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

[Operator Instructions] At this time, it is my pleasure to turn the program over to our host, Jason Gerberry.

Thank you, and good day, everybody. Thanks for joining us at the Bank of America Biotech Virtual Conference here. My name is Jason Gerberry. I'm one of the Biotech Analyst and I'm pleased to be introducing FibroGen, our next company presenter and CEO, Enrique Conterno. Enrique, first off, just thanks for joining us.

Well, thank you very much for the invitation, Jason.

Great, great. So I think it probably makes sense if we talk a little bit about pipeline first and then we can work our way backwards to some of the commercial elements of the FibroGen company story if that works for you. Maybe -- we'll start with pamrev and the IPF indication, which is a market that a lot of investors like in general as a therapeutic opportunity. It's a pretty big established commercial market, and it's a pretty high unmet need. So there's not a lot of ambiguity around whether good drugs will work and could be attractive revenue generative drugs. And so with that in mind, maybe if you can just talk about -- I think if you can slow IPF disease progression, give these patients a better quality of life, I mean, that's the goal here. So just curious how you're thinking about the ZEPHYRUS trials that you've run the Phase III ZEPHYRUS trials, how they could inform potential use of pamrev in this setting. A lot of this, I understand, is probably extrapolating off of what you saw in the Phase IIb PRAISE study and assuming that you can replicate those results. But maybe I'll stop there, and then we can go into more specific questions.

Yes. So great to start with ZEPHYRUS-1 study, which is a study as you mentioned in IPF. We're very excited because the ZEPHYRUS-1 data is expected in the middle of 2023. And you're right, I think we have very compelling results in Phase II, it's called the PRAISE study, where we basically showed statistically significant attenuation of the lung function decline. And in addition to that, we also showed the attenuation of the lung fibrosis, as measured by quantitative high-resolution tomography. So we're pretty excited about the effect size on those results, basically a 60% relative difference to placebo, which is very significant. And what's important for us is that we've designed the Phase III study utilizing PRAISE, our Phase II as the basis. So we are measuring the same endpoint. We're looking at FVC. The PRAISE study was a 48-week study that we're looking at here as well when it comes to our Phase III. So it's same dosing, so very similar design. And therefore, we have a high level of conviction when it comes to replication.

Okay. So one of the things I got pushed back from investors when we published a deep dive on the IPF opportunity was, hey, maybe when you think about bull case scenarios here, the study results from ZEPHYRUS to highly positive that this drug could actually be used in frontline, right, or in combination with frontline agents. The way that you're running the ZEPHYRUS trials as a monotherapy design is kind of effectively a second line study. So maybe talk just a little bit about aspects of the study that could inform earlier use effectively as a frontline in naive patients or combinations. These are -- it's a high unmet med need disease area, but these are also expensive medicines. And so payers, I imagine will have a little bit of a say in how pamrev could be used if you're successful in your clinical program.

Yes. So just to recap, we are enrolling patients that are both treatment experience and naive patients, right? So in a certain way, we are both pursuing first line or second line. So we will have a broad level of use. Maybe a way to think about this and to think about the opportunities to basically go to the number of patients, what is the incidence of IPF in the United States. So there's about 30,000 patients that are diagnosed every year. Only about 10,000 of them are basically treated, okay? So that gives you a sense of what is the overall opportunity, but also what is the number that is treated. I think a big question to ask is why are some patients not being treated? And part of it is because of the profile of the products or the tolerability profile in particular of what is considered standard of care. So the first thing that I would offer is that pam offers an additional option. By the way, we've tested the target profile of pamrevlumab and I think it does very well. I think it's fair to say that if we replicate PRAISE, physicians will view the efficacy of the product to be comparable or slightly better than existing therapies. So we believe that treatment rates are going to increase and pam is going to drive some of that. But also, I think importantly, when we think about those 10,000 patients that today are getting treatment, about half of them discontinue therapy because of tolerability reasons within the first 12 months. So those patients are also quite eligible now. So when we think -- if we do the math and we think about the opportunity, it's a very, very significant opportunity. We do believe that treatment rates will increase. We also believe that we will be a candidate for those patients that are treatment experienced patients. But also, I think any patient that is seeking to start therapy, if our data is as we expect it to be, I believe many of those patients will opt for pam as the first line in -- and of course, so that adoption is going to come over time, right?

Yes. So I would think that it would be tough to enroll a naive patient. I just wouldn't think there would be a lot of those types of patients out there. Do you think you'll have a meaningful subgroup of naive patients to inform like a pre-specified subgroup to do an analysis in ZEPHYRUS-1 or 2 or is that just going to be kind of -- you have some data, but it's not large enough to be kind of a robust subgroup?

No, we do believe it's going to be a meaningful number of naive patients in our studies. We were also surprised by how many naive patients we've enrolled. So it is a meaningful number. I think what we shared that we expect that there will be more experienced patients than naive patient. We have not broken it down more than that.

More experienced than naive, but it doesn't sound like it's majorly tilted 1 versus the other. Is that fair?

Yes. What I'll say, it is a sizable number of naive patients. So -- it is a significant number.

Okay, okay. And then, obviously, the something that you've intimated at with patients on drug is probably the tolerability of existing therapies. OFEV is the biggest selling brand. I think it's roughly $3 billion in global sales. So based on what you understand of the pamrev profile that you've seen in PRAISE, what do you think are the key kind of tolerability differences? We hear mainly the diarrhea is the biggest issue with OFEV, either the lingering AE, which may not be severe, but it's problematic or leading to discontinuation, but I'm curious to get your perspective.

Yes. What we've heard from physicians is really the diarrhea, it's quite persistent and it happens in a large percentage of the patients. So when it comes to tolerability patients in some cases, despite the fact that we know that OFEV works right, basically it slows down the progression of the disease. We basically see patients basically making choices to, in some cases, discontinue therapies and it's a significant number. It's throughout the first year, as I mentioned, about 50% of patients discontinued therapy of standard of care today.

Yes, okay. Now one of the things -- when I hear only 10,000 people are treated, and then you layer on top of it IV infusion as a delivery modality, right, versus current treatment with your pills, right? Can you talk about that as a barrier to pamrev adoption? Just sort of curious like the prescriber base, do they have much IV delivery capability or would these patients need to be referred out to like a chemotherapy centers? Just as you think about sort of the practical realities of like what you hope to accomplish in the marketplace versus sort of the delivery format?

Yes, clearly, all starts with the data, right? So to the extent that we have greater efficacy data, the product will be sought after. I think let me try to breakdown maybe, first, the access to an infusion center, right? So this product is going to be prescribed by pulmonologists and the question is, do they have ready access to infusion centers, and they do. Of course, it's in a variety of different settings, either it's in their office, maybe some multidisciplinary-type clinic, maybe in the hospital as part of an academic institution, for example, or a local infusion center. So we believe that a great number of -- or minority will be able to have this ready access. There are some community pulmonologists that won't have this type of access. But as we look at some of those community pulmonologists, in many cases, they actually refer IPF patients. In many cases, those pulmonologists are really looking at asthma and COPD as the type of patient that they basically see. So first, I think we see that there's going to be ready access. This product is infused every 3 weeks, right? Physicians do like the fact that they have the ability to see the patients and understand the adherence to therapy of those patients because they're going to the infusion center. So they view that as a positive. And of course, we also know from our current trials, we do see many patients basically continuing to opt for the open-label extension. So all in all, quite frankly, I think the clinical data is really where we see -- what we believe is going to be the North Star if the data is as we expect. We don't believe that the infusion centers are going to be a true barrier.

Okay. Now I think if you look at kind of the stock price, I think investors, IPF is a complicated disease. There is potentially, I think, 20 different mechanistic hypotheses out there for what is sort of the driver of the disease. And I think by our math, there's about 8 different programs that have failed Phase II or Phase III in the last decade. So there's -- that's in the back of investors' minds, right? And so as you think about pamrev, I'm just curious where you think other companies have gotten tripped up, where you think that's less of a risk for you guys with pamrev?

Yes, I'll make some general comments. But as you know, I think in some other cases, the Phase II data from some of these companies was shorter in duration, in some cases as short as 12 weeks. In some cases, it's 28 weeks. I think it's different to have a 12-week data than to have 48-week data. I think also we have to examine the progression over those weeks, right? In some cases, I think the 12-week data, what is the data telling you how quickly is the separation, but replication, I think is difficult because now you're extrapolating all the way to 48 weeks and 52 weeks. That's not our case, right? I think our case is -- our PRAISE study was 48 weeks, and that's basically what we are replicating with. I think also we need to look at the consistency of the result, right? Is the result driven by just a few outliers or how consistent is the result. And in our case, we do have not only the FVC measurement, but we are really the only product that also has the quantitative lung fibrosis score and really the correlation between FVC and lung fibrosis. So to me, I think it's the overall consistency of the results. So no other product has shown that, right? So I think that's another way to say that I really like our chances. And I think it's -- I don't look at the other programs. While I acknowledge the difficulty is treating the disease, we're looking at our own data to make our assessment of, and it is the reason why our conviction is so high.

I think in the past you've also mentioned maybe the monotherapy design, at least offering a little more simplicity, right, and straightforwardness. I know there's some competitors out there running adjunctive trials and Galapagos also ran an adjunctive trial and obviously didn't get through its futility analysis in their category. But I guess…

You raised an additional good point, which by keeping it a monotherapy trial, we have the cleanest possible signal from an efficacy and a safety perspective. So to that end, I think that we believe well, in some way, you could say, well, that decreases the enrollment success, but we've been able to enroll those trials. So we're meeting our time lines that we highlighted. And we are going to have a very clean signal of the effect of pamrevlumab and how does it basically help with pulmonary function. And we are -- we will be conducting the quantitative fibrosis and measuring that fibrosis score, which is a great reason to believe, right, for the prescribers to see how this product is working.

Yes. Okay. And so you've, in the past, indicated that base case, you'll need both ZEPHYRUS-1 and ZEPHYRUS-2 trials to secure approval. But have also communicated that you plan to meet with FDA if ZEPHYRUS-1 is positive and haven't completely shut the door on the potential for there to be an accelerated pathway on the combination of PRAISE in ZEPH-1, assuming, again ZEPH-1 is positive. So I'm just curious what sort of outcomes in your mind if there are any that you'd point to, to say, hey, this may give us at least a better chance of getting just to be able to file on the basis of ZEPH-1. Is it more of a treatment effect size, safety, consistency of subgroups, just curious how you might frame that?

Yes, it's probably all of the above, right? But clearly, the effect size is very important because -- and in fact, some of the competitors are conducting one large study, right? So if we have a high enough effect size, basically, I think that would mean that we would be looking at the category, okay, maybe this is -- this is something that we can just follow in one study. Of course, you need to look at the overall safety profile of the product and the consistency of the results and so forth. But you're right, we have stated that our base case is to look at both studies in order for us to file. But if the ZEPHYRUS-1 looks very positive, we do intend to have the discussion with the FDA because our intention would be to file with that plus PRAISE.

Would you have enough safety exposures in the short-term? I assume at 52-week you have enough, but just curious like on the short-term side it's a new molecular entity and curious like just from that standpoint.

We believe we do. Of course, at the end, it's not just the exposure, but it is what is it that we're seeing. As you know, the profile of pam is very clean, very tolerable. We expect that to be the case. But once you run it in many of our patients, you never know. But all in all, I think -- yes, I think it's inappropriate to discount the possibility that we could be filing just on the basis of PRAISE -- sorry on the basis of ZEPHYRUS-1.

I'm sorry, could you repeat that? It was...?

Yes, we should not discount the option that we may have based on the data filed on the basis of ZEPHYRUS-1.

And so the -- and the data that you would have with pamrev in combination with other standard of care therapies is something like 5% to 10% of ZEPHYRUS-1 patients have gotten rescue. And so you have some data from that. And then in the safety cohort PRAISE, I want to say it was like 50-some-odd patients as well. So is that enough? I'm just curious from that standpoint, especially like FDA may be looking at it like out in the real world, these doctors are going to start combining these things. And just kind of curious how the -- I wouldn't expect DDI to be an issue here, but just curious what you kind of put on that point.

Yes. Clearly, the way that we design those studies, it's a monotherapy study, but you're right, there's rescue therapy. So that will provide some combination data. But that combination data is going to be limited because the number of patients that will be rescued -- have been rescued is small. We do expect a broad label. I think it's difficult to say, right, how physicians will utilize the product and whether they will utilize the product in combination and so forth. From the research that we've done, I think it's -- in some cases, I think they will. They believe that the patient needs additional efficacy, right? They continue to see FVC decline, and they basically want to have maybe another therapy, but don't want to take them off the current therapy. So yes, we do know that there will be an option for physicians. In a certain way, I think at the end, we have to wait for our data, right, so what that cohort really looks like, right? But our -- the expectation that we have, as you mentioned, is there going to be a small number of patients on combination therapy. And once again, these are patients that would be basically where -- the standard of care is being utilized as rescue because none of the patients when they're enrolled are on standard of care.

Yes, okay. Well maybe we'll shift gears to your DMD program for pamrev. And I'm curious like what underpins your confidence regarding connected tissue growth factor here as an important mediator of this disease. And when in the disease course, you think you can kind of best alter progression of this disease given this mechanistic approach?

Yes. I think when we look at CTGF, we know that CTGF is up-regulated, right, in the skeletal muscle of patients with DMD. So we know that is the case. There's a good scientific rationale. We also see it, by the way, pre-clinically in the mouse model, the MDX model of DMD. So the signs, if you wish, the biology is there. We do know that DMD is challenging, right? It's a progressive disease and new therapies are desperately needed. So we are also excited about having 2 trials, right? We have the LELANTOS-1, which reads out in the first half of 2023. This is a non-ambulatory trial. And LELANTOS-2, which is an ambulatory trial that reads in the second half of 2023. Those are 2 different -- the same disease, but 2 different populations because the disease has progressed. I think you were asking about the likelihood and we are thinking about the impact of pam in each one of those groups. I think if you speak to opinion leaders and scientists, they would tell you that it is likely that the better chance is in the ambulatory population. We of course, are doing both trials, and we -- there's a good scientific rationale to be able to have a positive result in each one of those trials. Something that is important is that we don't need both trials. We can -- for us to be able to be positive to commercialize, we believe that we have functional -- we meet our primary endpoint, which, by the way, are functional improvement endpoints relative to placebo. We do believe that we would be -- we will have a filing package for that particular patient population, whether it's non-ambulatory or ambulatory. Of course, the FDA will also want to look at the safety data for both groups, but that's how we're thinking about the clinical results, the regulatory strategy and the fact that we could need just 1 study to be able to support each one of those subpopulations.

Can you talk about the support of clinical data here? To my knowledge, I think you've got like something like 20-odd patients open label in the non-ambulatory setting and how that compared to natural history and just sort of how you went about thinking about trial design and the endpoint that you're powering for?

Yes. So we are looking at different endpoints for non-ambulatory and ambulatory. In the case of non-ambulatory, we're looking at an endpoint of which is -- it's really a DMD endpoint, which is the performance of the upper limb. The performance of the upper limb is basically, you're looking at the strength and flexibility of everything from the fingers, the wrist, the elbow, the shoulder. Keep in mind, these patients are non-ambulatory. So that's really a functional measure that is very important. In the case of the ambulatory patients, we're looking at the North Star assessment, which is a very common assessment where you look at the number of once again functional measure. But in this particular case, you're looking at 4 steps there, then walk a number of different measures that comprise this overall North Star assessment. The data that we have, you're right, is really non-ambulatory data. And I think it's important to note that, that data is -- was an open-label study. And the data we basically look at relative to natural history. I think we saw relative to natural history, some attenuation of the progression when it comes to grip strength and when it comes to FVC and other measures, right? But we also have to keep in mind that this was not a randomized controlled study. It's really an open-label study, so we need to understand those limitations. We like our -- each one of the indications, we think is meaningful for us, whether it's non-ambulatory, ambulatory IPF. We also have unresectable pancreatic cancer. But collectively, I think there are massive opportunity I'm very excited about the program.

Yes, okay. So it sounds like, obviously, clinical support of that is limited. Some of these trials where the decisions were made under a prior management team, but you guys feel -- still feel pretty good about heading into the outcomes of these next year. I don't know how you kind of rank, what are the view on probabilities of success say DMD program versus IPF?

Well, I think you're going to look at the data right, and the supporting data that we have and the strength of the data that we have with PRAISE, I think, is very, very strong. So I would rank that at a very high and just relative to -- within the pam program, but despite the challenges with IPF, even when I think about general Phase III programs. So I really like our chances and the ability to replicate. And when it comes to DMD, yes, we do recognize that the risk is higher, but the product should work. So we are excited about each one of those opportunities as well.

Yes. And then maybe quickly, just roxa, just kind of curious, the U.S. development pathway, I guess, on the one hand, you've got an AdCom for a competitor potentially another regulatory event. You also have MDS where there's a little bit of a different risk-benefit dynamic, say, versus CKD setting. So these decisions are all rest with AZ ultimately and maybe just if you can give us a little color on what to look for going into next year?

Yes, clearly, I think we are looking at the MDS trial. This is pivotal data for us, Phase III trial. We've also seen the success of luspatercept. And we like the chance to -- we believe that the product will show good efficacy. We will need to see, of course, the overall benefit risk profile for the product. What we're measuring here in patients with MDS is basically within those -- first 28 weeks, we are measuring -- what we call transfusion independence because many of these patients with MDS they require frequent transfusions. So we look at 56 consecutive days of transfusion independent on the primary endpoint. In the case of luspatercept, they basically -- luspa had a 38% transfusion independence in terms of the percentage of patients that achieved that, I think placebo was maybe 13% or so. And what we like to see are basically numbers that are comparable to that. And then we need to look at the overall safety profile. Like you mentioned, I think in this particular case, the benefit risk profile is different than in anemia of CKD. So another exciting pivotal study that we have, in this case, we expect this data in the first half of 2023. So it's basically coming up on us. I think that's the big message for -- in the case of FibroGen. We have next year, 5 pivotal readouts: 3 with pam, we discussed LELANTOS-1, LELANTOS-1 and IPF. And in the case of roxa, we just discussed MDS, but we also have a chemo-induced anemia Phase III trial in China for regulatory approval in China that basically readouts in the middle of the year.

Got it. We're up against our time, Enrique. So thank you for joining us, and I always enjoy the conversation.

Very good. Thank you very much, Jason. Pleasure speaking.