Hello, everyone. Welcome to the H.C. Wainwright 8th Annual MASH Virtual Conference. Joining, I'm Thomas Yip, part of the H.C. Wainwright Research Team. Joining us today, next, is Gyre Therapeutics. Presenting for Gyre, we have CEO, Mr. Han Ying, and also we have Miss Suzana Carattori. She is the clinical trial advisor for Gyre Therapeutics. Good having you both with us today. Please go ahead.
Thank you, Thomas, and good morning and good afternoon. I want to first thank HCW for giving me the opportunity to present about our company, Gyre Therapeutics. I'm also looking forward to learn from everyone during the discussion and also during the conference. The title of my talk today is Hydronidone, our lead compound, is a anti-fibrotic drug candidate with safety profile that potentially supports long-term use. Then a little bit of highlight about our program. Number one, Gyre has a proven track record. We developed the Pirfenidone from R&D to commercialization. So that really established our team expertise and also our position in the field. We are a financially sustainable company. We have profit from our commercial sales, and then this also supports our new drug development.
And then, our innovation and strategic direction is really focused on the anti-fibrotic mechanisms that also involves the chronic inflammatory signaling pathways. And then, very importantly, we adopt a de-risk R&D approach. For example, our lead candidate, Hydronidone F351, is a next-generation anti-fibrosis drug candidate based on the Pirfenidone. And then, last but not least, we have a big rigorous and efficient clinical trial execution, which we quickly validate the clinical results of our compounds in PRC, and then that supports our trials in the U.S. So that's our highlights. And then, this one shows two of the most important drugs in our company, Pirfenidone and then Nintedanib. As you all know, those are the two drugs approved for idiopathic pulmonary fibrosis, and we are the only company in the world that owns both drugs for commercial.
This is a summary of our pipeline. The first one is Hydronidone, which we have already completed the phase one in the U.S. In China, we target hepatitis B-associated liver fibrosis. I'll explain why in a couple minutes. Then, this one is currently in phase three right now, and then the last patient will be out, I believe, by next week. We have a few months to complete analysis, and then the pivotal result will be announced in early 2025. The next one is F573. It's a caspase inhibitor targeting acute liver failure. This one, we have already completed sixteen patients. We are doing more patients, but the result is encouraging, and we hope we will announce the result once we complete the phase two study.
And then, the next one is F230. This one we licensed from the Japanese pharma, Eisai, targeting pulmonary arterial hypertension, and this one, the IND has been approved, and we plan to start enrolling patients soon. The F528, we own the global right of this compound, targeting COPD, and we have already completed all the preclinical validation, and it's a planning for a submission for IND. So that's the summary of our pipeline. Next, I'm going to focus on our lead candidate, targeting liver fibrosis. I'll give you an update on the status. This compound, like I said, we took a de-risk approach strategy. What we did is, we select for the compound, Hydronidone.
That has a more favorable phase two metabolite, which in theory will give us a lower toxicity, a better safety profile, and that also maintain the efficacy. This compound, Hydronidone and the Pirfenidone, they both target the TGF-beta signaling pathway, particularly on the Smad7, and then the Smad2, and then the Smad3. This result was already published in 2023 about the preclinical mechanism of action. This slide just one of the data shown in the paper, which shows Hydronidone upregulated the expression of Smad7 and inhibited phosphorylation of Smad2 and Smad3 in CCl4 animal model, as well as a DDC animal models. In 2024, we published another preclinical study.
It shows Hydronidone induced apoptosis of hepatic stellate cells, and then the targeting the mitochondrial pathway, in. We show the data, including several key molecules. Here, I show the result on two of the key molecule. One is ASK1, one is IRE1 alpha. But you can look at the more data. It's available online with the publication in twenty twenty-four, and this one basically summarize the protective effect of Hydronidone on the MASH. In this study, you can see on the right panel, it improves the fibrosis score as well as the ballooning score in the CCl4 animal models. And then we provide this preclinical data to propose the mechanism of action.
To summarize, Hydronidone is a structural derivative of the approved drug Pirfenidone, and it improves liver fibrosis in the CCl4 and also the DDC-induced mice. It may act on the antifibrotic TGF pathway by acting on the Smad7. Additionally, it induces apoptosis of hepatic stellate cells by triggering the IRE1α/XBP1 JNK signaling pathway. These data are available online in the publication. Next, I'm going to give a report on our clinical studies. First, in my humble opinion, the drug safety is really one of the key differentiating factors among the drugs for fibrosis patients. The patient's toxic tolerance really depends on the different key factors, particularly related to our different disease stage.
They are maybe more willing to tolerate mild but manageable side effect. However, severe or life-threatening toxicity would make the adherence to the drug very challenging. In my humble opinion, like the early KOLs discussed the diagnosis, some of the early-stage MASH patients do not even have symptom. Therefore, if there's a drug that could potentially affect their life quality, would also make the long-term adherence to the drug difficult. This is just my personal humble opinion. We have completed a phase I trial, both in PRC and also in the U.S. The manuscript is in preparation.
Sorry, I cannot review the data in this slide, but however, in the study, both in China and also in the U.S., Hydronidone was very well tolerated at a single or repeated doses, with almost no severe adverse events. This trial is a randomized, placebo-controlled phase II trial. This trial, the result has already been published. In this trial, we use three different doses for the patients with a Hepatitis B-associated liver fibrosis. The reason we select the Hepatitis B-associated liver fibrosis as the indication is because, as you all know, the biology of liver fibrosis is very, very complicated. It involve a lot of different factors, and also a lot of different mechanisms.
The reason we select HBV-associated fibrosis, and what we hope is that we will narrow down to a specific population, and then if we could demonstrate efficacy in this population, and then we can then expand the indication to other type of liver fibrosis. That was the rationale for start the trial in the HBV fibrosis. Also, you know, HBV fibrosis has a huge market in the Asian, particularly in the Asian countries. This result was also published, so I want to just give you a brief summary. As you can see on the two graphs, Hydronidone at the different doses have a significant improvement, particularly at the 270 mg per day gives the best improvement, both on the liver fibrosis score as well as the liver stiffness.
And then, based on this result, we initiated a pivotal phase 3 confirmative trial. In this trial, we compare Hydronidone with plus a antiviral drug, Entecavir, and with Entecavir alone. And this study, we run two groups, two trials. One is with the primary endpoint ends at the week 52, and also we have an optional trial to have a long-term extension for efficacy and safety. And then the status of this trial is, we've completed the enrollment at the beginning of 2024, and the last patient will be out. I believe it's at the end of this week, and we're going to have a disclosure on that one. And after that, it's just pending for analysis, and then we're going to disclose the top-line results in early 2025.
And then to summarize about this lead compound, it is a de-risked, potentially efficacious drug that could serve as a long-term solution for patients with liver fibrosis. It is the first in class HBV for HBV-associated liver fibrosis. And because of the antifibrotic mechanism action, it also allows for combination with a different type of drug, particularly the metabolic drugs, and then to enhance the efficacy as well as to reduce the adverse event, particularly in non-overlapping adverse events. As you all know about the GLP-1 agonist and also the THR receptor pathway agonist, and also others. And then the result, we will announce in early 2025. And these are the upcoming milestones for this compound.
In China, we are going to announce the phase three top-line result in 2025. We have already started the NDA preparation and hope we can submit NDA in 2025. In the U.S., we have completed the phase one trial, and then now Gyre is a Nasdaq publicly listed company with a good market value at the moment. And then by end of twenty twenty-four, Suzana, who is also with us today, she's going to submit the protocol to U.S. FDA, and then in 2025, we hope to start enrolling patients.
The takeaway message for our company is we own two approved drugs for IPF in the world, with commercial sales of $112 million in 2023. Our lead candidate, Hydronidone, demonstrated the efficacy and also encouraging safety profile. Last but not least, we have a robust pipeline, including one phase 3, one phase 2, one IND approved, and also one in IND preparation. With that, I want to thank you for your attention, and looking forward to any questions you may have. Thank you so much.
Right. Thank you so much, Han, for your presentation. Perhaps a couple of questions from me. So first, you and I earlier, just gonna stick with MASH, for today. For the phase one data, have not been made public yet, and the manuscript is in process of being prepared. When should we expect, either, through a manuscript or at a conference, when, you know, approximately what's the timing, that we can expect to see, first in human phase one data? Well, at least phase one in this study.
Suzana and I, we are putting together the manuscript, but to be honest, this manuscript is not really our priority because, you know, we are already in phase three. But anyway, so we would find a proper time to report the phase one data-
Got it
in conferences or yeah. We just, you know, focusing on the NDA right now, so,
Yes.
Yeah.
So perhaps for the U.S. phase two study, given as you've presented earlier, the fibrosis improvement data, both preclinical and other in multiple diseases as well with Hydronidone. What do you anticipate some potential combination that you can work with Hydronidone, and will that be explored in phase two program? I understand phase two-A explores three different doses. Will you add... Is there potential to add an arm to explore combinations?
We are currently testing combination in our animal models right now. You know, it would make sense to combine, you know, with Resmetirom and also the GLP-1 agonists. But in terms of what they can improve, I believe, you know, one, definitely one important one is the safety. And then on the efficacy, you know, we are a antifibrotic mechanism, so therefore, hopefully, we can see better efficacy with the combination. So, Suzana, do you have anything to add?
No, this is absolutely, in a nutshell, the essence of what is planned, and the process will be data-driven, and as Han said, safety is very important, even at the preclinical level, and understanding the activity of potential combinations is gonna be synergistic, is gonna be additive. These are all aspects need to be understood before decision is made for a proper combination. That's at the level of non-clinical, and later on, that proof of concept to be translated successfully in the clinic.
Yeah. Also, Tom, I think, for example, you know, all the drugs in the phase three right now, a lot of them have efficacy, but also have a certain type of safety issues. So therefore, we thought our drug perhaps, because the safety profile is a little better, so then perhaps we have a better opportunity to combine with the other drug. I don't know.
But also the basic starting concept for development of this drug is to shift metabolism towards pathway that will result in less toxic compounds, and the potential in mitigating potential for drug-drug interaction will be very important, because we heard today in the roundtable discussion about polypharmacy and how to use the even approved drugs in the context of that. So everybody will be looking for a drug that will offer some advantage. We hope that Hydronidone has such a potential, but that needs to be demonstrated in the currently ongoing studies.
Understood. Perhaps one last question for you, Suzana. Based on your experience so far with Hydronidone, what's the general feedback from investigators regarding, you know, speaking of safety, you know, what's the initial feedback to date? You know, keeping in mind that the data has not been released, but, you know, what's the general-
Right
opinion?
Well, you know, the investigators definitely look into safety, and the medicinal chemistry of Hydronidone being structural analog of pirfenidone. So, they will like to understand how the drug performs, especially in the liver, and liver safety is actually the most critical parameter of safety profile of any drug that will be successfully used for a long term in this medical condition. So far, the observations are favorable. I can't give you the result, the details, but you know, probably there will be a chance soon to understand a little bit more global picture. But definitely investigators will be looking into parameters of liver safety.
Understood.
If I answer your question correctly, but please do ask me maybe additional. I'm happy to provide more substance within the-
Right
limitations of what I can say.
Yeah. You know, I think that, you know, personally, you know, very interested to see the data readouts and of course, as Han mentioned, as somewhat validated as well, you know, safety is already in use.
Right
in clinical trials, so one can imply that it's relatively safe. But nonetheless, it will be, you know, I'm sure-
Yeah
investors would love to see the data as well.
Yeah, we yeah.
We will be very happy to provide the safety data based on the one-on-one meetings. But,
Okay
I think those data we to publish. We still need to have some work to do, but I will be happy to share the slides with the investor if they're interested.
And we encourage everyone to look into the published clinical safety data in the Hepatitis B-induced liver fibrosis. They're very encouraging, and especially there were no cases of drug-induced liver injury, DILI, which is one of the most critical parameter investigator will look for this compound, but also for other compounds. That's a starting point, and then focusing on other aspects, so this phase II, the data are published, and we encourage you to look into it and ask us questions if there's some more details to be provided.
Right. And this is basically our de-risk strategy. As you know, the biology of liver fibrosis is so complex, it is very hard to pinpoint, you know, which one, and how do you strike a balance between the efficacy and safety, and that's why we modify pirfenidone. So then, you know, we already have one foot in the door, you know? So then, we just need to demonstrate it's better and safer. So that, that's our strategy.
Understood. Thank you again, both, for presenting for Gyre today. I also want to thank everyone in the audience for joining this presentation as well. Hope everyone have a good rest of the conference, and take care.