Welcome to Kezar's Life Sciences 2023 Research and Development Day. Today's presentation will be followed by a question and answer session. During the course of this call, Kezar will be making forward-looking statements based on current expectations. These forward-looking statements are subject to a number of risks and uncertainties, and actual results may differ materially from those described. We encourage you to review the risk factors in our most recent Form 10-K filed with the U.S. Securities and Exchange Commission and available on our website. All statements on this call are made as of today, based on information currently available to us. Except as required by law, we disclaim any obligation to update such statements, even if our views change. With that, I would now like to hand the call over to John Fowler, Chief Executive Officer and Co-Founder of Kezar Life Sciences. Go ahead, John.
Thank you operator for the introduction and really thank you to everyone who's dialed in today for our R&D day. It's really my great privilege to kick things off today and speak with you just for a few minutes before handing it over to my teammates to walk through really all aspects of the Kezar development program. As you can see here from our agenda, we've got a busy hour and a half ahead of us. I will endeavor to be as brief as possible. You can see we'll get right to the meat of the matter on lupus nephritis up front with Noreen providing a nice summary of our PALIZADE phase II-B trial in lupus nephritis. Moving into from there, autoimmune hepatitis. You can see that both Noreen and one of our really valued partners, Dr.
Craig Lammert from Indiana University, will be able to speak to the current treatment landscape and frankly, big gaps in the treatment paradigm for patients with AIH. Moving over to our Head of Research and Discovery, Neel Anand, who will talk about the very exciting research directions in the protein secretion program, with Noreen bringing it home with an update on KZR-261, our first clinical candidate out of the protein secretion program, treating patients with solid tumors. Without further ado, I'll just walk through a handful of slides before letting Noreen talk to you about lupus nephritis. What I'll do is try and set the table at the highest level here on the Kezar opportunity.
I think and hope, what you'll hear today is really genuine excitement and enthusiasm informed by data from our team around our first-in-class small molecule therapeutics. We really feel that, both zetomipzomib and KZR-261 have the opportunity to represent real paradigm shifts in the treatment of autoimmune disease and cancer. On the zetomipzomib side of the house, many of you have heard us say this before, the opportunity to have broad immunomodulation without immunosuppression is very, very exciting. When paired with our data in lupus and lupus nephritis patient state, we have great reason to be optimistic for the future in our next two trials.
Similarly, the novel mechanism of KZR-261 attacking tumor cells from multiple directions gives us a lot of reason to be excited about the dose escalation data later this year with KZR-261 and beyond into multiple solid tumor types. Overall, I would just say that this is a carefully constructed strategy that is designed to deliver multiple ways to win, multiple avenues to value creation, both across zetomipzomib and KZR-261 and beyond from our discovery platform. Before handing it over to Noreen, I'll just offer a couple of visualizations of how these multiple ways to win come to pass. You can see here on a classic pipeline slide, the PALIZADE and PORTOLA trials listed here in phase II-B and phase II.
I think you'll hear from Noreen a nice description of PALIZADE as a trial that draws on the best of their precedent trials of successfully and recently approved drugs in LN, but also gives zetomipzomib the chance to flex its muscles and unique mechanism of action in ways that will set us apart over the long run. What we won't talk about much today is the PRESIDIO OLE, but it's on here because we do anticipate later this year or early next year, offering a really solid and positive safety and tolerability update from this trial which enrolled patients for well over a year, in one case over two years, in by offering valuable safety information on long-term administration of zetomipzomib. Similar depth is seen on the protein secretion side of the house.
As you can see here, KZR-261 is in the clinic. It's been in for just over a year now in a classic 3+3 dose escalation design, getting ready to move into dose expansion this year. It's not the end of the story. You'll hear from Neel a very, very exciting vision for the future of starting with oral anti-PD-1 small molecules, moving into other approaches to use the Sec61 translocon for therapeutic benefit. Finally, a way to visualize the ways to win outside of the pipeline is with a timeline. This has not been shared before, but I think it does a excellent job of showing how over the next few years, there's gonna be multiple catalysts and inflection points to drive value for Kezar.
The next two years really are gonna be focused on KZR-261 and its progress through dose escalation, which we're gonna present in its totality later this year, into five separate readouts as sort of denoted by that long green bar you can see below the timeline across our five different cohorts with specific tumor types that were picked specifically based on our predictive work to pick out tumors that were most sensitive to KZR-261. Also early this year, I'd be remiss to not mention Neel and his team's work on getting very close to clinical candidate nomination on our oral anti-PD-1 small molecule. Of course, once we get past a lot of these dose expansion readouts, we'll get into mid-2025 and readouts for both PORTOLA and then about a year after that, the PALIZADE trial.
Quite a few different and distinct data readouts over the course of 2023, 2024, 2025 and beyond, in a way that we are excited to deliver multiple ways to win for investors and most importantly, for patients. With that, I'd like to hand the mic over to Noreen, who will walk you through PALIZADE, and then we'll get into autoimmune hepatitis and beyond with the protein secretion program. Thanks again for joining in.
Thank you, John, and hello to everyone on the line. Today, I have the pleasure of providing you with development updates of Kezar's two clinical assets. Zetomipzomib, formerly known as KZR-616, for potential use in a multitude of autoimmune and immune-mediated diseases. KZR-261 for potential use in both solid and hematologic malignancies. Both assets are first-in-class and present unique opportunities as potential therapies with highly differentiated attributes for patients with significant unmet need. Zetomipzomib is a first-in-class selective inhibitor of the immunoproteasome, which modulates both innate and acquired immunity, resulting in potent anti-inflammatory effects without causing immunosuppression. As a potential therapeutic for patients with chronic inflammatory autoimmune disease, zetomipzomib has some favorable attributes, including no drug accumulation, no rebound of inflammation following discontinuation of treatment, and no evidence of immune cell depletion or dysfunction.
As patients with autoimmune disease are often younger patients and predominantly young women, it is useful to note that zetomipzomib has no off-target effects, no predicted clinically significant drug-drug interactions, no teratogenicity observed in non-clinical studies, and no need for serum monitoring. This is a favorable and differentiating list when stacked up to currently available therapies. Previously, we reported the results of the MISSION study, a two-part study to evaluate zetomipzomib in patients with lupus and lupus nephritis. The MISSION phase I-B study, the first part, demonstrated safety, tolerability, and preliminary efficacy in patients with SLE with and without lupus nephritis. For those of you following the zetomipzomib story, you will recall two patients from the MISSION phase I-B study who had lupus with manifestations of active lupus nephritis showed a brisk reduction in the protein in their urine while on the study.
One of those two patients went on to receive an additional 12 months of zetomipzomib under an investigator-led IND and had a similarly profound reduction in proteinuria and amelioration of her SLE symptoms. The patient was able to discontinue her background therapies and was successfully vaccinated. The MISSION phase II study highlights are shown here. 21 patients with refractory or difficult-to-treat LN received zetomipzomib 60 milligrams once weekly subcutaneously for six months. It is noteworthy that these patients did not receive induction therapy. 17 patients completed the trial. Of those 17, 11 reduced proteinuria by more than 50% at 25 weeks, and 16 of 17 reduced proteinuria by greater than 50% at week 37. 10 patients reduced absolute UPCR to less than 5.5, and seven achieved a complete renal response. The median UPCR was 0.3 at study end.
The reduction in proteinuria was achieved with a reduction in prednisone use in 82% of patients. Patients' eGFR remained stable. Very impactfully, there was amelioration of signs and symptoms of systemic lupus, including multiple biomarkers of inflammatory disease activity. Having fully read out the MISSION trial in November 2022, we are impressed not only with the clinically significant reductions in proteinuria, but also with the totality of the evidence that zetomipzomib is a potent anti-inflammatory without evidence of immunosuppression. Our investigators report that their patients just feel better. Importantly, no one got worse or required additional medications. The efficacy is promising and includes not only the primary endpoints but all other endpoints that signal active inflammation in a patient, such as resolution of low complement and diminution of anti-double stranded DNA antibodies.
We see a reduction in inflammation occurring within weeks of initiating therapy, the ability to reduce corticosteroids in a favorable safety and tolerability profile. While I'm about to introduce to you in our next step in development of zetomipzomib for lupus nephritis, I do want to also impress upon you that we are eager to move forward with the development program of zetomipzomib for patients with lupus as well. Looking across the lupus nephritis landscape, we have a highly differentiated molecule that can leverage a proven regulatory pathway. Zetomipzomib's differentiation comes from unique mechanism of action, rapid reduction in inflammation and lack of rebound, which permits additional healing of the kidneys. Ability to achieve meaningful clinical results without induction therapy, lack of immunosuppression, and a favorable safety profile.
To date, local injection site reactions are the most commonly observed adverse event. From our extension study, we know that safety and tolerability issues lessen rather than increase over time. For PALIZADE, we were able to study and learn from the recently published studies in LN, borrow the best from these studies, as well as make adjustments specifically to show off zetomipzomib. With the positive results of the MISSION trial in hand, we are moving swiftly forward with PALIZADE, a large global phase II-B study of zetomipzomib in patients with active lupus nephritis. PALIZADE will enroll a total of 279 patients with active LN. The patients will be randomized essentially into three arms. Zetomipzomib 30 milligrams subQ weekly, 60 milligrams subQ weekly, or placebo weekly for one year. The primary endpoint is the proportion of patients achieving a complete renal response at week 37.
A key secondary endpoint is the CRR at week 52. A CRR is defined as reduction in UPCR to less than 0.5 with a stable eGFR. There will be a protocol-prescribed taper of corticosteroids. Uniquely, we will enroll patients with proliferative LN, namely Class III or IV, as well as Class V. Class V patients will be capped at a total of 30. The study will be conducted at 250 sites in 30 countries around the globe. PALIZADE will initiate the first half of this year. PALIZADE is a robust phase II-B trial with pre-regulatory precedent and could serve as one of two registration trials if positive. The primary endpoint at 37 weeks is informed by protein reduction, which was observed in MISSION as early as 13 weeks, but deepened further over nine months.
As this is a placebo-controlled study, standard of care, including induction therapy, is available to all patients enrolled in PALIZADE. However, patients and their physicians can opt out of induction therapy, which is consistent with the real-world use of induction therapy and potentially enrolls patients previously excluded from studies which mandated induction therapy. A protocol-mandated steroid reduction will permit us to quantitate the reduction in corticosteroids to fully illustrate zetomipzomib's potential ability to be steroid-sparing. Patients will be able to self-administer zetomipzomib, which is the intended commercial format. The duration of the trial will allow us to demonstrate speed of response as well as durability without immunosuppression. While PALIZADE is our exciting next step in the development of zetomipzomib for LN, in parallel, we are exploring the potential benefit of zetomipzomib in patients with autoimmune hepatitis.
Few interventional trials have been conducted in patients with autoimmune hepatitis, and we believe this represents an important opportunity for us. It is my pleasure to introduce Dr. Craig Lammert, a leading international expert in AIH and the founder and executive director of the Autoimmune Hepatitis Association. Dr. Lammert is a practicing hepatologist and translational researcher with focus on autoimmune hepatitis. During his training at Mayo Clinic, he received special training in hepatogenomics specific to autoimmune liver diseases. Upon arriving at Indiana University eight years ago, Dr. Lammert launched a research program focused on autoimmune hepatitis and funding from the National Institutes of Health because of tremendous unmet patient need with this disease. He has established a prospective study of well-phenotype patients with AIH in order to study the genetic and environmental contributions to AIH.
Further, he has been able to invest energy into novel approaches to recruit patients with rare diseases such as AIH into research studies and is well connected to the autoimmune liver disease field as an active member of the International Autoimmune Hepatitis Group. Dr. Lammert will be joining us via audio from his office in Indianapolis.
Thank you for that wonderful introduction. Again, my name is Craig S. Lammert. I am a hepatologist at Indiana University. I serve as the executive director for the Autoimmune Hepatitis Association. Today, I'm pleased to talk to you about autoimmune hepatitis as an overview of current treatment options and clinical trial considerations. Let's start with what is autoimmune hepatitis. Autoimmune hepatitis, or also be referred to in this talk as AIH, is really a long-term autoimmune condition that results in inflammation, specifically B and T-cell-mediated inflammation of the liver. Unfortunately, this inflammation can cause substantial harm, and ultimately, this inflammation can drive stellate cell application of fibrosis, resulting in cirrhosis, as well as hepatocyte dropout, resulting in liver dysfunction and/or failure.
Unfortunately, the cause of autoimmune hepatitis is just not well understood. We think it's likely related to genetic underpinnings such as those linked in the HLA region, as well as other non-HLA genes and also specific environmental factors, which many of them are not understood but are rooted in some instances, such as drug-induced autoimmune hepatitis, as well as other environmental carcinogens. What is known about AIH is that this commonly affects young women. What is really important that patients and families want individuals to know is that it affects all ages and races. This includes the very young and actually the very old. In fact, this is important because certain demographics, including people of color as well as young onset AIH, tend to have worse overall outcomes in terms of fibrosis progression and hard-to-control disease. What is really important about this disease is early detection.
As a disease such as this, unfortunately, many patients go misdiagnosed or undiagnosed for many years, ultimately resulting in progressive fibrosis at presentation. Treatment is essential. As treatment helps to slow the progression of disease and prevent end-stage liver failure. Overall, treatment goals for AIH is really centered on the control of inflammation against specifically T-cell and B-cells and preventing liver injury and or damage. We have excellent surrogate markers for this that we'll highlight later, but we want to achieve biochemical remission, which for this talk would be identified as normalized AST, ALT, as well as immunoglobulin levels. With doing this, we'd like to prevent progression to cirrhosis and end-stage liver disease that may necessitate the utilization of transplantation for treatment. We want to maintain remission as well as impact the significantly reduced quality of life that AIH patients have as a part of this disease.
We want to minimize long-term effects of corticosteroids and immunosuppressive agents that have been used for many years to treat this disease. We'll talk about that more here on the next slide. Here we see a slide that shows a liver biopsy on top. What you can see are hepatocytes in this bright pink, as well as areas that used to be what are called portal triads. This is a functional unit of the liver that typically includes bile duct as well as a few other vascular structures. You can see that this is not very organized. In fact, many of these tightly packed nuclei represent lymphocytes that is really the calling card of autoimmune hepatitis. We see destruction of this interface of this portal triad with this hepatic parenchyma.
Ultimately, when we see inflammation like this, the liver cells or hepatocytes then release enzymes, specifically ALT, as well as a marker of inflammation, including IgG as well. This is often elevated in patients with autoimmune hepatitis, and then here showing that release by the cartoon hepatocytes next to it. Ultimately, with ongoing inflammation, we are seeing a stimulus to stellate cells as well, with the fibrosis of possible progression. Here is a liver core biopsy with normal liver parenchyma. However, with stage one, stage two, and stage three, and stage four fibrosis evolving with uncontrolled inflammation in the liver. Again, with treatment, which we'll discuss shortly, we see improvement of ALT and IgG, or at least this is the goal. We see normalization of the hepatic parenchyma as well as the portal triads and improvement of the integrity of the hepatic cells.
Ultimately, the goal is stability of fibrosis if in fact it has formed. However, an ultimate goal of therapy would like to see resolution of fibrosis and may be able to be done in up to 30% of patients. We have had 70 years of quote-unquote progress in AIH treatment. AIH was known as a chronic active hepatitis and was generally regarded as a new disease when reported in 1950 by Dr. Waldenström. With time, we realized that this was an autoimmune disease, one treatable by a newer medication at the time, corticosteroids. Inflammation returned when the steroids were withdrawn, and therefore a steroid-sparing agent was sought. On theoretical grounds, there was chosen azathioprine, a purine antimetabolite that limited the proliferation of B and T-cells.
The first clinical trials in AIH through the fifties and sixties were often observational, meaning that basically investigators gave steroids and followed to see if AIH patients got better. Even into the early seventies, trials that included the comparison of patients treated with steroids and patients that remained untreated serving as controls were still called for because of the superior design of two comparative groups. Here in these slides A and B, we see the results of a well-known study by Cook et al. The graphs here show the duration of treatment and survival for A, a non-treated control group of AIH patients, and B, a steroid-treated group. These are also the length of time in months of individual patients in either group had been in the study at the time of assessment. Let's summarize, and that can be seen by these fractions.
Ultimately, this is a survivorship. By the end of study, 56% of the not treated patients were deceased as opposed to only 14% of the treated. Steroids obviously have had substantial impact in the treatment of autoimmune hepatitis based on some of these early studies. In the past 10 years or so, a new compound outside of prednisone and prednisolone called budesonide has been utilized to use in AIH as a way to control inflammation. More recent data suggests budesonide may not be helpful when patients have very high elevated liver tests at diagnosis. The reassuring thing about budesonide is that it has seemed to be better tolerated.
No matter using prednisone or budesonide, we have used this historically as a means or a bridge to therapy to get patients started on steroid-sparing agents, as we don't like to have patients on steroids for very long. Here on the right side of the screen includes agents that we have utilized for autoimmune hepatitis over the years. In fact, the standard of care is centered on antimetabolites, including azathioprine and a sister drug called 6-mercaptopurine. Ultimately, mycophenolate mofetil also has early data that suggests it can be used as standard of care at new diagnosis of AIH. However, as we go down, we get less and less evidence for these compounds for use in this disease. Calcineurin inhibitors, including tacrolimus and ciclosporin, have been around for years. However, the data in its use on hepatitis is limited.
Even more limited are those called mTOR inhibitors, which include sirolimus and everolimus as a means to control disease and have often been limited to case series and or case reports for control of disease. Concerningly, much of our practice has continued to utilize and require substantial doses of prednisone or budesonide. In fact, in the Autoimmune Hepatitis Association study from last year, we collected information on patients' regimens of medication no matter what duration of disease they were at. This was a cross-sectional approach. What is the really important takeaway here is that no matter how many years diagnosed after disease, we're looking at patients cross-sectionally for the use of either budesonide or prednisone. We see here that budesonide and prednisone is present in at least 30% of patients at every interval beyond diagnosis.
This is highly concerning, obviously, because we have seen substantial issues with prednisone and budesonide as modifiers of infection risk requiring hospitalizations, as well as obesity, diabetes development, cataracts, as well as worsened quality of life in patients with autoimmune hepatitis. This data really highlights the importance of new novel therapies that lessen our dependence on steroids, but also to establish them potentially as a new standard of care, given that our new first current standard of care just does not work that well. As I was highlighting, our current treatment strategies have notable limitations. Just to reiterate that many patients within the realm of AIH have a high dependency on corticosteroids, as up to 40% of patients with AIH, no matter what year after diagnosis, will remain on corticosteroids to maintain or continue to improve liver tests.
We also, as a part of that, see inadequate response to standard therapies, as up to 30% of patients do not respond adequately or are intolerant to standard treatments beyond corticosteroids, as well as things such as azathioprine and mycophenolate mofetil. Historically, we have treated patients for up to two years and then tried to withdraw therapy. This has changed in more recent time. However, in that era, we saw with withdrawal, patients had a very high tendency to relapse, meaning return to high or elevated liver tests in upwards of almost 90% of patients when we remove their standard of care treatment, particularly those patients that had responded very fairly. Ultimately, this really codifies that AIH is a lifelong disease and requires lifelong treatment.
Ultimately, these other immunosuppressants that we use, such as azathioprine CellCept, still have other problems that relate to intolerance, but also toxicity. Long-term use of these immunosuppressants can lead to other side effects, such as increased risk of infections, as well as overwhelmingly bone marrow suppression, as well as linked to lymphoma, as well as skin cancers that are non-melanoma. Finally, the therapies we've used in terms of standard of care outside of corticosteroids have essentially been utilized as a global approach to attenuate or suppress the immune system as a means to treat AIH. Therefore, we have had no precision guidance in treating patients with AIH, ultimately just suppressing their immune system to control an overactive immune reaction. Autoimmune hepatitis has been well characterized and codified through the development of diagnostic criteria.
To establish disease, we really only need a suggestive liver biopsy, as well as autoantibodies and exclusion of certain viral causes of hepatitis as well. Despite these criteria being adapted and simplified over time, the treatment response and treatment of AIH has not necessarily followed suit. This slide highlights a recent consensus statement by the International Autoimmune Hepatitis Group on critical response criteria endpoints for AIH. I want to use this slide also to highlight some unmet needs in this disease as well. Looking here right after diagnosis, intolerance, which includes any adverse events related to treatment leading to stopping the drug to first-line treatment such as azathioprine, remains as high as 15%.
Within one month of treatment, data suggest that failure to reduce liver tests elevation more than 50% is related to overall worse outcomes as well, and may correlate with harder to control disease in 20% of patients. At six months, we seek normal ALT and IgG levels, and this may only be found in 50% of patients. The historical gold standard of histologic activity end deals in HAI are nesting fill out 18 has been maintained. We are uncertain what percentage of patients ever make it to this endpoint as routine follow-up biopsies has fallen out of fashion, given we have good serologic markers for histologic activity with the ALT and NRNG and IgG. Let's return to our progress. I've highlighted a number of pieces where we have shortcomings.
Ultimately, in 2015, beyond the 1960s and 1970s, we have had two novel agents in clinical trial, these both being non-steroid-based therapies. Unfortunately, there's been no published literature supporting their use in clinical practice. The state-of-the-art therapy, I hate to burst our bubble, but we are still back to where we started back in the 1960s, utilizing corticosteroids and azathioprine, despite their shortcomings that I highlighted with you today. As we think about clinical trial considerations for autoimmune hepatitis, I think it is imperative to highlight there have been very few trials completed since these initial landmark studies back in the 1960s and 1970s. Ultimately, this just does not spot innovation. This may be for a number of reasons, but there is an incredible need for both first and second-line treatment regimens that control inflammation well and are tolerated well by patients.
I think it is critical to think about future clinical trials as well, particularly things that center on what patients want and what doctors see as clinical unmet needs as well. Certainly, patients that have persistent abnormal liver tests or hard to control disease are a critical point to treat. Patients that are normal but then sporadically become abnormal with treatment, coined as loss of remission, also happens in approximately 40%-50% of patients over the course of this disease as well. Ultimately, more loss of remission may correlate with increased risk of fibrosis progression. Steroid dependency obviously is a major problem, as upwards of 30%-40% of patients may require steroids no matter what year after diagnosis, despite using other standard of care therapies. Poor quality of life is an important point for patients.
Approximately 30%-40% of patients have at least mild to moderate symptoms of fatigue, poor sleep, anxiety, and depression. These are aspects that have not been established or sought after in clinical trials to this point in time, but these are heavy on the patient's shoulder when carrying this disease. Finally, much of the clinical trial data that we do have, despite its limitations, have essentially been done in a majority of white or Caucasian individuals. In fact, there is a tremendous call to enrich these populations with diversity, including people of color. As of now, we've been extrapolating this clinical data from these populations to all patients with autoimmune hepatitis. However, the disease biology may be very different. Ultimately, too, we've now been utilizing non-invasive liver tissue assessments.
These are also a strategy we should be employing in clinical trials as well, as the future really is non-invasive. In fact, utilizing FibroScan in clinical trials would be efficacious as well as lessen the burden for patients to be involved as well. The PORTOLA trial is a randomized, double-blind, placebo-controlled trial that really looks to evaluate the safety, tolerability, and efficacy of six months of treatment with zetomipzomib in patients with AIH that have failed standard of care treatment, have incomplete biochemical response to more than three months of standard of care therapy. It also includes insufficient responders or those that have lost remission. The PORTOLA study will also have an optional open label extension where patients can receive zetomipzomib for up to an additional six months following the main study.
At Indiana University, we are encouraged by the PORTOLA design as there are quite a few differentiating factors related to prior studies looking at autoimmune hepatitis. Just to name a few of those, PORTOLA is going to try to address steroid dependency. I've highlighted this today that a large proportion of patients are required to maintain on steroids for disease control many years beyond diagnosis. What is exciting is the study is instituting a protocolized mandated steroid taper by week 14. This is quite novel for the AIH clinical trial. PORTOLA is hitting head-on difficult to treat patients, those who have failed standard of care, or those that are not adequately controlled by not having normal liver tests or those that have relapsed. This represents the patient population for PORTOLA.
In fact, including this varied population really encompasses many of the unmet needs in the patient sector for those that are not having controlled liver inflammation. PORTOLA will have a greater pool of background therapy as those patients that are going to be harder to control and having relapse are going to be on a multitude of different standard of care agents, including azathioprine, but also things such as tacrolimus or mycophenolate mofetil or 6-MP. Allowing patients to maintain on this while entering into the PORTOLA study will lead to higher recruitment numbers. PORTOLA will also use FibroScan. This is the non-invasive ultrasound technology that can be employed to measure liver stiffness as an exploratory endpoint. Again, seeing improvement in inflammation with PORTOLA and the novel agent zetomipzomib should show improvement in stiffness throughout the treatment course.
Patients also will have this option of enrolling in open label extension following this main study, which will allow us to evaluate zetomipzomib safety, tolerability, and efficacy, as well as we can see the risk of disease, particularly over a much longer period of time as well. Finally, another exciting piece is the utilization of the GTI or the glucocorticoid toxicity index, which is a quantifiable and validated assessment tool to really assess glucocorticoid associated morbidity, which is a major issue for patients with autoimmune hepatitis. Finally, zetomipzomib, a selective immunoproteasome inhibitor, has potential as a novel therapy in AIH treatment landscape and could really dramatically minimize current treatment shortcomings as I've highlighted with you today.
We know that immunoproteasome expression is increased in liver cells of patients with chronic active hepatitis or cirrhosis, and zetomipzomib can target multiple immune effector cells through this mechanism. These are all important T-cells that are related and involved in the pathophysiology of autoimmune hepatitis. The PORTOLA study will look to evaluate zetomipzomib as a potential immunomodulatory agent and steroid-sparing agent for the management of autoimmune hepatitis. Thank you for your time today.
Craig, thank you so much for illustrating the significant unmet need for new and potent therapies for patients with AIH, why zetomipzomib could be good for patients, the attributes of the PORTOLA study that you are excited about. We also thank the Autoimmune Hepatitis Association, which has been supportive of our efforts to launch the PORTOLA study. Autoimmune hepatitis is a meaningful opportunity for the development of zetomipzomib. As you just learned, AIH affects 100,000 to 200,000 patients in the U.S. alone, which is a similar market opportunity to lupus nephritis. Patients are highly dependent on steroids, which results in significant comorbidities and reduction in quality of life. The pathophysiology of AIH, as Dr. Lammert just illustrated, is complex and dependent on multiple immune effector cells, which is what we believe is the sweet spot for zetomipzomib. Patients are dependent on high-dose steroids.
By design, a meaningful new therapy for AIH would need to be a potent anti-inflammatory that had no off-target effects or result in immunosuppression. Let's summarize what is attractive about the AIH opportunity. Current therapy is inadequate and relies on high-dose steroids. AIH is a real market opportunity, similarly sized as LN, and there is no appreciable competition. There is biologic reason to believe selective inhibition of the immunoproteasome would result in potent anti-inflammatory effects. In addition, the PORTOLA study endpoint employs quantitative endpoints, which are used in clinical care to monitor patients. There's a strong patient advocacy community, the Autoimmune Hepatitis Association, which is supporting our efforts. The PORTOLA study is currently ongoing, and we anticipate results in this six-month study in mid 2025.
If positive, the PORTOLA study will demonstrate control of liver inflammation in the absence of steroids, and we expect that patients will feel better and enjoy better quality of life. We also hope for a similar favorable safety and tolerability profile like we saw in MISSION. Here's the study schema for PORTOLA. We will enroll 24 subjects in this randomized placebo-controlled signal-seeking study. The primary goal is safety and tolerability. We are looking for reduction in signs and symptoms of liver inflammation, namely the transaminase ALT in the absence of steroids. In addition to the primary study, we will offer an open label extension trial of weekly zetomipzomib for an additional six months. Let's turn our attention to Kezar's first-in-class efforts to inhibit the Sec61 translocon to treat solid and hematologic malignancies. It is my pleasure to introduce Dr. Neel Anand, Kezar's Senior Vice President of Research and Discovery.
On to you, Neel.
Thank you, Noreen. Hello, everyone. It's my pleasure to take you on a tour today of our protein secretion platform. I'll provide an update on two exciting programs that stem from that platform. Let's start off by talking about the biology behind this. This is the Sec61 translocon channel, otherwise known as the translocon. This is the initiation of the protein secretion pathway. This is a highly conserved process which is functional in all cells. Approximately 6,000 secreted transmembrane proteins utilize Sec61 to enter the endoplasmic reticulum. What's really important to understand here is that every single protein has a unique signal sequence domain that guides it to the Sec61 translocon. As we look at the cartoon below, you can see the signal sequence as this purple line connected to the peptide of the protein.
The signal sequence binds to the signal sequence binding site of Sec61, which guides the protein to translocate through the channel. Sec61 translocon is a master regulator for secretion or membrane expression of most validated targets for biologics. Some examples are shown on the right-hand side of this slide. Biologics work by targeting the proteins after they've been made and released. In the case of the way we're approaching this, Kezar's value proposition is to actually use small molecules with unique and differentiated properties and profiles compared to those biologics to actually inhibit production of those proteins and co-translation out to the expressed or secreted sites on the cells. That's a very high-level overview of the biology. Let's talk a little bit about the drug discovery capabilities that we have in-house.
We have a primary screen, which is a cell-based inducible reporter assay. This is an assay which has a target protein signal peptide, which is connected to a luciferase enzyme. When we treat that with a small molecule, we can see based on the luminescent readout whether that signal peptide has been inhibited from co-translating through that Sec61 translocon. In-house, we've expressed over 200 different target signal peptides across a broad range of therapeutic targets and anti-targets.
This assay is also very valuable because we can miniaturize this assay such that it is amenable to high-throughput screening, which enables us to discover new chemical matter to utilize in our programs. As you can tell, this assay is a way that we can very quickly get very valuable cell-based information regarding potency and selectivity. For compounds of interest, we can then further characterize them through functional cellular assays, to confirm pharmacological activity and to compare to standard of care. We also apply proteomics and genomics. Proteomics in the sense of differentiating Sec61 client sensitivity per cell type, and genomics in the sense of looking at indication profiling. I'll show you an example of that for KZR-261 in a few moments.
Beyond our in vitro assays, we also have all of the regular in vivo capabilities. PK/PD, a variety of efficacy models and also toxicity studies. Those we do both in-house and with preferred CRO partners. On the bottom right, I'm showing you a cryo-electron microscopy structure which we've got for our Kezar compounds, and this helps us with structure-based drug discovery for our current programs. So far we've given you an update or a high-level overview of the biology and also our robust drug discovery capabilities. Let's take a look at how we're interrogating this biology. The Sec61 translocon can be targeted broadly or selectively.
My background is in kinase inhibitor drug discovery, and I find this very much akin to that in the sense that the inhibitors can be either very broad or extremely selective. When we talk about this program, sorry, the two programs that we have, I will be showing you both sides of that spectrum. KZR-261, which our first candidate, is a very broad inhibitor, and KZR-540 is extremely selective. Let's start off by talking in more depth about KZR-261. We view KZR-261 essentially as a combination therapy in a single small molecule. The looking at the reporter assay data along the top of this heat map.
You can see a variety of immune checkpoints and oncogenic factors. You can see KZR-261 is extremely potent across the board. What this allows us to potentially do is have a very effective attack on cancer via both direct effects on the tumor cells and modulation of the tumor microenvironment to allow for anti-proliferative and anti-metastatic effects, as well as activation of the immune system to also attack the cancer cells. Currently, KZR-261 is in a phase I trial, which Noreen will update you about. Before we complete this section, I'd like to talk to you about how we selected the tumor types for our solid tumor phase I trial.
As you can imagine, with a highly, broadly selective, compound like KZR-261 , preclinically, it would be very, very difficult to expect that we could find a single biomarker which we could utilize to correlate with sensitivity. We took a novel diagnostic bioinformatic approach to look for sensitive cell lines. We start off by taking an analog of KZR-261 and treating over 450 cell lines. What we looked at was assessment of 7,000 gene modules. Out of that, what we found was that six gene modules correlated with sensitivity. Interestingly, those modules linked with target biology, which is what we would have obviously potentially anticipated. That's a great correlation there. We've got Sec61 client term, vesicular transport, mRNA translation.
What we then did was we cross-referenced with public databases, what we found was that when looking at different cancer cell lines, primary cancer samples, and normal tissues, we got a number of results, which I will show you on the next slide. What we first found was that tumors are predicted to be more sensitive than normal tissues. If you take the top 25% of both tumors and normal tissues and consider the gene modules correlating with sensitive cell lines, what you can see is that in terms of solid tumors, we have melanoma, we have mesothelioma, prostate and colon cancer, and we selected those as named arms in our phase I trial.
Beyond that, we can also see at the top ALL, which is a hematologic tumor, so that suggests that we have the possibility to look forward into hematologic malignancies as well. We also looked at normal tissues, and what we noted was that pancreas was observed in our preclinical studies to be a target tissue for tox. This gave us some confidence that our predictive methods through this bioinformatics work was correlating with our experimental observations. Utilizing bioinformatics, the preclinical data, and considering market opportunity, I mentioned the four named arms, and when we move over to Noreen's part of the presentation, she will go into more detail regarding that. At this point, I'm going to switch gear and look to the other side of the spectrum in terms of selectivity.
Now we're looking at a highly selective down regulator of PD-1 in particular. Let's talk about the biology behind PD-1. As you may be well aware, PD-1 is expressed on T-cells, and when PD-1 binds to PD-L1, a signal is sent which inactivates T-cells. As you are probably well aware, there are blockbuster drugs, KEYTRUDA, OPDIVO are examples of those multi-billion dollar therapeutics, effective cancer agents, which block the expressed PD-1 or PD-L1. These anti-monoclonal antibodies are intravenously infused and often dosed at a three-week interval. We've taken a new approach to this, I'll introduce you to KZR-540. KZR-540 is a small molecule. It's oral. In preclinical studies, we dose it once a day.
Both PD-1 and PD-L1 are clients of Sec61, they are translocated through Sec61 to get expressed on the cell. In the case of KZR-540, it selectively blocks the expression of PD-1, although not PD-L1. By not having the PD-1 available, the T-cells do not get inactivated. I'll show you data to support that rationale and the work that we've done there. The potential advantages of an oral PD-1 inhibitor is reduced treatment burden and convenience for patients, as an oral QD dosing regimen would be anticipated. I think very importantly, I think a key differentiator would be the dose modulation. Adverse events can be more efficiently controlled by modulating administration.
When you think about this in the context of a combination therapy, if safety signals are seen, what you can consider is optimizing the dosing regimen such that you can maximize the therapeutic index for that combination. We think that there's value to be had there potentially. Beyond that, the cost benefit improvement of a small molecule in terms of lower cost of goods and orally administered compounds and not having to go to infusion centers in terms of lower healthcare infrastructure costs are also considerations. Let's look at the data for KZR-540. Let's start with the in vitro side. What we've got on the left-hand side is the reporter assay.
What you can see is KZR-261, which is broadly inhibiting a number of targets shown on the left-hand side there, compared with KZR-540, which is extremely potent and selective versus PD-1. Looking into primary cells or human PBMCs, you can see that there's very nice dose-dependent PD-1 cell surface downregulation when treated with KZR-540. When we go to the proteomic side, we can see in stimulated human T-cells that when KZR-540 is administered at 100 nanomolar, what you can see is that there's extremely strong and selective downregulation of PD-1. That summarizes the in vitro data that I'd like to share with you today, and let's move to how that translates to the in vivo data. I mentioned earlier that every protein has a unique signal sequence.
That is also the case across species. Human PD-1 and mouse PD-1 do not share similarity in their signal sequence. To test our molecule as it is selectively a human PD-1 downregulator, we utilized a human PD-1 knock-in mouse, and in that model we used a human PD-L1 tumor line MC38, which is a colorectal cell line. Looking at the bottom left panel, you can see the results of an efficacy study where KEYTRUDA is dosed in the red line, and that is dosed at 10 mgs per kg intraperitoneally, twice a week, a very robust dose. What you can see is that we have similar efficacy when KZR-540 is dosed at 30 milligrams per kilogram, orally once a day.
When we look across to the right-hand side of the body weights, you can see that there's increase in body weights in all groups, indicating that all of those groups are well-tolerated. Looking at the middle panel, you can look at the PD marker here of the PD-1 expression on tumor-infiltrating T-cells. What you can see is very robust downregulation of PD-1 at the 30 mg per kg dose level, which is correlated very nicely with that strong efficacy that we see on the left-hand panel. We're currently more thoroughly characterizing KZR-540 and related analogs, and we will look to go for a DC nomination go/no-go decision later this year.
What I've shown you today is really how our team at Kezar has developed a leadership position in research on Sec61, giving us the opportunity to go after multiple therapeutic applications. KZR-261 is we view as a combination therapy in a single molecule, and it's in phase I clinical trials. I've also talked about our PD-1 downregulation program, with KZR-540 as our lead compound. This has the potential to be an IO partner of choice in combination therapies. We continue to expand our knowledge around Sec61 and apply that knowledge to our new and current programs. We will look forward to updating you on those programs in future. With that, I'd like to thank you for your attention and hand over to Noreen to discuss the KZR-261 clinical update.
Thank you, Neel. Let's now move into an update of the KZR-261 clinical program. KZR-261 is the first clinical asset from our Sec61 translocon platform. It is a potential first-in-class anticancer agent as it has demonstrated action against tumor proliferation, metastasis, and immune evasion, as Neel has shown. KZR-261 is a potential combination therapy in one molecule that could target a variety of solid and hematologic malignancies. KZR-261 is currently being studied in a combined dose escalation, dose expansion study of solid tumors. In the dose escalation phase, patients with any type of solid tumor that has demonstrated growth and for whom there are no other treatment options available can be enrolled.
The study utilizes a 3+3 design that allowed us to escalate quickly through lower dose cohorts given the absence of safety or tolerability concerns. A cycle includes three infusions in a four-week period at the predefined dose. After two cycles, scans are performed and tumor growth is measured. If there is no interval growth in the tumor, patients can receive an additional two cycles and are then reassessed. We will identify the maximally tolerated dose and move into the dose expansion phase of the study. We anticipate this to occur by the end of this year, given our rapid escalation to date. In the dose expansion, we will run a basket study of four named tumor cohorts and 1 all-comers arm. The dose expansion cohorts were identified through the bioinformatics which Neel described to you, preclinical studies and market opportunity. Cohorts where efficacy is observed can be expanded.
In November, I provided the first update to our dose escalation portion of the trial and will provide an additional update now. We escalated rapidly from 1.8 milligrams per meter squared to 12 milligrams per meter squared in four cohorts without significant safety or tolerability signals. Cohort five, which is 18 milligrams per meter squared and 10x where we began, is also the dose which approximates our minimally efficacious dose in preclinical studies. Six patients were enrolled in cohort five, and two of those patients are currently receiving their fifth cycle of KZR-261, indicating tumor stability and no concerning safety or tolerability signals. One of these patients has metastatic melanoma, and the other has metastatic colorectal carcinoma. Both melanoma and colorectal carcinoma are named tumors for the dose expansion study, potentially validating the bioinformatics work which we did.
Cohort six, which is 27 milligrams per meter squared, is currently enrolling. To date, we have seen only one dose-limiting toxicity event. This occurred in cohort four, where the patient experienced isolated elevation of serum lipase with no symptoms. We also observed one serious adverse event of an infusion reaction in one patient in cohort five. This patient received prophylaxis with the usual medications and tolerated subsequent infusions without recurrence. We've seen dose proportional exposure, no signs of drug accumulation, and an apparent half-life of approximately 25 hours. No pharmacodynamic data is available at this time. However, taken together, we believe that we are finding a meaningful therapeutic window for KZR-261. We anticipate sharing top-line data from the dose escalation portion of the study in the second half of this year. Thank you so much for joining us today.
I am now going to hand the baton back to John.
Thank you very much, Noreen, also thank you to both Neel and Dr. Lammert for those excellent presentations, which I think you all agree provided an outstanding overview of autoimmune hepatitis, of lupus nephritis, of the PALIZADE trial, the PORTOLA trial, and all the exciting work that's going on across our entire discovery platform focused on the Sec61 translocon. Before taking some questions from our analysts, let me just summarize maybe in three or four slides kind of what we've reviewed today. I'll start that summary by going back to a slide you already saw, which is our timeline.
Given what Noreen just shared around the excellent progress in the dose escalation portion of our KZR-261 study, I think we should all be very excited to see what comes in the second half of this year with the full quantum of dose escalation data with KZR-261. We all have heard and we all know that this is a very novel target, and this data set has the potential to really validate this target and launch into dose expansion in a very vigorous and exciting way that'll expand the Kezar story dramatically.
[But not included] on this timeline, but I feel bad that I didn't include it given Neel's excellent presentation, is how much more inflection could come over this three- to four-year timeframe with the continued progress on KZR-540 across the oral anti-PD-1 program and further research directions. We have not included that here, but I know and can assure you that there's an incredible team of scientists working under Neel's leadership to progress that as well. Finally, of course, both PORTOLA and PALIZADE trials are something to be excited about. They're thoughtfully designed. I thought that Dr. Lammert did an amazing job explaining just what a desert it has been in terms of innovation in the AIH space in the last 70 years, and I can't wait to see what that trial brings us in mid-2025
Putting zetomipzomib into context and putting those two trials into context, I feel very comfortable really leading a company on the zetomipzomib side that is focused only on those two diseases, autoimmune hepatitis and lupus nephritis, because these are really significant unmet needs and significant commercial opportunities for our company. I would be derelict of duty not to mention the entire back drop to the zetomipzomib story and this unique mechanism of action, which has so much potential across so many different indications. What this slide shows is just a very small subset of the roughly 20+, both smaller market and large market autoimmune diseases where either a selective immunoproteasome inhibitors have been tested pre-clinically or proteasome inhibitors have been used clinically for great clinical benefit.
We believe that over the long run, that this drug can do not only tremendous things for patients with AIH and LN, but help patients beyond. We're very excited over the next few years as we turn over additional data cards to think about ways to bring this drug to other unmet needs across the autoimmune landscape. It's all because of the unique mechanism of action, which, as a way of segue into a slide, last slide here about KZR-261, is obviously the secret sauce to this drug as well. You heard Neel and myself mention this as a combination therapy in a single drug, but that's exactly what it feels like when you look at the broad array of IO targets and oncogenic growth factors get knocked down here.
What this means is that it might have the potential to overcome class-focused chemo resistance in patients across a variety of both solid, where we've started, but also liquid tumor types, because liquid tumors also respond in our preclinical work with KZR-261. In a world where targeted oncology has been more the du jour, followed track in oncology, it's worth reminding everyone just how much blockbuster revenue is generated every year by traditional chemotherapeutics, over $42 billion a year in sales. Then, of course, the PD-1, PD-L1 access has been one of the great innovations for patients and commercially in recent memory. Very excited to bring 261 into the next two years of data. By my count, there's six separate catalysts between our expansion cohorts and the dose escalation.
we are at Kezar very excited to share those with you over the next couple of years and turn this into a springboard into dramatic development across the protein secretion platform. Just as my last slide before handing it over for questions with our analysts, superpowers here are the mechanisms of action and our targets. You can see these nice illustrations of an immunoproteasome and the Sec61 translocon. These are really master regulators of immune cell and cellular function. And what that means is potential for huge therapeutic benefit. You've heard now before and today that zetomipzomib mechanism can lead to amazing immunomodulation without immunosuppression, even immediate rapid responses in disease activity without immediate rebounds when this drug is removed.
Of course, steroid-sparing potential, which is a huge, huge need for patients across the autoimmune landscape. With KZR-261, it's more than just KZR-261, it's KZR-261 and the discovery platform. KZR-261 alone as a first-in-class Sec61 inhibitor is unique and special in its broad combination in therapy and a single drug potential with readouts in the very near future. We can't wait for Neel to speak to you again about further advances and progress across the discovery platform. I'll just reflect that, you know, 7+ years ago when starting this company, this was really a dream to bring first-in-class drugs into the clinic. We are very, very proud of this team to have done just that with both KZR-616 zetomipzomib and KZR-261. The future is bright.
Look forward to hearing your questions, and thanks for listening today.
Thank you. We will now go into the question and answer portion of today's webcast. In order to be mindful of time, please try to limit yourself to one question each. To ask a question, please use the raise hand feature. Our first question is from Derek Archila with Wells Fargo. Please unmute yourself to ask your question.
Hey, everyone. Thanks for the very thoughtful and comprehensive R&D day. Just maybe this question is for Noreen. Just first on the lupus nephritis phase II-B that you highlighted today. Maybe just your thoughts on the decision to go with two doses in that trial. Is that something, you know, the agency wanted to see? Or is that something you feel that you need to do? Maybe there's some more dose ranging work that you think is needed. Also, if you can disclose the powering of the study and whether those Class V patients will actually be included in a primary endpoint analysis or not. Thanks.
Great.
You're right.
Thanks, Derek, for that two-part question. With respect to the dose finding, we are very confident about the 60 milligram weekly dose. With that dose, we've seen very potent anti-inflammatory effects across the board, therapeutic benefits, both in terms of reduction in proteinuria as well as reduction in extrarenal manifestations of lupus. That dose is very well-tolerated, safe. We're not seeing any drug accumulation. As I mentioned, is over time, what we've seen in some of our longer studies is that any kind of tolerability issues diminish over time rather than accumulate. We're very confident with the safety and tolerability of 60 milligrams. However, from a regulatory perspective, less is often more, we are looking at a comparative dose of 30 milligrams.
30 milligrams is kind of the floor dose that we believe achieves the pharmacodynamic effect that we are aiming for, namely, greater than 80% inhibition of the LMP7 with very significant inhibition of the LMP2 subunits of the immunoproteasome to get the selectivity and the actions that we've observed to date. We believe that 30 milligrams could have a chance at working, and we would be confident to bring either dose forward into a confirmatory trial.
With respect to the powering, the study is powered so that either the 30 or the 60 milligram dose arm is powered to show us a treatment effect of 15 points or more and with a significant P value to kind of underscore that. Thanks for noticing the question about the patients with the Class V membranous lupus nephritis versus the classically enrolled proliferative lupus nephritis patients who have Class III or Class IV, plus or minus Class V. Essentially, the study would be sufficiently powered with 249 patients. We've added an additional 30 patients, essentially 10 in each arm.
They can have the diagnosis of Membranous LN exclusively. This gives us an opportunity to see if zetomipzomib could work in this particular class of patients who have really been left behind with respect to any meaningful therapy. It does not have any downside risk to us. If there's no evidence of effect in this population, we will still be statistically significant in the remainder of the study and have a good informed decision for a single next step study. If we do notice a positive efficacy signal in this Membranous LN population, that would lead us to include them in our next study.
Got it. Excellent. Thanks so much.
Our next question is from Matthew Phipps with William Blair. Please unmute yourself to ask your question.
Hello. Thanks for taking the question, hosting this event. Well, I'll try to kind of make it a two-part question as well. Do you plan to publish the baseline characteristics and, like, background meds once the trial is fully enrolled, just to give us a better sense of, I mean, what to expect in the control arm? It's, you know, it has been common for some other larger phase II trials. Would you wait until this phase II-B is done until running that subsequent phase III trial? I guess it could be applied, like you kind of mentioned, based on what you see from this trial.
Yeah, certainly on the question of publication of what we will show from any of our trials, I mean, Kezar, I think as you've seen, has been very transparent and proactive about putting our data into the public domain. This would not be an exception.
Sorry. There's I guess, I mean, put out the backline, the baseline characteristics before you get to that week 37 endpoint. After enrollment's completion, you could maybe do a trial in progress poster with some of the background characteristics just to give us an idea of who actually got into the study and what they were on.
you know, we'll take that under consideration. I think that a lot will just depend on how the study proceeds, and, you know, what we could learn from that. There's no reason upfront why we would not. With respect to the question about initiating a phase III, before we finish the phase II, I mean, it's, I think what's important for us to recognize about this PALIZADE trial is we are operationalizing this in the most fulsome and robust way possible.
As you heard, we're going to 250 sites in 30 different countries. That really is the goal so that we can hopefully rapidly enroll this study and then move quickly to phase III, whether that is kind of actually enrolls in parallel versus is just operationalized in parallel. Again, time will tell us. We will be in a position to move as quickly as the data allows.
Great. Thanks, Noreen.
Our next question is from Philip Nadeau with Cowen. Please unmute yourself to ask your question.
Hi. Thanks for taking our question. Our question's on the timelines for both studies, PALIZADE and PORTOLA. It does seem like given the number of sites that you have and the number of patients you're trying to enroll, and in light of the number of patients that have both the conditions, the timeline guidance seems conservative, two and a half years for PALIZADE and maybe a year for PORTOLA. Can you talk a bit more about why you expect the trials to take that length of time to enroll? If there's anything you can do to accelerate the timelines? Thanks.
No, Phil, thanks for the question. Maybe Noreen and I will each hear correct in observing that they are conservative. I think that's a good reputation in general to have as a management team. We absolutely view them as conservative timelines as well. Please also hear that we will be kind of leveraging all possible creative avenues to accelerate and enroll in the quickest way and rationally possible. And I think Noreen alluded to our approach in the LN trial going really global with 250 sites as really a springboard into phase III. And we're just being mindful of the increased overall interest in this disease area by a number of both biotechs as well as large pharma companies.
We feel that our profile will allow us to compete for patients very effectively given the efficacy rates seen in MISSION. At this point, it's also nice to be conservative and that's what we've chosen to do with these timelines. Noreen, anything to add to that answer? No, I agree that there are all those considerations, and we are very conservative and there is kind of the external conditions that are also have been very unpredictable over the last few years, specifically with the COVID pandemic, and not just the pandemic itself, but its impact on regulatory authorities and their timelines around the globe. That's also influenced our conservatism. In the hopefully, we will get back to a more business as usual pace, and our timelines can be pulled forward.
Our next question is from Maury Raycroft with Jefferies. Please unmute yourself to ask your question.
Hi, congrats on the updates, and thanks for taking my questions. I had a follow-up to one earlier, well, where Noreen mentioned potentially enrolling the phase III in parallel. I guess, can you talk a little bit more about how that would work, and if you have any initial alignment with FDA on some of the options there on how that would work?
Again, I think that you should hear that what we've done is plan for a number of possibilities to accelerate it. In general, I think that we are confident in just saying that we will complete phase II-B and move immediately to a fully operationalized phase III.
Our next question is from Catherine Novack with JonesTrading. Please unmute yourself to ask your question.
Hi, everyone. I did have a question for Dr. Lammert, if he's still with us.
Sadly not.
If not.
Try Noreen. She's pretty good.
I'm happy to be the in expert on the phone about AIH, Catherine.
The question I had was about, you know, getting a sense of the percent of patients in his practice that might fall into this hard-to-treat category that PORTOLA is enrolling, and just the level of excitement of a practitioner around a non-immunosuppressive treatment.
That's... The level of excitement is palpable. I will say that our team went to AASLD last fall, we met with a number of clinicians and investigators who treat patients with autoimmune hepatitis, they were just kind of really stunned by the data that we'd showed in MISSION, they could easily imagine the potential in their patients.
This is a patient population that literally, you know, they often feel like either pulling their hair out or absolutely just breaks their heart, because many of their patients can be doing, you know, well or well-ish on steroids or in combination with a steroid-sparing therapy such as azathioprine, only within, you know, one year's time to either experience a significant flare or to suffer significant complications from the medicines that may have been controlling their disease, better than it had been before. It's just kind of a constant long-term relationship of tug-of-war with the disease, and anything that can, change the trajectory of the disease would be welcome.
They do talk a lot about the comorbidities that their patients experience because, we even had one investigator said, "You know, if I could give my patients 60 milligrams of prednisone every single day for the rest of their life, that would be okay, but I can't." That's just unconscionable given the comorbidities that come with that. They are very enthusiastic and because of that, we have, you know, gained a lot of support and are able to conduct this study in the U.S. only.
Okay.
Our last que-
Helpful. Thank you.
Our last question is from Mitchell Kapoor with H.C. Wainwright. Please unmute yourself to ask your question.
Hey, everyone. thanks for taking the questions. Just wanted to kind of ask about the protein secretion inhibitors and the potential for combination. I wanted to ask, you know, could you see a situation where you would combine KZR-261 and KZR-540, or if you were to do some type of immunotherapy combination with KZR-261, would you look for an approved PD-1, PD-L1 inhibitor to kind of minimize the risk for multiple development agents?
That's a super question and one that I can't answer today, and I don't think anyone can answer today. When you're working with a molecule with such a novel mechanism of action, we don't know exactly what to predict in terms of efficacy and what actually might get left behind. There are some scenarios where some patients may respond beautifully to monotherapy alone. Others may seem to need a combination therapy. What we don't know today, if that combination therapy will be directed by kind of the tumor type itself, or if it will be directed by kind of that patient-specific tumor and what has been left behind. Do we need additional antiproliferative? Do we need an additional checkpoint inhibitor?
That's something that I think we will be able to essentially customize going forward, given the great work coming out of Neel's lab. We are open to that in the beginning, or excuse me, as terms of thinking towards the future. Right now, I think, as you heard, we're extremely encouraged by the fact that we already have two patients at just what we thought was approximately our minimally efficacious dose that have shown lack of progression of disease over five months. These really were quite sick patients going into the study. That alone is the monotherapy signal that we were looking for.
It does give us a sense that we are gonna have a nice therapeutic window, especially given the very bare minimum of safety signals that we've seen so far, and certainly nothing that defines a dose-limiting toxicity.
Great. Thank you. Thank you. Congrats on the progress with KZR-261 so far.
Thank you.
Thanks, Mitch.
There are no further questions.
Great. Thank you all once again for tuning in today. It was really fun for us to share the updates across both of our programs. Thanks to all of our analysts for the excellent questions as well. Look forward to being in touch in the future.