Transcription
We're going to get started with just our last little segment here at the end of the day. I know you're eating lunch and by all means, you get to do all kinds of discussion beyond as well. Is my volume up? Okay. Okay.
So, thanks for participating in that think tank. That was something that was kind of fun for me to put together, and it's kind of was a hit list of the things I hear in clinic constantly. So, sorry everyone's criticized me for the downers at the end. But I was just discussing with a few that this is the real-life piece of this disease. And, uh, so if anything you've learned this far, the gaps in this disease are quite wide, right? Not only from treatment all the way to the other aspects of mental health and the things of invisibility and fatigue and such as well.
So, I just want to tell a quick story, um, before I introduce Kurith. You know, a few years ago, we were approached by Kazar. This was a company that was looking to do some work in the autoimmune space. Uh, they had a novel compound that they thought could be impactful for this disease. In fact, through a lot of different communications, we invited them to our last conference where they touted doing the trial for autoimmune hepatitis. We worked closely with them the past few years to help recruit for their phase two study. And, uh, you know, what was really great about this company is they listened to patients, they listened to us, and in fact, tried to develop these clinical trials around what patients' needs were. Um, so it was a really, it was one of our first times we've ever worked with a company from a nonprofit perspective. We learned a lot along the way as well.
But what is exciting now is that we've come full circle. So, not only have you heard about the study from us, not only did they educate you a little bit about clinical trials on Facebook, social media, but we're here with the phase two results. This is a trial that you, us, our organization helped to support that couldn't be done without you. So, on that point, I consider this a real success, no matter what the results are. Um, but I want to introduce Kathy. Kathy gave me a lot of things to tell you about herself. It's really long. She's really smart, and she's really important. Uh, but at the heart of this, I think the things I want to echo is, you know, she's at the heart of patient communication, um, and collaboration, and she's shown that throughout our interaction. So, I was just really pleased that Kazar would come back and share this data with you, but also support the conference as well, uh, just like many of our other, uh, industry sponsors as well. So, Kathy, I'll hand it over to you for the results of the Portola clinical trial.
Great. Thanks. Thank you. Can you guys hear me? Awesome. Um, so as Dr. Lambert said, this is actually a full circle moment for us. Um, I, uh, back in, I think the first virtual conference during, um, the pandemic is when Kazar first got introduced to the autoimmune hepatitis association. And at that time, um, the Portola study was in its infancy. And so we had an opportunity to really talk about what we were planning on doing conceptually. Uh, in 2023, the study was in, you know, a full-blown study. We were actively recruiting patients. So to be able to stand here today and share with you sort of the results from, um, this study is really a privilege and an honor. And I do want to sort of, um, emphasize what Dr. Lambert said in that this, um, would not have been feasible without the support from, um, thought leaders such as Dr. Lambert, Dr. Goell. Um, it's really been, um, an honor working with the AIHA trying to come up with ways to get, uh, the study, um, out there. So I'm really excited to share with you, um, what we have, uh, from the Portola study.
Um, so just for those of you that don't know who Kazar is, we are a company that was founded in 2015 and we're based in South San Francisco. Um, we are a small but mighty team of about 45 employees that really are actively working on, um, our drug which is called Zetamib. It's a, um, investigational drug that hasn't been approved yet, but it's in clinical studies for autoimmune hepatitis. And really, our goal is to develop new treatments, um, for difficult to treat, uh, diseases like autoimmune hepatitis. I'm not going to, um, I was planning on sort of giving a little bit of an overview of AIH, but I think a lot of you already know that and after Dr. Goell's talk this morning, I'm not sure there's a whole lot that I can, um, add to that. So what I will say is maybe just highlight some of the things that she mentioned in her talk. So we know that it's a rare chronic disease. It's when the immune system, um, uh, I'm going to actually hold on to this. Um, it's when the immune system mistakenly attacks the liver, causes inflammation and tissue damage, and it does have a severe impact on, um, one's physical health and quality of life, which we heard in our, um, breakout sessions. Uh, signs and symptoms vary, but these are some of the things that Dr. Goell highlighted. You get pain, fatigue, um, abdominal discomfort. There's things like, um, dermatologic manifestations, jaundice, joint pain, and as she mentioned, there are, women are affected, um, more than men. There's about, females are affected about nine times more often than males. And it is often associated with other autoimmune conditions. So, usually, if you have one autoimmune condition, there's already another one that you may have.
So there are many unmet needs in autoimmune hepatitis. One of the things that we know is that over the last 50 years, there have been really limited advancements in, uh, standard of treatments. It continues to be, um, steroids as a mainstay of therapy, and then you add on, um, immunosuppressants such as Azathioprine on top of that. Um, but there are limitations to the current standard of care. So there's inadequate response. So if you remember from Dr. Goell's talk this morning, about 60, only 60% of patients really achieve that biochemical remission and are required to be on, um, long-term steroids. Toxicities are also a big thing. We know that with steroids, there are issues such as osteoporosis, diabetes, weight gain, cardiovascular disease, um, and there's also toxicities that are associated with chronic immunosuppression, and there's really a lack of specific targeted therapy. So steroids and immunosuppression are sort of this blanket, um, uh, treatment for autoimmune disease. So really, when you think about the inadequate response combined with the long-term, um, adverse events, there really is a need for a steroid-sparing or a steroid-free approach to autoimmune hepatitis.
Um, so I'm going to talk about the Portola clinical trial. Before I get into that, I want to give a little bit of background on what, um, the drug is. The drug name is Zetamib. I know it's a, it's a mouthful. So, we even within the office refer to it as ZTO. And it's a selective immunoproteasome inhibitor. It's a lot to, it's a lot to process, but I'll just quickly talk about what the immunoproteasome is. So we know that, um, with autoimmune hepatitis, it's when you have an overactive immune system. So basically, your immune cells such as macrophages, T-cells, and B-cells, which normally respond when you have things like an infection, these are overactive in autoimmune hepatitis and essentially they mistakenly attack, um, healthy liver cells and cause, um, liver damage and inflammation. Now, the immunoproteasome is actually a special structure and that's found within these immune cells. So it's usually, um, upregulated in, um, in, uh, autoimmune diseases and, um, what we have seen is that by blocking the immunoproteasome, you can actually, uh, potentially rebalance the activity of that overactive immune system. And this could potentially have a therapeutic benefit in autoimmune hepatitis.
So as I mentioned, these are the, um, immune cells that are, uh, normally found when you have an infection. And in, um, autoimmune hepatitis, they are, um, overactive and attacking the liver. And what we see is that by blocking the immunoproteasome, we can actually rebalance that immune response. And what's unique about this approach is that you're not just targeting one pathway. You can, um, by inhibiting the proteasome that's found in macrophages, in T-cells, and B-cells. It's taking a broad approach to the overactive immune system and, and, um, potentially rebalancing that.
So, uh, this is a first-in-class drug and it's different from current autoimmune, um, hepatitis treatments and it's actually been studied in, um, in, uh, in pre-clinical, phase one, phase two, and phase two studies in, um, a variety of autoimmune diseases, and we've had patients that have received up to two years of Zetamib. Um, it's a once-weekly subcutaneous injection, which means it's given under the skin. It's not a steroid, and I think what's really important is that it's, even though it has this broad effect or impact on the immune system, it hasn't been shown to be immunosuppressive, and I think that's really important from a safety perspective. So it is different from current treatments and as I said, it has this potential to rebalance that overactive immune response without directly, uh, suppressing the immune system.
Now, the Portola clinical trial was a six-month trial with an optional open-label extension. So, during the first six months, we had, and again, this was, this was actually, I should mention that this was a proof of concept study. So, Kim before was talking about the different phases of studies that you have. So, this is a phase 2A study. So, we're looking to see if there's actually activity of Zetamib in autoimmune, um, hepatitis. So, it's a small proof of concept study of 24 patients, um, where patients were randomized to receive ZTO plus at least 20 milligrams of steroid versus placebo plus 20 milligrams of steroid. Patients could also be on other agents. So, they could either be on a steroid plus MMF, a steroid plus Azathioprine. Um, so there are other options as well.
Um, the one thing that I want to point out is that, um, what we did leave up to the investigators is a protocol, is a protocol suggested steroid taper. So as I mentioned, at the start of the study, all patients needed to be on prednisone 20 milligrams, whether you were on the active drug ZTO arm or whether you were on the placebo arm. But what we did suggest is that if it was clinically warranted, we asked investigators to attempt to taper their steroid. So try to lower the dose over the course of the six weeks. We did provide them with a suggested taper schedule, but it was really up to the investigator to follow, uh, their, the clinical presentation of the patient to determine whether or not they should taper that steroid.
Now, after the six-month treatment period, patients had the option of enrolling into an open-label extension. So, essentially, what that means is that whether you were on a Zetamib treatment arm or placebo, which you didn't know, um, after the end of the six months, you had the option to receive Zetamib for an additional six months. So, anyone that was on placebo for the first six months, if they chose to go into the open-label extension, were able to get the active, um, ZTO treatment.
Now, um, in terms of who the patient population was. So these were, um, adults that had a clinical diagnosis of autoimmune hepatitis and had to have active signs of clinical disease despite being on at least three months of standard of care treatment. So if they were either on prednisone, prednisone plus MMF, prednisone plus Azathioprine, but despite having that treatment, they were still, um, experiencing active disease and, as I mentioned, there was the, we did suggest a protocol taper of steroids. So patients had to be willing to taper their steroid therapy to participate.
Now, um, you know, one of the things that Kim talked about is how clinical studies are regulated and how it's really important, um, how, you know, we share data. So one of the things that I want to quickly talk about is, um, Zetamib was actually studied in another disease called lupus nephritis, which is a chronic, it's a serious and life-threatening complication of lupus. And in that study, there were four deaths that occurred. One was on placebo, three were on the active treatment arm. And, and because of those deaths and because it's regulated, we, um, we paused that study and, and essentially was to allow for a comprehensive safety review to assess whether or not Zetamib contributed to these deaths. Full disclosure, later on, after the assessment was done, we did terminate the study for business reasons, not because of any new safety concerns.
Now, as, because there are two different, the lupus nephritis division is managed by the rheumatology division, and AIH is managed by the hepatology division. We provided this information to the hepatology division to let them know that these happened in the, these fatalities happened in another study. Based on what happened in Palisade, the FDA placed the Portola study on what's called a partial clinical hold, which essentially meant that we could continue with the study with some minor modifications. So patients had to remain on at least 5 milligrams of steroids, and then there were four patients that were still in the double-blind treatment period. They were allowed to finish that, but those four patients could not roll over into the open-label extension. Anyone else that was, um, enrolled in the study could continue on. It's just those four patients were not able to roll over into the open-label extension.
So, so what after, um, so as part of our comprehensive safety review, one of the things that we did is look at all our entire clinical program. So, we looked at clinical data from our, um, early clinical studies in healthy volunteers, in lupus, in phase one, and phase two studies, and we presented a comprehensive finding to the FDA. And based on that, the FDA did lift the partial clinical hold of Zetamib in Portola, um, based on our safety data assessment.
So, what does that mean? So in Portola, I want to just go back to the safety profile here. So this is a list of all of the sort of overview of the adverse events that were experienced in the double-blind treatment period for Portola. You'll see that most patients experienced, or all patients experienced at least one treatment-emergent adverse event, whether you were on placebo or ZTO. And the most common AEs were injection site reaction and systemic injection reactions. Now, injection site reactions. Remember I said this was a subcutaneous injection. So these are things like pain at the injection site, redness, maybe a little bit of a bump, some itching. Um, and then systemic injection reactions are actually specific adverse events that we've noted that occur, um, with Zetamib administration. So they typically occur within 8 to 24 hours. They resolve within about 48 hours and, um, it consists of things like nausea, vomiting, dizziness, hypotension, tachycardia. Um, and what we've, what we found is that these symptoms can be mitigated by having, um, hydration with things like Gatorade before they get the dose or even some premedication with Tylenol. Um, the all of the injection site reactions were mild or moderate. So they were grade one or grade two in severity, and same with the systemic injection reactions. So they were very self-limiting, um, and, um, again, were not, um, were mild and moderate in severity.
Now, a few things that I want to call to your attention. There's, you'll see the line of serious treatment-emergent adverse events. There was one in the placebo arm, two in the ZTO arm. All three of these were considered unrelated to, to the, to their respective treatments. All patients continued on in the study and were able to complete the double-blind treatment period. But I think most importantly, what I want to call your attention to is that last line of deaths. You'll notice that in the Portola study, we did not see any fatalities, um, in this study.
Now, going on to the actual efficacy results. So I want to first focus your attention on, um, the all complete responses or CR. So CR is, um, was our clinical trial endpoint. So CR is a complete response, which we defined as ALT, AST, and IGG normalization if it was elevated at baseline. So you'll see that, um, in the ZTO arm, eight of the 14 patients that were enrolled, so about 57% of patients had a normalization or a complete response of their, of their liver enzymes compared to two in the placebo arm that, and remember placebo is placebo plus standard of care. So steroid plus possibly immunosuppressant.
Now, in the middle, um, graph where you have CR plus steroid taper. So these are patients that achieved a full biochemical response. So they had an ALT, AST normalization as well as an IGG normalization and were also able to reduce their steroid dose to less than 5 milligrams per day. And you'll see that, um, five of 14 patients, so 36% of patients in the ZTO arm were actually able to normalize, have a complete response, and also taper their steroids compared to none in the placebo arm or the standard of care arm. And then, and these are actually in line with treatment, um, treatment guidelines from both the, um, the American Association as well as the European Association. And then finally, I think what's really encouraging for us is on the left-hand side, you have steroid-free CR, which means that these are patients that are able to completely come off of steroids and still have a biochemical response. So you'll see three patients in the ZTO arm compared to none in the placebo arm were able to have a normalization of their ALT, AST, and IGG.
In addition, when we look at the steroid dose over time, that light blue line is the reduction of the steroid dose over the 24 weeks of treatment with ZTO compared to the placebo arm. And you'll see that there's a steady decrease in the steroid requirement over the course of the 24 weeks compared to the placebo arm.
So, um, just in summary, what we've, what we've seen so far is that there have been limited advances in AIH treatment and there is a significant unmet need to have, uh, new treatments that are targeted and, um, reduce the need for chronic steroids and immunosuppression. Zetamib does, in fact, selectively inhibit the immunoproteasome, offering broad immunomodulatory activity, and it's been studied as a potential new treatment for AIH. And it does demonstrate, um, in the Portola study, the potential for ZTO as a safe, tolerable, and durable, um, once-weekly treatment, uh, option for difficult to treat AIH. And the immunoproteasome is a promising new target for AIH.
So in terms of what's next for us on the horizon, we have requested a meeting to meet with the FDA to discuss the next development plan. So that'll include things like what's our next study design, how do we move forward, um, with bringing Zetamib for AIH, and, um, the full clinical data. So as I mentioned, there's an open-label extension. We, I presented to you the double-blind treatment period, but the full clinical data will be presented at, um, this year's, um, liver meeting in November. And, uh, these are social media platforms if you'd like to follow us for updates.
[applause]
So maybe just pause for a second and, you know, I want to make sure you realize that this, these are hard-to-treat patients, and so this is a major step forward. Again, I think we still need to see the data as it kind of evolves, but, but I think this is really hopeful, um, particularly being a first-in-class approach. And again, this is one of the biggest unmet needs in this disease space. So, so thank you, Kathy. Did anybody have a question for Kathy while she's here?
Please. The deaths in the other study that get chased down as whether that even had anything to do with the drug.
Can I just say that one more time for the online asking about the deaths in the other study, if it had anything to do with the drug? So, just to clarify, we presented that data to the hepatology division before they removed the, before they removed the clinical hold. So as I mentioned, there were four deaths. Two were considered, um, in the initial assessment in the ZTO arm to be related to the study drug. Now, part of that comprehensive review assessment is to look at what's happening to the patient prior to getting the drug, when they got the drug. And what we were able to find is that there were actually some pretty, um, significant pre-existing conditions to these patients. So, they had, um, evidence of adrenal insufficiency, which means they had very low cortisol levels, um, which can inhibit your ability to mount a response. Um, and there were also signs of, um, some, uh, pretty significant systemic infection that were missed before they even got dosed. Um, so we can't definitively say that they were not, that ZTO did not cause these deaths, but there is a lot of significant confounding factors to that. Um, I would also, um, um, yeah, I'll, I'll sort of leave it at that.
[applause]