Akebia Therapeutics Inc (AKBA) 2020 Q1 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to Akebia Therapeutics INNO2VATE Top Line Data Readout Call and its First Quarter Financial Results and Business Highlights Conference 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 at Akebia. Thank you so much for joining us to discuss Akebia's top line data from INNO2VATE, our global Phase III program of our product candidate vadadustat for the treatment of anemia due to chronic kidney disease and adults dialysis dependent patients.

On today's call, we will also discuss Akebia's first quarter 2020 financial results and other recent business highlights. We issued 2 press releases this morning, one containing INNO2VATE's top line data, followed by one containing our financial results and other recent business highlights. Both of these exciting press releases are available on our Investor Relations website along with the slides for today's call. For your convenience, an audio replay of today's call with the slides will also be available on our website shortly after we conclude today's webcast. Joining our call today are John Butler, President and Chief Executive Officer; Dr. Steven Burke, Chief Medical Officer; and Jason Amello, Chief Financial Officer.

Before we begin, I'd like to remind everyone that this conference call includes forward-looking statements. Each forward-looking statements contained in this call is 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 Risk Factors and Management's Discussion and Analysis sections of our most recent quarterly and annual reports filed with the SEC and in the cautionary note on forward-looking statements in the slide. 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 to everyone. We are thrilled to be able to announce positive top line data from INNO2VATE, the first of our 2 global Phase III programs studying vadadustat, our investigational oral hypoxia inducible factor, prolyl hydroxylase inhibitor or HIF-PHI to treat the anemia of chronic kidney disease. It is extremely rewarding to see this program yield clear, consistent and compelling positive results.

This is a very important day for Akebia, but it was not accomplished by the Akebia team alone. I want to sincerely thank our investigators and their staff for participating. But most importantly, I want to thank the nearly 4,000 patients who participated in this program. Dialysis patients are among the most at-risk and hardest hit by COVID-19. During these uncertain times, we're reminded of both, the critical nature of our work and a significant need to advance care for these patients. I'd also like to thank our collaboration partner, Otsuka, our partner in dialysis, Vifor Pharma, and their shareholders for supporting Akebia and our efforts thus far.

The Akebia team did an extraordinary job closing the studies collaborating and analyzing the data despite the logistical challenges of operating under the present COVID environment, bringing INNO2VATE to a timely and successful conclusion. I'm extremely proud of all of our employees. We believe our collective efforts bring us one step closer to fulfilling our purpose to better the lives of each person impacted by kidney disease. Again, my sincere thanks to everyone. We wouldn't be here today without all of you.

In terms of an agenda for today's call, we're going to start with looking at how COVID-19 is impacting our business, and how we are working to mitigate potential impacts. We issued our initial response to COVID on March 15, and today I'll provide some updates. The rest of our discussion will be focused on the positive top line data that we announced this morning and the exciting pathway that we've developed for vadadustat. We have a lot of exciting data to cover and so in the interest of time, Jason will not review the Q1 results, but is available for any questions you might have. As always, following our discussions, we'll open the call for Q&A.

In this challenging environment, our purpose to better the lives of each impacted by kidney disease is more relevant and important than ever. Our innovative therapies are critical to dialysis and non-dialysis CKD patients who are among the most at risk. Continuing to provide and support our critical therapies is a priority, as is protecting the health and safety of our patients, customers and employees. To that end, we're doing all we can to limit the spread of the virus as well as support kidney disease patients and our community.

Our team has been incredibly productive under our work-from-home policy. While ensuring business continuity, our team has continued to support local and national response efforts to the COVID-19 pandemic by donating supplies and meals to front-line healthcare workers in Boston, volunteering to provide medical care at clinics treating COVID patients, and donating to the American Kidney Fund coronavirus emergency fund to support the needs of kidney patients.

In terms of our financial and operational performance, to date, we have not experienced any significant adverse impact from COVID-19 and our fundamentals have remained strong. As of the end of Q1, our cash runway extends well into 2021. With that said, these are unprecedented times and via COVID-19, we have no clear visibility on what to expect for the upcoming weeks and months. We are closely monitoring demand for our marketed therapy. And we're also mindful of the potential macro risks from the impact on the healthcare system and the potential impact on payer mix. Given this uncertainty, we continue to take precautionary measures and actively monitor this evolving situation.

Our focus on our clinical programs and ongoing studies is as important as ever. Our PRO2TECT studies for vadadustat have advanced significantly, and we continue to expect top line data mid-year as planned. Also, our forward 2 trials for vadadustat is fully enrolled and we expect top line data by year-end as planned. COVID precautions are however causing a delay in enrolling new clinical trials. For ongoing trials, we're using remote monitoring and performing remote patient visits where possible. Our commercial and customer-facing teams are leveraging tools and technology to interact virtually with healthcare providers including dialysis centers and responding to their needs. We believe Akebia can play an important role in supporting our customers and our patients during this crisis, and we are here to help enable continuity of care with important programs like AkebiaCares.

We're fortunate that even before the COVID pandemic, we had already begun implementing new business continuity plans across our supply chain with the goal of safeguarding our ability to provide our therapies to patients who rely on them and driving operating efficiencies across our business. These measures look to ensure that critical materials are not sourced from any single supplier for either Auryxia or vadadustat. At this time, our supply chain is functioning, our manufacturers are operating, and while we don't currently anticipate a supply disruption, we believe that we have inventory to help mitigate the impact, should one occur.

In sum, this uncertain COVID environment has presented new risks to our business. While we're working hard to mitigating any potential impact, we're mindful that many of these risks and the impact of the larger healthcare markets are outside our control. The bright spot is that our team is more committed than ever to deliver on our purpose, and we believe we have tremendous value enhancing opportunities ahead. And that's a great segue to our INNO2VATE data.

Again, we are very excited with the clear, consistent and compelling efficacy and safety, particularly MACE data that we announced today. Vadadustat succeeded in meeting the primary and key secondary efficacy endpoint in each of the 2 INNO2VATE Phase III studies confirming that once-daily oral therapy with vadadustat can increase, and maintain hemoglobin in the target range similar to the current standard-of-care, in this case Aranesp for darbepoetin alfa. Vadadustat also achieved the primary safety endpoint of the INNO2VATE program, defined as non-inferiority in time to first occurrence of major adverse cardiovascular events or MACE which is a composite of all-cause mortality, non-fatal myocardial infarction or non-fatal stroke. Confirming vadadustat safety and demonstrated no increased cardiovascular risk of vadadustat compared with the standard-of-care in adult dialysis patients with anemia due to CKD.

These results were clear and remarkably consistent across all patient populations in dialysis with anemia due to CKD, whether the patient was new to dialysis, an insulin patient or had been on for many years, a prevalent patient. Importantly, all of these analysis were based on a statistical analysis plan and non-inferiority margins agreed to with regulators.

Today, there are approximately dialysis 500,000 dialysis patients in the US. In general, this is a population with significant health issues. Approximately 90% of dialysis patients are being treated with erythropoiesis stimulating agents or ESAs to manage their anemia. The impact of this disease on patients with CKD is profound. In addition to the well-known symptoms of fatigue, dizziness and shortness of breath, anemia has been associated with more severe adverse outcomes, such as cardiovascular complications including left ventricular hypertrophy, and congestive heart failure. Multiple large peer-reviewed studies have demonstrated the increased cardiovascular risk associated with the ESA use in both, dialysis and non-dialysis patients. Physicians associate that risk with the EPO levels achieved by the doses of ESA, the speed of hemoglobin increase, and excursions of hemoglobin above 12 grams per deciliter.

INNO2VATE data further support what our vadadustat development program has consistently demonstrated and what research suggests nephrologist want in a new treatment option for their patients. Vadadustat treatment was designed with the goal of maintaining physiologic EPO levels, increasing hemoglobin in a predictable manner, minimizing hemoglobin excursions, and providing a convenient oral dose. We believe our data uniquely positions Vadadustat as a potential new oral standard-of-care for treating all populations of dialysis patients, included in both incident and prevalent dialysis patients with anemia due to CKD, subject to approval.

The headline for our global Phase III INNO2VATE program continues to be that we believe it is designed for clinical, regulatory and commercial success, and the results continue to support that belief. INNO2VATE consists of 2 non-inferiority studies designed to evaluate the efficacy and cardiovascular safety during long-term treatment of anemia with vadadustat using an active control, darbepoetin, an injectable ESA, which is the current standard-of-care. Simply put, we believe that in order to change the standard-of-care, you need to compare to the standard-of-care. We thoughtfully constructed this program and our trial design after extensive dialog with the FDA and European regulators. We have a straightforward statistical analysis plan prospectively defined and agreed to non-inferiority margins with the FDA and EMA, and we also agreed with the FDA on the key components of our statistical analysis plan.

Our INNO2VATE trial design has enabled a straightforward collection and analysis of MACE across our program and yielded a clear and compelling data readout on both, efficacy and safety. We can't wait to share these data with regulators and ultimately with physicians, dialysis providers and payers. We are more confident than ever that the clinical success we've demonstrated with INNOVATE supports vadadustat's potential for success on the regulatory front. We are also confident that the INNO2VATE data will be highly informative for physicians, patients, dialysis providers and payers as they make important decisions about patient care once vadadustat is approved.

I know we're all excited to get into the specifics, so let me hand the call over to our Chief Medical Officer, Dr. Steven Burke. Steve?

Thank you, John, and good morning, everyone. On behalf of the R&D team at Akebia, we are very excited to share these data today.

As John mentioned, anemia due to CKD is a serious condition characterized by decreased hemoglobin, it is associated with cardiovascular events, hospitalization and mortality, as well as increased risk of CKD progression. The burden of CKD has a significant impact on patient quality of life, and adds significant costs to our healthcare system. Anemia is currently treated with injectable ESAs along with iron supplementation or red blood cell transfusions; while ESAs are effective in raising hemoglobin levels, there are well documented safety risks associated with their use. In particular, there was evidence that patients administered higher doses of ESAs experienced an increased risk of adverse cardiovascular events, particularly stroke and also mortality. Considering the unmet medical need for a safe and effective treatment, we believe INNO2VATE data are compelling and advance our plans for an NDA and potential approval of vadadustat.

Based on Nobel Prize-winning science, vadadustat was designed as a once daily orally administered investigational HIF-PHI to mimic the body's natural physiologic response to hypoxia or low oxygen. By stabilizing HIF, vadadustat up regulates transcription of endogenous erythropoietin and proteins involved in iron absorption, transport, and utilization. The increase in erythropoietin and delivery of iron to the bone marrow leads to increased red blood cell production and higher hemoglobin. The INNO2VATE program was well powered for efficacy and cardiovascular safety, and included 2 Phase III studies, correction conversion and conversion, which collectively enrolled 3,923 dialysis 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.

As illustrated on Slide 4, both INNO2VATE studies were global, multi-center, open-label, but sponsor blind, non-inferiority studies. The protocols, efficacy and safety endpoints in non-inferiority margin summarized on the right side of the slide were reviewed and aligned with FDA and EMA. In both INNO2VATE studies, the agreed upon 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 efficacy endpoint also agreed with FDA and EMA was the non-inferiority during a secondary evaluation period between weeks 40 and 52. The INNO2VATE program's primary safety endpoint was non-inferiority of vadadustat versus darbepoetin for time to first MACE in the combined INNO2VATE studies. MACE was defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke. The MACE events were independently and blindly adjudicated by the Brigham and Women's Hospital's Clinical Endpoint Center.

As shown on Slide 5, in both studies, patients were randomized one to one to receive either vadadustat or darbepoetin. Vadadustat was initiated 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 milligrams to 600 milligrams daily. Darbepoetin was administered intravenously or subcutaneously. Patients already receiving darbepoetin maintained their prior dose, and those in 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. Iron supplementation, ESA rescue medication, and red blood cell transfusions were allowed as necessary, according to protocol specified criteria, aligning with clinical practice guidelines. The correction conversion study evaluated 369 incident dialysis patients, who were on dialysis for less than 16 weeks prior to screening. The conversion study evaluated 3,554 prevalent dialysis patients receiving ESAs.

Slide 6 summarizes the patients' baseline characteristics, which were similar between treatment groups, and representative of the general dialysis population. 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 conversion study of prevalent dialysis patients, vadadustat was non-inferior to darbepoetin. The difference in mean hemoglobin change was minus 0.17 grams per deciliter with a 95% confidence interval of minus 0.23 to minus 0.10. The lower bound of the confidence interval was above the pre-specified non-inferiority margin of minus 0.75. The mean hemoglobin at weeks 24 to 36 was 10.36 for vadadustat and 10.53 for darbepoetin. The hemoglobin response was maintained in the secondary evaluation period of 40 to 52 weeks. The mean hemoglobin at weeks 40 to 52 were 10.4 for vadadustat and 10.58 for darbepoetin, with a difference in mean hemoglobin of minus 0.18. Again, the lower bound of the confidence interval was above the pre-specified non-inferiority margin of minus 0.75.

In the correction conversion study of incident dialysis patients, vadadustat was non-inferior to darbepoetin. The difference in mean hemoglobin was minus 0.31 with a 95% confidence interval of minus 0.53 and minus 0.10, with the lower bound not crossing the pre-specified non-inferiority margin of minus 0.75. The mean hemoglobin at weeks 24 to 36 was 10.36 for vadadustat, and 10.61 for darbepoetin. The hemoglobin responses were maintained in the secondary evaluation period of 40 to 52 weeks. The mean hemoglobin at 40 to 52 weeks was 10.51 for vadadustat and 10.55 for darbepoetin, with a difference of minus 0.07. Again, the lower bound of the confidence interval was above the pre-specified non-inferiority margin of minus 0.75.

We are very pleased with these efficacy results. They are very consistent with what we saw in the Japanese Phase III studies which were presented at ASN last year.

Now, moving to safety. Slide 8 summarizes the primary safety endpoint time to first MACE. MACE includes death, non-fatal MIs, and non-fatal strokes. Analysis of time to first MACE was based on the hazard ratio from a COX model comparing vadadustat to darbepoetin. The hazard ratio for MACE was 0.96, and the 95% confidence interval was 0.83 to 1.11. The upper bound of the confidence interval was below the non-inferiority margin of 1.25 agreed upon with FDA and the 1.3 agreed upon with EMA.

Slide 9 displays the Kaplan-Meier curves for time to first MACE event in the 2 groups. The red line is the darbepoetin group, and the blue line is the vadadustat group.

Slide 10 summarizes treatment-emergent adverse events and the most common treatment-emergent adverse events occurring in greater than or equal to 10% of patients in either group in the 2 studies. The comment events included diarrhea, pneumonia, hypertension, and hyperkalemia; these events were similar between treatment groups in both INNO2VATE studies. It is great to have obtained such clear, straightforward, positive efficacy and safety results. The data demonstrate the potential of vadadustat to treat anemia of CKD in adult patients on dialysis, subject to regulatory approval.

We are pleased with the findings and excited to present the full data from INNO2VATE, together with our data from our PRO2TECT program, later this year at a medical conference, and publish the results in peer-reviewed journals. The R&D team is already working on the NDA, which we will file as quickly as possible following the PRO2TECT data readout.

I will now turn the call back over to John. Thank you.

Thanks, Steve. We believe we have a strong, compelling, and very straightforward dataset for vadadustat. In terms of what's next, I'll remind you that INNO2VATE is the first of many potentially transformational near-term milestones. We believe we've developed an exciting path forward for vadadustat and Akebia. And although the COVID-19 environment remains uncertain, we continue to make solid progress advancing these activities. In collaboration with our partner, Mitsubishi Tanabe, we are advancing key pre-commercial activities in support of the first regulatory approval of vadadustat expected in Japan this year. Upon approval, vadadustat is expected to be the first HIF-PHI that would be available to treat anemia due to CKD in both, dialysis and non-dialysis dependent adult patients in a major market.

As I mentioned earlier, we have significantly advanced PRO2TECT, our global Phase III study evaluating the safety and efficacy of vadadustat in non-dialysis dependent adult patients with anemia due to CKD. We've achieved the target number of MACE events for the study, and expect top line data mid-year, as planned. In addition, we reinforced our intellectual property position for vadadustat, confirming for both, Akebia, and our collaboration partner, Otsuka, are positioned to execute on plans to launch Vadadustat in the U.K., and potentially the rest of Europe upon approval. We can't wait to get these data in front of the FDA and other regulatory agencies as soon as possible.

Upon successful completion of our Phase III program and with PRO2TECT data in-hand, we plan to submit the regulatory filings for marketing approval of Vadadustat for both, dialysis dependent and non-dialysis adult patients in the U.S. as quickly as possible. And then in other regions, in collaboration with Otsuka. And that's not all, we have an agreement with Vifor Pharma to potentially access a priority review voucher or PRV for the vadadustat NDA with the FDA to expedite review. While there is more work to be done, we believe this path would meaningfully enhance the potential of bringing vadadustat to patients as quickly as possible, subject to regulatory approval.

We have a tremendous amount of confidence in these data. So we're also working very hard on pre-commercialization activity. Here again, we believe the agreement we have with Vifor to distribute vadadustat as their exclusive HIF in the U.S. to Fresenius clinics and certain other dialysis centers has the potential to build momentum and support rapid adoption of vadadustat upon approval in up to 60% of dialysis patients in the U.S. We believe these data support vadadustat's potential to be the new oral standard-of-care for anemia due to CKD in dialysis patients, upon approval.

Wrapping up, we're extremely excited about the top line data. The team is working as quickly as possible to prepare the full data for presentation and publication at an upcoming medical conference. We are right where we want to be, well-positioned to continue advancing our purpose, to better the lives of each person impacted by kidney disease.

With that, I'll open up the call to questions. Please note, that we'll answer questions based on the top-line results disclosed in the press release. Jason is also available to answer any questions pertaining to our first quarter financial results.

Operator, we're ready for the first question.

(Operator Instructions) Our first question comes from Chris Raymond with Piper Sandler.

This is Ally Bratzel on for Chris. Congrats on the data. So first, just on PRO2TECT, I know you talked about this a bit in the prepared remarks but can you just talk about your confidence in being able to disclose the pre-dialysis data mid-year? And the ability to file an NDA later this year? And how maybe we should adjust our timing of expectations as COVID is still in full swing at that point? And then just generally on the actual pre-dialysis readout, how does INNO2VATE change your confidence in enriching the MACE endpoint and PRO2TECT?

Thanks, Ally. Thanks for the questions. So as I mentioned, PRO2TECT is on time for mid-2020. I mean we're obviously continuing to monitor the COVID situation, but as of today, we feel very confident that we'll be able to deliver that data in mid-2020 and then we'll move as quickly as possible to a filing and obviously, the timing will be dependent on when we get the PRO2TECT data, but it is an incredibly exciting moment for us. And to your second question around how does INNO2VATE influence, how we feel about PRO2TECT. Look, I think it's important that the design is identical, basically and that we are looking at PRO2TECT with the same active control, the same data collection, etcetera. And at the same time, it's a different program; so we'll see this data very, very soon and we can't wait to see it, and we couldn't be more excited about the path we have going forward.

Great. And then maybe another question on the non-inferiority margin. So you indicated, you'd agreed to -- prospectively agreed with FDA to a MACE non-inferiority margin of 1.25 but 1.3 for EMA. Could you talk about why the agencies differ, or maybe how you and FDA came to the agreement on that 1.25 number when -- I think in the past for renal drug, they've only asked for 1.3? And then, maybe if you can address if there is any reason to think FDA would look for a different non-inferiority margin for PRO2TECT for the pre-dialysis program?

So it was extensive dialog with both regulatory agencies, and we're very comfortable with where we landed with both. And most importantly, when you look at the data with a upper bound of 1.11, we're comfortably within the non-inferiority range for either regulatory authorities. So we are very, very pleased with what we've shown you today, and again, we're hoping to show the same from PROT2ECT.

Great. And then, maybe just last question from me. Could you talk about your current expectations for a potential outcome for vadadustat?

Well, let's -- and that comes up to the FDA. So we'll wait and see. We'll have both sets of data to put in front of them as quickly as we can, and you know what, we can't wait to put this data in front of the regulators. So if they want to have an outcome, we'll be very ready for it.

Our next question comes from Eric Joseph with JPMorgan.

Congrats on the Phase III readout here. John, I wanted to pick up on your comments about how these studies were designed, and you deliberately chose to go against the design 2 comparative studies against standard-of-care. Can you just speak to how nephrologists view the relative risk benefit of Aranesp versus Epogen or darbepoetin alfa versus epoetin alfa, whether there is any meaningful distinction here? And that sort of might aid in our ability to make sort of cross-trial comparison from INNO2VATE to the dialysis-dependent studies with vadadustat?

Eric, I didn't understand the last part of that question. I guess, I didn't hear you clearly.

Sure. There's going to be some motivation to try to make cross-trial comparisons between vadadustat and roxadustat. You have different comparators between the 2 outcome studies; you're using darbepoetin versus epogen. I'm just wondering if you can speak to how physicians view the relative risk benefit profile of the 2 comparator -- the different ESAs?

So what physicians are looking for Eric, is clear, straightforward and consistent data, and that's what we've delivered them today. And importantly, when you think about vadadustat, the fact that we have the same comparator in INNO2VATE and PRO2TECT, this is all part of how we designed the program for clinical, regulatory and commercial success. We've got the first step with clinical success with INNO2VATE and we believe the clarity of this data and how straightforward it is will lead to regulatory and commercial success for us as well.

Got it. And just coming back to potential -- I'm just wondering to coming back to this potential impact from the COVID pandemic; I guess is there any -- was there any impacts in the INNO2VATE readout here where patients were unable to come in for their -- I guess secondary efficacy follow-up assessments? And I guess whether you can see any impact on whether -- sorry, whether there is any impact from COVID in the full collection of the data in INNO2VATE? And how you might anticipate any impact on PRO2TECT from the pandemic as well?

Sure, Eric. I'll ask Steve to address that.

Yes. No, there wasn't any issue because we announced completion of -- we meet our MACE at the end of last year, and so we told the sites to bring their patients back as soon as possible. And so they made their end-of-treatment visits and the end-of-study visits were allowed to be done by phone in any case by the protocol. So it had really no impact on our ability to collect the data.

And with PRO2TECT, obviously it's -- there is still some time to come. But given the experience we've had with INNO2VATE, we feel like we are confident in the mid-2020 timeline. But we'll update that if we need to on COVID, but obviously, we've been looking really closely at it and feel very confident in the timing.

Our next question comes from Difei Yang with Mizuho Securities.

First of all, congratulations on the Phase III readout, and just a couple questions. How should we think about non-inferiority margin for the NDD population? Is it the reasonable assumption what have you reached agreement with the regulatory agency NDD can be carried over to NDD? And then, the second question is that would you give us an update on whether the final agreement with Vifor was signed and what's the status on that? And then finally, maybe, if Jason could comment on cash runway?

Great. So -- thanks, Difei. So the 1.25 non-inferiority margin that we have for INNO2VATE is the same non-inferiority margin we're using for PRO2TECT. So that's very clear and similarly with the EMA of 1.3. That was the first question. The second question was -- Vifor agreement; yes, thank you. So that's still -- we're still working through that. There was no urgency to get that finalized, we feel very confident in being able to make that happen, and obviously, with these data in hand we're all very excited to put that in place.

And then, on the cash runway side, Jason, you want to take that?

Sure, it's Jason. So our cash runway remains on guidance as we previously communicated with our year-end earnings release, and with this release as well, saying well into Q2 2021; we feel very confident with our cash position, with that kind of a runway, and so that hasn't changed. And we've also -- to get to that level of runway, previously we've identified cost savings and efficiencies to enable us to do that which also positions us well, given the current pandemic situation. So we feel very confident with our cash position.

And just one quick follow-up with regards to the FDA filing time frame. So is it a reasonable assumption typically for HIF PRO2TECT is positive? The typical lag time between filing and that readout is a couple of quarters?

Sorry about?

Timing.

So Difei, we're not guiding on exact timing for filing. When we have PRO2TECT in hand, then I think we'll be better able to do that. And the message I want you to hear is that, when we get PRO2TECT, we will work -- actually, not when we get PRO2TECT -- we're working already to be -- to move as quickly as possible to an NDA filing. But with PRO2TECT in hand, that will be the gating items, so we'll be moving. And like I said before, we're so excited about this; we want to get this in front of regulators as quickly as possible.

And I mean, kind of going back to your last question; you know, it's so excited to be in a place where we have a strong cash position, one set of Phase III data in hand, and then multiple other exciting milestones that are right in front of us, the Japan approval and PRO2TECT data. So the company is in incredibly strong position right now.

And congrats, again.

Thanks so much, Difei.

Our next question comes from Bert Hazlett with BTIG.

And let me offer my congratulations as well, quite an effort and a terrific result. In terms of the MACE end point that read out, were there any components of the MACE all-cause mortality MI or stroke that were stronger than others? I know you're releasing top-line data today, but if you could guide a little bit, that might be helpful.

Yes, Bert. You said I think we're releasing top line data today, but -- I mean, I think the headline for you is consistent. This data was incredibly consistent across efficacy, safety and MACE as the most important safety, and that includes all the components as well.

Okay. And then let me try to come at the same question with regard to treatment -- serious TEAEs. It looked like there was a little bit lower serious treatment-emergent adverse events on the vadadustat -- with utilizing vadadustat. Can you make any general comments about what you're seeing there on the safety side?

Again, I mean we're incredibly pleased with the safety, but I'll ask Steve to make some comments.

Yeah, I think the overall safety profile was very positive and including -- there was no cases of Hy’s law for instance. As you remember, we had a single case a long time ago. And when we looked at hepatotoxicity, no difference between the treatment groups; so very, very pleased with all of the safety data that I've seen to date.

Okay. And then just one more question regarding Vifor Pharma and the use of the Priority Review Voucher. Could you just go through the decision tree that you're going to use to -- whether or not you effect that transaction? Just a little bit more color would be helpful.

Yes. Sure, Bert. So obviously, the first step will be to come to agreement on the final economics around the PRV, and that's -- like I said, that's an active process, and I don't have any concerns that we'll get that done. The data that we have generated here with INNO2VATE would support -- absolutely support using a PRV. Like I keep saying, I can't wait to get this data in front of regulators, it's that clean, clear, and consistent. So -- but obviously, we'll have that conversation with Vifor. And again, I think they'll agree. I think they'll be as excited about this data as we are.

Terrific. Let me slide in one more, if I could. The WuXi supply deal -- could you just comment on why you felt the need to have a third commercial supply agreement in place for vadadustat?

So we actually have 2 API suppliers, and that is obviously just minimizing any kind of supply risk. So on the API side, we have Esteve and WuXi. And then, we also have the third supplier is for drug product, Patheon.

Congratulations, again.

Thanks, Bert.

Our next question comes from Chad Messer with Needham.

Great. And let me add my congratulations on the data. We've obviously been working hard to get to this point. Is there any comment you can make on excursion data and how that looked? I know in your opening remarks, you commented on HIFs and how one of the great promises of this class is giving very physiological and consistent hemoglobin response.

Yes. Again Chad, what you should hear from me is the level of excitement. We're not going to go into specifics of that data, it will be presented with the data hopefully at ASN, that's our expectation. But again, I mean, we talked before about the Spherix data that was done, this independent research, and we talked about it from Q1, at what are physicians looking for in order to adopt a new treatment for anemia. And that is one of the key areas. First and foremost, it is a physiologic EPO level, a gradual increase in hemoglobin, avoiding excursions, and a convenient oral dose. We have proven across our development program that we can do that, and INNO2VATE data absolutely supports that as well. So we feel like we are positioned incredibly well from a commercial perspective, as well as from a regulatory perspective.

Okay, thanks. That's helpful. I mean, of course, we look forward to seeing the rest of the data when it's available. And maybe just also an update on the regulatory process in Japan. I know your partner filed last July. Is the expectation still for potential approval this summer? And any updates on regulatory interactions there? And maybe, can you comment on how long it takes to sort of launch and get reimbursement in Japan in general?

So thanks for the question. We are working closely with Mitsubishi on pre-commercialization activities; everything seems to be on track there. And as we've talked about before, if PMDA takes the normal 12-month cycle, it will be a July approval. And as I said, we're working on pre-commercialization, it will be -- we will move or our partner, Mitsubishi, will move as quickly as possible to launch the product. We certainly expect it to be launched this year.

Okay. Great. And congrats, again.

Thanks, Chad.

Our next question comes from Ed Arce with H.C. Wainwright.

And congrats on this very positive data set for your Phase III, and look forward to the next one soon. Few questions for me, mostly for Dr. Burke. First is, were there any deaths in either of the study -- or either study? Second is, if you could discuss a bit more on how the titration of the drug, either up or down, compares to the level of titration, other words, how active that was relative to Aranesp in the study? And then, thirdly, with the treatment-emergent events, I see here that the numbers were very consistent and similar. But if you look at, in particular, hypertension and diarrhea, the 2 studies look like, numerically one was higher and one was lower; perhaps you could discuss anything you might have seen there with those 2. And then I have a follow-up.

Sure. We had a technical difficulty here, so I heard the first question and the third, but not the second. So let me answer the first 2 that I remember. Starting with the third question; so the conversion study was much larger, it was almost 10 times as large as the correction conversion study. So I would put more stock in the AE table for that study. And the smaller the study, the less reliable are the results. And the first question was deaths, yes. Well, as you know, the primary safety measure was MACE, which includes death, all cause death, and the non-fatal stroke and non-fatal MI. The majority of the events in the MACE analysis were deaths.

And when you look across the entire study, there were fewer deaths in the vadadustat treated patients than there were in the darbepoetin treated patients. So again, as John alluded to earlier, very consistent safety results around the MACE endpoint. And I missed the middle question, I'm sorry.

Okay, fair enough. So the second question was around the titration schedule. You started with 300, and then went either up or more likely -- or down or more likely up after Week-4. I was just wondering how active throughout the study that titration was on drugs relative to the comparator, Aranesp, and its own schedule?

Yes, the drugs could be titrated starting at Week-4, and they were titrated up or down, as you indicated. I am still analyzing that data, so I don't know how frequently the doses were adjusted in a very granular sense. But we have that data, and that will be presented. I mean, the key was you were titrating to get into the target range for both, and we were successfully able to do that, unsurprisingly, with both drugs, so -- and it was very, very clear.

Great. And then just one last question from me. On the slide deck that you presented this morning, Slide 9 here on the Kaplan-Meier curve, it does look like there is a sudden increase on the darbepoetin events at about 168 weeks. Any comment you wish to make there?

Well, that's just the nature of the Kaplan-Meier curves. If you look at the bottom of the slide, the number of people at risk for having a MACE event decreases over time. And when you get to the very end of the study, one event can have a significant impact on the appearance of the Kaplan-Meier curve. But I would discourage you from looking at the end of Kaplan-Meier curves, and look towards more the beginning in the middle. Once you see big jumps or long, flat stretches, it means there's very few patients at risk.

Our next question comes from David Lebowitz with Morgan Stanley.

When you look at this data as of thus far and you see potentially bringing this to market in the dialysis population, how do you see yourself differentiating this versus the EPO versus darbepoetin when, yes, your drug is an oral, but they are already going in for dialysis anyway, so they're used to getting infusions and whatnot? What's the message with this data for dialysis?

We think this data absolutely supports our commercial opportunity in dialysis, David. Again, I go back to the answer I gave earlier. When you look at what physicians are looking for, physicians, they look at that difference in EPO levels in excursions, and in a gradual increase in hemoglobin. Those are all related to safety for them. And then of course, the convenient oral dose matters a lot in the non-dialysis patient and home dialysis patients, which of course we're moving to, but will be very important in dialysis as well. So vadadustat positions extraordinarily well in both dialysis and non-dialysis versus darbepoetin alfa, or any other ESA.

Our next question comes from Kennen MacKay with RBC Capital Markets.

And congrats to the whole team, and a big congrats to you, John, for getting vadadustat from the start all the way to the finish line here. This is really impressive data.

Thanks, Kennen.

So these data, along with those from roxadustat, I think really do validate the class, especially versus Aranesp in dialysis dependent CKD. Actually, really eerily similar data, with the exact same MACE hazard ratio. So maybe with that in mind, I'd really love your perspective and the team's perspective on how this changes your thinking in pre-dialysis CKD around the PROT2ECT trial, and maybe sort of specifically regarding how the control arm that you're using here, active Aranesp control, could influence results coming out of that control arm and out of that trial versus what we've seen from roxadustat that have utilized a placebo.

And then separately, 2 quick housekeeping questions, one financial, one clinical. Financial first. Now that the dialysis data is mature and there's going to be a much higher focus here, can you help us with sort of a ballpark for how we should model the royalty and revenue split in dialysis dependent CKD with the Vifor and Fresenius sales agreement? And then on the clinical side, you'd mentioned no cases of Hy's law, which is a big relief. Can you maybe just elaborate? Were there any other liver signals, liver function test elevations, that were seen, to just help put that to bed? And congrats again.

Thanks so much, Kennen. So go back to (inaudible). We've had a lot of questions moving in a lot of different directions. No, it's great. So again, your question about non-dialysis and PRO2TECT. I mean, look, from our perspective, and you've heard me say this for 4 years now, this is all about the design. We designed our program in collaboration or certainly consultation with the FDA and EMA. And having the active control -- remember, this is about regulatory success, clinical success, commercial success, and having an active control in non-dialysis is what the regulators asked for, and we're going to deliver that to them. And we wanted a design that was as consistent as possible across the entire program, INNO2VATE and PRO2TECT, and that's how we've designed it.

Now again, with INNO2VATE data in hand, as I said earlier, it's the same analysis, same design, same structure, et cetera, for PRO2TECT. Now, it's a different patient population, separate study. We all have to see the data. But I think that that similar design is an important aspect of thinking about PRO2TECT.

On the Vifor agreement, we haven't disclosed what the profit share with Vifor is. We've said that it is -- that we keep the vast majority of the profits, and of course we split those with Otsuka. So Vifor takes their piece, and then the balance is split between Otsuka and Akebia. And then the third -- oh, Steve, you want to talk about the LFTs?

Yes, the LFTs. You're right, there was no cases of Hy's law in the study, and we had hepatotoxicity as an adverse event of special interest. There was no difference between the treatment groups. We also looked at the proportion of patients who had ALT, AST ability et cetera, above a certain threshold. And there was no increase in that with vadadustat. So it looked very good from a hepatic safety perspective. Just one more area where we're very pleased with the data.

Go ahead, Kennen.

No, congrats again on the clean safety profile. Maybe just going back to that first question of mine. In your mind, thinking about the pre-dialysis setting, CKD, would you expect an Aranesp arm to compare maybe better or worse on MACE versus placebo? Again, just thinking about the very similar data in dialysis dependent with the active control, and thinking about maybe what the hazard ratio could look like in pre-dialysis, especially on MACE. It seems like if you were numerically under one with that hazard ratio, it could give you a real commercial advantage in that setting computing versus some of the other players out there.

Thanks and congrats, again.

Thanks, Kennen. Yes, we are obviously just a few months from seeing that data, so we're excited to see it. We do think that the similarity of design between INNO2VATE and PRO2TECT matters a lot, and we just can't wait to share the data when we get it. I mean, just like -- we honestly couldn't be more happy with the data that we're sharing with you today. I wish ASN was next week so that we can share the full data package. And I'm sure I'll feel similarly around PRO2TECT, but we all have to wait to see that data. The next question, please.

Oh, that's it?

Thank you. This concludes our question-and-answer session. I would now like to turn the call back over to John Butler for closing remarks.

Thanks, Joella, and thanks to all of you for joining us today. I started with -- you know dialysis patients are among the most at risk during this pandemic, and we're doing all we can as a company to support them. That is clearly our mission. It really feels wonderful today to announce data that is a true innovation that we believe has the opportunity to significantly help these patients. Again, I want to thank the investigators and their staff. I want to thank the patients who participated in the trial, and I want to thank the Akebia team for all they did to deliver this outstanding result to us today. Thanks so much for joining us. We look forward to updating you in the future.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.