We'll be continuing with our afternoon session. I'd like to welcome everybody back to our second annual BioConnect conference. We'll be continuing this session with FibroGen, and from the company is CEO Thane Wettig. Welcome, and, happy to have you here. For context, my name is Andres Maldonado. I'm a biotech analyst here with the firm, and I welcome everybody here to the session. So, I guess before we get into some of the more nuanced questions of the company's pipeline, you know, it would first be great to get an overview of the evolution of FibroGen and where the company is today.
Yeah. Now, great to be here, Andres. Thanks for having us. So, I think if you just rewind just a few short years ago, we were a company that we were the leaders or the originators in the HIF-PH space for anemia associated with chronic kidney disease, an approved product in China and in Japan, and a review undergoing at the FDA as well as the EU. And Roxadustat ultimately got a complete response letter from the FDA in the fall of 2021. At that point in time, we had pamrevlumab in phase III development for idiopathic pulmonary fibrosis, DMD, and pancreatic cancer. And so we shifted then the majority of our focus to pamrevlumab into three indications that were in phase III development.
Mid last year, unfortunately, we had a negative setback in IPF as well as DMD, and now we have the two upcoming readouts of pancreatic cancer right in front of us. During that period of time as well, we were really shifting our focus primarily to an oncology-focused organization. In 2021, we in-licensed a couple of immuno-oncology assets from HiFiBiO. We can talk about those later if you'd like.
Mm-hmm. Sure.
And then in May of last year, so a year ago, we in-licensed from Fortis Therapeutics, a CD46 targeted ADC, that we have in development for metastatic castration-resistant prostate cancer. And so with the pamrevlumab upcoming readouts in pancreatic cancer, with the phase II ready asset with an ADC in prostate cancer, and then in IND, we recently filed for an anti-galectin-9 antibody and then a CCR8, anti-CCR8 antibody. We really have made that pivot almost entirely to a focused oncology company.
Great. No, that was very helpful context. So, I guess we'll start with first asset, Pamrevlumab. So, ahead of the upcoming readouts in pancreatic cancer, could you frame us some of the historical clinical data that's been generated to date that gives you conviction towards a positive readout? And maybe talk a little bit about the different pancreatic cancer settings that you're going into.
Sure, yeah. That's a, it's a key area of focus for us right now, as you can imagine. There is, we think, a compelling both preclinical and early clinical data with our anti-CTGF, or connective tissue growth factor, antibody, which is pamrevlumab. In the preclinical setting, we do know that connective tissue growth factor promotes tumor cell growth in pancreatic models. We also demonstrated with pamrevlumab in a genetically engineered KPC mouse model, that we showed meaningful survival benefits with pamrevlumab relative to control. That gave us then the proof of concept to take it into the early-stage clinical trials, where we had a Phase I/II trial in both locally advanced unresectable pancreatic cancer, 37 patients.
There was another phase I/II trial of 75 patients, the majority of which, 66 of the 75, were metastatic pancreatic cancer patients. In that second trial, the one in the metastatic-dominated patient cohort, we did a post hoc analysis of exposure response, and we looked at median response, which was a trough threshold of 150 micrograms per ml.
There were, of the 75 patients, 38 that had greater than 150 micrograms per mL, and then 37 that had less than that. And in the group that had the higher exposure of pamrevlumab, there were some really important differences relative to that lower exposure group. The first one being that one-year survival was 37% in the higher exposure group and 11% in the lower exposure group. And these patients, this was an escalation cohort, and these patients were dosed anywhere from 3 mg per kg all the way up to 45 mg per kg.
There was also an important difference in median overall survival and median progression-free survival at the end of that trial, which then gave us the confidence to then take pamrevlumab into the phase III realm in both metastatic disease as well as the locally advanced patient population. In the locally advanced phase I/II trial, the primary endpoint was resection rate, determining patients who were eligible for resection and those that underwent surgical resection. There was a significant difference between pamrevlumab and standard of care in surgical resection as well.
Great. No, very helpful. Two different studies. You have the Precision Promise study and the LAPIS study. Same indication, but slightly different settings.
Yeah.
So I guess for investors, can you maybe set a clear-cut bar for how you define success in the different settings, given the high bar for drug development in for pancreatic cancer?
Yeah, you bet. Two very distinct patient populations, right? Locally advanced unresectable pancreatic cancer versus metastatic disease. The similarity in the two trials is both of them are overall survival trials. There are some key differences in the two trials as well. In the metastatic trial, it's being run by the Pancreatic Cancer Action Network, so it's not a FibroGen-sponsored trial, but we're very closely involved with PanCAN. It is a trial that looks specifically at first line and second-line metastatic patients. It's not an event-driven trial like the locally advanced trial is. It's a treat to progression trial.
We disclosed in January that the pamrevlumab arm of the Precision Promise platform design trial had graduated from Stage One to Stage Two, meaning that in the first 100 patients that were analyzed, the pamrevlumab arm, compared to standard of care chemotherapy, had reached or exceeded a pre-specified hurdle of at least 35% likelihood of showing a positive OS benefit by the end of the trial. So that was after the 100 patients, and then subsequently, there were 75 patients enrolled in the pamrevlumab treatment arm on top of standard of care gemcitabine and nab-paclitaxel. In that interim period of time when they were doing the graduation analysis to determine if it would graduate from Stage One to Stage Two and then go on to treat an additional 75 patients, 38 patients were enrolled as well.
So, there are a total of 213 patients in the pamrevlumab arm to then be compared with the standard of care, gemcitabine, nab-paclitaxel. And so, we'll see those results sometime mid this year, so we're close. And related to the, you know, the bar or the hurdle, you know, there have been drugs approved in pancreatic cancer for 4 weeks of incremental-
Yeah.
Overall survival improvement for 1.7-1.8 months of incremental overall survival improvement over standard of care. You know, we hope that we would do better than a month, but we think even a month would draw the attention of the FDA, just given how dire the unmet need is in this patient population. We think, you know, 2 months would be incredibly meaningful to clinicians and to patients, and then we think it would be a, you know, really meaningful result for the company as well. For the locally advanced patient population, obviously, median overall survival just with standard of care today is much longer than it is in the metastatic patient population. So we think we'd need at least a 3-month improvement in overall survival, and hopefully, we would get more than that.
I think one additional, you know, point to raise with the metastatic trial is, it is a U.S.-only trial, that is focused on about the top 20 cancer institutions across the country, that enroll 213 patients on pamrevlumab relative than standard of care, compared to standard of care. Whereas the locally advanced trial, 284 patients across both pamrevlumab and standard of care treatment arms, in about 100 sites across multiple countries. That's a key difference as well, and that is an event-driven trial-
Mm.
that we expect to then release top-line results sometime in the third quarter of this year. So, we're really close to getting that final number of OS events that we need to lock the database.
Great. No, very clear, and we'll look forward to those future results. And in the interest of time, just a couple quick questions on Roxadustat before we dive a little deeper into the clinical pipeline. Just curious on, you know, the program seemed to have experienced an uptick in sales, 47% in the first quarter. So, curious how investors should be looking at this program going on to the future, and if you could touch upon maybe some of the dynamics from generics penetration in the market in China.
You bet. So, roxadustat is available in Japan, China, and, Europe, and in many other countries. It's approved in about 45 countries, around the world. In China, roxadustat did about $284 million in top-line revenue last year. We've guided $300-$340 million this year. That's in collaboration with AZ, where we have a very close relationship with them in China. We do lose the composition of matter patent, in early June, so in a few weeks. There are a number of generics that, have applied for and are under review, relative to an ANDA in China. What we do know about the China, generic market is it's vastly different-
Mm.
-than the U.S. generic market, whereas in the U.S., with a small molecule like roxadustat, it would not be uncommon for the originator to see 90%-95% value erosion within 12 months. In China, the market, the way it's constructed today, doesn't necessarily work that way. If you have a generic that gets approved, they're gonna have to go account by account to get listed on the individual hospital formularies before they can then be prescribed. And for many generic companies in China, they just aren't set up to handle that sort of commercialization effort, just because it's cost-prohibitive for them, relative to then the price they ultimately would charge for a generic product.
Ultimately, when there are four or more generics that have been approved, the government has the ability to call what they call volume-based purchasing or VBP. It's in essence a national tender, which the originator drug, in our case, roxadustat, would also participate in. It's common in the China market that the originator typically holds on to, you know, roughly speaking, about 30% of the pre-VBP value on a revenue basis. So, if you think that we'd be at a run rate, if and when VBP were called at about $350 million a year, you could, you know, use rough guidelines of $120 million a year or so, almost in perpetuity. In other words, the VBP's been around for a number of years, not 20 years, but a number of years.
You know, there are multinationals who have many drugs that are associated with VBP and still generate sizable revenue. There's one multinational, the largest multinational, I think, has 12 brands that are impacted by VBP, and those 12 brands contribute $1.5 billion in revenue for that multinational. And so there is a, an important analog there for us to consider. So, yes, we do have in the near term, the, composition of matter patent expiring. We do believe that at some point in time, VBP will be called when the fourth generic is approved. We don't know when that will be.
Okay.
Our base case scenario would say sometime in 2025, but then we would expect to hold on to an important revenue stream in the out years.
Great. No, very helpful. So, I guess in the interest of time, circling back to the clinical pipeline, given there's, you know, the investor appetite for ADCs is at an all-time high, as you know, company's been able to generate some interesting data with your FG-3246, which is a novel CD46 targeting ADC. So curious on why the selection of CD46 has such a compelling target in prostate cancer?
Yeah. So, the target was discovered at UCSF. Fortis Therapeutics, who we licensed the asset from, it's an Avalon Ventures company, was working very closely with UCSF to ultimately develop the CD 46 target. I won't go into detail about how that target was synthesized or originated. We've got some information that we can share that really talks about the science behind it. But what they were looking for was a target that was preferentially expressed on tumor cells and not in normal tissue. So, if you were to do just a screen of CD 46, it wouldn't necessarily jump out at you as a logical target for prostate cancer.
But when the additional scientific work was done, it was pretty clear that CD 46 was highly expressed in prostate cancer, colorectal cancer, and some other important tumors as well. And then ultimately, the antibody was synthesized, and it works out really nice to be then combined with an antibody drug conjugate. And we think that the unique part of our program is not the linker and the payload because it uses a standard Seattle Genetics linker and MMAE payload. The-
Sure.
The uniqueness of our program is the target CD46. And so we know the target's clinically active. We've seen that in the phase 1. We saw it in the preclinical setting, and we saw it in the phase 1 monotherapy trial, where we showed a PSA50 result of 36%. But importantly, and I think we're one of the few, if not the only, programs, of, of, you know, of recency that also disclosed a radiographic progression-free survival number of 8.7 months in a patient population that was heavily pretreated-
a median of 5 lines of previous therapy, and it was in an all-comers population. And the all-comers population, part of this is important because we're also developing a companion PET46 diagnostic, also, at UCSF. And we believe that based on preclinical data, that about 50%-70% of patients with prostate cancer express CD46.
And we think that a good portion of those are high expressers of CD46, whereas with PSMA, you get 90%+ of the population that express PSMA. With this one, it's a more targeted approach, and that's why we think the PET46 biomarker is critically important for us. And so what we plan on doing, based upon the phase 1 results that we've disclosed, is doing some additional dose optimization work as part of the phase 2 program. And we're gonna have a conversation with the FDA in the next few months to confirm our path forward. But our thinking at the moment is to do some additional dose optimization work, hit everybody in the phase 2 trial-
... with the PET46 biomarker to begin with. It'll be an open label trial, and we'll be able to look at both the expression of CD46 and then the response to the drug as the additional dose optimization work is ongoing, and then be able to do a post-hoc correlation to see if, in fact, there is a relationship between CD46 expression and response to the drug, which we believe there will be, but we have to prove it. And if it proves itself out, then that will allow us to really enrich the phase 3 patient population with high CD46 expression to give them a better chance of response to the drug.
This rPFS number that we showed in the phase 1 monotherapy trial of 8.7 months, we think actually could be a low water mark relative to what can be achieved if, in fact, the patient population can be preselected with the PET46 biomarker.
Great. No, that was very helpful. So, I guess in the context of some of the data from the phase one, the 8.7-month PFS with the 36% decline of greater than 50% PSA, could you help us contextualize where that data falls in the development landscape, and how should we be benchmarking it against some of the data that you're presenting at ASCO, which is gonna be in combination with enzalutamide?
Yeah.
How should we be thinking about-
That's a good question.
The data.
There's a lot there, so let me see if I can-
Yeah
... I can hit on it. You know, there have been some, there's been some data released from some early-stage prostate cancer programs. Ambrx traded for $2 billion to J&J. And I think they had 52% PSA50. They had a similar ORR that we did in our-
... phase 1 monotherapy trial. Corbus released data on 7 patients. They've got a market cap of $500 million right now. Janux, again, released data, some impressive PSA50 data. They're trading for $2.5 billion right now. So there's a lot of excitement in the ADC category.
Sure.
So, it's difficult to do kind of cross-trial comparisons just because the enrollment criteria-
Sure
... can be different. Ours was a heavily pretreated patient population. I think if you look at some of the recent later-stage trials, if you look at PSMA fore or SPLASH or maybe TRITON, where your control arm or your comparator of an ASI switch is roughly about 6 months' worth of median overall survival. I think these later-stage trials are showing, you know, 9-10 months of median overall survival advantage. We think that if we can show an OS benefit of, you know, 9+ months or so, we think we'd be right there of a PFS. We think we'd be right there in the game because we would believe that the OS number would be higher than the PFS number. And so that's what we're aiming for.
And then in the enzalutamide combination trial, which you referenced, there will be. An abstract was submitted and accepted for ASCO. So, on June 2, there's a poster presentation from Rahul Aggarwal, who's the PI of the FG-3246 program. He's also the PI of his IIS at UCSF in the enzalutamide combination trial with FG-3246, and he'll show some safety and efficacy data in the escalation cohort of this combination patient population.
Great. We'll look forward to seeing that at ASCO this year. So, I guess, you know, in the interest of time, and I wanna cover most of the stuff from the pipeline, just outside of 3246. You know, what can you tell us about some of the early-stage pipeline assets like 3165 targeting galectin-9 or 3175 targeting CCR8, and maybe the cadence of some of the data we can expect to see?
Sure. Yeah, so we, we filed the IND for the anti-galectin-9 antibody at the end of April, and so, the next step is for the FDA to clear the IND so that we can get started then with the phase one trial. Anti-galectin-9, there's one other company that's in the clinic right now, PureTech, and they've kinda spun off Gallop Oncology, and they've shown some pretty interesting early-stage data. And so, we're excited about the target, but we've got some additional proof points that we're gonna have to go through, and that's why you do the initial escalation and expansion work. And then the other antibody that we have is an anti-CCR8 antibody. It's a much more competitive space.
A number of companies, Gilead, BMS-
Sure
and some smaller ones as well are in the clinic with an anti-CCR8 approach. And we would anticipate filing an IND with ours sometime next year. We've done some pretty deep comparisons of the antibodies across the different programs.
feel really good about the construct or the makeup of our antibody, and so we're excited to be able to take that one forward into the clinic sometime next year as well.
Great. To wrap it up, just curious, given the cash runway to 2026-
You know, what can you tell investors about the company's balance on execution of its current clinical programs, potential future partnerships, and then maybe additional business development that is also going on?
Yeah, it's a great question, something we, you know, spend time each and every day thinking about, because you've got some really exciting near-term prospects with pamrevlumab and pancreatic cancer, and if one or both of those trials turns out to be positive, our intention would be to commercialize on our own in the U.S., and then partner ex-U.S., and, you know, partnering ex-U.S. could be meaningful from a cash infusion perspective. And the reason we feel so bullish about our ability to commercialize on our own in the U.S. is, you can put in place a pretty efficient commercial model to go after pancreatic cancer in the U.S.
And if we can generate two or more months of, you know, OS benefit, you know, we think that the ability to commercialize would be fairly straightforward. And so opportunity for cash infusion from a partnership perspective, and then, if we have positive data as well in one or both of those trials, the ability to gain additional infusion of capital from an equity perspective is also potentially in play as well. And if unfortunately, pamrevlumab doesn't, you know, hit the mark, you know, we have done a significant amount of work internally as well-
to define what our company would look like in the event that we don't have a pancreatic cancer opportunity, and we're gonna be most wholly focused in the near term on the CD-46 ADC, which again, is a really-
Yep
exciting opportunity for a company like ours.
Great, so, that was a great overview. Really appreciate your time, and, you know, on behalf of the whole Wainwright family, thank you for joining us, and we'll look forward to all these catalysts coming up.
Yeah, so do we. Thanks.