Akebia Therapeutics, Inc. Q1 FY2020 Earnings Call

Good morning, ladies and gentlemen, and welcome to the 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 for INNO2VATE, our global Phase 3 program of our product candidate, vadadustat, for the treatment of anemia due to chronic kidney disease in adult dialysis-dependent patients. On today's call, we will also discuss Akebia's first quarter 2020 financial results and our recent business highlights. We issued two 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 statement 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 slides. 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 two global Phase 3 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 the 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 our 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 person 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 frontline 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 are 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 are 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 are working hard to mitigate any potential impact, we are mindful that many of these risks and the impact to the larger healthcare market 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 about 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 endpoints in each of the two INNO2VATE phase 3 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 or darbepoetin alfa. Vadadustat also achieved the primary safety endpoint of INNO2VATE program, defined as non-inferiority in time to first occurrence of Major Adverse Cardiovascular Events or MACE, which is the composite of all-cause mortality, nonfatal myocardial infarction, or nonfatal 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 incident patient, or has been on for many years, a prevalent patient. Importantly, all of these analyses were based on a statistical analysis plan, and non-inferiority margins agreed to with regulators. Today, there are approximately 500,000 dialysis patients in the U.S. In general, this is a population with significant health issues. Approximately, 90% of dialysis patients have been 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 ESAs 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 excretions of hemoglobin above 12 g/dl. INNO2VATE data further support what the vadadustat development program has consistently demonstrated and what research suggests nephrologists want in a new treatment option for their patients. Vadadustat treatment was designed with the goal of maintaining physiological EPO levels, increasing hemoglobin in a predictable manner, minimizing hemoglobin excretions, and providing a convenient oral dose. We believe our data has uniquely positioned vadadustat as a potential new oral standard of care for treating all populations of dialysis patients including both incident and prevalent dialysis patients with anemia due to CKD, subject to approval. The headline for our global phase 3 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 two non-inferiority studies designed to evaluate the efficacy and cardiovascular safety during long treatment of anemia with vadadustat using an active control of darbepoetin, an injectable ESA, which is the current standard of care. Simply put, we believe that in order to change the standard of care, one must compare to the standard of care. We thoughtfully constructed this program and our trial design after extensive dialogue 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 INNO2VATE 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're very excited to share these data today. As John mentioned, anemia due to CKD is a serious condition characterized by decreased hemoglobin and 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 is 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 safe and effective treatment, we believe INNO2VATE data are compelling and advance our plans for an NDA and the 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 physiological response to hypoxia or low oxygen. By stabilizing HIF, vadadustat up-regulates transcription of endogenous erythropoietin in proteins involved in iron absorption, transport, and utilization. The increase in erythropoietin in 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 two Phase 3 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 in 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 Clinical Endpoints Center. As shown on slide five, in both studies, patients were randomized one-to-one to receive either vadadustat or darbepoetin. Vadadustat was initiated in a dose of 300 milligrams once daily and starting at week four 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 maintained 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. Iron supplementation and ESA rescue medication in red blood cell transfusions were allowed as necessary according to the 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 six summarizes the patients' baseline characteristics which are 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 seven 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 was 10.40 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 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 of vadadustat and 10.61 for darbepoetin. The hemoglobin responses were maintained in the secondary evaluation period of 40 to 52 weeks. The mean hemoglobin of 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’re very pleased with these efficacy results. They're very consistent with what we saw in the Japanese Phase 3 studies which were presented at ASN last year. Now moving to Safety, slide eight summarizes the primary safety endpoint time to first MACE. MACE includes deaths, 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 nine displays the Kaplan-Meier curves for time to first MACE event in the two groups. The red line is the darbepoetin group and the blue line is the vadadustat group. Slide 10 summarizes treatment emerging adverse events and the most common treatment emerging adverse events occurring in greater than or equal to 10% of patients in either group in the two studies. The common events included diarrhea, pneumonia, hypertension, and hyperkalemia. These events were similar between treatment groups in both INNO2VATE studies. It is great to obtain such clear, straightforward positive efficacy and safety results today to demonstrate the potential of vadadustat to treat anemia of CKD in adult patients on dialysis, subject to regulatory approval. We’re 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 will remind you that INNO2VATE is the first of many potentially transformational near-term milestones. We believe we have 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're 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 3 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 3 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 to 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. So 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, and 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 your 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.

Thank you. Our first question comes from Chris Raymond with Piper Sandler. Your line is now open.

Hi this is Ally Bratzel on for Chris. Congrats on the data. So, first, just on PRO2TECT, I know you've 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 expectations if 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 reaching the main endpoint in 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's an incredibly exciting moment for us. And to your second question around how does INNO2VATE influence how we feel about PRO2TECT, now look, I think it's important that the design is identical, basically that we're looking at PRO2TECT with the same active control, the same data collection, et cetera. 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. Regarding the non-inferiority margin, you mentioned that you reached an agreement with the FDA on a MACE non-inferiority margin of 1.25, while for the EMA it’s 1.3. Can you explain the reasons for the differences between the agencies, and how you and the FDA settled on the 1.25 figure, especially since past renal studies only required 1.3? Also, is there any indication that the FDA might seek a different non-inferiority margin for PRO2TECT in the pre-dialysis program?

So, it was extensive dialogue 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 an upper bound of 1.11 we're comfortably within the non-inferiority range for either regulatory authority. So we're very, very pleased with what we've shown you today, and again, we're hoping to show the same from PRO2TECT.

Great. And then, maybe just last question for me, could you talk about your current expectations for a potential Advisory Committee meeting for vadadustat?

An Advisory Committee is at the discretion of the FDA. We will prepare both sets of data to present to them as soon as possible, and we are eager to share this data with the regulators. If they decide to hold an Advisory Committee meeting, we will be fully prepared for it.

Okay, great. Thanks so much, and congrats again.

Thanks, Ally.

Thank you. Our next question comes from Eric Joseph with JPMorgan. Your line is now open.

Hey guys, thanks for taking the questions, and congrats on the Phase 3 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 to compare the studies against standard of care. Can you just speak to how nephrologists view the relative risk benefit of vadadustat versus darbepoetin, or any potential differences between the two, and whether there's any meaningful distinction here that might aid in our ability to make comparisons from INNO2VATE to the dialysis clinic studies with roxadustat?

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

Sure. There will be some interest in comparing vadadustat and roxadustat. The outcome studies utilize different comparators, with darbepoetin being used against Epogen. Can you discuss how physicians perceive the relative risk-benefit profile of these two competitors or 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 design the program for clinical, regulatory, and commercial success. We've got the first step with clinical success with INNO2VATE, and believe the clarity of this data and how straightforward it is will lead to regulatory and commercial success for us as well.

Got it. Regarding the potential impact from the COVID pandemic, are there any effects on the INNO2VATE readout considering that patients might not have been able to attend their secondary efficacy follow-up assessments? Do you expect any impact on the full collection of data in INNO2VATE due to COVID, and how do you foresee the pandemic influencing this?

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

Yes, hi, Eric. There wasn’t any issue because we announced the completion of this. We met our MACE at the end of last year, so we instructed the sites to bring their patients back as soon as possible. They conducted their end-of-treatment visits, and the end-of-study visits were permitted to be done by phone according to the protocol. Therefore, it had no impact on our ability to collect the data. Regarding PRO2TECT, there's still some time ahead, but based on our experience with INNO2VATE, we are confident in the mid-2020 timeline. We will provide updates if necessary due to COVID, but we are closely monitoring the situation and feel very confident about the timing.

Got it. Thanks for taking the questions.

Thanks, Eric.

Thank you. Our next question comes from Difei Yang with Mizuho Securities. Your line is now open.

Hi, good morning, first of all, congratulations on the Phase 3 readout, and I have a couple of questions. How should we consider non-inferiority margins for the NDD population? Is it reasonable to assume that the agreement you've reached with the regulatory agency in DD can be applied to NDD? My second question is whether you can provide an update on the final agreement with Vifor and its current status. Lastly, could Jason comment on the cash runway?

Great. So thanks, Difei. So the 1.25 non-inferiority margins that we had for INNO2VATE is the same non-inferiority margin we're using for PRO2TECT. So, that's very clear, and similarly with EMA at 1.3. That was the first question. The second question was?

On Vifor…

Thank you. We are still working through that and there is no urgency to finalize it. I feel very confident that we can make it happen, and with this data in hand, we are all very excited to implement it. Jason, would you like to address the cash runway?

Sure. Hi, it's Jason. So our cash runway remains on guidance as we previously communicated with our year-end and with this release as well, staying well into Q 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.

Thank you, Jason. And just one quick follow-up with regards to the FDA filing timeframe, so is it a reasonable assumption typically for, if PRO2TECT is positive, the typical lag time and the readout is a couple of quarters?

I'm sorry, about…

Timing.

We are not providing specific timing for the filing. Once we have PRO2TECT, we will be in a better position to provide guidance. I want to emphasize that we are already working to expedite the NDA filing, and having PRO2TECT will be a key factor in that process. We are eager to present this to regulators as soon as possible. It’s remarkable to be in a situation where we have a strong cash position, one set of Phase 3 data, and several exciting milestones ahead, including approval in Japan and PRO2TECT data. The company is currently in a very strong position.

Thank you so much for taking my questions, and congrats again.

Thank you, Difei.

Thanks so much, Difei.

Thank you. Our next question comes from Bert Hazlett with BTIG. Your line is now open.

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

Yes, Bert, you mentioned we are releasing top-line data today. However, I think the main point for you is that this data has shown remarkable consistency across efficacy, safety, and MACE, which is the key safety measure and encompasses all its components.

Thank you. Let me address the same question regarding serious treatment emergent adverse events. It seems that there were slightly fewer serious treatment emergent adverse events observed with vadadustat. Can you share some general insights on what you are observing in terms of safety?

Again, we are incredibly pleased with the safety that I will ask Steve to make some comments.

Yes, I think the overall safety profile was very positive, and including there was no cases of high prevalent incidents. 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 have seen today.

Okay, thank you. 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 are going to use to whether or not you effect that transition? Just a little bit more color would be helpful.

Yes, of course, Bert. The first step will be to agree on the final economics surrounding the PRV, and that's an ongoing process that I’m confident we will complete. The data we have generated from INNO2VATE strongly supports the use of a PRV. I'm eager to present this data to regulators as it is very clear and consistent. We will discuss this with Vifor, and I believe they will share our enthusiasm for the data.

Terrific. Let me slide in 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 two API suppliers, and that is obviously just minimizing any kind of supply risk. So, on the API side, we have multiple suppliers, and then we also have the third supplier is for drug product, API.

Okay, thank you. Congratulations again.

Thanks, Bert.

Thank you. Our next question comes from Chad Messer with Needham. Your line is now open.

Great, thanks. Good morning, and let me add my congratulations on the data. We have obviously been working hard to get to this point. Is there any comment you can make on excursion data and how that looks? I know in your opening remarks, you've commented on guests 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've talked before about the Spherix data that was done, it's 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 physiological 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. INNO2VATE data absolutely supports that as well. So, we feel like we're positioned incredibly well from a commercial perspective, as well as from a regulatory perspective.

Okay, thanks. That's helpful, and of course, we look forward to seeing the rest of the data when it's available. And maybe just also 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 general?

Thank you for the question. We are collaborating closely with Mitsubishi on pre-commercialization activities, and everything is on track. If the PMDA adheres to the typical 12-month review period, we anticipate approval in July. As mentioned, we are focused on pre-commercialization, and Mitsubishi will act as swiftly as possible to launch the product. We expect it to be launched this year.

Okay, great. Thanks, and congrats again.

Thanks, Chad.

Thank you. Our next question comes from Ed Arce with H.C. Wainwright. Your line is now open.

Hi everyone. Thanks for taking my questions, and congrats on this very positive data set for your Phase 3, and look forward to the next one soon. A few questions for me, mostly for Dr. Burke; first is, were there any deaths in 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? In 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 two studies looked like numerically, one was higher, and one was lower, perhaps you could discuss anything you might have seen there with those two? And then, I have a follow-up. Thank you.

Sure. We had a technical difficulty here. So, I heard the first question and the third, but not the second. So, let me hear two the first two that I remember. Starting with third question, so the conversion study was much larger, it's almost 10 times this largest Correction/Conversion study. So, I would put more stock in the AD table for that study, and the smaller the study, the less reliable are the results. So, and the first question was death, yes, well, as you know the primary safety measure was MACE, which includes death all cause death in non-fatal stroke and non-fatal MI, and 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 and they were in the darbepoetin-treated patients. So, again, as John alluded to earlier, very consistent safety results around the MACE endpoint, and this is 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 down after week four, I was just wondering how active throughout the study that titration was on drugs relative to the competitor Aranesp, and its own schedule?

Yes, the drugs could be titrated starting at week four, and they weren't titrated up or down, as you indicated. I am still analyzing the last data. So, I don't know how frequently the doses were adjusted in a very granular sense, but we have that data, and that'll be presented, and 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, 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 nine 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 and the middle. Once you see big jumps, or long flat stretches, it means it's very few patients at risk.

Understood, thanks again.

Thanks, Ed.

Thank you. Our next question comes from David Lebowitz with Morgan Stanley. Your line is now open.

Hello. Well, thank you for taking my question. 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 Epo versus darbepoetin? 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?

Yes, 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, you know, 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. That 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.

Thank you for taking my question.

Thank you.

Thanks, David.

Thank you. Our next question comes from Kennen MacKay with RBC Capital Markets. Your line is open.

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

Thanks, Kennen.

So, do you start along with those from roxadustat, I think really do validate the class, especially versus Aranesp in dialysis-dependent CKD actually, really yearly 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 PRO2TECT trial, and 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 vadadustat that have utilized the placebo? And then separately, two 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 Vifor and Fresenius sales agreement? And then on the clinical side, you had mentioned no cases of Hy's law, which is a big relief, can you maybe just elaborate, were there any other liver signals, motor function test elevations that were seen to just help put that to bed? Thanks so much, and congrats again.

Thank you, Kennen. We're experiencing some technical difficulties, but it's great to be here. Regarding your question about non-dialysis and PRO2TECT, from our standpoint, this is primarily about the design. We developed our program in consultation with the FDA and EMA, ensuring that we included an active control, which was essential for regulatory, clinical, and commercial success. We aimed for a design that was as uniform as possible across the entire program, including INNO2VATE and PRO2TECT. With the INNO2VATE data available, we maintain the same analysis, design, and structure. PRO2TECT involves a different patient population and is a separate study, and we need to evaluate the data, but I believe that the consistent design remains a vital consideration for PRO2TECT. Regarding the Vifor agreement, we haven't shared the specifics of the profit share with Vifor, but we do retain the majority of the profits, which we then split with Otsuka. Vifor takes its share, and the remaining profits are divided between Otsuka and Akebia. Lastly, Steve, do you want to discuss the LFTs?

Yes, the LFTs, you’re right, there were no cases of Hy's law in the study, and we had hepatic toxicity as an adverse event of special interest. There was no difference between the treatment groups. So, we also analyzed, look at proportion of patients who had elevated liver function tests above the certain threshold, and there was no increase in that with vadadustat. So, it looked very good from hepatic safety perspective. This is one more area we are very pleased with the data.

No, congrats again on that clean safety profile, maybe just going back to that first question in mind, in your mind thinking about the pre-dialysis settings, 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 that hazard ratio could look like in pre-dialysis, especially on MACE, it seems like if you look under one with that hazard ratio could give you a real commercial advantage in that setting competing others as some of the other players out there? Thanks and congrats again.

Yes, we’re just a few months away from seeing that data, and we're eager to review it. We believe that the design similarities between INNO2VATE and PRO2TECT are significant, and we can't wait to share the findings. We're genuinely pleased with the data we present today. I wish the ASM was next week so we could provide the complete data package, and I know the same goes for PRO2TECT, but we all need to wait for that information. Next question, please. That's all.

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.

Thank you, Joanna, and thank you all for being with us today. I want to emphasize that dialysis patients are particularly vulnerable during this pandemic, and our company is committed to supporting them. It brings me great joy to share data today that represents a genuine innovation with the potential to greatly assist these patients. I would like to express my gratitude to the investigators and their teams, the patients who took part in the trial, and the Akebia team for their efforts in achieving this remarkable outcome. Thank you for your participation. We are eager to provide further updates in the future.

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