Good morning and welcome to the FibroGen Virtual KOL Investor Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a 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. Thank you, Tara, and good morning, everybody. We're excited that you have been able to join us for our first virtual KOL Investor Event, where today we're going to have the opportunity to review the pamrevlumab Clinical Program in pancreatic cancer and its two near-term readouts in pancreatic cancer as well. First, a quick mention of our disclosure statement. We will have information in this presentation which contains forward-looking statements that involve substantial risks and uncertainties, and so please keep this in mind. We have an important next few months at FibroGen, given our purpose to accelerate the development of novel therapies at the frontiers of cancer biology. And in fact, we have a couple of very important near-term catalysts. There are three primary pillars of our investment approach right now for FibroGen. The first is related to our robust oncology pipeline, where we do have important near-term catalysts. First and foremost, we have upcoming readouts in pancreatic cancer, a Phase III LAPIS top line expected sometime in the first quarter of 2024, and then the Precision Promise top line, Phase II/III readout expected in the second quarter of this year, both of these representing substantial commercial opportunities. We also then will have the opportunity to share Phase I monotherapy data within the next few months on our CD46 targeting ADC for metastatic castrate-resistant prostate cancer. We also then have we'll expect to file an IND in the first quarter of this year for our galectin-9 targeting monoclonal antibody for solid tumors. And then early in 2025, we expect to be able to file an IND for our CCR8 targeting monoclonal antibody for solid tumors as well. So some important near-term catalysts, given our pivot and our focus on oncology going forward. In addition to that, we also have an important and growing roxadustat revenue and cash flow. It's approved, as many of you know, in more than 40 countries, commercialized by AstraZeneca and Astellas. In fact, it's a positive cash generator for us in China, where we do commercialize with AstraZeneca. We expect an approval decision mid this year for the SNDA that we filed in China for anemia associated with chemotherapy-induced anemia. Finally, we have a strong balance sheet. We announced at the end of the third quarter of last year, $283 million in cash and cash equivalents, with a sufficient runway to fund us into 2026. A number of not only near-term catalysts but also some significant strength within the core business for FibroGen. So today, we are going to focus on the two pancreatic cancer programs, and we're so fortunate to have two of the leading experts in pancreatic cancer join us: Dr. Andrew Ko, Professor of Clinical Medicine and Associate Chief of the Division of Hem/Onc at UCSF, who will discuss the unmet medical need and the current treatment landscape for pancreatic cancer. Then following Dr. Ko will be Vincent Picozzi, who is Director for the Pancreatic Cancer Center of Excellence at Virginia Mason Medical Center in Seattle. Dr. Picozzi will discuss the clinical development program for pamrevlumab for pancreatic cancer treatment. Again, we're so lucky to have two of the world's leading experts in pancreatic cancer. If you'd like information, more information on their CV, they were included in the program announcement. We'd probably spend most of the morning if we had to cover more of their CV. But again, we're so fortunate and lucky to have their expertise guide us this morning. So I will now turn it over to Dr. Ko. Well, thanks so much. I appreciate having the opportunity to speak this morning. I hope those of you joining from the East Coast are staying safe and warm. I have the privilege of trying to frame this discussion by talking about the current state of pancreatic cancer treatments and to provide you sort of an overview of where we're at as of 2024 in terms of how we treat patients with pancreatic cancer. After that, I'll turn it over to my illustrious colleague, Dr. Picozzi, to focus specifically on pamrevlumab. Just to start by discussing the scope of the problem in pancreatic cancer, and this really is becoming a real issue as we progress in time. And probably by the end of this decade, pancreatic cancer is actually going to be the second leading cause of cancer-related mortality in the United States, trailing only lung cancer. Stage for stage, it is the cancer associated with the poorest survival of any major cancer type. These are some of the statistics, I will say, updated as of 2024. We're talking about approximately 66,000 new cases, 51,000 deaths attributable to pancreatic cancer. We'll talk a little bit about the biology of this disease, but one of the major points is that too often, by the time patients come to see myself or Dr. Picozzi, they are already inoperable, have advanced or metastatic disease, and are really what I describe as treatable but not necessarily curable. When we talk about pancreatic cancer for the purposes of this discussion, I'm focusing really on what we call pancreatic ductal adenocarcinoma. So we know that there are different cellular compartments within the pancreas. There's a whole separate type of tumor called islet cell or neuroendocrine tumors of the pancreas that has completely different biology, different prognoses. But the vast majority of cancers that arise from the pancreas arise from the ductal epithelial, and thus we term these pancreatic ductal adenocarcinomas. Pancreatic cancer does fall into a TNM staging, but really for clinical purposes, we categorize pancreatic cancer by their clinical and therapeutic implications. So you can see here the stage breakdown from localized disease, meaning patients who are fortunate enough to be diagnosed with very early-stage cancers that are amenable to an operation, even upfront. But you can see that really comprises fewer than 10% of the population based on current statistics. The majority, unfortunately, are diagnosed with metastatic disease and a significant proportion with locally advanced or unresectable disease. We're not going to talk too much about the anatomy of pancreatic cancer, but where the tumors are situated, they can grow just through local extension to either involve or even encase some of the key mesenteric blood vessels, the celiac artery, the superior mesenteric artery, the portal vein, that can render them inoperable. And then there's this whole separate category of borderline resectable tumors, where patients may have a localized tumor that is not felt to be operable initially, but with appropriate downstaging and successful neoadjuvant treatment, can be taken to surgery successfully at a later time. And you can see the associated five-year survival rates with each of these. The numbers may be trickling upward somewhat optimistically, but you can see even for patients with localized and potentially curable disease, it is still only a minority who ultimately are cured. We're going to focus, or I'm going to focus my points today primarily on the advanced and metastatic disease setting in the interests of time. I want to say that the mainstay of treatment for advanced metastatic disease remains chemotherapy. These are just sort of the primary data sets specific for the Phase III studies that have informed the use of FOLFIRINOX as sort of a go-to frontline standard compared to the erstwhile standard of gemcitabine alone. You can see that this French study that's now more than a decade old produced significant improvements with the use of FOLFIRINOX, which is a combination of 5-FU, leucovorin, irinotecan, and oxaliplatin. This combination was actually quite transformative in terms of seeing patients with metastatic disease hit a median survival of almost one year. In fact, some contemporary data sets with FOLFIRINOX suggest that the median survival now actually exceeds one year for patients with metastatic disease, highlighting, though, that patients who are treatable with FOLFIRINOX tend to be the more robust individuals with a good performance status. Now, the other very commonly used regimen is the combination of gemcitabine plus nab-paclitaxel. This study, compared to the FOLFIRINOX trial I showed you previously, was really a little bit more broad in terms of its scope. It was an international trial and included folks who were older, up to age 85, as well as with a performance status as low as two. So this gemcitabine-nab-paclitaxel regimen is actually perhaps a little bit more broadly applicable to a greater swath of patients with metastatic disease. You can see here, again, an improvement in median survival. This study showed a median survival of gemcitabine/nab-paclitaxel of 8.5 months. Although, again, if you look at some contemporary data using this regimen, it is now approaching one year with the use of gemcitabine/nab-paclitaxel. So if you just look at these studies side by side, of course, we want to avoid too much in terms of cross-study comparisons. But you'll see that the gemcitabine/nab-paclitaxel study, or what we call the MPACT trial, was much larger in scope. And if you look at the toxicity profiles, you can see some of the differences, the nuanced differences in terms of toxicities. Now, for the longest time, there was the question, well, what about a direct head-to-head comparison between FOLFIRINOX and gemcitabine/nab-paclitaxel? And lo and behold, at this year's ESMO meeting, this Japanese study called GENERATE was presented. And this really kind of surprised all of us because this was, again, this direct head-to-head comparison we were looking for. And you can see here, just looking at the efficacy data, that if anything, there was a trend towards an improvement in survival and PFS with the gemcitabine/nab-paclitaxel combination compared to FOLFIRINOX, and really an almost unheard-of median survival of 17 months for patients treated with gemcitabine/nab-paclitaxel. And this study was actually terminated for futility after pre-planned interim analysis, where there clearly was originally powered to look for an improvement, what everyone thought, in FOLFIRINOX, but this turned out not to be the case. Now, again, whether this is specific to the Japanese patient population or whatnot, it's not quite clear. But I think it provides further justification in terms of gemcitabine/nab-paclitaxel serving as a very appropriate chemotherapy backbone or for clinical trial purposes. Now, just to add a little bit additional confusion to the mix, we have the Phase III NAPOLI-3 trial that was originally presented last year and just published recently. This is basically using FOLFIRINOX with the substitution of nanoliposomal irinotecan, a drug we currently use in the second-line setting, and moving that up to the frontline setting in place of free irinotecan in the FOLFIRINOX regimen. This was the basis of the NAPOLI-3 trial, which compared this so-called NALIRIFOX regimen to the combination of gemcitabine and nab-paclitaxel. Again, a very large international study of approximately 770 patients. If you look at the results here, you see that NALIRIFOX did, in fact, confer an improvement in survival compared to gemnab-paclitaxel, so improvement in survival with a median of 11.1 months, improvements in PFS. But I called to your attention the fact that that 11.1 months, for those of you who remember the data that I showed you specific to the FOLFIRINOX trial from more than a decade ago, those results from NALIRIFOX are essentially identical to those that we saw seen historically with FOLFIRINOX. So it's just raised a lot of questions in terms of, will once nanoliposomal irinotecan gets approved for use in the frontline setting, whether we're going to be calmly adopting NALIRIFOX as a potential frontline standard. So here are what I view as sort of some of the outstanding issues in the treatment of metastatic pancreatic cancer. I've shared with you some studies specific to gemcitabine/nab-paclitaxel and FOLFIRINOX and NALIRIFOX, but the decisions about which drugs to use are still decided primarily based on clinical criteria such as performance status, age, comorbidities, and then certainly patients' goals of care, practicalities, patient preferences. And we're, I'll say, not yet at the point of being able to adopt what I call precision oncology to the majority of our patients. Now, there are emerging pieces of evidence to show that there are specific molecular and genetic subtypes of pancreatic cancer that may help guide the selection of therapy. But again, this applies only to a minority of individuals. This slide is just a reminder that now national guidelines recommend that all patients, irrespective of whether they have a striking family history or not, should be seen ideally by genetic counselor, undergo germline testing to see whether they have any hereditary pathogenic mutations, which is perhaps applicable to maybe up to 10%-15% of patients who have some sort of familial or hereditary component to their disease. The other side of that coin is, in addition to germline testing, for patients who are being considered for treatment, we now almost routinely perform next-gen sequencing, molecular profiling. Obviously, there are many commercial assays that now do this. This now has been adopted, I think, fairly routinely into our standard practice. Why do we do that? Well, it's to look for the, I'll say, still relatively uncommon types of mutations or genetic alterations that can inform our treatment paradigms. In fact, we know that patients who are able to receive so-called matched therapy, which means treatment tailored to their molecular findings, that if you have a biomarker and it's truly actionable, that actually does improve their outcomes compared to those who don't have any sort of targeted molecular finding. The problem is some of these mutations are quite rare, so at least the common problem for those of us who lead or design or try to enroll to trials in that sometimes you have to screen a lot of patients just to identify one eligible patient for your targeted therapy. There's also sometimes limited tumor tissue available to perform molecular profiling. With the turnaround time it takes to do some of these assays, sometimes patients can't afford to wait a long time for those readouts before they need to start therapy. Previously, I had a lot of slides showing these sort of the different so-called therapeutically actionable genetic alterations and mutations. But again, in the interest of time, I'm just encapsulating them all on this table. This is not meant to be comprehensive, but these are what I'll call some of the leading findings that we have. First of all, there is this whole homologous recombination deficiency pathway, or HRD. And there are core and non-core genetic mutations in this pathway. The most common ones that I'm guessing the audience has heard of quite a bit are so-called BRCA1/2 or PALB2 mutations. Depending on the demographics of your patient population, we'll see BRCA mutations in about 5%-10% of individuals. And what we know is that those individuals are responsive to platinum-based chemotherapy and are candidates for so-called maintenance treatments if they respond well to their frontline platinum-based chemotherapy with a class of oral agents called PARP inhibitors based on this principle of synthetic lethality. Then a number of these other mutations are much less common. So there's a huge interest, obviously, in KRAS biology. And specifically, G12C mutations do have now a number of different agents, adagrasib, sotorasib, that are approved for non-small cell lung cancer, not quite yet for pancreatic cancer, but for the 2% of individuals with G12C mutations, we're actually seeing reasonable response rates in the second, third-line setting. And there's a whole class of other types of even pan-RAS inhibitors and even G12D inhibitors coming down the pike, not quite ready for prime time. The only other one I'll mention on this table is the, again, small percentage of patients who have high microsatellite instability or deficient mismatch repair. Again, for those that 1% of individuals or so, they are candidates for immune checkpoint inhibitors based on the disease-agnostic FDA approval of drugs like pembrolizumab. Again, I'll highlight that even in those patients, the response rates associated with these immune checkpoint inhibitors specific to pancreatic cancer tend to be lower than that seen with the same class of drugs for other solid tumors, highlighting the immunologically cold nature of these pancreatic tumors. So this is the current state of treatment for advanced pancreatic cancer in 2024. I'm going to add a couple additional points here just for the, as I mentioned, some of the tailored therapies and the option for maintenance treatment. But you see sort of the frontline treatment options of chemotherapy, generally gemcitabine/nab-paclitaxel, FOLFIRINOX, NALIRIFOX. Historically, about 50% of patients were candidates for second-line treatment. I actually think that number is increasing. And in my practice, it's probably about at least 80% of patients who are well enough to try some second-line therapy. But as we get to second- and third-line therapies, etc., we're also really starting to look more at clinical trial opportunities for those patients. In the last couple of minutes, I'm just going to touch upon sort of earlier disease settings, specifically locally advanced disease, since that's a primary focus of one of FibroGen's trials. But you can see here, as I mentioned earlier, these categories of truly resectable disease where patients can technically go to surgery upfront, to the other end of the spectrum where patients have locally advanced unresectable disease. And I highlight in sort of the red italic bold-faced sort of what our general treatment approach is. And specifically for locally advanced unresectable disease, meaning tumors that are not just big and bulky, but that really are engulfing those key blood vessels that provide and draw blood supply through all the abdominal organs, our general approach for these individuals starts with systemic therapy, very analogous to what I shared with you about patients with metastatic disease. And we'll generally treat for this in induction period for maybe up to six months or so, with the goal not just of shrinking the tumor down, but try to try to prevent or eradicate any micrometastatic disease from settling down. And then thereafter, for patients who achieve a good response, they have a number of options. One is obviously we readdress, are they candidates for surgery? Even if they were initially truly unresectable, have we now successfully treated them to the point where, yes, now maybe with some vessel reconstruction, maybe with a very aggressive type of operation of trying to render them disease-free? I highlight in bold here consolidated radiation treatment for these individuals. This remains very controversial in terms of what, if any, benefit radiation adds. It may provide some measure of local control, but so far it has failed to demonstrate just an overall survival benefit compared to patients just getting chemotherapy without radiation. So this differs institution to institution. I do still use radiation quite commonly for many of my patients as consolidation with locally advanced disease for those who cannot undergo surgery. Finally, I'll just give you a whiff of novel and investigational approaches for treatment of pancreas cancer and then turn it over to Dr. Picozzi. This is just the point of trying to move beyond conventional chemotherapy for pancreatic cancer. I like to think of it in these sort of broad terms with this Venn diagram to show that these really overlap, including I've already mentioned a few molecularly targeted agents, but these other categories of obviously agents to try to prime or unleash the immune system, starting with but by no means limited to immune checkpoint inhibitors, and then a whole category of stromal targeting agents, which obviously we'll be talking about in greater detail. This is just to point out that there is a tremendous interest in this so-called pancreatic tumor microenvironments. Not just the pancreatic tumor cells themselves, but the whole environment of different cellular and extracellular components that comprise a pancreatic tumor. The issue with this microenvironment is actually it tends to create a very immunosuppressive milieu. You don't really see a ton of these cytotoxic T cells. They're just not getting in there as a surveillance mechanism against pancreatic tumors. And then additionally, you have this very dense desmoplastic component that's, in simplistic terms, but much more complicated than this, may actually just represent a physical barrier to effective drug delivery. And so just in these classes of drugs, these are just a smattering of the novel immune-based approaches that have been or are currently undergoing evaluation, oftentimes in combination with chemotherapy, including even such forward-thinking ideas as T cell therapies and vaccine-based approaches. And then finally, I'll just note here, and this is my final slide, as we talk about stromal depleting or modifying agents, a number of very interesting molecules that have been looked at. And highlighting here, obviously, as I turn it over to Dr. Picozzi, connective tissue growth factor as one potential target that can be used to try to exploit and modify this peritumoral stroma. So with that, I will stop and I'm happy to turn it over to Dr. Picozzi. I look forward to your questions afterwards. Thank you. Thank you for the very kind introduction, Dr. Ko, and the wonderful overview of the use of drug therapy in advanced pancreatic cancer. And thanks to all of you for participating today. Although I live in Seattle, I grew up in upstate New York, and so I'm well familiar with the impact of ice and snow in the Northeast. So thanks for joining us. My charge today is to discuss the development of pamrevlumab in pancreatic cancer. And in so doing, I'm going to take about 15 years of work and try to condense it down to about 15 minutes. And I'm going to divide my remarks into three groups, three sections. First is the preclinical development of pamrevlumab. The second is the use of pamrevlumab in some key early-stage clinical trials. Finally, discussion of the current Phase three registration trials, which are prepared to read out sometime this year. Okay, now I don't see my arrows for advancing the slides on the screen. Okay, here's the preclinical data for pamrevlumab to be presented. Fortunately, pamrevlumab has a very robust preclinical data set. If I could have the next slide, please. There we go. The clinical story of pamrevlumab really begins with a molecule called connective tissue growth factor. Connective tissue growth factor is a protein that exists. It's secreted by fibroblasts and endothelial cells. It seems to have a very central role in the molecular crosstalk between pancreatic cancer cells and the surrounding stroma, as Dr. Ko described. It also has a role in fibrosis in benign conditions. You will see that CTGF has a variety of molecular outcomes with respect to pancreatic cancer. It promotes tumor cell proliferation. It decreases apoptosis and thereby promotes survival of tumor cells. It supports tumor cell invasion. With respect to the stroma itself, it stimulates fibroblast activation, proliferation, and deposition of the extracellular matrix. CTGF expression has been shown to be increased in most patients with pancreatic cancer. Its over-expression seems to contribute in an important way to tumor cell growth. Now, what pamrevlumab does is actually inhibits the activity of CTGF in pancreatic cancer. Pamrevlumab is a novel, fully humanized anti-CTGF antibody that binds to one of the domains of CTGF, domain II. When pamrevlumab is used in pancreatic cancer clinical models, it reverses the effects that I just showed you. It reduces tumor cell proliferation. It promotes tumor cell apoptosis. It decreases tumor cell vascularization and seems to, in animal models, increase survival. I'm sorry, I can't get the slides to advance. And in particular, with respect to the KPC mouse model, addition of pamrevlumab to chemotherapy, as was shown by Neese working in David Tuveson's lab, was shown to decrease tumor volume in comparison with gemcitabine alone as chemotherapy, decrease metastatic spread, improve survival of laboratory animals significantly, and reduce the formation of ascites. Okay, and in more detail, you can see here that the effect of pamrevlumab on survival seemed to express itself primarily through inhibition of an enzyme called XIAP, which is an enzyme that is linked to the X chromosome. And what pamrevlumab does is inhibit this enzyme, which in turn inhibits apoptosis. So in essence, what it does, it inhibits an inhibitor of cell death, thereby promoting cell death. And this effect, as you can see, was very strongly correlated with reduction in tumor growth. So with these data, pamrevlumab was poised to enter Phase I and Phase II clinical trials. There were two important trials that really support the use of pamrevlumab in more advanced trials. The first was executed in a Phase Ib fashion in combination with gemcitabine and nab-paclitaxel. This trial, which was published in 2017, included 75 patients, the vast majority of whom had metastatic disease. The initial intent of the trial was to settle on a dose, trying to achieve the concentration level that you see. The second important aspect of it was to examine survival. What could be seen was that in patients who achieved a particular concentration of pamrevlumab, actually experienced a median survival of 9.4 months, which is very much akin to the combined drug therapies that Dr. Ko showed us in advanced pancreatic cancer. This effect also produced a one-year survival, again, parallel to what we saw for other drug combinations, particularly FOLFIRINOX. This effect was achieved at a dose of 35 milligrams per kilogram given every two weeks. Importantly, there was no significant incremental toxicity that was noted in addition to the two other antineoplastic agents. With this encouraging start, the use of pamrevlumab advanced into a Phase II trial in pancreatic cancer. Locally advanced pancreatic cancer was selected in order to test the use of the drug with chemotherapy in a neoadjuvant position, and also to examine its impacts on other treatment modalities, most particularly surgery and micrometastatic disease. It was paired, in this case, with gemcitabine and nab-paclitaxel to provide a more active chemotherapy backbone. The essence of the trial is taking patients with locally advanced pancreatic cancer, as Dr. Ko has described, their stage confirmed by staging laparoscopy, and divide them into two groups: a first group of 24 patients that received gem, nab-paclitaxel, and pamrevlumab; and then a second smaller group who received gemcitabine and nab-paclitaxel only. Those patients were treated for six months, at which point in time they were assessed for surgical extirpation and then followed over time. The primary endpoint of the study was safety, but the secondary endpoints related to treatment endpoints: resection rate, progression-free survival, and overall survival. Here you see what I think is the important result of the study. If we focus principally on Arm A, which is the experimental group on the left-hand side of the slide, we see that three-quarters of patients were able to complete six months of therapy. But perhaps more importantly, a very large number, about 70%, were potential candidates for surgical exploration, which is equivalent to candidates for treatment with curative intent, this taking place in a group of patients in whom surgery is not commonly able to be utilized. And of those patients, a third actually achieved a successful resection. And here you see that of the patients treated, a number of them not just responded to therapy but had very robust responses. This is a slide that looks at individual patients and the degree of normalization of their PET scan SUV uptake. You can see there were a number of patients who actually achieved a complete normalization of their SUV, implying a very major effect on the cancer itself and its response, and providing a prognostic substrate for the use of surgery, again, in this group of patients in whom surgery is generally not contemplated. So to summarize the safety aspect, which was, of course, the primary endpoint, the drug again was very well tolerated. There was no added toxicity to the chemotherapy regimen. And in fact, if you were to look at the toxicity of pamrevlumab with gemcitabine and nab-paclitaxel versus the native drug combination alone, you would see that the side effect profile was virtually identical. There was no notable change in laboratory data. The treatment-associated AEs reported were fatigue, nausea, alopecia, decreased appetite, and peripheral edema. There were no fatal treatment-associated adverse events. And again, the TEAEs were very characteristic of what you would see with gemcitabine and pamrevlumab alone. So with that, there was a very encouraging safety signal. There was evidence of enhanced activity, particularly as pertains to surgical candidacy. And with that, a decision was made to advance pamrevlumab into Phase III trial. And with that, FibroGen has launched two Phase III registration trials. And here they are shown side by side. The first trial launched is the so-called LAPIS trial. This trial is based on the trial I just showed you in locally advanced pancreatic cancer. And I think the important point, as Dr. Koh made previously, is that between the patients in these two trials, it subsumes the potential for use of pamrevlumab in virtually all patients with pancreatic cancer. The LAPIS trial is being run by FibroGen. It's a global trial. It has registration intent. The eligibility criteria are similar to those that you saw in the previous trial, with one exception, and that is that staging laparoscopy was not used. Another important difference in that trial is that patients were able to receive FOLFIRINOX as opposed to gem, nab-paclitaxel as a chemotherapy backbone. The second trial, which was done through the auspices of the Precision Promise framework, sponsored by the Pancreatic Cancer Action Network, is a U.S.-only trial for patients with metastatic pancreatic cancer. Importantly, the drug is being tested with gemcitabine and nab-paclitaxel, both as first- and second-line therapy simultaneously. The goal of both trials is overall survival. Another important difference is the statistics are somewhat different. In the LAPIS trial, the statistics are based on events using hypothesis testing and p-values. The Precision Promise trials you'll see in a second are based on Bayesian statistical design. Here is the LAPIS trial schematically. Again, I'll highlight the ability to use either nab-paclitaxel or FOLFIRINOX. Otherwise, the study design is essentially the same. This trial actually has a number of unique elements to its study design, one of which is an external review of the surgical decision to proceed with surgery. Another is EFS analysis, not just on overall survival, but what is known as events-free survival, which is akin to the probability of being potentially eligible for treatment with curative intent. The Precision Promise trial, as I mentioned, is based on Bayesian statistics on an adaptive platform. Its primary endpoint is also overall survival, and as I mentioned, includes patients with both first and second-line disease. This trial is being executed through the Precision Promise framework at about 25 centers around the United States. If you examine it, I think you'll see that virtually every leading center in the country, including Dr. Ko's, is a member in this clinical trial. So with that, there's a tremendous resource with respect to clinical and scientific leadership in the field of pancreatic cancer, with the engagement of these key opinion leaders being central to the whole endeavor. The trial is also supported by state-of-the-art translational analysis with biomarkers and supportive care. This trial is actually supported by PanCAN itself in part, both operationally and financially. Important to note as well is that this trial was vetted by the FDA prior to initiation to hopefully produce a facilitation for drug approval if successful. This is an overview of the trial, which is very complicated in its nature. It also is an extremely innovative trial with a number of unique clinical and statistical aspects. But the trial, in essence, is a randomization 70-30 of the experimental arm or experimental arms (because multiple arms can be supported at the same time) to one of two control arms, gem, nab-paclitaxel, and FOLFIRINOX, recognizing their current equivalency, as Dr. Koh has pointed out to us. With 50 patients enrolled into an individual investigational arm, patients begin to be analyzed from a statistical standpoint as to probability of success. This analysis reoccurs every 10 patients. At 100 patients, a decision is made as to whether the probability is great enough to take the trial to what we call the second stage and accrue an additional 75 patients. This is all done completely blinded from the investigators and is done in a seamless fashion. So if we summarize what we've learned about pamrevlumab to date in pancreatic cancer, the drug itself has a novel mechanism of action targeting what seems to be the important molecule of connective tissue growth factor in pancreatic cancer biology and growth. There is a robust preclinical rationale to support its use. I showed you just one important study. There are many others. In earlier Phase trials, pamrevlumab was extremely safe without added toxicity to the chemotherapy regimen, supporting the Phase III work. Significant activity was shown both in the Phase I and Phase II experience. As a result of that, we have the 2 late-stage trials, which are currently pending readout, which are applicable to the vast majority of pancreatic cancer, again, with the hopes that results will come very soon. I want to thank you for listening to these remarks. On behalf of Dr. Ko and myself appreciate your attendance. I believe now our session is open to questions and answers. Thank you very much. Dr. Picozzi, thank you. Dr. Ko as well for the pancreatic cancer overview and the overview of the pamrevlumab clinical development program. We're now going to. We've got about 15 minutes or so for Q&A. Joining Dr. Ko and Picozzi are John Hunter, who is FibroGen's CSO, who's here in the room with me. Ewa Carrier, who's FibroGen's clinical development lead with a special focus on pancreatic cancer. We also are joined by Ben Saville, who is president and lead statistical scientist at Berry Consultants. Ben is an expert in innovative Bayesian and adaptive clinical trials. Tara, I will now turn it over to you to begin the Q&A session. Great. Thank you, Thane. So at this time, we'll be conducting a question-and-answer session with our speakers. As a reminder to the audience, if you'd like to submit a question, please use the Q&A text box at the bottom of the webcast player. And to our analysts who are joining us live, please use the raise hand feature to indicate that you have a question. So please hold for a brief moment while we pull for questions. So our first question comes from Andy Hsieh from William Blair. Please go ahead, Andy. Oh, great. Thanks for taking my question. Really appreciate putting together this panel all of them. Super helpful in terms of, you know, kind of setting expectations, heading into the two meaningful readouts. I have three. They're all relatively short questions. You know, in terms of the Precision Promise trial, obviously the 35% chance of probability of success is very provocative, especially given the, you know, dire medical need in pancreatic cancer. I'm just curious about the mechanics of that 35%. What is it comparing to? Is it comparing just the FOLFIRINOX arm, the gem/Abraxane arm? Is it or both, blended average, just a little bit more on that comparison from a statistical perspective? The second question has to do with the surgical exploration. I think Dr. Picozzi mentioned about that assessment following the neoadjuvant treatment in a LAPIS study. I'm curious about the protocol in terms of how the surgical resection is being called. Is there a blinded third-party committee, or is it basically called by the treating investigator? And then the third one, probably a very easy question for you guys. But I'm just curious about the FOLFIRINOX and the modified FOLFIRINOX. How do you choose between the two from a patient perspective? And maybe in the real-world setting, how common are they used respectively? Thank you for taking my questions. Andy, thanks much for the questions. I'm going to defer the third one to later, given the likely queue that we have and the fact that it's not necessarily pinpointed on the pamrevlumab program. But I'm going to ask Dr. Picozzi and Dr. Ko to speak about this 35% threshold, and then perhaps also ask Dr. Saville to discuss it as well. Even though Dr. Saville has not been involved in the design of the Precision Promise program, he does know quite a lot about Bayesian clinical trial design. So, Dr. Picozzi, if you'd like to maybe take a crack at the 35% threshold that Andy asked about. Okay. The way I think of this is that it's not a comparison directly to a control, but an assessment of probability. You saw that the statisticians who do extensive modeling, statistical modeling, before the experimental arm is introduced have a sense of the likelihood of success of the experimental arm occurring based on the parameters, statistical parameters set down by the trial. So that as time goes on, these probability assessments take place. And once 100 patients are reached (remembering, again, it's an adaptive trial, so randomization can increase or decrease based on probability), a decision is made whether to advance to the final 75 patients. The analogy I think of when I think about this is a baseball team in a pennant race. You start with a certain sense of the likelihood of the team winning the pennant. It's actually the same for all teams at the start of the season. But as the season progresses, a team may win more games or lose more games. And therefore, the likelihood of the team winning the pennant becomes higher or lower. In this case, once 100 games are played or 100 patients are treated, the probability of the team winning the pennant is thought to be greater than 35% based on the statistical modeling. And then the protocol says, "OK, hurry up. Let's play the last 75 games and see if the team actually wins." So it's not a hypothesis testing like it is in more traditional statistics, but a testing based on probability that relates to incorporating previous data. And our statistician can probably give a more sophisticated answer than that. So that's how it came to be. The 35% threshold related to the hazard ratio that the study asked for, combined with the number of patients in the control arm at that time, and ergo, the power of the conclusion. Thanks, Dr. Picozzi. Dr. Ko, would you add anything to that? And then we'll ask Ben for his comments as well. No, I just want to say that this was a pre-specified sort of idea in terms of—and I think we can gauge whether we what we've viewed 35% as sort of the likelihood of success. I mean, it is at least—I will say it's not 30%—it is at least 35%. And yes, the study did randomize patients for the control arms to equal ratios of receiving either gem, nab-paclitaxel, or FOLFIRINOX. So even though it's not necessarily a direct head-to-head comparison, the aggregate of those control arms is being looked at as sort of as the reference standard. And Ben? My understanding is that you have the two control arms, but you have a Bayesian model that's basically calculating the probability that you're superior to these control arms used in a hierarchical model. And so I think of that kind of more like a weighted average. What do we think about that? I could be wrong in terms of the logistics, the mechanics of that. But that's my understanding based on what I know. The predictive probability of success, I think the sports analogy is a great one. The sense is that you have data when you calculate a predictive probability of success, given the current data and the uncertainty left in the trial. In other words, how much time is left, how many events are left. If it's the very end of the game, you know the result. If you're halfway through the game, there's a lot of uncertainty left. So given the data you have and the uncertainty left remaining, what's the predictive probability that you would be successful at the end of the trial? And if that is sufficiently high, in this case, 35%, then it graduates. 35% is actually probably rather positive data. So even though it sounds kind of low, it means you have a point estimate that's probably quite impressive, maybe not quite large enough to win if you observe that point estimate at the end of the day. But it is going to be very favorable data. You're trending in the right direction. Things are looking good. You need more data. You need more events. Thank you, Ben. Dr. Picozzi, if you could just touch on this surgical exploration question that Andy asked and how it's being called. The surgical assessment is primarily made by the local investigator. However, it's being reviewed by a board, a central board, that receives the clinical data from the treating site. The clinical group reviewing the case makes its own independent recommendation, which may agree or disagree with the local recommendation. The local surgeon, in this case, has the ultimate say-so as to whether a patient proceeds to surgery or not. But if their decision differs from that of the central review board, they are asked to provide a written justification for why they made the decision that they did. The purpose of this was to try to provide some standardization and objectivity to the surgical decision, which can at times be somewhat subjective. Thanks, Dr. Picozzi. Andy, again, thanks for your question. Tara? Next question, please. Yes. Thank you, Andy. The next question comes from Khalil Fanina at Goldman Sachs. Please go ahead, Khalil. Everyone, can you hear me? Yes. Hi, everyone. So thanks to FibroGen, and thank you, Dr. Ko and Picozzi, for your time today and for setting up this session. I guess one question from us. I suppose this might be directed towards Dr. Ko, and it would be great to hear commentary from everyone else as well. On the Precision Promise trial, so I know you brought up the FOLFIRINOX and gem/nab-paclitaxel, excuse me, comparison in the head-to-head trial that came out at ESMO last year. Given the sort of discrepancy between that head-to-head trial in terms of OS and previous trials of those two treatments, what would you like to see from pamrevlumab in Precision Promise in order to think about where to place it, whether that be in a first-line or second-line setting? Yeah, it's a good question. You know, I will say our bias, or even up to this point, has been sort of, "Oh, yeah, for a good performance status patient, I'm tending to use FOLFIRINOX," because at least based on sort of the earlier data, it seems that FOLFIRINOX really came out on top. And again, if you think of NALIRIFOX, it's very similar to FOLFIRINOX. That did beat gem/nab-paclitaxel in a direct head-to-head comparison. So you've got sort of very disparate datasets between the Japanese study and then NAPOLI-3 and putting that in the context with sort of the original trials with both FOLFIRINOX and gem/nab-paclitaxel. It's a very roundabout way of saying, you know, I think we are approaching now, looking at median survivals for a trial population with metastatic disease, you want to see it reach at least the 12-month threshold in terms of median survival. Now, again, for the LAPIS trial, locally advanced disease, and we didn't talk that much about the prognosis there. But there, especially for those folks who do make it successfully to surgery, we are talking about much better outcomes, which is why in the past you had sort of metastatic and locally advanced disease lumped together. And now it's very clear that you need very separate studies because of both different biology and different treatment paradigms. You know, we talk about median survivals, and it's just a very quick and dirty way. Look, I've tried to graduate now to more looking at sort of hazard ratios and things to get a really better sense of sort of a meaningful survival benefit and what it, you know, what might be statistically significant versus what might actually be very clinically meaningful in those situations. So, you know, you'll see some studies with a positive readout with a hazard ratio of 0.84. And, you know, we might sort of raise an eyebrow there. I do try to look for a little bit more robust activity vis-à-vis the hazard ratio. Got it. And then I guess a quick follow-up to that. Would you perhaps, from the LAPIS study, look at maybe resection eligibility, or would there be a secondary endpoint that's more important to you, given your point of that it can be disparate, like, you know, given the disparity? Yeah, you know, I'll let Dr. Picozzi speak a little more about the trial itself. But because there's so much subjectivity in terms of what someone calls resectable or not, I actually think the LAPIS trial did a really nice job of being very rigorous in trying to define both someone who is truly unresectable at baseline and then those folks who are really going to be reasonable candidates to at least take to surgical exploration following chemotherapy. Again, there's no question that those folks who do make it to a successful R0 resection are going to have better outcomes compared to those who don't. So, you know, I think the ability to get to a successful R0 resection is certainly a meaningful endpoint as far as that goes. Dr. Picozzi? Yeah, I think with respect to the Precision Promise trial, if the pamrevlumab gemcitabine/nab-paclitaxel experience is successful, it will generate median survivorship that will be competitive with the 5-FU-based regimens and encourage it for the use and exploration. The LAPIS trial has more complex and loftier goals. It's an issue of not just improving overall survival, but seeing what fraction of patients can actually be treated with curative intent in a group that normally cannot be. As Dr. Ko points out, and actually a slide we had but didn't show, patients who undergo surgery in locally advanced pancreatic cancer do have a very significant improvement in their median overall survivorship to those that do not. But more importantly, they become candidates for treatment with curative intent. Khalil, thank you. Got it. Thank you so much for taking my questions. Have a good day. Thanks, Khalil. So our next question comes from Jason Gerberry at Bank of America. Please go ahead, Jason. Sorry, can you hear me? Yes. Yes, you can. Great. Yeah. So my follow-up is just on the Precision Promise and the 35% probability based on hitting the predetermined OS hazard ratio. Can you just help clarify? You know, does that typically tie to a hazard ratio that, you know, we think of triggering positive interims in the 0.6-0.7 territory or closer to the threshold of clinical meaningfulness, which we think of as around 0.81 per the ASCO guidelines? And then I don't know if this is getting too far off topic, but I'm just curious from the physician's perspectives, real world with metastatic pancreatic cancer, is the treatment rate lower versus, you know, most other malignancies in the metastatic, just given the relatively poor OS prognosis? Thanks. Jason, thanks. Dr. Picozzi, do you want to take the first one? Okay. So to answer the first question, the hazard ratio that Precision Promise demands of an experimental arm is very aggressive. It is in the 0.6-0.7 range. And that's how the trial is able to be executed with as few as 175 experimental patients. With respect to your second question, if you look at the United States and most of the Western world, about 85% of people with metastatic pancreatic cancer will elect to undergo therapy. That does vary to some extent in different countries. But if you look at the U.S., Europe, Japan, that's the approximate rate of patients who undergo initial treatment. Dr. Ko, anything to add to that? Yeah, you know, I do think there's real value to real-world data because at sort of an academic center like UCSF or Virginia Mason, or a lot of the Precision Promise sites, you know, they have outstanding care and ancillary and support services. So no doubt, we perhaps see a slightly skewed patient population. I think it's important to recognize that there are wide swaths out there where there's less access to care, less supportive care. That being said, I do think that we're, as we are changing both maybe the biology of this disease and maybe the previously nihilistic philosophy of this disease, I do think as we get the word out there more with treatments that patients are getting more access, more availability, and willing to try treatments. And that includes both in the front and second-line settings. As I pointed out before, oftentimes it was a one-shot deal. Patients would try some, and then they would stop after that. I think we're now moving more to seeing patients be sequenced through multiple lines of therapy. Thanks, Dr. Ko. Thanks, Jason, for your question. Tara, we probably have time for one more. Yes. So our next question comes from Michael Okunewitch from Maxim Group. Please go ahead, Michael. Hey there. Thank you very much for taking my questions today. Thanks for putting together this KOL event. I guess I'd direct this towards Dr. Picozzi. I'd like to follow up a bit on my colleague's prior question regarding the LAPIS study. First off, what survival benefit is the LAPIS trial powered for? And then how exactly do you plan to break that out between those who successfully reach resection, the resection fails, or the ineligible patients? So thank you for that question. The LAPIS study also has a very aggressive hazard ratio associated with it and a significant difference in overall survival. The study is going to be stratified based on patients who undergo surgery and those that do not, and in an attempt to try to tease out what impact the treatment has on patients who end up becoming surgical candidates versus those that are not. Yeah. Michael, thanks for your question. So just to wrap up, guys, thank you so much for joining us today. Thanks to Dr. Ko, Dr. Picozzi, Ben as well. We appreciate you joining. The questions were excellent questions. As a reminder, FibroGen has its Q4 earnings call on February 26th, where I'm sure we'll take additional questions related to the pancreatic cancer program as well as our other programs that are in development. And we also look forward to hosting a similar event that will be targeted on our CD46 targeted ADC sometime in the next couple of months as well. So thanks, everybody. Have a great rest of your day.