Good day, and thank you for standing by. Welcome to Akebia Therapeutics Corporate Conference Call. At this time, all participants are on a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. I would now like to turn the conference over to your first speaker today, to Mercedes Carrasco, Director of Corporate Communications. Please go ahead. Thank you, and thank you for attending the Akebia conference call to discuss a recent regulatory update related to vadadustat. Please note that a press release was issued on wednesday, March 30th, detailing the regulatory update, and that release is available on the investor section of our website. For your convenience, a replay of today's call will be available on our website shortly after we conclude. Joining me today for today's call is John Butler, Chief Executive Officer, Dave Spellman, Chief Financial Officer, Dell Faulkingham, Chief Commercial Officer, and Dr. Steven Burke, our Head of R&D and Chief Medical Officer, are available for questions at the end. Before we begin, I'd like to remind everyone that this call includes forward-looking statements. Each forward-looking statement on this call is subject to risks and uncertainties that could cause actual results to differ materially from those described in these statements. Additional information describing these risks is included in the press release that we issued on March 30th, as well as in the Risk Factors and Management Discussion and Analysis section of our most recent annual and quarterly reports filed with the SEC. The forward-looking statements on this call speak only as of the original date of this call, and except as required by law, we do not undertake any obligation to update or revise any of these statements. With that, I'd like to introduce our CEO, John Butler. Thanks, Mercedes, and thank you all for joining. As many of you likely know by now, Akebia received a complete response letter from the FDA to inform the company that it has completed its review of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia associated with CKD for adult patients on dialysis and adult patients not on dialysis. Vadadustat has not been approved by the FDA for this indication. Before we go on, I want to express my extreme disappointment and frustration at this outcome. I'm disappointed for our team at Akebia, our collaboration partners, and most importantly, for patients suffering from chronic kidney disease. Our team is deeply aware of the unmet needs of CKD patients with anemia, and we're disheartened that we cannot yet deliver a therapeutic that we believe could address those needs to patients in the U.S. Sadly, kidney disease patients continue to suffer from a lack of innovation in their care. The complete response letter outlined concerns that were discussed in our press release, which was issued earlier today. In the CRL, the FDA concluded that the data in the NDA do not support a favorable benefit-risk assessment of vadadustat for dialysis and non-dialysis patients. The FDA expressed safety concerns noting failure to meet non-inferiority in MACE in the non-dialysis patient population, the increased risk of thromboembolic events driven by vascular access thrombosis in dialysis patients, and the risk of drug-induced liver injury. The CRL stated that Akebia could explore ways to potentially demonstrate a favorable benefit-risk assessment through new clinical trials. We'll discuss the details of the CRL with our collaboration partners and request a meeting with the FDA. At this time, it's too soon for us to outline next steps beyond noting that we believe it's critical that we engage in a discussion with the FDA. The notification of the CRL came as a surprise, especially with respect to the dialysis patient population. The dialysis data from our global phase III clinical development program were clear and consistent. Those trials met both primary and secondary efficacy endpoints and the primary safety endpoint. Further, data was published in the New England Journal of Medicine and was presented at ASN in 2020 and 2021. In 2021, we presented a detailed poster on thromboembolic events across our phase III program at ASN. That data showed that the rate of dialysis access thrombosis in the study across vadadustat and the comparative drug were the same. We've also extensively discussed, both publicly and with the FDA, the patient who had very elevated liver enzymes in our phase IIb study back in 2014. We also reported to you when we announced our phase III data that we'd had an expert panel perform a blinded analysis of LFT elevations in both PRO2TECT and INNO2VATE. In this analysis, there were no difference between vadadustat and the active comparator, darbepoetin alfa. With these data, we believe that any remaining concerns with respect to hepatotoxicity could have been managed through labeling. We believe there were compelling data supporting a positive benefit-risk profile for the use of vadadustat broadly in patients with CKD, including non-dialysis patients, though we'd always remain cautious about receiving a broad label for vadadustat that would extend to non-dialysis patients with anemia due to CKD. As for our company's path forward, we acknowledge that we are no longer in a position to have multiple commercial products in the near term. However, we're very proud that we're coming off of Auryxia's strongest net revenue quarter in Q4 and look forward to continued Auryxia growth. We will be making adjustments to our cost structure to reduce spend while still enabling us to invest in the future. We look forward to updating you on those changes. Finally, I'd be remiss if I didn't take the opportunity to thank the committed Akebia team, our collaboration partners, physicians, investigators, site coordinators, and most importantly, the patients who participated in our clinical studies. As a company, our purpose is to better the lives of people impacted by kidney disease. All that we do is for them. With that, we'll open it up to questions. Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, please press the pound key. Please stand by while we compile the Q&A roster. I show our first question comes from the line of Chris Raymond from Piper Sandler. Please go ahead. Yeah, thanks for taking the question. John, I express my condolences here on the outcome here. I know you guys have put a lot of effort into this. I guess just a couple things. You know, John, you raised the two of the things that were most puzzling to us. You know, the thrombosis risk and the liver tox language that the FDA had. To your point, you know, at ASN, you know, you gave pretty compelling data indicating very similar risks in a real, you know, arguably big contrast to the other HIFs that FDA looked at. I guess, you know, did FDA not agree with that analysis, or did they conduct their own analysis? Was there some sort of sensitivity analysis that they looked at, that might have differed from what you guys presented? Also on that liver tox, you know, signal, you know, I guess that's another sort of similar question. You know, you guys painstakingly looked at that event, which I think you first disclosed in 2016, if memory serves. You know, I guess, you know, what was it about that analysis that the FDA, you know, took issue with? Or was there some other signal of liver tox besides that one patient? Thanks. Yeah. Yeah. No, thanks, Chris. Appreciate it. From the thrombosis question, you know, as you know, there's two types of thromboembolic events to think about, right? There's a very serious thromboembolic events like PEs and DVTs. You know, very clearly there's no difference. This was in the poster that we presented at ASN, I think you're referencing. You know, the difference was that we had more patients in the vadadustat group who had a vascular access thrombosis event. But when you looked at the number of events, there was no difference. The rate of events was the same between the groups. You know, even as you look at the briefing book from roxadustat, FDA talked about, you know, percent, simple percentage differences, which we saw, you know, from an access perspective, is deceiving. You really need to look at the rate of the events. That's why we were so confident that the rate of the events and thromboembolic events were the same, 6.6 per 100 patient years between vadadustat and darbepoetin. We believe that was the difference. 'Cause remember, you saw a hazard ratio of 1.2 in the paper, but this is a time to first event analysis. Anyone in the darbepoetin group who had a first event, they were then censored for any other events. Of course, as you know, with dialysis access, you know, they have frequent event rates. It's like 0.2-2 per year per patient. Is it? Does that access stay open? Can they continue to use it? It's really the fact that patients are having multiple events that's more of a concern. You know, our perspective was, in this case, FDA looked at the number of patients, and I believe it was, Steve, 21 more patients out of 3,800 in the study that had an event in the vadadustat group, but the number of events was virtually identical. Mm-hmm. From our perspective, this is a new analysis that FDA did. They simply prioritized a different way of looking at the data that That's fair. Yep. We also did a multiple, you know, event analysis, and they were identical, you know, time to multiple events. Really no difference. That's what really matters, is events, because if you have an event, it puts you at risk for fistula abandonment and then dialysis via catheters. That's what really matters about this. Yeah. We are, you know, equally, I don't want to say confused, but, you know, it is frustrating obviously that that was one of the areas that was focused on. If any of you remember from roxadustat, there was a difference not only in the vascular access events, but also in severe events, which, when you look at the hazard ratio in dialysis population for the severe events, it was something like 0.71 or something. That was definitely something that confused us also when we look forward to talking to them about. Then the liver tox question as well is an important one. You know, we've talked for many years about the patient in 2014. you know, as we've said, this was a serious patient who had significant elevations in LFTs and jaundice. she was never symptomatic, was never hospitalized and recovered. you know, we thought that was certainly mitigating. we had significant screening in our phase III study because we did recognize, you know, that this was something that the FDA would be interested in. You know, again, this was a huge program, almost 8,000 patients across the program, having an outside expert hepatology panel review these in a blinded basis because, you know, these are patients who are on multiple drugs, so many patients have elevations in liver enzymes. You know, is it possibly or probably related? When you looked at attribution in a blinded fashion, you saw no difference at all. I think that the FDA basically said, "Well, we know darbepoetin alfa isn't associated with elevations in liver enzymes, so we won't look at this comparative data. We'll just look at the patients in the vadadustat group who had elevations." Well, no one had any elevation anywhere near as serious as that patient from 2014. As I said, there were patients who had elevations in LFTs, and they just looked at those vadadustat patients. Now, we said there's just as many patients in the darbepoetin group, and your guidance says you look at comparative data. It seems they didn't choose to do that there. Those were, you know, this is why you probably sense the frustration in my voice as well. You know, we really did think that any of these issues, either of these issues, you know, could certainly be handled with putting labeling in, letting physicians understand the data and make a choice, you know, with the patient. That's not the way it was approached by FDA. Thank you. Just maybe one follow-up. I know you said it's too early to talk about next steps, but I just, you know, given the, you know, the way you set this up, I guess I have to ask is, you know, FDA does have an appeals process in place. Is that, you know, on the table? Or one would argue, are all options on the table here for you guys? Oh, all options are definitely on the table. I mean, you know, obviously, we've only had this for, you know, hours now and very, very late last night. You know, we need to first discuss this with our collaboration partners, who've been great and then have a conversation with the FDA and, you know, kind of work through the process here. There's certainly nothing that's off the table at this point, Chris. Yeah. Thank you very much. Thanks, Chris. Thank you. I show our next question comes from the line of Mara Goldstein from Mizuho. Please go ahead. Great. Thank you so much for taking the questions. So I just wanted to ask just around, maybe just for more, you know, general knowledge perspective. As the FDA was going through the review, I mean, you said you were surprised at the outcome in the dialysis-dependent population. Can you maybe just talk about the process that you went through with the FDA and when you had an idea that they were going to, you know, be quite resistant to an approval here? And the other thing is that the press release says, you know, path forward with trials. Is that indicated to mean multiple trials for the dialysis-dependent population? Or when you refer to trials, you mean for both non-dialysis-dependent and dialysis-dependent? Yeah. I think you are referencing, you keep saying diabetic, but I think you mean- Sorry. Thank you. It's a long day. Yeah. I apologize. Yeah. No. I know you guys as well. Trust me, I completely agree. You know, as we've said before, you know, kind of the play-by-play of the review kind of isn't. We've never gone into that and we won't now. I mean, you know, we've always said, I mean, anytime you have an application in front of the agency, a CRL is always a possibility. Mm-hmm. You know, as we said that when we looked at the concerns that they expressed, particularly around the issues we put in the press release, we believed that, you know, we addressed those, as I described in Chris's question in the press release, but they could handle anything through labeling. That's why it was a surprise when they made the decision to issue a CRL. Mm-hmm. Instead. So, you know, the second part of the question around studies, we haven't had that conversation yet. You know, we want to sit down with our collaboration partner, talk about our strategy to go forward, you know, really dig through you know, all of the information that we have and how we wanna approach this, and then have that meeting with FDA and then update you post that. You know, these are significant issues that we thought we addressed. Yeah. The fact that FDA stayed, you know, kinda in this, you know, with this decision mode, you know, we wanna, you know, be clear that, you know, it's a challenging path forward with them, though we believe we're, you know, the way we've presented the data is the way that they should review it. So we're determined, but we're also pragmatic and, you know, the idea of clinical trials, we wanna understand what that is, what we would have to do and whether that's something we want to engage in or not. That's all to come. Okay. If I could just ask a clarification also on the press release, and you mentioned it as well, the agency expressed safety concerns noting failure to meet non-inferiority, right, in MACE in the non-dialysis patient population. Was that element also extrapolated to the dialysis-dependent population? No, I would not say that was extrapolated. Okay. That's one that was, you know, shouldn't be a surprise, right? Right, right. Exactly. Right, right. Exactly. We knew we had the safety net point there. We always said that was a high risk. They called it out specifically in the CRL, which is not surprising. You know, we felt for completeness, you know, we should include that. Okay. All right. Well, thank you very much. Thanks, Mara. Thank you. Our next question comes from the line of Eric Joseph from JP Morgan. Please go ahead. Good evening. Thanks for taking the question. I also want to just impart my condolences on the CRL here. I guess I'm curious to know sort of what your sense is of the MAA review process in Europe. I know that's being led by Otsuka, but any reason to think that the decision here might impact prospects for approval in Europe? Thanks. Eric, thanks for the question. It's an important one. You know, I think, as you know, different regulatory authorities look at products very differently, have a different approach. I think we have a pretty good analog in that roxadustat received a CRL, you know, for data that's well known to everyone, and yet they were approved in Europe. I can't remember exactly when that was, but for both dialysis and non-dialysis patients. That's an active review. As you said, Otsuka is leading that for us, so we're working very closely on that review, but you know, we expect a very different outcome there, given the very different approach EMA seems to take vis-a-vis FDA. Okay, got it. Thanks for taking the question. Thank you. Thank you. Our next question comes from the line of Serge Belanger from Needham & Company. Please go ahead. Hi, good evening. Thanks for taking my questions. Just a couple. First, did the agency consider separate approvals for both a dialysis and non-dialysis setting, or was it just one broad approval that was considered? Second, at least based on the press release, the agency doesn't appear to have any concerns with the product's efficacy. Most of the issues were focused on safety. In hindsight, would you have benefited from an FDA AdCom to further clarify these issues, and were you surprised it wasn't convened? Thanks. Thanks, Serge. The first question on the dialysis versus non-dialysis. As you saw in the press release in my remarks, I mean, there were safety concerns expressed by the agency in both dialysis, non-dialysis, the thromboembolic events dialysis access was in the dialysis population. The DILI questions were obviously across the population. Remember, it was one indication, one NDA for treating anemia in two patient populations. You know, I don't know what the agency considered. Obviously, we just have the letter, but we don't think there would have been any difference if we asked for just dialysis versus non-dialysis because they were assessing the entire package of data. You know, I still think the way we approached it was the right way. Your question about an AdCom is an interesting one. You know, obviously, I do think it's always good when you have the opportunity to pre-present your data, you know, your argument to an expert panel. You know, FDA had always indicated that it wouldn't be necessary to have an AdCom. You know, that's at this point, I suppose that's just conjecture whether that would've benefited us. I certainly as I presented the thromboembolic event data and the liver data, you know, a panel of expert nephrologists, cardiologists, I think, you know, it might have been helpful to have them weigh in on that. You know, again, Monday morning quarterbacking. Thank you. Thank you. Our next question comes from the line of Ed Arce from H.C. Wainwright. Please go ahead. Hi, thanks for taking my questions. Let me add my condolences to the whole team. I know there's a lot of work on this, and I'm sure more to come as you work through the process here. I wanted to focus on the vascular access events, and you know, you noted on this call as well as on the 10-K that the hazard ratio of 1.20 refers to the time to first event analysis. Correct me if I'm wrong, but there isn't really a perhaps in the guidance or any other way that any assurance that the FDA, the agency would particularly look at one analysis versus another, versus, I think you referred to just simply the number of events overall. A related question, just remind us, what was the hazard ratio when you looked at it, in that way? Thank you. Ed, that's a very perceptive question. The fact, you know, from our perspective, reading the briefing book for roxadustat and seeing that the FDA talked about how looking at a simple difference in percentage, you know, difference in patient numbers could be deceiving and that you have to look at a rate for something like, you know, the rate of dialysis access thrombosis, that was very reassuring to us that, you know, that we were looking at it the right way, and that seeing no difference, that we would have a clear path forward there. You know, with a different reviewer, you have a different, potentially a different look. I suppose it's difficult when there isn't that consistency of approach. You know, sense my frustration based on that. Your second question was about Was it- was asking about the hazard ratio. I can't remember which analysis that was. I think you referred to it earlier as sort of simply the number of events overall. If you looked at multiple events. Right. Your hazard ratio is essentially one. This is Steven Burke. Did you get that, Ed? Yes. Yes, I got that. Just to follow up, yeah, I don't have it in front of me, but, I'm sure the whole team has gone over this many times. The guidance that the FDA has, you know, in particular reference to the kinds of data that they were looking at in your application, really there isn't anything in particular that is explicitly stated in there, other than perhaps what you pointed out before, which is that they, in general, do look at data in a comparative sense, in other words, versus their comparator. Is that- Yes. Is that fair? Yes. I mean, I think their own guidance documents suggest that that's how its data should be reviewed. Okay. Yeah, absolutely. Yes. They stress that having a comparative is critical in looking at liver events. As John mentioned earlier, he didn't say this, but there's actually more liver events in the ESA control group than there is in the vadadustat group. When you look at the ones that are possibly or probably related, again, there's more events in the control group than in the vadadustat group. This is why you run a controlled trial and an active control trial, right? I mean, it's, you know, to suggest that, well, we know this drug doesn't have events, so we're not gonna compare it. You know, we're being held to, you know, the one patient from 2014, and if that was always going to be, you know, a roadblock, well, then I guess it would have been nice to know that in 2014. Yeah. I guess as a follow-up, John, I'm curious as you think about the aspect of liver tox in general, which was part of the CRL, what leads you to believe that the overall liver tox issue is simply and solely related to that patient in 2014? That patient was central to the reason we did more monitoring in the study, the reason we did the review, you know, the blinded review. You know, as I mentioned, you know, you had other patients who had elevated LFTs. No one who had, you know, the level of jaundice or like that patient had. But given these patients are on, you know, eight, nine drugs on average, they're going to have elevation in liver enzymes. But that's why you do a comparison to your active control, which has the benefit of being a drug that isn't associated with elevated liver enzymes. Showing no difference in a blinded fashion should give comfort that even though you're seeing elevations in liver enzymes, it's something you see in a CKD dialysis or non-dialysis population. You know, the reason for their concern isn't solely that patient. They looked at other patients and saw elevations in liver enzymes, but they discounted what they were seeing in the active control group and only focused on those patients in the vadadustat group and said, you know, there are more patients who have had elevated liver enzymes. We, you know, basically pointed out that you have the same number or more, as Steven pointed out, in the control group. That wasn't the way they chose to look at the data. It all stems from that patient in 2014, and there's no question about it. As I said, if that was, you know, going to have that kind of impact, you know, after that 2014 patient, they allowed us to start a 7,500 patient trial. When you add in the patients in Japan who have been exposed to the drug in a commercial setting and haven't seen elevations in liver enzymes, we have a pretty good history now that we think it will allow the product. Certainly, when you look at other products that have been approved, you know, have hepatic profiles that look significantly worse, if you will, than what we've seen here. You know, that's why we felt that we can label around this. We can inform physicians about this patient, you know, create a warning, etc., and let physicians make a choice. But that's not how it was approached. That's very helpful. Thank you. Again, I think it goes to benefit risk, and it also could speak to the FDA not seeing the degree of benefit for these patients that we see and that physicians see, and that's disappointing as well. Right. Yeah, there are other options that could have pursued other than straight a CRL. Correct. Yeah. Correct. Thank you. We appreciate it. Willing to have a discussion on all of those. Thanks, Ed. Thank you. Thank you. As a reminder to ask a question, you will need to press star one on your telephone. Our next question comes from the line of Bert Hazlett from BTIG. Please go ahead. Thanks. Thanks for holding the call. Just, I guess one or two for me. And thanks for the additional clarity on the LFT elevations. Just with regard to the comment that you could explore ways to potentially demonstrate a favorable risk benefit with new clinical trials. Was that John or anyone, was that in relation to any specific patient group, the dialysis patients, the non-dialysis patients? Was that a general comment? Was that for the DILI, the liver injury issue? Or what was that in the context toward? Thanks. Yeah. Well, I think that was and Steve, you can jump in here too, but I mean, it was offering up the opportunity that, you know, we could explore the benefit in, you know, particular patient populations, you know, to show a positive risk-benefit profile, right? I mean, it's so it could be the idea of exploring a subpopulation. I mean, we have to have a conversation with FDA to understand this, but, you know, this is so we're overinterpreting what we read in the letter, I think. You know, there are opportunities that exist there. Again, I wanna point out, I mean, there may be opportunities, and we may feel that there's a path forward, but we have to decide whether, you know, another clinical trial is something we wanna embark on. I don't know, Steve, if you have anything to add to that. No, I agree. You know, we could explore any number of different trials, or look at existing trials that we are running today and see if that provides sufficient- Mm-hmm. Information to shore up FDA's impression of our benefit-risk equation. Until we speak with them, it's hard to speculate what they're actually thinking and what we could propose. Exactly. I mean, as you consider total patient exposures, for liver injury, I mean, you've got a ton with the numbers of patients that have experienced data. Agreed. Yeah. I mean, it's just interesting commentary that they didn't really assess the competitor in the context of that induced data. It's kind of astonishing, actually. Yeah. We agree. I agree with everything you said there, Bert. I don't have anything to add. You're spot on. Yeah. I get. Well, so again, what the specific question, I guess, were they offering clinical trials with regard to the liver issue? Were they offering it with regard to the dialysis patients? Were they offering it with regard to the potential thrombosis risk? Or can you tell that from the document at this point? My interpretation is it wasn't specific to a particular, it wasn't that specific, right? So I think that's why to really understand, you know, have that conversation with them and understand what would be necessary in each of these areas to you know to demonstrate what they would need to approve the drug. It's obviously very frustrating when we think about the thromboembolic events and liver when we feel like we've demonstrated that we have a data that we think demonstrates the safety of the product. We have to sit in front of them and understand, you know, if there's something specific that they're thinking, but I don't think they were. They were definitely not that specific in the letter. Okay. Thank you. Thank you. I show no further questions in the queue at this time. I'd like to turn the call over to Mr. John Butler, CEO, for closing remarks. Thanks so much, operator. Thank you all for joining us late this evening. Obviously, this is a disappointing day for us and I think particularly for patients. We look forward to coming back to you to further discuss, you know, if and there's a path forward here and to update you on our regulatory conversations, but importantly, update you on how we're thinking about the company moving forward as well. You know, we're pleased that we have a product that is growing, generating revenue, and now it's our job to look at our spending and think about the future of the company and have those come together to build a future for Akebia. We look forward to updating you on that as well. Thanks, everyone. This concludes today's conference call. Thank you for participating. You may now disconnect.