Akebia Therapeutics, Inc. (AKBA) Earnings Call Transcript & Summary

Welcome to Akebia Therapeutics PRO2TECT top line data readout call. As a reminder, this call is being recorded. I would now like to introduce your host for today's conference, Kristen Sheppard.

Thank you, and good morning. My name is Kristen Sheppard, Senior Vice President of Investor Relations of Akebia. Thank you for joining us to discuss Akebia's top line data from PRO2TECT, the second of our 2 global Phase III cardiovascular outcomes program, evaluating vadadustat for the treatment of anemia due to chronic kidney disease. We issued a press release containing this top line data this morning. It is also available on our Investor Relations website, along with the slides for today's call. For your convenience, an audio replay of today's call and the slides will also be available on our website shortly after we conclude today's webcast. Joining our call today are John Butler, our President and Chief Executive Officer, and Dr. Steven Burke, our Chief Medical Officer. Before we begin, I'd like to remind everyone that this conference call includes forward-looking statements. Each forward-looking statement contained in this call are subject to risks and uncertainties that could cause actual results to differ materially from those described in these statements. Additional information regarding these factors is described in the forward-looking statements section of the slides for today's call and the press release we issued this morning as well as in the risk factors in Management's Discussion and Analysis section of our most recent quarterly and annual reports filed with the SEC. The forward-looking statements on this call speak only as of the original date of this call, and we do not undertake any obligation to update or revise any of these statements. With that, I'd like to turn the call over to our CEO, John Butler. John?

Thank you, Kristen, and welcome. We appreciate everyone joining us on such short notice. In terms of the agenda for today's call, I'll provide some opening remarks, then Steve will provide more detail around the top line data. As always, following our discussion, we'll open the call to questions. This morning, we announced top line data from PRO2TECT, the second of our 2 global Phase III programs, which evaluated vadadustat, our investigational HIF-PHI as a treatment for anemia due to chronic kidney disease, or CKD, for patients not on dialysis. Before I get to the top line results, I want to talk about our clinical program and vision for vadadustat. We launched our global Phase III program, consisting of both INNO2VATE and PRO2TECT because we recognize the significant unmet need of patients with anemia due to CKD and see a promising opportunity in vadadustat to advance the standard of care for these patients. Our global Phase III program consists of 4 large well-executed studies of patients on dialysis and not on dialysis. Some of the largest of their kind in the industry. To report data on 4 studies over a few months is a significant milestone. To do the work during a global pandemic is nothing short of remarkable. And make no mistake, we believe these studies have succeeded in providing us with extensive datasets in support of establishing vadadustat as an oral once-daily standard of care for the treatment of anemia due to CKD. This is incredibly important, not only in terms of what it means to Akebia and our path forward, but also and more importantly, because of what it means to patients. At Akebia, our mission is to better the lives of people impacted by kidney disease. And I'm very proud that we are moving forward towards that goal with data in hand that we believe supports vadadustat's approval. Our first global Phase III program, INNO2VATE, delivered positive top line efficacy and safety data for vadadustat in dialysis. With these clear results, we believe we have a straightforward path to submission and approval for a dialysis indication, and with approval, the significant opportunity to help the 500,000-plus adult patients on dialysis. We believe this translates to a potential multibillion-dollar market opportunity in the U.S. alone. The top line results from our second global Phase III program, PRO2TECT, have also been highly anticipated and are equally important as another step towards fulfilling our vision for vadadustat in nondialysis. I'm pleased to report that vadadustat achieved both PRO2TECT's primary and secondary efficacy endpoints. The efficacy data was very clear and consistent with previous studies. Unfortunately, PRO2TECT did not meet the primary safety MACE endpoint. The MACE result is disappointing to all of us and presents challenges to achieving our goal of bringing vadadustat to patients in nondialysis. That said, while achieving the safety endpoint would have made our path here much easier and more straightforward as it is in dialysis, we still believe we have a path forward in nondialysis. We and our collaboration partner, Otsuka, believe this path is built on the totality of the data from our global Phase III studies, including important key regional and patient subpopulation analyses from PRO2TECT that has been submitted for presentation at the upcoming ASN meeting in October as a late breaker. This data-rich presentation will allow us to share a more detailed view of our path to submit an NDA and secure approval for vadadustat for both indications at a scientific venue, which has always been our goal. Although the top line data makes our path forward in nondialysis more challenging, we believe our potential with vadadustat to address the significant unmet clinical need of patients with anemia due to CKD, not on dialysis, remains a multibillion-dollar market opportunity. I want to stress that while we believe we have the opportunity to secure indications for both dialysis and nondialysis markets, it's important not to lose sight of the fact that we believe each of these markets, on its own, presents a compelling multibillion-dollar market opportunity for vadadustat. With data now in hand, let me remind you of our next steps. We are highly focused on our U.S. regulatory filing. Our teams have already started working on the NDA for vadadustat. At this time, we're planning for a pre-NDA meeting with the FDA before the end of the year, followed by our NDA filing for both dialysis and nondialysis indications as early as possible next year. In parallel with these activities, we're continuing to work with Otsuka on the European filing for vadadustat. Over the near term, we're working hard to secure and prepare the full INNO2VATE and PRO2TECT data presentations for ASN. We've already submitted INNO2VATE for presentation. And as I mentioned, we just recently submitted PRO2TECT as a late breaker. If accepted, we will be presenting these datasets in about 7 weeks at the ASN meeting. As well we're actively working to secure publication within peer-reviewed journals. Beyond the work to move to filing, we are already supporting the commercialization of vadadustat in its first major market, Japan. All of these remain critical initiatives for us and we're fortunate to be executing from a place of financial strength with a cash runway that extends beyond the expected U.S. launch of vadadustat. In closing, we believe we have a straightforward path to add a second commercial product in vadadustat to our renal portfolio for patients on dialysis upon approval. We believe we have a path forward in nondialysis as well. The Akebia and Otsuka teams are continuing to prepare for the launch of vadadustat, if approved, for both dialysis and nondialysis patients. I want to pause here and take a moment to thank all of our patients who participated in PRO2TECT and recognize our clinical investigators and their staff who worked harder than ever to close out these studies. Kidney patients are among the most at risk during this pandemic, and we're reminded of both the critical nature of our work and the significant need to advance care for these patients. I couldn't be prouder of the Akebia team for their work. I'll now hand the call over to our Chief Medical Officer, Dr. Steven Burke, to discuss the PRO2TECT top line results in more detail. Steve?

Thank you, John, and good morning, everyone. On behalf of the entire R&D team, I would also like to thank all the patients, investigators and staff for their dedication to our mission. The PRO2TECT program was well powered for efficacy in cardiovascular safety and included 2 Phase III studies, correction and conversion, which collectively enrolled 3,476, nondialysis-dependent patients with anemia due to CKD. This is a very large, rigorous and thoughtfully designed program to compare vadadustat to a current standard of care, darbepoetin alfa, an injectable ESA. Both PRO2TECT studies were global, multicenter, open-label, but sponsor blind, non-inferiority studies. In both PRO2TECT studies, the primary efficacy endpoint was non-inferiority of vadadustat versus darbepoetin, as measured by the difference in mean change in hemoglobin between baseline and the primary evaluation period, which was between 24 and 36 weeks. The key secondary endpoint was non-inferiority during a secondary evaluation period between 40 and 52 weeks. The PRO2TECT program's primary safety endpoint was non-inferiority of vadadustat versus darbepoetin for time to first MACE in the combined PRO2TECT studies. MACE was defined as all-cause mortality, nonfatal myocardial infarction or nonfatal stroke. The MACE events were independently and blindly adjudicated by the Brigham and Women's Hospital Clinical Endpoint Center. As shown on Slide 5, in both studies, patients were randomized 1:1 to receive either vadadustat or darbepoetin. Vadadustat was initiated at a dose of 300 milligrams once daily, and starting at week 4 was adjusted up or down in increments of 150 milligrams within the range of 150 to 600 milligrams daily. Darbepoetin was administered intravenously or subcutaneously. Patients already receiving darbepoetin maintain their prior dose and those on other ESAs were switched to darbepoetin and dosed according to the approved product label. Study drugs were titrated to achieve target hemoglobin of 10 to 11 in the U.S. and 10 to 12 outside the U.S. Slide 6 summarizes the patient's baseline characteristics, which were similar between the treatment groups and representative of the general CKD population with anemia, not on dialysis. As expected, there was a high percentage of patients with cardiovascular disease and diabetes. Slide 7 summarizes the primary and key secondary efficacy endpoint data. In the correction study of patients without recent ESA use, PRO2TECT met the primary efficacy endpoint, demonstrating that vadadustat was non-inferior to darbepoetin. The difference in mean hemoglobin change was plus 0.05 grams per deciliter, with a 95% confidence interval of minus 0.04 and plus 0.15, with the lower bound not crossing the prespecified non-inferiority margin of minus 0.75. The mean hemoglobin at weeks 24 to 36 was 10.39 for vadadustat and 10.35 for darbepoetin. The hemoglobin responses were maintained in the secondary evaluation period of 40 to 52 weeks. The mean hemoglobin at weeks 40 to 52 was 10.48 for vadadustat and 10.45 for darbepoetin, with the difference of plus 0.04. Again, the lower bound of the confidence interval was above the prespecified non-inferiority margin of minus 0.75. In the conversion study of patients on active ESA, PRO2TECT again met the primary efficacy endpoint, demonstrating that vadadustat was non-inferior to darbepoetin. The difference in mean hemoglobin change was minus 0.01 grams per deciliter, with a 95% confidence interval of minus 0.09 to plus 0.07. The lower bound of the confidence interval was above the prespecified non-inferiority margin of minus 0.75. The mean hemoglobin at weeks 24 to 36 was 10.77 for both vadadustat and darbepoetin. The hemoglobin responses were maintained in the secondary evaluation period of weeks 40 to 52. The mean hemoglobin at weeks 40 to 52 were 10.80 for vadadustat and 10.79 for darbepoetin, with the difference in hemoglobin of 0. Again, the lower bound of the confidence interval was above the prespecified non-inferiority margin of minus 0.75. Having reported clear top line efficacy results for vadadustat with INNO2VATE, our Phase III program for dialysis a few short months ago, the team is very pleased with these consistent and straightforward efficacy results for nondialysis. Unfortunately, PRO2TECT's top line MACE results did not deliver the same level of strength as INNO2VATE's. As you can see on Slide 8, PRO2TECT did not meet the primary safety MACE endpoint. The upper bound of the 95% confidence interval was 1.36, which was above the prespecified non-inferiority margin of 1.25. The hazard ratio was 1.17 and the 95% confidence interval was 1.01 to 1.36. As John stressed, we believe the totality of the data from across our global Phase III program supports the cardiovascular safety of vadadustat, particularly when considering the data within key regions and across certain patient subpopulations. We look forward to sharing a full review of the data at an upcoming medical conference. Slide 9 summarizes the treatment emergent adverse event data and the most common treatment emergent adverse events, those occurring in greater than or equal to 10% of patients in either group. These common events included end-stage renal disease, hypertension, hyperkalemia, urinary tract infection, diarrhea, peripheral edema and nausea. The events were similar between treatment groups in both PRO2TECT studies. Consistent with the INNO2VATE data, there were no Hy's law cases and no difference between treatment groups in any liver-related safety parameters. In closing, I want to reiterate that we believe we have a very extensive data package in support of vadadustat's approval for the treatment of anemia due to CKD in both indications and the team is already hard at work on our NDA. I'll now open the call to questions. Operator, we're ready for the first question.

[Operator Instructions] Our first question comes from Chris Raymond with Piper Sandler.

So I guess I get a sense from your commentary that there's an awful lot you want to save for the ASN meeting, but maybe I'm just hoping that you can put a little bit of meat on the bones, I guess, in terms of this commentary on subpopulations in key geographic regions. So is the premise here that there will be some subpopulation perhaps ESA naive versus having been exposed to ESAs? Or is there some other subpopulation you're thinking that will become completely obvious at ASN? Or is -- maybe just any sort of color you can get as to what that will look like when we see the data at ASN?

Chris, thanks so much for the question. So we really recognize how important it is to present this data in scientific session. And again, I mean, let's step back, what we talk about here is the totality of the program, right? We have a global program with 4 different studies across both dialysis and nondialysis, first and foremost. We have an efficacy story that is outstanding, extremely clear. The dialysis indication clearly a straightforward path. PRO2TECT, not a straightforward. No matter what we would say to you today, you don't -- you can't get away from missing the primary safety endpoint. But when you look at that totality of the program, including these other analyses, which is absolutely critical for us to present at ASN, you see a path forward. It's a clear path forward. Because beyond that, we have a path forward, right? We've identified that, but this is an incredibly rich dataset, right? So over the next 7 weeks, we get to do further analysis to continue to strengthen that dataset and deliver that all. ASN isn't 6 months away, right? It's less than 2 months away. And giving you the complete story at that point makes a lot more sense for us. And it's the best thing for the product going forward.

All right. So I get that. So I guess, just to be clear, so the path forward is only incorporating the existing dataset. Is that correct? Like you don't...

That's absolutely correct. Yes. It's -- our expectation is we'll be filing for both indications with the current dataset.

Our next question comes from Difei Yang with Mizuho Group.

Just a couple here. With regards to the MAA submission, would you walk us through the strategy there? Would that be contingent upon the FDA regulatory pathway? And secondarily, with regards to today's data, how do you view the potential implication to vadadustat launch in Japan?

So the first question, Difei, was around Europe and the MAA and that strategy hasn't changed. We are supporting Otsuka on that MAA filing. And again, it's -- nothing has changed in our approach to Europe. The second question was around the launch in Japan. And again, there's no change there. They are actively launching the product, our partner, MTPC, in both indications. We're doing everything we can to support them. And I know their expectations for vadadustat are high.

Just a quick follow-up. Do you see a scenario with regards to the subgroup analysis, which you think there may be a possibility to do additional trial to solidify that data analysis?

Right. So we look at the totality of the data, including these key regional and patient subpopulation analyses from PRO2TECT. We think when you see that data together, you'll agree we have a path forward. Not a straightforward path forward, not an easy path forward. But when you look at the totality of the data, we think it supports approval in both dialysis and nondialysis.

Our next question comes from Eric Joseph with JPMorgan.

John, just interpreting your comments about regulators looking at the totality of the data, does that suggests an integrated analysis of MACE across both the nondialysis and dialysis populations? Have you discussed that type of integrated analysis with both regulatory bodies, FDA and EMA? And also just on the regulatory path forward in Europe, what's your sense of whether that path in the nondialysis population is more or less challenging than in the U.S. with FDA?

Thanks, Eric. So the analysis of the data was -- it was always going to be about the totality of the data, right? Every FDA meeting we've had, as we were designing this, was talking about the totality of the data, I know we all focus on kind of 1 number here. That's not the FDA -- the way the FDA does drug reviews. So it's always been about looking across the entire program. They've always preferred to see dialysis and nondialysis data together. And so given -- I'm very pleased with how we design these studies. We did this, and I think we've talked about this many times, Eric, about how we design both the dialysis and nondialysis programs extraordinarily similarly so these kinds of analysis could be done. This was always our expectation. And that's the way we're thinking about that. Now we are -- as I mentioned, we are planning to have a pre-NDA meeting before the end of the year. And that's where we'll have the opportunity to lay out our strategy to the FDA. Obviously, they won't be opining on data, but we'll talk about the strategy forward. We don't really see a difference from a strategy standpoint with the EMA. And again, Otsuka is leading that filing. But obviously, we're working very closely together on it. But we see the same path forward for both dialysis and nondialysis.

Our next question comes from David Lebowitz with Morgan Stanley.

[indiscernible]

Dave, I'm sorry, we can't hear you.

Can you hear me now?

Yes.

When you compare the hazard ratio on the nondialysis to the dialysis population, it seems to be quite different with the nondialysis population [indiscernible]

David, you're breaking up a lot. I know you're asking about the hazard ratio, difference between INNO2VATE and PRO2TECT. But beyond that, I didn't get the question.

Just was asking why is the hazard ratio on INNO2VATE and PRO2TECT [Technical Difficulty]

Why is there a difference, I think, the question is.