Kezar Life Sciences, Inc.KZRNASDAQ
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Operator: Greetings and welcome to the Kezar Life Sciences Second Quarter 2020 Financial Results and Corporate Update Conference. At this time all participants are in listen-only mode. A question-and-answer session will follow the formal presentation. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Miss Celia Economides. Thank you, you may begin.
Celia Economides: Thank you, Donna. Good afternoon everyone and welcome to Kezar Life Sciences conference call to discuss our clinical business and financial updates for the second quarter of 2020. With me on the call today from Kezar are John Fowler, Co-Founder and Chief Executive Officer; Christopher Kirk, President and Chief Scientific Officer; Noreen Henig, Chief Medical Officer; and Marc Belsky, Chief Financial Officer. This afternoon we issued a press release detailing our second quarter 2020 financial results and updates for our clinical development programs. The press release is available on our website. I'd like to remind you that today's call is being webcast live on the investor relations page of Kezar's website, and a replay will also be available following today's call. During the course of this call, we will make forward-looking statements based on current expectations. These forward-looking statements are subject to a number of significant risks and uncertainties and our actual results may differ materially from those described. We encourage you to review the risk factors in our most recent Form 10-Q 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, let me turn the call over to John.
John Fowler: Thank you, Celia. Good afternoon, everybody. And thank you for joining. First off, I hope that you and your loved ones are staying safe and healthy. These are trying times for all of us and I'd like to start by praising my team's amazing dedication and focus during this unprecedented health crisis. I've been incredibly impressed by my team's unrelenting efforts over the last several months, which underscores how deeply motivated we all are to help patients struggling with devastating autoimmune diseases and cancers. With each passing quarter, my optimism grows for the profound potential for our novel mechanisms of action. Both of our drug candidates target master regulators of cellular function, whether by inhibiting the Immunoproteasome with KZR-616 or by disrupting the Sec61 Translocon with KZR-261. Over the last several months, we've continued to generate both clinical and preclinical data that speaks to the powerful role of our targets and the potential therapeutic benefits that we can unlock by targeting them with our exquisitely selected small molecule drugs. I'm excited for all of you to hear about some of these data from our new Chief Medical Officer, Noreen Henig, who I believe was drawn to join us based on the broad applicability and potential of our high science approach to make major impacts in the most difficult to treat diseases. As you may recall, we have been evaluating our lead product candidate KZR-616 for the treatment of a number of severe autoimmune diseases. These last few months, we've been working closely with our clinical sites to assess COVID-19 impacts and provide them with guides for patients to safely continue on study. Even with the situation being fluid, we've certainly seen that our sites have been impacted with some clinics halting screening altogether while others have remained open but with reduced activity. Thankfully, given the growing understanding of KZR-616's mechanisms as immunomodulatory rather than immunosuppressive, we believe that we are not layering another level of systemic risk into the equation for investigators who need to remain laser-focused on protecting their [indiscernible] patients during this pandemic. Based upon the encouraging updated results from the Phase 1b portion admission that we released in June and the slowdown in recruitment and enrollment activities across our trials, we've taken this opportunity to reevaluate our clinical strategy with KZR-616. Noreen has been instrumental in bringing her fresh perspective to the KZR-616 development strategy and will outline changes that I've strongly believed increase our likelihood of success treating a wide range of immune-mediated diseases. But before turning the call over to Noreen, there are a few points I'd love to highlight. First, the positive learnings that we've gained from the nearly complete Phase 1b ambition study has our team, our investigators and patients very excited about the prospect of KZR-616 to be a game-changer. We're more confident than ever that inhibiting the immunoproteasome as a master regulator in immune cell function has profound therapeutic potential to transform the lives of patients living with severe autoimmune disease. Additionally, as many of you know, we've never been content to be a single asset company so we are also pioneering small molecule approaches against another novel target with platform potential, the Sec61 Translocon. Our R&D activities for this program have largely continued to pace and we remain on track to submit an I&D for a first in human clinical trial of our protein secretion inhibitor KZR-261 in patients with solid tumors early next year. Despite not being in the clinic yet this program has already been highlighted in both oral and poster presentations at Ash and ASCO, which speaks to the novelty of the mechanism and its powerful therapeutic potential. Kezar's president and CSO, Chris Kirk will be reviewing some of these data later in the call. Finally, we are pleased to be well-capitalized with a strong balance sheet that provides for an ample runway for us to accomplish our goals with these studies. Our CFO, Mark Belsky will walk you through all the details on our financials at the end of the call. With that, I'd love to turn the call over to Noreen to walk you through a comprehensive clinical update. Noreen?
Noreen Henig: Thank you, John. First off, I'd like to echo John's sentiments regarding this stellar team that I've had the pleasure of working with for the last three months. It's been a whirlwind joining Kezar especially in the midst of a global pandemic, but the compelling and elegant science combined with the commitment to patients, that is the heart of Kezar drove me to join this dynamic and motivated team. I've always believed that hard clinical problems can be solved with increased understanding of the mechanism of the disease. What really excites me about Kezar's two lead assets KZR-616 and KZR-261 is that both have real potential to target key mechanisms of some of the hardest clinical challenges physicians and patients face, namely, autoimmune and other immune-mediated disease and cancers. Therapeutic approaches to autoimmune and neoplastic disease leave much to be desired even when they work. It's a rare opportunity to bring transformative therapies with novel mechanism and actions to patients. Turning our attention now to our clinical program. John briefly touched on the fact that in light of the new positive data we shared earlier this summer with KZR-616, combined with the slowdown in enrollment activities imposed by the COVID-19 pandemic this is a very good moment to take a good hard look at our strategy around clinical development of KZR-616. You'll recall that KZR-616 is the first in class selective inhibitor of the immunoproteasome. As the immunoproteasome is a key piece of machinery in all effector cells of the immune system, but only cells of the immune system unless disease is present is quite compelling to think that inhibition could be disease-modifying. There are many well-established animal models of autoimmune disease, and in most of them selective inhibition of the immunoproteasome is disease-modifying. We've also established through a series of studies that the effect of KZR-616 is immunomodulatory rather than immunosuppressive, which could be of significant benefit to patients with chronic immune-based disease. Today, based on safety studies with 100 healthy volunteers and 39 patients with systemic lupus erythematosus, we believe KZR-616 is a highly selective inhibitor of the immunoproteasome that has pharmacologic properties consistent with chronic administration, and that it is an active immunomodulatory drug. We will focus development on doses of 45 and 60 milligrams once per week administered via subcutaneous injection with our lyophilized formulation. I'd now like to take you through each of our three clinical programs with KZR-616 MISSION, PRESIDIO and MARINA and provide updates to the protocols and program. Let's start with Mission. As you know MISSION is a combined Phase 1b2 study of KCR-616 in patients with lupus with and without lupus nephritis. The Phase 1b portion which is 25 weeks in total, 13 weeks of dosing followed by 12 weeks observation provides important safety tolerability, pharmacokinetic and pharmacodynamic data for KZR-616. We completed enrollment of five of six cohorts exploring doses of 30 to 60 milligrams with different dosing strategies. The sixth and final cohort is evaluating the 75-milligram weekly dosing and will complete enrollment shortly. We expect the Phase 1b part of MISSION to complete in early 2021. In June, we shared some of the exciting exploratory efficacy data that we learned from the MISSION Phase 1b. In patients who receive doses of 45 or 60 milligrams weekly, there was disease improvement measured across seven indices of lupus disease activity. Most strikingly, two of two patients with active biopsy-proven proliferative lupus nephritis experienced a greater than 50% reduction in proteinuria. This was quite noteworthy, and it's worth focusing on lupus nephritis in these two patients. Lupus nephritis abbreviated LN is a severe complication of lupus and associated with significant morbidity and mortality. It is not normal or healthy to have protein in the urine. The finding of proteinuria has serious consequences for patients and is associated with renal failure. Proteinuria can be quantified by the urine protein to creatinine ratio or UPCR, which is an objective and well-known marker of disease severity and activity in LN. Reducing proteinuria significantly and quickly is the goal of therapies for LN and a 50% reduction in UPCR within six months of starting therapy is highly correlated with a long term clinical benefit. The two subjects with LN who entered this portion of the study had previously diagnosed LN that was refractory to all therapies available to them. The patients were stable enough to enroll in the 1b safety and tolerability study. In both cases, the patient experienced a drop of greater than 50% in their UPCR and did so in response to up to 13 weeks of therapy with KZR-616. These two patients also had reduced SLE disease activity scores and had supportive changes in specific biomarkers such as anti-double-stranded DNA. While a very small number of patients, the rapid and meaningful response is encouraging. The Phase 2 portion of MISSION was originally planned as a safety tolerability and dose exploration study in patients specifically with active LN and in patients who were carefully selected for their background therapy. In response to the learnings from the Phase 1b trial, the MISSION Phase 2 has been amended. The primary endpoint is now an efficacy endpoint, renal response measured by a 50% or greater reduction in UPCR at six months. We will include patients with LN with histologic Class III or IV +/1 Class V being treated with current standard of care. We plan to enroll 20 patients into this single-arm open-label trial, evaluating a target dose of 60 milligrams weekly for 24 weeks. Barring any other potential slowdown that could be imposed by COVID over the coming month, we expect to have interim data for this trial in late 2021. As a new addition, we are planning a 12-month extension study to collect data on the long term safety and durability of benefit of KZR-616. The patients to be included in this trial will reflect a range of real-world clinical situation and thus we believe we will be well-positioned to assess the benefits of KZR-616. If KZR-616 demonstrates benefit, it could represent a paradigm shift in treating patients with lupus nephritis. Let's move on to PRESIDIO which is evaluating KZR-616 in dermatomyositis abbreviated DM and polymyositis abbreviated PM to the most prevalent forms of immune-mediated myopathies. Both DM and PM are serious autoimmune diseases with significant morbidity and mortality. The existing cornerstone of therapy for these diseases is high dose corticosteroids which are associated with significant untoward effects which accumulate over time. There is a clear need for an immunomodulatory therapy that can be used chronically to control these disabling diseases. Excellent work on the pathophysiology of DM and PM shows increased presence of the immunoproteasome even in adult muscle cells where it is not usually found. Selective inhibition of the immunoproteasome with a drug like KZR-616 has been shown to be effective in animal models of immune-mediated muscle disease. PRESIDIO, which is actively enrolling, is a placebo-controlled crossover design study of KZR-616, 45 milligrams weekly in patients with DM and PM. Patients will receive 16 weeks of either KZR-616 or placebo and then cross over to receive 16 together. We are not making changes to PRESIDIO but we will be adding an open-label extension study for patients completing the trial. Our third clinical trial is MARINA, a Phase 2 trial to evaluate KZR-616 in autoimmune hemolytic anemia and immune thrombocytopenia or AIHA and ITP. Effective immediately, we are withdrawing the study. Despite the strong interest from investigators and the patient community, the decision to withdraw the study was informed by the need to substantially amend the current protocol and the COVID related slowdowns. No new clinical data-informed this decision. Our scientific conviction remains high that kZR-616 and the mechanism of selective inhibition of the immunoproteasome could be an important new therapy for patients with autoimmune cytopenia. In support of our conviction, gene signature data from the MISSION 1b study shows that KZR-616 does not down-regulate production of important hematologic cell lines, a known consequence of current or borrowed therapies for these diseases. Going forward, we can generate a new robust study designed that will incorporate our learnings about KZR-616 and current clinical practice patterns. We are working closely with key opinion leaders in the medical community to design a meaningful study to evaluate the efficacy and safety of KZR-616 in patients with AIHA and ITP with the goal of bringing a new therapy to patients as quickly and efficiently as possible. I would like to reiterate how excited I am to work with this phenomenal team and to continue to leverage the broad therapeutic potential of KZR-616 as a treatment option for a wide array of autoimmune diseases. With that, I will turn the call over to Chris Kirk, President and Chief Scientific Officer to briefly discuss our protein secretion platform and the work being done to bring our initial assets into clinical trial.
Christopher Kirk: Thanks, Noreen. Before Marc reviews our financials, I wanted to briefly touch on our drug discovery program focused on the protein secretion pathway and more specifically, small molecule targeting of the Sec61 Translocon. Sec61 is the initiation point of the protein secretion pathway for nearly all secreted in transmembrane proteins. That means that Sec61 regulates the expression of many proteins that are already targeted by biological therapies, such as JAF [ph], PD-1, HER3 and many others. By inhibiting the Translocon, we can potentially target multiple recognized hallmarks of cancer, such as the checkpoint that allow tumors to evade immune detection, growth factors that promote tumor cell proliferation, and cytokines and their receptors that mediate metastatic spread. We see Sec61 as a very promising therapeutic target in multiple solid and hematologic tumors, as well as many other diseases. Across a wide range of preclinical models, our novel inhibitors exhibit a very broad anti-cancer activity with minimal toxicity seen in vitro and in vivo, and we can see enhanced T-cell responses in validated models of immuno-oncology. We nominated KZR-261 late last year as our first clinical candidate from this platform and the compound is currently in the midst of IND enabling activities. We anticipate submitting an IND in Q1 of 2021 and are planning a first in human clinical trial in patients with solid tumors to begin soon thereafter. KZR-261 has a very unique profile of multi-target inhibition that we hope will translate into a broad anti-cancer activity seen in a wide range of tumors. Because KZR-261 can target immune checkpoints and many oncogenic drivers, it can be thought of as a combination therapy in a single trial. We've already had the opportunity to present our research at major conferences and we look forward to unveiling even more on this novel and profound therapeutic target as we progress both KZR-261 and our discovery effort. With that, I'll turn the call over to Marc Belsky, our chief financial officer to provide a financial update on the company.
Marc Belsky: Thanks, Chris. As John mentioned, we have a strong balance sheet. Cash, cash equivalents and marketable securities totaled $157.5 million as of June 30, 2020, compared to $78.2 million as of December 31, 2019. This increase was primarily attributable to the net proceeds from the underwritten public offerings in February and June of this year, net of cash used in operations to advance the KZR-616 and 261 program. Research and development expenses for the second quarter of 2020 increased by $200,000 to $7.1 million, compared to $6.9 million in the second quarter of 2019; this increase was primarily related to advancing the protein secretion pre-clinical program. General and administrative expenses for the second quarter of 2020 increased by $300,000 to $2.7 million, compared to $2.4 million in the second quarter of 2019; this increase was primarily due to an increase in personnel expenses, including non-cash stock-based compensation. Net loss for the second quarter of 2020 was $9.5 million or $0.22 per basic and diluted common share, compared to a net loss of $8.7 million or $0.46 per basic and diluted common share for the second quarter of 2019. Finally, there were 45.8 million shares of common stock outstanding as of June 30, 2020, and pre-funded warrants outstanding to purchase 3.8 million shares of common stock at an exercise price of $0.001 per share as of June 30, 2020. I'll now turn the call back over to John for some closing remarks.
John Fowler: Thank you, Marc. As we look ahead, at the remainder of this year, I can speak on behalf of the entire Kezar team in saying that we're more excited than ever about the potential of our therapeutic platforms. We derive meaning and hope from our commitment to serving patients and we believe that our novel approaches targeting master regulators of cellular function have the potential to generate huge wins for those most in need. We also believe that to make a big impact on the hardest to treat immune-mediated diseases and cancers, you need to affect multiple drivers of those diseases, which is exactly what our drugs do. We have a busy road ahead of us and we look forward to providing important updates in the quarters to come. At this time, I'd like to thank you all for joining us today. I'll now turn the call over to the operator for questions. Operator?
Operator: [Operator Instructions] Our first question is coming from Maury Raycroft of Jefferies, please go ahead.
Unidentified Analyst: This is Kazeem [ph] on for Maury. Can you help us understand better what factors predominantly contributed to better tolerability on Cohort 2c? Was it the lyophilized formulation like the triple dosing on the [indiscernible]?
Noreen Henig: Hi, Maury, this is Noreen. I'm happy to take that question. The better tolerability was seen to be through a combination of factors. First, we had moved from a frozen solution to a lyophilized formulation of KZR-616. Second is we used a step-up dosing where patients received 30 milligrams the first week and then the target dose thereafter. And lastly, we introduced a number of supportive measures of suggestions to patients and physicians to help them feel comfortable with this new drug. These kind of pre-dose suggestions are relatively light touch, including oral hydration or non-sedating antihistamine, and then all of those measures together contributed to the increased tolerability.
Unidentified Analyst: Okay. To the new formulation, does this basically make the drug more stable or what is special about it?
Christopher Kirk: Hi, I can answer that. It does not change the stability of KZR-616. What it does is remove one of the excipients that was used in the initial formulation, an agent called polysorbate 80. That while enhancing solubility does come with the potential for adverse drug reactions and so to simplify the formulation in order to move into a life formulation, and ultimately, patient self-administration. We went to this next generation formulation that we're currently using.
Unidentified Analyst: That's great. Thank you. One final question is, in the Cohort 2c are there any more lupus nephritis patients.
Noreen Henig: Sorry, can you repeat the question?
Unidentified Analyst: In Cohort 2c are there any more lupus nephritis patients?
Noreen Henig: No, there are not any more lupus nephritis patients in the Cohort 2c.
Unidentified Analyst: Thank you so much.
Operator: Thank you. Our next question is coming from Ram Selvaraju of H.C. Wainwright. Please go ahead.
Blair Cohen: Hi, this is Blair Cohen on for Ram, just a couple coming from me. When do you think we could expect another update from the Stage 1b MISSION study and how many patients do you think we should expect in that data? Has the progression of the trial been impacted by COVID-19 at all? Any update on that?
Noreen Henig: Hello. So I think that our goal is to be able to provide an interim update by the end of this year, as we believe we will have fully enrolled our third and final cohort this month, and therefore we should have at least some initial interim data by the end with a follow-up phase to come in the first half of 2021.
Blair Cohen: Okay, great. To what extent would you say the PRESIDIO timeline has been impacted by COVID-19? Do you expect any issues with the integrity of the data?
Noreen Henig: Two good questions. So the PRESIDIO is enrolling a very rare disease patient population and there definitely has been some slowing of enrollment in the PRESIDIO trial. So we had initially guided to the end of 2021 for the completion of that trial and we are now looking to bring that into mid-2022. In the final question about data integrity is no, we do not at this point believe there will be any impact to data integrity.
Blair Cohen: Okay. And as far as your cash guidance with the new public offering, where does that take you?
Marc Belsky: Our cash runway gets -- our current balance is $157.5 million. That cash runway gets us through 2023 based on our current plans.
Blair Cohen: Okay. And then, just lastly for me for KZR-261, when do you plan on initiating a study and what could that design look like? Thank you.
Christopher Kirk: So, we will be filing the IND in Q1 of 2021 and hope to start the first clinical trial in solid tumors soon thereafter. We'll provide updated information on the trial design at a later date.
Blair Cohen: Great. Thank you very much.
Operator: Thank you. Our next question is coming from Kenneth Atkins of Cowen & Company. Please go ahead.
Kenneth Atkins: Hi, guys, thanks for taking my questions. You mentioned that a 50% reduction in proteinuria is associated with long term clinical benefit in patients with LN. Could you just elaborate on that a bit and sort of help us better understand how that specific cutoff was chosen for the primary endpoint?
Noreen Henig: In general, the proteinuria is a sign of disease activity and if you can modify the disease activity, the expectation is that the amount of protein spilled into the urine goes down significantly. Based on past clinical trials, to look at evidence of renal response, a reduction of proteinuria by 50% has become standard in current care. It is not ideal. Obviously, we'd love to reduce it to even more than 50%. For our first trial, that's what we have chosen to benchmark against existing and other trials.
Kenneth Atkins: Okay, thanks. That makes sense. Then with regard to the discontinuation of the MARINA study, what was driving the highest screening failure rate? And just wondering, if you're also seeing that across the other studies at KZR-616?
Noreen Henig: So, MARINA was unique; in that the inclusion-exclusion was very, very selective kind of a precious patient population that probably doesn't really exist or at least didn't exist in the setting of trying to time patients to enter into a clinical trial. So while we saw a lot of interest from investigators and a lot of patients put forth for potential entry into the MARINA trial, there were actually no patients enrolled in the trial. So given the time that MARINA has been open without active enrollment and then added to the fact that we've learned a lot about KZR-616 since we initiated that trial, the decision was taken to withdraw the study and then to rework the protocol so that it's much more inclusive, reflects the existing current care and patient population more accurately, and then incorporates the learnings of KZR-616 that we have at hand.
Kenneth Atkins: Okay, that's helpful. Thank you.
Operator: Thank you. Our next question is coming from Matt Phipps of William Blair. Please go ahead.
Matt Phipps: Hi, guys, thanks for taking my questions. I just wanted to walk through a little bit of the changes to the MISSION trial Part 2 Phase 2 portion of it. So you drop the 30 mg dose because it already talked about adding the 60 mg dose but did you also drop the placebo dose? It's no longer a randomized trial, and then it mentions an open-label trial enrolling 20 patients in a single-arm treatment of 60 mg so that means there's also no longer 45 mg dose because last I'd seen on your updates, there was 4 arms and 16 patients per arm.
Noreen Henig: Yes, you've got it right. So we're focusing on the 60-milligram dose alone. That's because we didn't see a significant difference from pharmacodynamic effects or tolerability effects in the 1b portion of the study. So we've selected this as a dose that has a good chance of having therapeutic potential in this patient population and it is no longer a randomized controlled study. The reason for that is that we believe that we can enter 20 patients who are at various levels of their disease in terms of the duration of their diagnosis and exposure to different therapies and treatments that have obviously failed because they're being defined by their proteinuria when they enter the study and we're looking to see if KZR-616 can make an impact on these patients. So the primary analysis is essentially a responder analysis of how many patients respond to KZR-616. We believe that in the best-case scenario, similar to the two patients we've already seen benefit in that regardless of kind of duration of the disease and exposure to a variety of different backgrounds, KZR-616 has a potential therapeutic benefit.
Matt Phipps: Okay, thanks. And I guess you mentioned some modifications, including an exclusion criteria. Is it still a UPCR over one? And is there any cap on the upper end? Then, you talked about it but just debating whether a renal response is a 50% reduction in UPCR versus getting below 0.5 of mix per mg UPCR?
Noreen Henig: Those are great questions. So yes, the patients will come in with a proteinuria level greater than one, which helps define patients with active proteinuria that you could then measure a reduction in reliably. Then the goal in this initial six-month study is to see how many patients get to below 50% in that period of time. Obviously, we would love to do better than that, and doing better than that would have even more therapeutic benefits for patients. But for now, I'm setting the bar as a 50% reduction in the six months is our target goal.
Matt Phipps: Okay. And just one question at trial. What's the required length of therapy on standard of care without I guess, achieving a response, and how long do they have to be on that stable background meds to be enrolled in the trial?
Noreen Henig: Essentially, patients have to have essentially active proteinuria based on their stable medications and with an expected time to treatment. So if they've received induction, then they need to be a specific number of months outside of their induction. If we're testing on induction, having or never had a response to induction or on what is considered best maintenance that still have a proteinuria greater than one, they will be entered into the study.
Matt Phipps: Okay. As far as thinking about how obviously the COVID pandemic has gone here in the U.S. potential for kind of rolling challenges with the trial enrollment, are you guys exploring more geographies or anything to try to -- additional clinical trials to try to speed up enrollments, try to make sure you can hit these timelines because it has pushed things back a little bit from what people were originally expecting?
Noreen Henig: Yes, we are looking at enlarging our footprint not just in MISSION but in PRESIDIO and for future trials as well.
Kenneth Atkins: Thank you.
Operator: Thank you. Our next question is coming from Jim Birchenough of Wells Fargo, please go ahead.
Unidentified Analyst: Hi, thanks for taking our question. This is Yan [ph] dialing in for Jim. So first off a couple of questions on the MISSION UPCR data. Could you may be talk a little bit of the rationale whether you have seen IGG reduction as seen with Velcade in a small study in lupus nephritis? And whether you think there is additional mechanism of action originating from affecting T-cells and macrophages? Thanks.
Noreen Henig: So, Chris, I think you would speak most eloquently to all of the mechanism of action data that we have.
Christopher Kirk: Sure. First, Yan, into your first part of your question which was looking at immunoglobulin responses. In both cases of the patients with lupus nephritis, they had high levels of anti-double-stranded DNA antibodies and you could see a reduction in those anti-double-stranded DNA antibodies occurring and actually pre-feeding in one case the improvement in renal function. We've also seen reductions in anti-double-stranded DNA antibodies in other patients with lupus in the trial, though, not patients with active LN. We've also seen improvements in serologic markers like complement that suggests that we're having an impact on pathogenic autoantibodies. At the gene expression level, we see reductions in inflammatory gene modules that cover innate immune effector cells like Type 1 interferon responses over-activated T-cells and B-cells, suggesting that there is more at play than merely reducing autoantibody levels being driven by plasma cell changes, though we do see reductions in circulating plasma cells in our patients as well and presented on that at ACR back in 2019.
Unidentified Analyst: Got it. Thank you. That's very helpful, Chris, thank you. Then on the amended protocol for MISSION, could you provide a little bit more context on the enrollment criteria comparing the new versus the old? What is the implication for the ultimate label or any other implications with this enrollment criteria change? Secondarily, you talked about the primary endpoint, but what might be response rate that you deem successful and could we look at Velcade in this indication or that's not entirely fair because Velcade has neurotoxicity and other AE problems? Thank you.
Noreen Henig: To your first question about the Criteria, I think the best way to think about it is that we've written the inclusion criteria to more reflect real-world practices of physicians. So often the guidelines talk about going from a sequence of quote-unquote induction therapy, which is often more potent but also more toxic or intolerable medications followed by maintenance strategies of what you've achieved with induction or following depletion of whole-cell lines. In practice, physicians tend to be more fluid without specific induction followed by maintenance phases in response to patient's lupus nephritis, as well as their other disease activity, that extra-renal but also due to lupus. So we've attempted to write our inclusion-exclusion criteria to be very inclusive and reflective of the real-world patient experience. With respect to if KZR-616 shows therapeutic benefit on what the indication could look like is our expectation is that it would be KZR-616 for the therapy of lupus nephritis and that it would not necessarily be reflected or restricted to any language around induction or maintenance but essentially, it has the potential to be open. We do see this as a bit of a paradigm shift if a drug like KZR-616 could work. I think that paradigm shift actually kind of speaks also to your follow up question about Velcade and could Velcade do the same thing. Velcade is actually not a medication that is likely to be useful in a chronic maintenance regimen because of accumulated toxicity, neurotoxicity and others and so it's very difficult to take medication overall for maintenance therapy for autoimmune diseases which are considered quite chronic in nature. So we believe KZR-616 is a selective immunoproteasome inhibitor that has a much better chance at being a meaningful chronic therapy for chronic care of these patients.
Unidentified Analyst: Got it. That is very, very helpful. Thank you so much for walking us through that. And lastly, MARINA, just curious how many patients have been enrolled? Maybe I have missed it on the call. Also, the screen failure rate was that mainly ITP or mainly AIHA or both? Thank you.
Noreen Henig: So, there have been no patients enrolled in MARINA to date, which is what's allowed us to just withdraw the study. The screen failure, there was a large number of patients referred to this study and the background disease was proportional to the prevalence of the diseases and the reasons for failure were myriad. But essentially, the stages did not reflect real-world conditions.
Unidentified Analyst: Got it. Okay. Thank you very much.
Operator: Thank you. At this time, I'd like to turn the floor back over for closing comments.
Celia Economides: John, do you want to provide a couple of closing comments before the end of the call?
John Fowler: Happy to do that too. I didn't want to steal your thunder, but appreciate your team for that and appreciate the whole team out here fielding those questions quite well. And I know there's a bunch of excellent thoughts from our covering analysts. I appreciate everyone dialing in and sharing those. Once again, just to reiterate the appreciation and gratitude for the hard work of the entire Kezar team, not just at the management level, but all the way down the ranks to push forward and make really thoughtful and logical amendments and changes with the backdrop of these unsettled times we're all navigating together right now. So, we look forward to being in touch and being available to our covering analysts and investors in the months and quarters to come. Again, thank you, everybody, and thank you, Celia, for working with the operator to make this such a successful call.
Operator: Ladies and gentlemen, thank you for your participation. This concludes today's teleconference. You may disconnect your lines at this time. And have a wonderful day.