Kyntra Bio, Inc. (KYNB) Earnings Call Transcript & Summary

Good morning, and welcome to the FibroGen Virtual KOL Investor Event Series Part II. [Operator Instructions] As a reminder, this call is being recorded, and the replay will be made available on the FibroGen website following the conclusion of the event. I'd now like to turn the call over to Thane Wettig, Chief Executive Officer of FibroGen. Please go ahead, Thane.

Thanks, Tara, and good morning, everybody, and welcome to the second event in the virtual KOL Investor event series from FibroGen. The first was back in February, where Dr. Andrew Ko from the University of California in San Francisco focused on the unmet need in pancreatic cancer and covered the pamrevlumab development program. Today's event is focused on the unmet need and the evolving landscape in prostate cancer as well as the FG-3246 development program in metastatic castration-resistant prostate cancer. I want to cover just a brief overview of FibroGen before I hand it over to Dr. Aggarwal. And so if you could go to the next slide, which is after the forward-looking statement. And what I'd like to do is just touch on the strategic pillars and the investment highlights for FibroGen. There are 4 areas of focus for us currently. The first and the most near-term potential catalyst for the company is with pamrevlumab and the upcoming readouts we have in pancreatic cancer, which represents a significant unmet medical need, one of the most significant unmet medical needs in oncology and corresponding substantial commercial opportunity. There are 2 upcoming readouts in the near term. The first is in metastatic pancreatic cancer, and that's the Precision Promise program, which is being run by the Pancreatic Cancer Action Network, where we expect top line OS results in the middle of this year. So we're very close to being able to present those results. The second trial is the FibroGen-sponsored trial, we call LAPIS in locally advanced unresectable pancreatic cancer, where we expect top line results in the third quarter of 2024. So clearly, pamrevlumab is an important opportunity for FibroGen, and we expect results in the near term. Second area of focus for FibroGen is roxadustat, which is approved in more than 40 countries and where we continue to see substantial revenue growth in the territories that are commercialized by AstraZeneca and Astellas. In China, we have an sNDA that is under review for chemotherapy-induced anemia, which represents an important incremental opportunity for roxadustat in China, and there's an approval decision expected in the second half of this year. In addition, we recently regained rights to roxadustat in the former AZ territories, excluding China and South Korea, which primarily focuses on the U.S. and we continue our potential partnership outreach in indications such as anemia in patients with low-risk myelodysplastic syndrome. In fact, just last week, the MATTERHORN Phase 3 trial of roxadustat in low-risk MDS was published in the Journal of Hematology. And in addition to detailing the Phase 3 results, the authors can highlight and conclude that there still represents a substantial unmet need in low-risk MDS and their belief that roxadustat deserves further development in this particular indication. Third area of focus is our early-stage oncology pipeline, which now I think we would represent as our early and mid-stage oncology pipeline. The most near-term asset for us is FG-3246, which you will hear more about today from Dr. Aggarwal and Dr. Adib. In addition, we recently had an IND clearance for FG-3165, which is a galectin-9 targeted monoclonal antibody for solid tumors, and we would expect the Phase 1 start later this year. And finally, FG-3175, which is a CCR8 targeting monoclonal antibody for solid tumors, where we would expect to file an IND in 2025. Last area of focus and importantly, is our strong balance sheet, where we have sufficient cash, cash equivalents, investments and accounts receivable to fund operating plans into 2026. Now what I'd like to do is turn the area of focus over to prostate cancer and the FG-3246 development program. We are really fortunate to have Dr. Aggarwal join us today. Dr. Aggarwal is a Professor of Medicine and Thomas Perkins Distinguished Professor of Cancer Research at the University of California at San Francisco, and the Associate Director for Clinical Research in the Helen Diller Family Comprehensive Cancer Center and the Program Lead for the Genitourinary Oncology program, specializing in translational and clinical research in prostate cancer. He has been involved with what was formerly known as the FOR46, which we now refer to as the FG-3246 program, since its inception. So he's been involved with this program for a number of years, and we couldn't have a more experienced and qualified clinician and researcher to be able to cover the evolving landscape in prostate cancer and the results to date that we've seen with FG-3246 than Dr. Aggarwal. Dr. Aggarwal, I'd like to turn it over to you.

Great. Thank you so much for the introduction, and good morning, everyone. Go to the next slide. Great. So we'll provide some background on prostate cancer and then certainly delve into the clinical data with the FG-3246 compound. Next slide. So just some background on prostate cancer. I think we're all aware, this is a very common cancer type, the second most common after breast cancer, and 13% of men will be diagnosed with prostate cancer at some point during their lifetime. The majority of men do present with localized disease, but of those, about 30% to 50% will have recurrence. In addition, 5% to 10% of patients are diagnosed with de novo metastatic prostate cancer and ultimately end up with metastatic CRPC. So in total, about 60,000 to 70,000 patients in the U.S. annually are treated with systemic therapy for mCRPC and with 5-year survival of approximately 30% and about 40,000 deaths in the U.S. every year. So a very high unmet need for this patient population. Clearly, a lot of activity in drug development. I think there's multiple opportunities and unmet needs to develop new therapies in this disease space. Really therapies that extend survival in patients that have progressed on one or more AR targeted agents or what we call ARSIs and/or chemotherapy. We definitely need new targets going beyond PSMA and some of the others that are in clinical development and clinical care, the new mechanisms of action, new targets. And increasingly, we know that mCRPC is a heterogeneous disease. And so biomarker selection to really select out the patients that are going to benefit the most. It's crucial. And as I'll show you, a lot of the recent FDA approvals are in selected patient populations in mCRPC. We need more predictive biomarkers and get us closer to where we are, for example, in breast cancer. And then, of course, combination therapy, rational combinations, those that can be well tolerated in the clinic and achieve true synergy as well as developing sort of optimal sequences of therapies, I think, is a clear need for our patient population. Next slide. So this is just a flow chart of how do patients end up with mCRPC. You can see, as I said, that majority of patients who are diagnosed with localized disease, of those that are treated with surgery and/or radiation for localized prostate cancer, 30% to 50% will have PSA recurrence or what we call biochemical recurrence. And of those, many will progress eventually to initially castration-sensitive disease and eventually castration-resistant disease. In addition, about 5% to 10% present with de novo metastatic hormone-sensitive cancer, majority of which will progress to mCRPC unless they die of other causes. We think that really FG-3246 could be well positioned in this first to second-line mCRPC population. Could you advance the slide? And so really a first and second-line mCRPC either as monotherapy in combination, first-line mCRPC, particularly for those patients that received an oral ARSI inhibitor in the castration-sensitive setting, which has become the standard of care, what we call intensification of therapy in the hormone-sensitive setting means that patients reach first line mCRPC having already become resistant to one ARSI therapy, and we think there's a need and an opportunity to develop new therapies in that disease space. And in the second-line mCRPC setting for those patients that did not receive an oral ARSI in the hormone-sensitive setting but instead in this first-line mCRPC. And certainly globally and in the U.S., this is still a pretty reasonably sized patient population as well. Next slide. So just talking a little bit about the therapeutic landscape in mCRPC. And gratifyingly, we've seen the acceleration in the number of FDA approvals in this setting as you go from left to right in the time line with mitoxantrone approved way back in 1996 for bone pain palliation, to where we are now with lutetium PSMA-617 approved in the post-chemotherapy setting. And as you go from left to right, what you see is also increasingly biomarker selection used for drug development in mCRPC. So the PARP inhibitors with the specific genomic subsets, lutetium and PSMA PET avid disease. And so I think increasingly, this is a trend that we'll see in terms of maximizing benefit and prediction of response based on validated biomarkers. Next slide. And this is really reflected in the NCCN treatment guidelines. About 10 years ago, this would have just been a homogenous mCRPC and a few therapies listed. And now you have all these different subsets of disease as shown in the top row of the chart. You have MSI high, you have the BRCA and other HRR altered prostate cancer, those that are PSMA PET avid. The aggressive variant or neuroendocrine prostate cancer space also potential opportunity for FG-3246, all represented by different buckets of mCRPC. And you can see the different sequences of therapies that can be proposed based on the biomarker selection. Next slide. So the treatment landscape in the post ARSI chemotherapy-naive mCRPC population. This is where we really want to focus our discussion today. And the good news here is we have a number of contemporary trials that give us benchmarks for how the control arm and experimental arms have performed. And so you can see 4 trials that were performed in the post-ARSI, pre-taxane space. We have TRITON3. That was in a molecularly selected population, randomizing patients to rucaparib versus a dealers-choice of an AR switch or docetaxel. And we have PSMA4, which was lutetium PSMA-617 randomized to an AR switch in the pre-chemotherapy setting. A very similar trial design with SPLASH study, a different lutetium agent. And then CONTACT-02, which randomized patients to cabozantinib plus atezolizumab versus ARSI switch. I think the caveat with that study is this was a pretty sick patient population that had to have measurable soft tissue disease. So a high proportion of patients with visceral metastases. And that's really reflected in the shorter median PFS that you see there. But in general, this gives us the benchmark for what a median rPFS would look like for an ARSI switch somewhere in the 5- to 6-month range as well as docetaxel chemotherapy from the TRITON3 study, approximately 8 to 8.5 months in terms of benchmarks. And you can see with the efficacy for the experimental arms, what the target really is for rPFS somewhere in that 10- to 12-month range as you see depicted by the purple bar graphs there. Next slide. So our surrogate or intermediate endpoints for mCRPC. This is certainly a very, very active area of discussion and Prostate Cancer Working Group 4 guidelines should hopefully come out sometime later this year or early next. But we know that radiographic progression-free survival based on conventional imaging, so cross-sectional imaging of the chest, ab and pelvis and whole-body bone scan remains the regulatory accepted intermediate endpoint in the mCRPC setting. And this is the one that's led to multiple FDA approvals and really the primary or co-primary end point for a number of our Phase 3 studies. We certainly do look at PSA50, PSA90 and objective response rates to provide those early signals of antitumor activity but not used as a surrogate for overall survival and not from a regulatory perspective used for approval of an agent. And I would say, in addition, we know that PSA declines are probably the most well validated for agents that target the AR signaling pathway and may not be as representative of overall clinical activity of an agent when you're targeting a separate pathway. For example, Radium-223 really FDA approved on the basis of overall survival benefit, but a minimal change in PSA seen with this agent. Objective response rate is also very useful, but challenging in that many of our patients have bone-only disease, 50% to 60% or more. And so this really limits to a higher risk subset where you're getting the objective response data. Next slide. This is just a slide that summarizes some of the other investigational agents that are in early phase trials in prostate cancer. I think probably many of you are familiar with these agents and these data. So I'm not going to walk through all the details. But just to tell you that there's certainly multiple ADCs, multiple different modalities of therapies and bispecifics that are in early phase testing that have shown some activity in terms of PSA50 and objective response. But we need longer follow-up to really get into the median rPFS and the duration of response and those are sort of critical questions as well as tolerability and how long patients can stay on. So still a lot to learn, but definitely a lot of agents in development for sure. Next slide. Let's go to FG-3246. We'll first talk about the background of this agent and the target and then get into the clinical data. Next slide. So this is really a novel target that was discovered actually in a laboratory of Dr. Wen Lu here at UCSF using an unbiased page library screen of prostate cancer tissues that identify this extracellular epitope of CD46. CD46 is a negative regulator of the complement system and may be involved in evasion of the tumor from innate immunity. But what's really interesting about this epitope is it tends to be very tumor selective and that this confirmationally dependent epitope is really expressed in minimal levels in normal tissues. And we've seen that from pretty extensive tissue screens that we've done of human tissue systems as well as now our PET imaging agent that we now translated in the clinic, where we see the same tumor specificity with a high tumor to background uptake. So the 3246 therapeutic is an ADC. It's a fully human IgG1 monoclonal antibody targeting this tumor-selective extracellular epitope of CD46. The payload is MMAE, which is a potent antimicrotubule agent. On CD46, expression in prostate cancer is significantly upregulated in metastatic versus the localized setting. And one of the other key distinguishing features as compared to PSMA, it seems to be expressed more homogeneously at least at the RNA level and in a less lineage-dependent fashion, which we see high levels of expression in both adenocarcinoma as well as some of the more differentiated phenotypes like neuroendocrine prostate cancer. Next slide. So we'll talk about the clinical data here. Next slide. We recently completed the Phase 1 first-in-human study of 3246 in patients with mCRPC. Next slide. The study design for this first-in-human study was fairly straightforward. This is a 3 plus 3 dose escalation in which we enrolled a total of 33 patients and then a dose expansion of 23 patients. That was predominantly an adenocarcinoma. We did enroll a few patients with neuroendocrine prostate cancer, but haven't enrolled enough to really be able to speak to the potential efficacy in this disease subset. It was initial accelerated titration followed by 3+3 with a starting dose of 0.1 mg per kg. We did not mandate primary prophylaxis with G-CSF, but secondary prophylaxis required for Grade 3 and higher neutropenia. The endpoints of the study were pretty typical for a first-in-human Phase 1 study, the safety and tolerability and NPD, RP2D were the primary endpoints. Secondary endpoints included the PK as well as the efficacy endpoints, including rPFS, PSA50 and objective response rate. Next slide. Eligibility criteria for this study are fairly in line with where we think this drug is best positioned. So this was a mCRPC patient population with prior progression on one or more prior androgen signaling inhibitors. No prior chemotherapy in the metastatic CRPC setting. However, chemotherapy was allowed in castration-sensitive disease. In dose expansion, we did require the availability of CRPC tumor tissue to be able to perform IHC testing. This CD46 expression by IHC was not required for eligibility, but what was retrospectively done. It's important to note that at the time that we did the Phase 1 study, the IHC marker was really not an epitope-specific biomarker, but more a general level of expression of CD46. Hence, we're really excited about the CD46 PET imaging agent, which uses the same antibody backbone as the ADC. Next slide. Here's the baseline characteristics of the study, so we included all the patients in the adenocarcinoma cohort plus dose escalation for a total of 51 patients. Worth highlighting a few things here. This was a pretty heavily pretreated patient population, so a median of 5 prior lines of therapy, including about 70% of patients that had had both abiraterone and enzalutamide as well as about 25% of patients that had prior docetaxel in the hormone-sensitive setting. There was also a patient population with a pretty large disease burden at baseline, a median PSA of 41. 60% of patients had measurable soft tissue disease. And importantly, when we think about interpreting the radiographic PFS data that I'll show you in a minute, the majority of patients came on to the study with radiographic progression as opposed to PSA-only disease. And we do see a basket definition of progression that we use for entry into most of our studies. So it's important in terms of looking at how are patients really progressing at the time that they came on the study. Next slide. This is top line summary of the safety. Generally, this drug was safe and well tolerated. The adverse event profile, I think, was consistent with some of the other MMAE-based ADCs that we see in the clinic. All-grade neuropathy was 34%. Grade 3 or higher was low at 2%. Neutropenia grade 3 was 36%. I would say that having treated many of these patients in clinic, that neutropenia tended to be pretty transient, and the rates of febrile neutropenia were very low. I think we had maybe 1 patient in the Phase 1 study, so a very low rate of febrile neutropenia and can be mitigated well with the use of G-CSF for subsequent cycles of treatment. Infusion-related reactions, low-grade, were fairly common at 47%. High-grade events were uncommon, 2%. We do use premedication, which seems to mitigate that. And then we didn't really see any ocular toxicities in the early portion of the Phase 1 study. We did mandate ophthalmology assessments at baseline and during treatment and didn't really see any ocular toxicity, which was good to see with this agent. Ultimately, the MTD was determined to be 2.7 mg/kg using adjusted body weight dosed on day 1 of a 21-day cycle, so once every 3 weeks. We did see that the overall sort of severity and toxicities were dose exposure related. And we did see patients dosed at 2.7 mg/kg. Although this was a tolerable dose, did lead to fairly frequent dose reductions due to neuropathy in subsequent cycles. And so that has helped to inform our strategy in terms of dose optimization for the upcoming Phase 2 where we're really looking at 2.4 and 1.8 mg/kg adjusted body weight. Next slide. This is just for your reference, kind of in a table format, the various AEs. So you can look at this, but I called out the sort of adverse events of special interest on the prior slide. Next slide. So getting to the efficacy results. We really looked at the cohort of patients, the subset that received dose levels of 1.2 mg/kg and higher as we thought that would really reach the efficacious level based on the preclinical models as well as other MMAE ADCs. And in this cohort of 40 patients, the median rPFS was 8.7 months, which was quite encouraging given how heavily pretreated the patients were as well as, again, to reiterate, most of these patients did have radiographic PD at study entry. So although this is a nonrandomized Phase 1 data, we do think this is a pretty encouraging median rPFS and in line with some of the other agents that have been tested in Phase 3 studies, as I showed you in the prior slide. Next slide. Here's a PSA waterfall plot. Again, looking at the efficacy cohort. The PSA50 response rate was 36% and 31% with confirmed PSA50 response. You can see that the majority of patients did have a PSA decline on study. There were a subset of patients without a PSA decline as depicted on the left side of the waterfall plot. There were declines seen across a range of dose levels from 1.2 mg/kg and higher, as shown in the color bars and the bigger legend there at the bottom. Next slide. The objective response rate. So in total, we had 25 patients that were evaluable, measurable soft tissue disease by RECIST at baseline. In this subset of patients, the confirmed objective response rate was 20%, all of which were partial responses, as shown in the waterfall plot. We do get a sense of some of the dose efficacy relationship here with the majority of the patients with tumor regressions having been dosed at the higher dose levels. Next slide. Here's a swimmer's plot showing the duration of treatment across the patients with measurable disease. Overall, the median duration of response was 7.5 months amongst those patients that had a response. In addition to that, I would say that there were a number of patients with pretty durable stable disease as shown in the different swim lanes there on the right. Next slide. So to summarize the data, we did see encouraging single-agent activity in a heavily pretreated patient population in the context of this being a Phase 1 dose escalation and limited dose expansion study, meeting rPFS of 8.7 months, ORR 20%, duration of response 7.5 months, PSA50 of 36%. Safety profile, I think, well in line with other MMAE containing ADCs, with neuropathy being dose limiting at 2.7 requiring some level of dose reductions and dose delays. So the doses we've selected for moving forward in the Phase 2, 3 are 1.8 and 2.4 mg/kg as part of the dose optimization with G-CSF prophylaxis as needed to really mitigate the risk of neutropenia. Next slide. I want to also discuss an ongoing investigator-initiated trial we have at UCSF that we're quite excited about combining 3246 with enzalutamide. And this is an ongoing study. We presented the dose escalation results just at the ASCO meeting earlier this month, and I'm happy to share some of those data as well. Next slide. The rationale for the combination really is based on some nice preclinical data showing that when you give an AR-targeted agent, you can see upregulation of CD46 cell surface expression. And that's shown on the graphs there on the left. And when you combine the ADC with an AR targeted agent, you certainly see a combination in vitro activity, as shown on the right curve. And what we're doing as part of the ongoing clinical trial is really testing this in the clinic and utilizing the ability to get the CD46 directed PET imaging pre and post AR-targeted agent lead in with enzalutamide to really see if we see that same upregulation in patients because that would really present a great opportunity for combination treatment moving forward. Next slide. So this is a primary and secondary exploratory endpoints of the study, also pretty straightforward, just like the first-in-human study. This is a pre-taxane post ARSI mCRPC patient population with a determination of MTD and RP2D as the primary endpoint. You can see the secondary and exploratory endpoints. In particular, the PET imaging is a crucial one for us and now a mandatory component for patients to receive PET imaging at baseline and on treatment. Next slide. This just shows the overall schematic of the trial. So we just completed the Phase 1b dose escalation. Determined the MTD to be 2.1 mg/kg adjusted body weight in combination with enzalutamide, and we're now accruing in the Phase 2 portion of the study with mandatory PET imaging. Next slide. Here's the adverse event profile from the dose escalation study. So these are patients treated across a range of dose levels. You see a pretty similar pattern as that observed in the first-in-human study. Neuropathy was pretty common. These were all low-grade events, but we did have several grade 2 neuropathies that ultimately did lead to treatment discontinuation. Next slide. The very preliminary data from the dose escalation cohort because we do still have patients ongoing. So I think these numbers will change. And probably we'll see some rightward shift as we continue to follow patients that are on treatment in dose escalation. But you can see median duration of treatment was 6 months. And very early but encouraging rPFS of 10.2 months as shown in the Kaplan-Meier plot on the right. We're quite encouraged by that and hope to really get more events. There's still a fair amount of censoring here. So we'll see as we get further follow-up. Next slide. The PSA waterfall plot is shown here, and this is really across all the dose levels we tested. So this is not at one fixed dose, but across the different dose escalation cohorts. Majority of patients did experience the PSA decline. 5 out of the 12 patients that had a PSA decline actually had prior progression on enzalutamide. That tells us that, and we do think there's something potentially for the combination. 2 patients had a PSA50 response in this dose escalation. We'll certainly be looking at that in the Phase 2 portion of the study as well. Next slide. We're really excited about the CD46 PET imaging. All of the patients that we've imaged before have had at least 1 or more positive tumor lesions with strong tumor-to-background uptake, both in the bone and in the soft tissue. So you can see some representative images from a patient that we recently enrolled that has been treated with both abiraterone and enzalutamide at a baseline PSA of 53. This is the CD46 PET, again, same antibody backbone. We use Zirconium-89. This is a tracer that's injected and then you image 5 days to 7 days later. You sort of incorporate this within the baseline screening procedure before a patient starts the study. And so we're in the process of now mandating this. And then hopefully, with larger sample size, we'll be able to really get at that crucial question of how well does this predict for clinical benefit and be able to understand better the range of distribution of PET uptake. Next slide. So our conclusions thus far from the ongoing study, we did determine the MTD to be 2.1 mg/kg, and that's the dose we are taking forward in the Phase 2 portion of the study. We will be integrating PK to really try to get at that drug interaction question. That's a crucial one for us to be able to answer. We did see some preliminary evidence of antitumor activity with PSA declines and the encouraging rPFS of 10.2 months as I showed you, and really excited to hopefully have the Phase 2 trial approved by the end of the year as the approval rate has been pretty brisk and we've been happy to see that. Next slide. So I'll turn it over to Deyaa to really conclude the last portion of the slide presentation.

Thank you very much, Rahul. Next slide, please. At FibroGen, we truly believe that we have a unique opportunity in patients for metastatic CRPC. This ADC is a novel mechanism of action with potentially first-in-class opportunity. So the antibody by itself is a new target against a new target that's associated with a validated chemotherapy payload being an MMAE that is currently approved with 4 other ADCs in different hematologic as well as solid tumors. It is binding to a unique epitope on CD46 that is present on cancer cell surface, including prostate and also colorectal cancer, but it's absent in most other normal tissue. As Rahul mentioned, we are investigating PET biomarker diagnostic to enable us to preselect those patients with high CD46 expression, and those are the patients we are looking at to derive the highest level of clinical benefit. In the Phase 1 monotherapy trial, as we have seen, the results are very, very encouraging. In fact, when we talk to a few key opinion leaders, they tell us that we got our proof of concept right there and that we should move very quickly towards a registration strategy, and I will share that with you momentarily. In terms of safety profile, we have not seen any new safety signals. So anything that has been on the adverse events board is essentially consistent with MMAE and it's a close cousin to tubulin polymerase inhibitor, just like Taxotere, but at a much, much less extent, especially when it comes to bone marrow toxicities, infections, bleeding events, we have not seen any of that. So the safety profile is so far very, very encouraging. We also see that there is a potential opportunity in other tumor types and other lines of therapy. In metastatic CRPC, we are starting off here with great results in the second line pre-chemo setting, but we are looking also forward to move it up the treatment lines in combination with enzalutamide based on our learnings from Dr. Aggarwal's IHC being conducted as we speak. Next, please. So the biomarker strategy is going to be a very critical component of our development program. It's very encouraging to start with to see those patients and clinicians looking forward to see the PET uptake, especially at the high expression tumor sites. So it is something that has been well established with prior approvals in the post-chemo stage, starting with lutetium. So it is something that is already out there. So we are not adding any additional burden in terms of introducing a radiopharmaceutical diagnostic to enable us to select those patients. We are estimating about 50% to 70% of the prostate cancer population to have overexpression of CD46 and we are going to do also PSMA PET biomarker to demonstrate whether or not there is correlation with CD46 high expression, and it has already been proven in other PSMA-targeted therapies. So the biomarker is also looking at CD46 expression using tissue. However, as we mentioned earlier, accessible or measurable disease is present in only about 40% of patients with mCRPC. The majority of patients actually show up with only bone disease. So the critical component here is that PET-based radiodiagnostic will cover the entire population, those with measurable disease and those with only bone disease. We are going to be using our Phase 2/3 trial design to confirm the utility of PET46 as a radiopharmaceutical diagnostic and also IHC for the subset of patients who will have archival tissue or will have accessible, measurable disease that will enable us to extract fresh biopsy. And these will all serve in the selection of high CD46 expression patients in the Phase 3 registration trial. Next. This is our current planned Phase 2/3 registration study. So it's going to be a randomized dose optimization biomarker-driven adaptive design in patients with high CD46 expression, especially in the Phase 3 component, and we are going head to head with our ADC against ARSI switch, meaning patients who have received previously abiraterone will get enzalutamide and vice versa. We are planning to start the Phase 2 component after we are aligned with the agency this year. I mean we are very soon going to be meeting with the FDA to discuss with them the design of the Phase 2, our selection process of the dose optimization between 2.4 and 1.8 and then kick off the decision after we complete the Phase 2 to identify the proper dose and to confirm PET46 as a companion diagnostic into a seamless design, moving from the Phase 2 to the Phase 3, and it will be 200 patients in each arm, whether 3246 or an ARSI switch. We will be looking at patients with high CD46 expression in the Phase 3. And our primary endpoint will be the very well validated radiographic progression-free survival. Secondary endpoint will be overall survival. And we are going to also quantitatively look at PET46 versus IHC for the future registration, which one of them will be the standard to preselect those patients for therapy. Next. We are looking also at a promising targeted product profile. So in high CD46 selected patients, we are looking at rPFS north of 10 months, overall survival of about 28.5 months. Our safety profile so far has been very, very benign and promising and no new safety signals. In terms of administration, it's IV every 3 weeks, again, mimicking standard of care, especially with other modalities like chemotherapy. We have not yet discussed the patient cost. And anyway, we are looking at this as a very highly unique and competitive treatment modality when we compare it to ARSI switch or chemotherapy alone or the current modern standard of care, which is PSMA-targeted radioligands. Next. We are also very optimistic about our vision and strategy towards the further development or life cycle expansion for the program. So we are looking to pursue accelerated registration Phase 2/3 seamless design trial, and we will get alignment with the FDA sometime this summer. We are also establishing 3246 in the pre-chemo in combination with enzalutamide, and that would be then our first-line setting. So we are expanding the footprint and also establishing PET46 as a companion radiopharmaceutical diagnostic to be part of the standard of care, especially now that we have seen that with lutetium PSMA target, it has been established. So there is no reason why we cannot make this happen as well. In terms of our second step, it will be moving up the treatment lines, as I mentioned, in combination with Enza and also to demonstrate clinical activity in other tumor types, for example, in refractory metastatic colorectal cancer, where it is considered an area of significant unmet medical need, especially after patients have failed first line with chemotherapy FOLFOX or FOLFIRI and then follow-on with Avastin in combination and then follow-on with EGFR antibodies like ERBITUX and panitumumab, and last, there is nothing else for those patients. I mean the third line and beyond setting in mCRPC is eventually Lonsurf. And with Lonsurf, the progression-free survival is only 2 months, and the objective response rate is less than 5%. So colorectal cancer is our second target here to study, and it's an area of unmet medical need. Beyond that, we will be looking over time by learning from data that we will be collecting to combine with other potential available standards of care and potentially other solid tumor types. So this is our vision and strategy for our ADC. Next. Back to you, Tara.

[Operator Instructions] So our first question comes from Andy Hsieh at William Blair.

So I have 3 questions for Dr. Aggarwal, if you don't mind. The first has to do with the 16% progressive disease rate. I guess if you look across, can you just contextualize for us compared to the standard of care, how that rate is in terms of the ADC's ability to exert some sort of disease control. So yes, the first question is the disease control rate of 16% versus other assets? And the second question has to do with the combination of enzalutamide. So the 14 days, I'm curious, is that enough to sufficiently upregulate CD46 just to kind of borrow some of the learnings from the ENZA-p study from Dr. Louise Emmett. And then lastly, in terms of the 5-day delay in terms of PET imaging, just from a practice perspective, just kind of share with us how patients feel about that after infusion and come back to getting a PET imaging in terms of the convenience factor.

Thank you for the questions. I think I'll take the second and third first and then maybe just ask a clarifying question for the first. So for the lead-in with enzalutamide, based on the preclinical data, this does seem like it's a fairly rapid upregulation of CD46. I think it's fair to say we don't know the optimal time point necessarily in terms of upregulation and priming and then subsequent dosing with the ADC. We chose 2 weeks because it was feasible. We thought we could get paired PET imaging and because for patients that are not already on enzalutamide, you're able to achieve somewhat close to steady serum concentrations. I think based on the clinical data that we see from the paired PET imaging, if it looks encouraging, one could then explore different time points and really get at that kinetics question. As well as further into the treatment course and at the time of progression, what's happening with CD46 levels in the tumor I think would be valuable information to have as one thinks about a combination approach. Louise's study certainly was very informative, both from a priming perspective of AR-targeted therapy but potentially very different mechanism of how that upregulation happens. I'm not sure it's necessarily directly applicable to CD46. I think we still have a lot to learn in terms of the timing, but our PET imaging data, I think, will help inform whether that's something really to explore. In terms of the feasibility of the injection and then coming back for the imaging, I think it's pretty straightforward. I guess I would say that in the context of patients having to do other things during screening, we try to combine they're getting the PET tracer injection with other things that might be happening such as labs or physical exam, things that our patients are doing to determine eligibility for the trial. I do think it's feasible in the context of a multicenter study but certainly does require some coordination and logistics there to really arrange for 2 different days for the tracer and then the injection. Consecutive days tend to be more challenging, to be honest. The patient comes in, get the tracer and then comes back a week later for the scan is generally doable. I would ask just for the first question, to clarify, what you meant by -- were you talking about the patients that were primary progression on 3246 or maybe just to clarify what you were [indiscernible] for that first one.

Exactly, primary progression, how that compares? Is that 16% pretty good, pretty encouraging, just to kind of share your view on that.

Yes. I mean, I would say it's definitely a minority of patients. You see that across different therapeutic modalities, right, even with lutetium-617. There is a subset of patients that just has primary resistance despite having high levels of uptake on PET scan. I think we'll learn more with 3246 in terms of once we have the imaging data, what's driving that resistance. I think it's still a question we haven't been able to answer. I do think if we can get PET imaging to understand what's happening with the target as well as biopsies and maybe some of our liquid-based biomarkers that we're looking at, hopefully, give us some insight in terms of how those patients may differ. We have some relative data from the Phase 1 study that we're still in the process of analyzing that really seems to indicate the host immune response may play a role in terms of who's driving sort of durable responses versus those that are not. We see upregulation of effector T cells, downregulation of Tregs and MDSCs in the patients that are responders. So I think there certainly could be some host factors there that are responsible as well.

Great. Deyaa, I have 2 questions for you, if you don't mind. So maybe from a tight CD46 definition perspective, are you going to rely that based on the PET in terms of SUV or is that IHC 1 plus 2 plus 3 plus? So that's a definitional question. And then the second one has to do with kind of trial design. You mentioned about the Phase 3 proposed design. So thanks for sharing that. Looking across the field, Novartis basically announced top line results and then they're submitting 2 years after that probably due to crossover. So just curious about how you could mitigate that risk just to shorten the time between top line and regulatory submission?

Sure. So the first question, actually, we are going to use our Phase 2 component to establish PET46 as a radiopharmaceutical diagnostic and as we move along to learn how to quantify or measure CD46 expression. Not just that, also, we will be learning from the 2 studies Rahul is conducting at UCSF. He has either the one with combination with enzalutamide or the other study that is dedicated only for PET46. All these information or data-driven trials will enable us to quantify or to apply a measurement for what would be high CD46 expression using PET. In terms of IHC, as I mentioned, it will be applicable only in patients with archival tissue and/or patients with accessible measurable disease. So it is not ideal. So we will use it to quantify CD46 expression by the level of uptake of those cells or staining. However, it's not ideal. Again, we are looking at PET46 because it applies to the entire population and not IHC, which will apply only to 30% or 40% best case. I mean if we cannot get a fresh biopsy or if there is no more tissue left in a paraffin block, then it's not going to be the ideal way to go. Does that answer your question, Andy?

Yes, that's helpful.

Okay. In terms of the registration trial, the way it is being designed is really to move very, very fast. First of all, the first objective here is to go after second-line pre-chemo setting. And as you mentioned, lutetium or Pluvicto is already approved post-chemo; it will be approved probably this year pre-chemo. And we are not precluding those patients from being included in our trial. So patients who have been pre-exposed to ARSIs or potentially Pluvicto will be allowed to enter our study. And because we are a very unique target, we don't think that this constitutes any hurdles in our path for fast registration. We are completely unique and different target. And patients who potentially have failed on PSMA therapy will be enrolled in our study. So we don't see here a threat towards our registration path. And that's how we are moving forward very quickly. And not just that, Andy. We have vetted also this type of design with 8 different key opinion leaders to begin with, with Dr. Aggarwal, with Eric Small, the President of ASCO, Maha Hussain, Johann de Bono and others, and they are very, very interested and excited about the results we have seen so far in the Phase 1. So really, we don't see a threat here because of the fact that we are a very unique target, first in class, and we are going to be preselecting those patients before we start the Phase 3. So we are almost capturing those subjects who will derive the highest level of clinical benefit. So this is our vision and strategy moving forward. Does that answer your question?

Yes, that's very helpful.

So our next question comes from Paul Choi at Goldman Sachs.

My first question is for Dr. Aggarwal regarding just sort of the treatment practicalities of incorporating a PET biomarker for diagnosing and [indiscernible] versus other diagnostic methods. Maybe just can you comment on how commonly PET is used versus IHC and other methods as described in sort of what are the practicalities of using this in a real-world clinical practice setting? My second question is regarding the waterfall plot with regard to PSA50 responses in the monotherapy study, just given that there are larger patient numbers there. If you could maybe just comment, doctor, on just your thoughts on the [ dose-relapsing ] step. It seems a little complicated to appreciate what the PSA50 impact is by dose cohort. And if the company has maybe some color on the median response by dose level and just sort of maybe elaborate on the relationship, that would be helpful. Sorry, one more, please. My third question is just on the Enza combination study. You commented a little bit on discontinuations due to neuropathy. Could you maybe just comment on what you've seen in terms of dose intensity you've been able to see and just how many patients can tolerate the treatment to get to a point when they have measurable disease to make an assessment and just sort of what the tolerability combination looks like in that respect based on your limited data set.

Thanks for the questions. So I think that in terms of the biomarker piece with the PET imaging, I think we're in mCRPC, I think, increasingly using PET imaging with PSMA PET, not just for selection for patients with lutetium, but also just in terms of monitoring response and progression. So I think PET imaging in general is increasingly utilized. We've never seen, despite pushing and we do this a lot at UCSF, pushing to get metastatic CRPC biopsy has always just been very difficult. We're quite specialized in it. But even in our hands, your evaluable rate from bone biopsies is probably at best 60%. So it's just very hard to use IHC as a selection criteria. So I think for agents that are using IHC based on a fresh biopsy as their main development strategy, that's a challenging one in prostate cancer, not to mention the heterogeneity, that we do expect to see some heterogeneity of targeted expression in mCRPC. And so of course, with a biopsy of a single metastatic lesion, you miss out on that. So I think you just capture so much information from the PET imaging to really help with patient selection, but also understanding response on treatment. Are all lesions responding the same and then what's happening at progression? So I do think that it provides a lot more information than the biopsy. I do think it's practical in terms of getting PET imaging. I do think, of course, the tracer and then imaging on another day does introduce sort of a 2-step process. But Zirconium-89 had been used for a long time. It's pretty straightforward. It can be shipped to the sites that can then do the imaging. And we'll learn a lot as we do the Phase 2 in a multicenter fashion and agreed PET imaging as sort of a mandatory component, but I personally think it's feasible to do that. In terms of the second question, the PSA response rate, I do think that overall there's encouraging activity there. Hard to compare across trials in terms of PSA50 response when you're talking about different targets, different mechanisms of action. I think there is a relationship with dose and efficacy with the objective response data where you tend to see the tumor regression of the higher dose levels, maybe not as clear correlation with PSA50, which may speak a little bit to the fact that it may not be the best biomarker of efficacy with this drug. I mean with the ADC in general, you do expect to see a relationship between efficacy and dose for sure. And then the third question with neuropathy, tends to occur in later cycles. So certainly, you're able to get patients at their original dose level through 3 to 4 cycles and be able to get the first scans and so forth. But for some patients, the grade 2 neuropathy can be pretty bothersome from a functional impact perspective, requiring some dose interruptions, dose reductions and ultimately for patients that it's persistent, they may elect to come off. We had a couple of patients come off with grade 2 neuropathy in the early sort of dose escalation portion of the study. We'll have to track those rates as we go on to the Phase 2 portion of the study. But I think in general, patients are able to stay on for a reasonable period of time at their full level. But then like you do with chemotherapy, you certainly might think about dose reducing as you get to later cycles just to prevent some of that accumulation of neuropathy.

Paul, this is Thane. Maybe one additional comment on the PET imaging piece. So for Pluvicto, if you look at their FDA-approved label, it requires the utilization of a PET imaging agent or a PET scan before Pluvicto was used. And maybe to give a perspective of how often the PET imaging is used, the PSMA PET imaging agent used for Pluvicto, at least the one that's now standard of care is greater than $1 billion a year product. And so that should give you, I think, a perspective of how often these PET imaging agents are being used in the real-world setting.

So our next question comes from Dina Ramadane at Bank of America.

This is Dina on for Jason. I just had 2 questions. I guess, my first one is, I just wanted to ask about the safety profile and sort of the risk-benefit dose selection. You mentioned the neuropathy as being a dose-limiting AE. Was that the only AE that caused dose reduction? Or were there any others? And then on the 1.8 and 2.4 doses you guys have selected, did you see any of that neuropathy at that 2.4? Or was there really no dose reductions at this level? And then is there any reason why we could see like a different AE profile in enriched CD46 expressers? My second question, sorry, is that I guess like is there any reason why selecting for CD46 expressers like would not lead to an improved response? And is it maybe because while we do have high expression in the tumor, it could still be present at low levels in other tissues. And I guess that maybe surprising scenario that enrichment doesn't lead to a better response. Are you still confident that FG-3246 could work in an all-comer setting, like just maybe looking at this 8-month PFS you showed in the Phase 1 and then your expectations on how it would translate into a Phase 3 in an all-comer setting.

Yes, Rahul, maybe you want to speak to the dose-limiting AEs, that question that Dina asked.

Sure. Yes, happy to speak to the first question in terms of the neuropathy. In terms of the Phase 1 first-in-human monotherapy studies, the majority of the dose reductions for neuropathy occurred with patients with a starting dose level of 2.7 mg/kg. And I don't know the exact percentage, but it was fairly frequent dose reductions necessary in later cycles, so beyond the DLT window. I do think the risk-benefit profile has improved if you start at a lower dose, but then able to keep people on at that dose level for longer. And that really informed the strategy in terms of picking 1.8 and 2.4. I think you asked specifically about the 2.4 level. In the Phase 1 study, there was just kind of the dose escalation cohort treated at that level. So we don't really have large numbers to speak specifically to kind of dose reduction rate at that level. I think we'll learn more from the dose optimization portion. I would expect the dose reduction interruption rates to be lower at 2.4 than 2.7. I think there's a pretty clear relationship there. But I think somewhere in that 1.8 to 2.4 is the sweet spot in terms of patients more tolerable, less neuropathy that accumulates, be able to stay at that dose level for longer.

And then maybe Rahul, just from your perspective, from a clinical point of view, if CD46 expression is not correlated then with response to the ADC based upon the preliminary data that we've seen to date, the 8.7 months of rPFS in the monotherapy trial in the 10.2 months, which is preliminary, but in maturing in the ARSI switch or the combo with Enza, how competitive would you think that particular profile would be in an all-comers population.

I think it still has the potential to be competitive. I mean I think it's always about the magnitude of the benefit when you're talking about PFS and what your comparator arm is. So I mean, clearly, there is activity in all-comers, and those are competitive PFS rates as you sort of look at the landscape and what's been reported. Given that it's a crowded landscape, though, if you're able to take a selection approach and really achieve a higher magnitude of benefit, I think that sets this agent apart in terms of having that diagnostic and the ability to really select. And I would be quite surprised if there wasn't a relationship between the CD46 expression levels and efficacy, just what we know with PSMA that certainly with a radioligand probably going to be true with the ADC targeting PSMA as well. So I think the likelihood is there. And I think there was a question about the off-tumor expression. It seems to be very low. That's based on both the tissue analysis we've done as well as the PET imaging. When you target this specific epitope, you really don't see much in the way of off-tumor on-target toxicity or uptake on the PET. And so we really think it's quite clean in that sense.

So we have a few questions coming from online. So the one is from Jay Olson at Oppenheimer. So Jay is asking, can you talk about the CD46 expression patterns in mCRPC patients and any subset of patients with higher expression levels? And is there any data on how well CD46 high patients respond to chemo and ARSI, and how long do you think recruitment will take for the Phase 2/3 study?

Maybe Rahul, if you want to take the first part of that, and then Deyaa, you can address the recruitment plans for the Phase 2.

Yes. So we've looked pretty extensively at CD46 expression at the RNA level, and I think we certainly have some IHC data, and then we'll learn, of course, more with the PET imaging. But at the RNA level, there really is pretty high and homogeneous expression of CD46 and all the metastatic CRPC biopsies that we've looked at. We have a collection of over 300 mCRPC biopsies, about half of which are bone. And so we interrogated that data set pretty extensively with CD46. It's certainly enriched in metastatic versus localized and intriguingly probably further upregulated in neuroendocrine prostate versus adenocarcinoma. And we've contrasted with full H1 their PSMA expression at the RNA level, and it's certainly higher and more homogenous, and that's been published with CD46. So we think it's quite enriched in the mCRPC patient population. In terms of response or outcomes with standard-of-care therapies like AR or taxane chemotherapy, it doesn't seem to be sort of a very strong negative prognostic factor. Obviously, we don't know from a prediction standpoint whether it might sort of predict for response or resistance to AR-targeted therapies. But I think it clearly is enriched in the mCRPC setting.

And Deyaa, do you want to talk about our expectations on the recruitment?

So in terms of our plans now for the kickoff of the Phase 2/3 registration trial, we are planning to start enrollment before the end of this year, and it is going to be the Phase 2 open label randomized between 2 different dose levels, 2.4 and 1.8, and we are targeting to complete enrollment in the Phase 2 towards the end of 2026. However, it's going to be an open-label study. So we will have the leverage to frequently be looking at signals of clinical activity, whether it is going to be a radiographic progression-free survival rate at 12 months, at 6 months. We will look also at objective response rate for patients with measurable lesions. We will be looking at PSA response as well. So it is going to be a learning process, and we are not going to be really blinded until end of the Phase 2. It's going to be open label. We will have an idea, a good idea how well we are moving forward in this population before we kick off the Phase 3 registration component in 2027.

Also because of the mandatory PET imaging, we'll also be able to ascertain the CD46 expression and drug response as measured by the efficacy endpoints that Deyaa spoke about all throughout the course of the Phase 2 portion of the program.

So our final question comes from a private investor. What's FibroGen's next plan of action if the leading drug fails, just talking in relation to the company's future?

Yes. So clearly not focused on the intent of today's discussion, which is the overview of prostate cancer and the FG-3246 development program. But clearly, we're appropriately planning for all scenarios related to the pamrevlumab readout in both the metastatic trial as well as in the locally advanced trial. And so we're very hopeful that 1 of those 2 trials, if not both of them, read out positive. In the event that we don't have a positive trial, then we have a number of plans in place that we will execute based upon those results.

Thanks, Thane. So that concludes our Q&A session. So I'll turn it back to you for closing remarks.

Thanks, Tara. I appreciate it. Dr. Aggarwal, again, much appreciated your perspective, not only in terms of the evolving treatment landscape as it relates to prostate cancer, but importantly, your perspective on FG-3246 and the significant experience you have in the development program with the drug. So thank you very much. And Deyaa, thank you. And for the audience, thank you for participating. I appreciate the questions. It's a really pivotal time point for FibroGen at this moment with the upcoming pamrevlumab readouts, the activity associated with FG-3246 in prostate cancer and upcoming FDA interaction, hopefully, a published manuscript, Rahul, on the Phase 1 monotherapy data coming up between now and the end of the year. And then the Phase 2 start between now and the end of the year as well. So a really important time for FibroGen, and we're looking forward to what the future holds for us. So thanks, everybody, for participating.