Kyntra Bio, Inc. (KYNB) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the FibroGen Provides Roxadustat Update Call. [Operator Instructions] And please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference to your speaker today, Michael Tung. Please go ahead.

Thank you, Victor. Good afternoon, everyone. I'm Michael Tung, Vice President of Corporate Strategy and Investor Relations at FibroGen. Joining me on today's call are Enrique Conterno, our Chief Executive Officer; and Dr. Mark Eisner, our Chief Medical Officer. Format for today's call includes prepared remarks from Enrique and Mark. After which, we will open up the call for Q&A. I would like to remind you that remarks made on today's call include forward-looking statements about FibroGen. Such statements may include, but are not limited to, statements regarding our collaboration with AstraZeneca and Astellas; results of clinical trials; our regulatory strategies and potential regulatory results; commercial results and results of operations; plans and strategy related to our business; and the planned FDA Advisory Committee Meeting and other anticipated FDA interactions. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated in that statement. A more complete description of these and other material risks can be found in FibroGen's filings with the SEC, including our most recent Form 10-K. FibroGen does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. The press release reporting our business update and a webcast of today's conference call can be found on the Investors section of FibroGen's website at www.fibrogen.com. And with that, I'd like to turn the call over to Enrique Conterno, our CEO. Enrique?

Thank you, Mike. Good afternoon, and thank you all for joining us on such short notice. As you saw in today's press release, FibroGen is clarifying certain prior disclosures of U.S. primary cardiovascular safety analysis from the roxadustat Phase III program for the treatment of anemia of chronic kidney disease. Let me explain more. The primary cardiovascular safety analysis included post-hoc changes to the stratification factors. The fact that this analysis included post-hoc changes to the stratification factors recently came to the attention of members of our senior management team, including myself, during our preparation for the upcoming FDA Advisory Committee meeting. Before I continue, it is important to emphasize that there is no change in the underlying roxadustat data or to the efficacy analysis from the Phase III program. Our conclusion regarding the comparability with respect to cardiovascular safety of roxadustat to epoetin-alfa in dialysis-dependent patients and to placebo in nondialysis-dependent patients is not impacted. So let me be very clear. We continue to have confidence in roxadustat's benefit risk profile, and we're committed to working closely with the FDA to bring this important new treatment to patients living with anemia of CKD. Nevertheless, we're taking this very seriously and promptly decided to clarify this issue with the FDA as well as communicate with the scientific and investment communities. We met with the FDA late last week. While all of the analysis set forth in the table provided today, including the differences in the stratification factors, were included in the NDA, we had a meeting with the FDA to ensure that it was clear. It was a productive discussion, and we agreed to continue our discussion with regards to the advisory committee meeting. The team continues to prepare for this meeting. Although this hasn't changed our confidence in roxadustat's benefit risk profile, and we believe this was limited to this particular set of analysis, we still want to understand how this happened. To that end, we have since begun a comprehensive internal review to ensure this doesn't occur in the future. This review is in its early stages. I don't have any additional details to share at this time. I'll now turn it over to Mark Eisner, our Chief Medical Officer. Mark?

Thanks, Enrique. The press release the company issued today includes a table that describes the cardiovascular safety results using the post-hoc stratification factors reported at the American Society of Nephrology Conference in November 2019 as well as the analysis with the prespecified stratification factors which have not been previously publicly reported. This table is shown on the slide here, too. As previously disclosed, the company agreed with the FDA in our pre-NDA meeting that the primary analysis in nondialysis would be ITT, or intention to treat, with long-term follow-up and in dialysis would be OT7, or on-treatment plus 7 days. MACE, a composite endpoint of all-cause mortality, stroke and myocardial infarction was the primary safety endpoint agreed on with the FDA. As you can see on this slide, the analysis with the prespecified stratification factors result in higher hazard ratios, point estimates of relative risk and 95% confidence intervals. For MACE+ in dialysis and for MACE and MACE+ in incident dialysis, the 95% confidence intervals include 1. While these hazard ratios remain below 1, based on these analyses, we cannot conclude that roxadustat reduces the risk of or superior to MACE+ in dialysis and MACE and MACE+ in incident dialysis compared to epoetin-alfa. Importantly, these analyses do not change the company's assessment that roxadustat is comparable to placebo in nondialysis-dependent patients and to epoetin-alfa in dialysis-dependent patients using MACE to measure cardiovascular safety. We have provided clarification, too, and we'll continue to work closely with the FDA, as Enrique mentioned at the start of today's call. I'd echo his comments that our recent discussion was a productive one, and our team remains focused on preparing for the upcoming Advisory Committee meeting. Before I pass it back to Enrique, I'd also like to briefly touch on how this relates to our other launches for roxadustat. As previously announced, roxadustat has been launched in China and Japan for treatment of anemia of CKD in both NDD and DD adult patients. These approvals were based on different studies conducted in the relevant geographies. As such, we do not expect there to be an impact in China or Japan, where the product has already been launched. And in Europe, the marketing authorization application for roxadustat for the treatment of anemia of CKD in patients both on dialysis and not on dialysis was filed by FibroGen's partner, Astellas, and accepted by the European Medicines Agency for review in May 2020. Based on our discussions with Astellas, we don't expect there to be an impact in Europe where the filing is currently under review. With that, I'll turn it back over to Enrique for some closing remarks.

Thank you, Mark. I want to reinforce that we continue to have confidence in the roxadustat data and the safety and efficacy profile demonstrated in the Phase III program. In the U.S., we look forward to discussing the data in the upcoming Advisory Committee meeting and ultimately, to bringing this important new medicine to patients living with CKD anemia. I hope it's clear that this team is focused on acting with full transparency and we're determined to ensure that something like this doesn't happen again. The senior management team is treating this with an utmost seriousness, as I emphasized at the start of today's call. I'm not going to let this overshadow the incredible work that we have put into this treatment or the incredible work we are doing across the company to harness groundbreaking science to meet medical needs. Our 3 areas of focus, which you heard me talk about before, do not change as a result. First, we continue to be focused on ensuring the regulatory and commercial success of roxadustat, as we've emphasized throughout today's call. Second, we continue to be focused on accelerating the development of pamrevlumab in 3 high-value indications: locally advanced and resectable pancreatic cancer, Duchenne muscular dystrophy and idiopathic pulmonary fibrosis. And third, we continue to be focused on strengthening our research productivity based on leveraging our medical leadership position in both HIF and CTGF biology and accessing external innovation. So what you're hearing from me is that while this internal review is ongoing, we'll continue to execute our business priorities to develop and deliver first-in-class medicines for the treatment of chronic and life-threatening conditions. Now we will open the call for Q&A, keeping in mind that we will be limited in our ability to comment much beyond the detail we shared today.

[Operator Instructions] Our first question will come from the line of Michael Yee from Jefferies. [Technical Difficulty] And our next question comes from the line of Geoffrey Porges with SVB Leerink.

My questions relate to what was agreed on with the FDA. Enrique, first of all, did you present to the FDA previously in the original application, the post-hoc stratification based analysis or the prespecified stratification analysis? So to be clear, is this an issue of what was presented at ASN being inconsistent with what was provided to the agency? Or have you had to present new statistical -- your new statistical results to the agency? And then secondly, it's fairly clear now that in the non-dialysis population, you have 2-point estimates that are above 1 in non-dialysis and the upper bounds of the hazard ratio -- of the confidence intervals above 1.25. Can you be clear whether the upper bound of the confidence intervals that was pre-agreed with the agency was 1.25 or 1.3 for noninferiority? And then lastly, Do you still believe that you are non-inferior to placebo in the non-dialysis setting?

Yes. Very good. Thank you very much for your question, Geoff. I'll try to provide some initial answers, maybe to the last 2 parts of your question, and then I'm going to have Mark Eisner complement that. Yes, we continue to believe that in non-dialysis, we basically show comparability relative to placebo. With regards to the 1 point to any measures of excess risk, you mentioned 1.25 or 1.3, I think I said in a number of different occasions that we do not have a pre-agreed non-inferiority margin with the FDA. That has always been a -- what we share as a review issue, an issue that needs to be looked at when the FDA looks at the totality of the efficacy and safety data for roxadustat. When it comes to the NDA, we did submit a number of different analyses, including both sets of this analysis that we are sharing with you with the FDA. I'm going to Mark to maybe provide a little more context to that.

Yes. Thank you, Enrique. So yes, building on what you stated, we had previously included in the new drug application, both the analysis for the prespecified stratification factors and the post notification factors. And we also had explained the changes to the stratification factors in the new drug application. We met with FDA last week just to make sure that it was clear which analyses used which factors, prespecified and post-hoc, and the agency appreciated the clarification. It was a very cordial and collaborative meeting, and we agreed to continue working toward the Advisory Committee.

[Operator Instructions] Next question comes from the line of Difei Yang with Mizuho.

Just a couple. The first one is on have you been formally notified on the Adcom meeting, and if there is a schedule set up for that? And secondarily with regards to the internal review, is that an internal review of FibroGen's process? Or is that part of a NDA approval? So meaning that the FDA will have to buy into the conclusions and they think there's enough control this will not happen in the future.

Yes. Thank you, Difei. Let me answer the second part of your question. The internal review I was referencing is an internal FibroGen process. As it relates to the Adcom and the timing, we expect to hear from the FDA in the coming weeks on the timing of the Adcom. As a reminder, we do not have an active PDUFA date at this time. And it would be, of course, consistent with prior practice for the FDA to make a decision on roxadustat NDA sometime after the Adcom. So we will be updating all of you once we learn more.

Your next question comes from the line of Michael Yee with Jefferies.

Hey guys, can you hear me okay now?

Yes.

Great. Yes. I'm not sure what happened, going on there. I have 2 questions related to dialysis. I just wanted to confirm that you are seeing that you cannot say you're superior in incident dialysis and get your view as to why you don't think that changes the overall benefit risk of the equation or perhaps even peak sales, maybe make a comment about that incident. And then related to that, going again to your chart where you talk about dialysis. You showed total dialysis, you showed incident dialysis, but you don't show stable dialysis, which is the other half of the population. Can you maybe just comfort us or give some clarity as to what that data shows and why you don't think that's relevant.

Let us maybe try to answer all of those questions, maybe not the same order that you asked them. But clearly, our conclusions when it comes, as I mentioned, to -- in NDD and DD that we're comparable to placebo in NDD and comparable in DD to EPO have not changed a from a safety perspective. I think that's a critically important message. When it comes to incident dialysis, the numbers continue to be quite positive. But at this stage, I think for MACE, it crosses 1. So we can no longer make the conclusion that we have a statistically superior result when it comes to MACE relative to EPO in this specific population. Michael, this goes all the way to before my time. But FibroGen has been pretty clear over time that the fairest setting to be able to compare roxa relative to EPO is in the incident dialysis population. Those patients that are new to dialysis, in most cases, new to treatment, to look at how do they basically respond in each one of these treatments. And of course, over time, those incident dialysis patients become stable dialysis. So the incident dialysis patients here reflect -- yes, patients that were initiated within 4 months. But in -- those patients continued treatment, either on roxadustat or EPO, for some time through the conclusion of this trial. When it comes to stable dialysis, that's something today, I think our focus has been, we have not published publicly data on stable dialysis today, I think our focus was really on providing an update on the data that we had publicly presented in the past. Clearly, this is something, when it comes to stable dialysis, we hear everyone that they want to see more data, and that's something we'll discuss with our partners. I'm going to ask Mark Eisner if he has something to add here.

Yes. Thanks, Enrique. I mean, the main thing I would add is that I would agree that the incident dialysis population is a very good population to look at the safety and efficacy of roxadustat because these patients are new to dialysis, they're just being started on the drug, and then they can transition onto dialysis with their anemia corrected. So that's point 1. Point 2 is that the incident dialysis point estimates are still below 1. And the overall analysis are consistent with comparable safety to placebo in the NDD population and to ESA in the dialysis-dependent population. And overall, we feel very good about the overall benefit-risk profile of the drug.

Our next question comes from the line of Paul Choi with Goldman Sachs.

I was wondering, first, if you could perhaps elaborate a little more on the stratification factors and which one, in terms of the change in between the post-hoc and the prespecified had the biggest impact with regard to the change to the point estimates and the confidence intervals? And then I have a follow-up.

Yes. I'm going to have Mark answer that question. We -- just to -- we have not conducted a specific analysis looking at each specific factor. So we looked at the combination of the factors, but I'll allow Mark to answer that question.

Yes. Thanks for the question. So the bottom line is that there were some post-hoc changes to the stratification factors. But to give you a little more detail, the cut point for GFR based on hemoglobin and definition of geographic region were changed after unblinding. And then in the dialysis-dependent population, there were some additional variables of sex, race and body mass index that were added. So this gives you kind of a sense for the types of changes that we're talking about.

Okay. And that clarification is helpful. My follow-up question is just with regard to the magnitude of the changes, specifically with regard to the incident dialysis population, which were -- which are larger than the changes to the NDD and DD population. And I guess here, just as you think about the comparability to the control arms here, I guess as you think about the incremental changes, especially to the upper ends of the confidence interval, I guess how -- what would your suggestion or what is the guidance here with regard to just thinking about the safety profile, given that the confidence intervals now are above 1 here.

So in the incident dialysis population, you're correct that the upper bounds for MACE and MACE+ now at 1. And for the dialysis-dependent population for MACE+, that's also true. But still, the overall results are very comparable in the NDD population to -- for roxadustat to placebo and in the DD and the incident dialysis subpopulation, comparable to ESA's in terms of cardiovascular safety. So overall, we continue to believe that the benefit risk profile of roxadustat is favorable.

And our next question comes from the line of Annabel Samimy with Stifel.

Most of them have been answered at this point. But I just want a little bit of clarification. First, when this issue came to your attention, was it something that you identified independently or was it brought to your attention by the FDA? Because I guess that changes maybe the tone of your conversations with the FDA. And then the second question I had with regards to the NDD population. Ultimately, do you believe that this -- if you have to recommunicate this to the physician population, does this change their perception of the safety with regard to whether they might want to use it in NDD population. And ultimately, I guess, that goes back to the initial question, which was does this is change your peak potential here?

Yes. Thank you very much for your question. No, we were not informed of this by the FDA. I think the way this happen, as members of our senior management team were preparing for the upcoming FDA Adcom meeting, we became aware that the primary cardiovascular safety analysis including post-hoc changes to the stratification factors. And upon becoming aware, we promptly decided to clarify this issue with the FDA and communicate with the scientific and investment community. So that's how we should think about how this was uncovered. I'm going to allow now Mark to answer the second part of your question.

Thanks, Enrique. So you asked about specifically the non-dialysis dependent population and how we would communicate that to the physician community. And I think we can clearly state that the results with the prespecified stratification factors continue to support comparable cardiovascular safety between roxadustat and placebo and a positive benefit risk profile. So although we're now presenting you this information with the prespecified stratification factors, it's a very consistent message to the one that was communicated with the post-hoc stratification factors.

And our next question comes from the line of Jason Gerberry, Bank of America.

This is [ Claudia Herman ] on for Jason. So to that point about the differences in MACE looking pretty minor, but in incident dialysis, it varies more presumably because of fewer events. Can you comment on the magnitude of the MACE components of stroke and MI, how those change in NDD? Is the lower end of the confidence interval still below 1?

So thanks for the question. As we've reiterated before, the primary analysis for cardiovascular safety is actually MACE in the nondialysis population and in the dialysis-dependent population, and we previously agreed that with FDA. And we also agreed in the NDD population with the intention to treat analysis in the OT7 approach for the dialysis-dependent analysis. So the primary safety is going to be based on the point estimate and the 95% confidence interval for MACE. So that's the most important thing to emphasize here. And we will be presenting the totality of the evidence at our Advisory Committee, including all of the other analysis that have been done to provide the most comprehensive picture of the benefit risk. And I think that's the most important thing to emphasize is the emphasis on MACE.

Okay. And then when you say that the FDA agreed to ITT analysis for NDD and on-treatment analysis for DD, did they -- did the FDA themselves suggest this analysis? Or was it proposed by FibroGen? And do you think the FDA will also focus on the alternate analysis in each indication?

If I understand your question correctly, the question -- is the question about what stratification factors were agreed with FDA? I kind of missed it.

It is on the ITT analysis for NDD and on-treatment analysis for DD. Did the FDA ask for that specifically? Or was it proposed by FibroGen? And do you think that the FDA will also look at on-treatment analysis for NDD and ITT analysis for DD?

I see your question. Apologies for not having it straight the first time. The FDA and FibroGen had a discussion at the pre-NDA meeting about the most appropriate analysis methodology. And both FibroGen and FDA agreed on the ITT analysis of MACE as primary for the non-dialysis population and the OT7 analysis for the dialysis-dependent population. So that was an agreement that was made, and it was thought to be, from both sides, the most appropriate way of presenting the data. Now the other point I alluded to earlier about the totality of evidence, we clearly are going to present other analyses, for example, with the subset with EGFR greater than 10, ITT analysis with a landmark at 12 months, other sets of analyses that can be informative. And we think together, this will support the positive benefit-risk profile of roxadustat.

Your next question comes from the line of Yaron Werber with Cowen.

This is Brendan on for Yaron. A lot of good ones here so far. So just a couple of quick ones here. Building on an earlier question about the stable dialysis patients, I just wanted to kind of check and narrow down. Do you have plans here or will you release data from the stable dialysis patients specifically to kind of offer this comparison versus full incident patients? And then I know you also mentioned that you don't really expect any impact to the China, Japan launches or the MAA filing. But have you had or maybe plan to have any conversations with EMA, for example?

Yes. The conversation in Europe really is led by Astellas. Astellas is the sponsor of the European submission. Our understanding, based on the discussion with Astellas, is that they don't expect this to impact the review. And I'm going to let Mark answer the first part of your question.

So the question again is about the stable dialysis data. And we, today, are really focusing on providing additional clarifications on scientific disclosures that have been already made, so we wanted to really focus on that. We do understand the SDD data are relevant for the investor and scientific community. And we are talking with our partners about the best way in which to present that information.

So the answer is yes, we intend to share that information in the future. Clearly, it is likely that, that information will be shared at the Adcom as well.

Your next question comes from the line of Andy Hsieh with William Blair.

So I have one kind of a follow-up to those question. So you mentioned that this discrepancy was discovered during the Adcom preparation. I'm just wondering is there any difference in the Adcom preparation last year versus this year that enabled the discovery of this discrepancy? And in your last week's discussion with the FDA, would you be able to share with us which division of the FDA you were speaking with? Was it the original NDA, the nonmalignant hematology division or the Adcom cardio-renal division?

Yes. I'm going to let Mark answer those 2 questions.

So in terms of your first part of your question, as Enrique said earlier, while we were reviewing the information, the NDA for preparing for the Adcom, it became clear that at the way the analysis have been done in terms of the pre versus post-hoc stratification factors has not been entirely clear. And recall that Enrique joined the company about 12 months ago, I joined about 4 months ago. So partly, this reflects fresh eyes on the same information. And we had a very good discussion with FDA, productive discussion about this, and they appreciated the clarifications. In terms of the FDA discussion, specifically it was with Division of Hematology, which is conducting the review, and senior leadership from the Office of Cardiovascular, Hematology, Endocrinology and Nephrology (sic) [ Office of Cardiology, Hematology, Endocrinology and Nephrology ], OCHEN. So it's kind of a combined discussion.

And one more follow-up, if I may. Obviously, the data was presented at a conference in 2019. Is there any strategy in terms of messaging to kind of [ prove ] that? And also related to one of the data presentations that you made last year at ASN, I believe one poster was -- talked about if the hemoglobin level beyond 10, you do see kind of a dose response in MACE and hemoglobin. Did this analysis, post versus pre, change that observation?

So first of all, in terms of clarifying prior presentations, in a particular publication of the pooled incident dialysis data that's come out in Kidney International, we are contacting leadership of ASN and the editorial -- editor, rather, of Kidney International to find the best way forward to provide clarification on those publications and communications. In terms of your specific question, that's not something we specifically looked at yet, but it's part of our overall review.

And our next question comes from the line of Edwin Zhang with H.C. Wainright.

Sorry, I'm late for the call. I apologize if my questions have been asked. I have two first. For the prespecified stratification factor, is this -- I know this is a new analysis. Is this the one that FDA and the headcount going to use?

So good question. We believe that the prespecified -- the analysis with the prespecified stratification factors is the primary analysis, which should be emphasized when it comes to the analysis of MACE in both NDD and DD populations. That said, it's always been the plan to provide a variety of sensitivity analyses and different approaches to look at the cardiovascular safety data that's supportive. So I do think that the Advisory Committee, during the FDA's review, they will take a totality of the evidence approach that takes a number of different analyses into account. At the end of the day, we do believe that the benefit/risk profile of roxadustat is positive and that the review will likely conclude that.

Okay. I just read through your press release. Looking at the table, I see the incident dialysis. Correct me if I'm wrong. Based on the new analysis, I guess, the superiority we had before in incident dialysis is no longer valid. Is that right?

Yes. Yes, we mentioned that. That is correct. Based on the prespecified stratification factors, we can no longer conclude superiority in that side.

Thank you. I would now like to turn the call back over to Enrique for any closing remarks.

I want to thank everyone for coming and joining us today at this conference call in such short notice. We remain focused on getting roxadustat through the approval at the FDA and look forward very much to presenting the full data at the Advisory Committee. Thank you very much to everyone for joining. Bye-bye.

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