunate to have him share his views. And again, once again, thank you for your interest. And at this point, we'll close the call.

This does conclude today's conference call. Thank you for your participation. You may now disconnect.