Akebia Therapeutics (NASDAQ:AKBA) Q1 2020 Earnings Call

0:00 Good morning, ladies and gentlemen, and welcome to Akibia Therapeutics Innovate Topline 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 Shepherd.

0:18 Thank you, and good morning. My name is Kristen Shepherd, Senior Vice President of Investor Relations at Akibia. Thank you so much for joining us to discuss Akibia's top-line data from Innovate, our global phase three program of our product candidate Vatadustat for the treatment of anemia due to chronic kidney disease in adult dialysis-dependent patients. On today's call, we will also discuss Akibia's first quarter 2020 financial results and other recent business highlights. We issued two press releases this morning, one containing Innovate'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.

1:09 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 Amelo, Chief Financial Officer. Before we begin, I'd like to remind everyone that this conference call includes four looking statements. Each four 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.

2:03 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?

2:20 Thank you, Kristen, and welcome to everyone. We are thrilled to be able to announce positive top-line data from Innovate, the first of our two global Phase III programs studying Vatadustat, our investigational oral hypoxia-inducible factor pro-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 Akibia, but it was not accomplished by the Akibia 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.

3:08 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 before pharma, and our shareholders for supporting Akibia and our efforts thus far. The Akibia team did an extraordinary job closing the studies, collaborating and analyzing the despite the logistical challenges of operating under the present COVID environment, bringing Innovate 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.

4:02 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 15th, 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 Veta-Dustat. 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.

4:51 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.

5:56 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 due to 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.

6:43 Our focus on our clinical programs and ongoing studies is as important as ever. Our PROTECT studies for Vatadustat have advanced significantly, and we continue to expect top-line data mid-year as planned. Also, our Forward 2 trial for Vatadustat 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're here to help enable continuity of care with important programs like Akibia Cares.

7:41 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 Orixia or Vatadustat. 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 mitigate any potential impact, were mindful that many of these risks and the impact to the larger healthcare market are outside our control.

8:34 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 Innovate data. Again, we are very excited with the clear, consistent, and compelling efficacy and safety, particularly MACE data, that we announced today. Vatadustat succeeded in meeting the primary and key secondary efficacy endpoint in each of the two Innovate Phase III studies, confirming that once daily, oral therapy with Vatadustat can increase and maintain hemoglobin in the target range similar to the current standard of care, in this case, ARIN-S for darbacoitin alpha. Vatadustat also achieved the primary safety endpoint of the Innovate program.

9:22 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 Vatadustat safety and demonstrating no increased cardiovascular risk of Vatadustat 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 had 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.

10:14 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 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 ESA use in both dialysis and non-dialysis patients.

11:03 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. InnovateData further support what our Vatadustat development program has consistently demonstrated and what research suggests nephrologists want in a new treatment option for their patients. Vatadustat 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 Vatadustat 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.

11:56 The headline for our Global Phase III Innovate program continues to be that we believe it is designed for clinical, regulatory, and commercial success, and the results continue to support that belief. Innovate consists of two non-inferiority studies designed to evaluate the efficacy and cardiovascular safety during long-term treatment of anemia without a DUSAT using an active control, darbatholatin, and 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 dialogue with the FDA and European regulators.

12:41 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 innovative 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 Vatavustat's potential for success on the regulatory front. We are also confident that the Innovate data will be highly informative for physicians, patients, dialysis providers, and payers as they make important decisions about patient care once Vatavustat is approved.

13:38 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?

13:49 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, Thank you for joining us. 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 Innovate data are compelling and advance our plans for an NDA and potential approval of Vatadustat.

15:02 Based on Nobel Prize winning science, Therapeutics, Inc. and Delivery of Iron to the Bone Marrow leads to increased red blood cell production and higher hemoglobin. The INOVAIT program was well-powered for efficacy and cardiovascular safety and included two Phase III studies, correction conversion and conversion, which collectively enrolled 3,923 dialysis-dependent patients with anemia due to CKD.

15:56 This is a very large, rigorous and thoughtfully designed program to compare Vatadustat to a current standard of care, Darby Poetin Alpha, an injectable ESA. As illustrated on slide four, both Innovate studies were global, multicenter, open-label, but sponsor-blind non-inferiority studies. The protocols, efficacy and safety endpoints, and non-inferiority margins summarized on the right side of the slide were reviewed and aligned with FDA and EMA. Thank you very much. also agreed with FDA and EMA was the non-inferiority during a secondary evaluation period between weeks 40 and 52.

17:03 The Innovate program's primary safety endpoint was non-inferiority of Vatadustat versus Darby-Poetin for time to first MACE in the combined Innovate 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 Endpoint Center. As shown in slide five, in both studies, patients were randomized one-to-one to receive either Vatadustat or Dibupoetin. Vatadustat was initiated at 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.

17:54 Darbopoetin was administered intravenously or subcutaneously. Patients already receiving Darbopoetin maintained their prior dose, and those and other ESAs were switched to Darbopoetin 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 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.

18:41 The conversion study evaluated 3,554 prevalent dialysis patients receiving ESAs. Slide 6 summarizes the patient's 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 7 summarizes the primary and key secondary efficacy endpoint data. In the conversion study of prevalent dialysis patients, Vatadustat was non-inferior to Darby Poitin. 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.

19:32 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 Vatadustat and 10.53 for Darby Poitin. Thank you very much. In the correction conversion study of incident dialysis patients, Vatadustat was noninferior to Darby Poetin. 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 noninferiority margin of minus 0.75.

20:40 The mean hemoglobin at weeks 24 to 36 was 10.36 for Vatadustat, and 10.61 for Darby Poitin. 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 Vatadustat and 10.55 for Darby Poitin with a difference of minus .07. Again, the lower bound of the confidence interval was above the pre-specified non-inferiority margin of minus .75. We are very pleased with these efficacy results. They're very consistent with what we saw in the Japanese Phase III studies, which were presented at ASN last year. Now moving to safety.

21:25 Slide 8 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 Vatadustat to Darby Poitin. 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 two groups. The red line is the darvopoietin group. and the blue line is the Vatadustat group.

22:16 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 two studies. The common events included diarrhea, pneumonia, hypertension and hyperkalemia. These events were similar between treatment groups in both Innovate studies. It is great to have obtained such clear, straightforward, positive efficacy and safety results. The data demonstrate the potential of Atadustat 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 Innovate together with our data from our Protect program later this year at a medical conference and publish the results in peer-reviewed journals.

23:06 The R&D team is already working on the NDA, which we will file as quickly as possible following the PROTECT data readout. I will now turn the call back over to John. Thank you.

23:18 Thanks, Steve. We believe we have a strong, compelling, and very straightforward data set for Vatadustat. In terms of what's next, I'll remind you that Innovate is the first of many potentially transformational near-term milestones. We believe we've developed an exciting path forward for Vatadustat 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 Vatadustat expected in Japan this year. Upon approval, Vatadustat is expected to be the first, if PHI, that would be available to treat anemia due to CKD in both dialysis and non-dialysis dependent adult patients in a major market.

24:12 As I mentioned earlier, we have significantly advanced PROTECT, our global phase three study evaluating the safety and efficacy of Vatadustat 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 Veta-Dustat, confirming for both Akibia and our collaboration partner, Otsuka, our position to execute on plans to launch Veta-Dustat in the UK 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 protect data in hand, We plan to submit the regulatory filings for marketing approval of Vatadustat for both dialysis-dependent and non-dialysis adult patients in the U.S.

25:09 as quickly as possible, and then in other regions in collaboration with Otsuka. And that's not all. We have an agreement with V4 Pharma to potentially access a priority review voucher, or PRV, for the Vatadustat 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 Vatadustat 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 VFOR to distribute Vatadustat 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 Vatadustat upon approval in up to 60% of dialysis patients in the U.S.

26:03 We believe these data support Vatadustat'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.

26:50 Operator, we're ready for the first question. Thank you. To ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Chris Raymond with Piper Sandler. Your line is now open.

27:12 Hi. This is Allie Brasselon for Chris. Congrats on the data. First, just on PROTECT, 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 expectations if COVID is still influencing at that point? and then just generally on the actual predialysis readout, how does Innovate change your confidence in reaching the base endpoint in PROTECT?

27:52 Thanks, Allie. Thanks for the questions. So as I mentioned, PROTECT is on time for mid-2020. I mean, we're obviously continuing to monitor the COVID situation, but again, As of today, we feel very confident that we'll be able to deliver that data in mid-2020. And, you know, then we'll move as quickly as possible to a filing. I mean, obviously, the timing will be dependent on when we get the PROTECT data, but it's an incredibly exciting moment for us. And, you know, to your second question around how does innovate influence how we feel about PROTECT, I think it's important that the design is identical, basically.

28:37 We're looking at Protect with the same act of control, the same data collection, etc. At the same time, it's a different program. We'll see this data very, very soon, and we can't wait to see it. We couldn't be more excited about the path we have going forward.

28:58 Great. Maybe another question on The non-inferiority margin. So you indicated you had agreed to a, 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 differed or maybe how you and FDA came to the agreement on that 1.25 number when I think in the past for renal drugs they've only asked for 1.3. and then maybe if you can address if there's any reason to think FDA would look for a different non-inferiority margin for PROTECT for the predialysis program.

29:33 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 a upper bound of 1.11 we're comfortably within The non-inferiority range for either regulatory authority. So, you know, we're very, very pleased with what we've shown you today. And, again, we're hoping to show the same from PROTECT.

30:05 Great. And then maybe just last question for me. Could you talk about your current expectations for a potential adcom for Vatadestats?

30:13 Well, that's, you know, an adcom is up to the FDA. So, you know, we'll wait and see. We'll have both Thank you. Our next question comes from Eric Joseph with J.P. Morgan. Your line is now open. Hey, guys. Thanks for taking the questions and congrats on the

30:51 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 comparative studies against standard of care. Can you just speak to how nephrologists view the relative risk-benefit of, you know, DARPA LNS versus Epigen or DARPA potent alpha versus So power and alpha, and whether there's any meaningful distinction here, and that sort of might aid in our ability to make sort of cross-trial comparisons from inovate to the dialysis-dependent studies with leucatastat.

31:43 Eric, I didn't understand the last part of that question.

31:48 I didn't hear you clearly. Sure. There's going to be some motivation to try and make cross-trial comparisons between beta-D-stat and ruxatastat. You have different comparators between the two outcome studies you're using, DARPA-POLIN, versus their epigen. I'm just wondering if you could speak to how physicians view the relative risk-benefit profile of the two comparators, the different ESAs.

32:23 So what physicians are looking for, Erik, is clear, straightforward, and consistent data. And that's what we've delivered them today. And importantly, when you think about Vatadustat, the fact that we have the same comparator in Innovate and Protect, 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 Innovate, and we believe the clarity of this data and how straightforward it is will lead to regulatory and commercial success for us as well.

33:06 Got it. And just coming back to potential, I'm just wondering to, coming back to just potential impact from the COVID pandemic, is there any... Was there any impact in the innovate readout here where patients were unable to come in for their, I guess, secondary efficacy follow-up assessments? And I guess whether you anticipate any impact on whether, yeah, sorry, whether there's any impact from COVID in the and many more. Thank you.

34:17 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.

34:30 And with PROTECT, you know, obviously there's still some time to come, but given the experience we've had with Innovate, we feel like we're confident in the mid-2020 timeline. But we'll update that if we need to on COVID, but and obviously we've been looking really closely at it and feel very confident in the timing. Got it. Thanks for taking the questions. Thanks, Erik. Thank you. Our next question comes from with Missoula Securities. Your line is now open. Hi. Good morning. First of all, congratulations on the phase three readout. And just a couple questions. How should we think about non-inferiority margins for the NDD population? Is it a reasonable assumption?

35:17 Would you have reached agreement with the regulatory agency in DD can be carried over to NDD? Then the second question is that would you give us an update on whether the final agreement with BIFR was signed and what's the status on that? and then finally, maybe if Jason could comment on Cache Runway.

35:47 Great. So thanks, Yifei. So the 1.25 non-inferiority margin that we have for Innovate is the same non-inferiority margin we're using for Protect. So that's very clear and similarly with EMA at 1.3. That was the first question. The second question was 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 this 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?

36:31 Sure. Hi, 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 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, you know, 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 that 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 protect is positive?

37:25 The typical lag time between filing and that readout is a couple quarters.

37:32 Sorry, about? Timing. Oh. So, Deepay, we're not guiding on exact timing for filing. You know, when we have protect in hand, then I think we'll be are better able to do that. The message I want you to hear is that when we get PROTECT, we will work, well, actually, not when we get PROTECT, we're working already to move as quickly as possible to an NDA filing, but with PROTECT in hand, that will be the gating item. So we'll be moving. 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 exciting to be in a place where we have a strong cash position, one set of Phase 3 data in hand, and then multiple other exciting milestones that are right in front of us, the Japan approval and protect data. So, you know, the company's in an incredibly strong position right now.

38:31 Thank you so much for taking my questions, and congrats again.

38:34 Thank you, DeFay. Thanks so much, DeFay. Thank you. Our next question comes from Bert Haslett with BTIG. Your line is now open.

38:45 Thank you, and let me offer my congratulations as well. Quite an effort and a terrific result. In terms of the MACE endpoint 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.

39:13 Yeah, Bert, you said it. We're releasing top-line data today, but 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.

39:33 Okay, thank you. And then let me try to come at the same question with regard to treatment, serious TEAEs. You know, it looked like there was a little bit lower serious treatment of urgent adverse events on the Vatadustat, utilizing Vatadustat. Can you make any general comments about what you're seeing there on the safety side?

39:58 Again, I mean, we're incredibly pleased with the safety, but I'll ask Steve to make some comments.

40:04 Yeah, I think the overall safety profile was very positive, including there was no cases of Heye'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.

40:28 Okay, thank you. And then just one more question regarding V4 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 affect that transaction? Just a little bit more color would be helpful.

40:48 Yeah, sure, Bert. So obviously the first step will be to come to agreement on the final economics around the PRV. And 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 Innovate would absolutely support using a PRB. Like I keep saying, I can't wait to get this data in front of regulators. It's that clean, clear, and consistent. But obviously we'll have that conversation with V4, and again, I think they'll agree. I think they'll be as excited about this data as we are.

41:26 Let me slide in one more if I could. The WUSHI supply deal, could you just comment on why you felt the need to have a third commercial supply agreement in place for Vatadustat?

41:42 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 Esteve and Wushi, and then we also have the third supplier is for drug product, Papion. Okay, thank you. Congratulations again. Thanks, Bert. Thank you. Our next question comes from Chad Messer with Needham. Your line is now open.

42:18 Great. Thanks. Good morning, 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 hits and how One of the great promises of this class is giving very physiological and consistent hemoglobin response.

42:52 Yeah, 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, we've talked before about The spherics data that was done, this independent research, and we talked about it from Q1, 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 Innovate Data absolutely supports that as well.

43:41 So, you know, we feel like we are positioned incredibly well from a commercial perspective as well as from a regulatory perspective.

43:50 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 a – Update on the regulatory process in Japan. I know your partner filed last July. Is the expectation still for potential approval this summer? Any updates on regulatory interactions there? Maybe can you comment on how long it takes to launch and get reimbursement in Japan in general?

44:29 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. We will move, our partner Mitsubishi will move as quickly as possible to launch We certainly expect it to be launched this year.

45:02 Great. Thanks and congrats again.

45:05 Thanks, Jeff. Thank you. Our next question comes from Ed Arce with HC Wainwright. Your line is now open.

45:14 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 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. In other words, how active that was relative to Aaron Espe in the study.

46:00 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 look 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.

46:32 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 two that I remember, starting with the third question. So the conversion study was much larger. It's almost ten 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 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 Vatadustat-treated patients than there were in the Darby-Powatin-treated patients. So again, as John alluded to earlier, very consistent safety results around the MACE endpoint. I missed the middle question, I'm sorry.

47:44 Okay, fair enough. So the second question was around the titration schedule. You started with 300 and then went either up or down or more likely up after week four. I was just wondering how active throughout the study that titration was on drugs relative to the comparator, Aranesp, and its own schedule.

48:17 Drugs could be titrated starting at week four, 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.

48:35 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.

48:51 Great. And then just one last question for 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 darbopoietin Events at about 168 weeks. Any comment you wish to make there?

49:19 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 a study, one event can have a significant impact. Thank you. Our next question comes from David Lebowitz of Morgan Stanley. Your line is now open.

50:05 So 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 the EPO versus darbopoietin 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? Yeah, we think this data absolutely supports our commercial opportunity in dialysis, David. Again, I'll 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, you know, Vata-Dustat positions extraordinarily well in both dialysis and non-dialysis, versus Darby Poet and Alpha, or any other ESA.

51:36 Thank you for taking my question. Thank you.

51:39 Thanks, David. Thank you. Our next question comes from Kenan McKay with RBC Capital Markets. Your line is now open.

51:49 Hi. Thanks for taking the question, and congrats to the whole team, and big congrats to you, John, for getting the data stats from the start all the way to the finish line here. This is really impressive data. So these data, along with those from Roxidustat, I think really do validate the class, especially versus ARINASP 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 predialysis CKD around the PROTECT trial and and many, many, many, many, many, many, many, many, 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 V4 and Fresenius sales agreement?

53:02 And then on the clinical side, you mentioned no cases of Heisla, 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? Thanks so much and congrats again. Thanks so much, Kenneth.

53:19 So I'll go back to... We have to write those down, Kenneth.

53:24 There's a lot of questions in a lot of different directions. No, it's great. So, again, your question about non-dialysis and protect. I mean, look, from our perspective, and you've heard me say this for four years now, this is all about the design. You know, we designed our program in collaboration or certainly consultation with the FDA and EMA. and having the active control. Remember, this was 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, innovate and protect. And that's how we designed it. Now, with innovate data in hand, as I said earlier, it's the same Thank you very much.

54:34 On the V4 agreement, we haven't disclosed what the profit share with V4 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, you know, V4 takes their piece, and then the balance is split between Otsuka and Akibia. And then the third – oh. Steve, do you want to talk about the LFTs?

55:01 Yeah, the LFTs, you're right. There was no cases of Heye'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 analyzed, looked at the proportion of patients who had ALT, AST, bili, et cetera, above a certain threshold, and there was no increase in that with hepatodustat. So it looked very good from a hepatic safety perspective. Just one more area.

55:27 We're very pleased with the data. Go ahead, Kenny. No, congrats again on that 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 ARNESP 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 were numerically under one with that hazard ratio, it could give you a real commercial advantage in that setting competing versus some of the other players out there.

56:14 Thanks, and congrats again.

56:16 Yeah, thanks, Ken. And, yeah, we're obviously just a few months from seeing that data, so, you know, we're excited to see it. We do think that the similarity of design between Innovate and Protect matters a lot. We just can't wait to share the data when we get it. 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 could share the full data package. I'm sure I'll feel similarly around Protect, but we all have to wait and see that data. Next question, please. 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.

57:05 Thanks, Joelle, and thanks to all of you for joining us today. You know, when I started, 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 Akiva 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.

57:52 Thank you for participating. You may now disconnect.