Welcome to Kezar Life Sciences 2021 Investor and Analyst Day. Today's presentation will be followed by a question- and- answer session. 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. Wonderful. Thank you, Alex. Good afternoon, everyone. I'd like to thank you all for joining us today for our Investor and Analyst event. We've had a very busy last few months here at Kezar, and we look forward to spending the next 90 minutes or so with you walking through the excellent progress that we've been making across both of our clinical stage programs. As you're likely aware, we recently shared we met our enrollment goals in both of our phase II trials with KZR-616. The fact that we're able to achieve these milestones while facing the persistent headwinds of the global pandemic speaks both to the high levels of unmet need for patients with lupus nephritis and in DM and PM as well, but also to the amazing persistence and creativity demonstrated by the team here at Kezar. I couldn't be more proud of the excellent execution by the whole team and by our amazing investigators. I'm also proud that today we'll have a chance to talk about our other clinical program targeting the protein secretion pathway with our drug candidate, KZR-261. Just as our phase II trial celebrated their last patients in, the phase I trial with KZR-261 marked its first patient dosed only days ago. My co-founder, Chris, will provide an overview of KZR-261 and the phase I study design and outline the broad platform potential we see in this novel therapeutic target. I think you'll come away impressed by the broad potential of our two product candidates and the deep platform potential behind each of them. Here are our disclaimers, and here's our agenda for today. I'll endeavor to be brief, so you can hear from the experts and leave time for some questions. We'll kick things off with Noreen reviewing the interim data from our MISSION study in LN, and I'm very pleased that one of the investigators from that study, Dr. Samir Parikh, is with us as well to share his experience with KZR-616. After a review of our PRESIDIO study in dermatomyositis and polymyositis, we'll describe KZR-261 and unpack the remarkable work that our research group has done unlocking the therapeutic potential of the translocon and the protein secretion pathway. Before handing it over to Noreen, I'll use the next few slides to briefly set the table on our programs here at Kezar. Now, since we've been around for the last six years, it's actually been a much longer journey of research and development that's gone into our two programs. My co-founders, Chris Kirk and Jack Taunton, have been working on our targets for quite some time, and that work has resulted in two novel drugs now in clinical trials. KZR-616, which is of course a first-in-class immunoproteasome inhibitor with profound immunomodulatory potential, and KZR-261, a first-in-class protein secretion inhibitor, which resembles really a combination therapy in a single small molecule drug. Finally, we enjoy a strong financial position that enables us to move ahead into the next phase of trials while providing a runway that gets us into 2024. Now, let's take a closer look at our drug targets, starting with the immunoproteasome. As a unique form of the proteasome found in the cells of our immune system, the immunoproteasome is responsible for regulating many aspects of immune cell function. When inhibited by KZR-616, we see broad anti-inflammatory effects without evidence of immunosuppression. Now, another target with profound role in cellular function is the Sec61 translocon. You can see that here outlined in green. The roughly 5,000-7,000 proteins that are destined for secretion or cell surface membrane presentation are dependent upon the Sec61 translocon for getting to their eventual destination. Our small molecule inhibitors disrupt that interaction between the translocon and the signal sequence of a newly created polypeptide, which can result in really exciting therapeutic potential. Again, our drug 261 is one that blocks approximately 9% of that secretome in transformed cells, resulting in really exciting preclinical anti-tumor data, and we look forward to unpacking that trial a little bit more for you today. Since I know many eyes are on the data in lupus nephritis that we released via press release recently, let me just take the last couple slides here to talk about the immunoproteasome and KZR-616. You can see this here near the barrel of the immunoproteasome, which as I mentioned earlier, is a very unique form of proteasome found in the cells of the immune system. Our molecule targets the immunoproteasome-specific subunits LMP7 and LMP2 in the immunoproteasome, resulting in a really exciting broad immunomodulatory effect without driving deep immunosuppression. This is working across both the adaptive and innate immune system and avoids the kind of dual proteasome-related tox profile that you see with approved drugs in Multiple Myeloma, which drive cytopenias and other side effects. This is exactly the kind of profile we want to see bringing a drug forward into chronic administration in patients with autoimmune disease. Now finally, the thing that gets me most excited about this unique mechanism of action is how it's so fundamentally different from the other drugs in the market today. The other drugs seen here targeting either macrophages, dendritic cells or monocytes target single cytokines at a time, and they can have profoundly wonderful effects and high sales numbers as well. Other drugs target the T-cell compartment or the B-cell compartment. These are all really well-known drugs, both in lupus nephritis and beyond. We know that KZR-616 covers the entire gamut, the full adaptive and innate immune system. We're hopeful that this unique mechanism will drive broad immunomodulatory activity and really help patients in myositis and lupus nephritis and beyond. Taking a look at our pipeline, we're definitely excited to review data from the MISSION study today, and I'm really grateful to Dr. Parikh for joining us. Over the coming year, we look forward to top-line readouts from both MISSION and PRESIDIO, as well as continued progress through our phase I study with KZR-261. As we move into 2022, we look forward to sharing more with you about the future for 616 development, both in these indications and beyond. The same applies for protein secretion, where 261 represents not the culmination of a journey, but only the beginning of our work on this important target. Thank you so much for joining us today. Now over to Noreen. Thank you, John, and hello everyone on the line. Today, I have the pleasure of walking you through the 2 clinical programs evaluating KZR-616, a small molecule selective inhibitor of the immunoproteasome in patients with severe autoimmune diseases. I'm Noreen Henig, the Chief Medical Officer here at Kezar. John introduced you to KZR-616 and its potential as an immunomodulating agent for the treatment of immune-mediated diseases. This table shows the 5 clinical studies, either completed or ongoing, that Kezar has conducted with KZR-616. We completed 2 healthy volunteer studies, which provided us with meaningful PK/PD and safety and tolerability information, and which will not be discussed further today. To begin, let's focus on the study named MISSION, which is a two-part study of patients with systemic lupus erythematosus with or without lupus nephritis. The phase Ib portion of the MISSION study completed earlier this year, and results were presented at the EULAR 2021 conference in June. I will summarize those findings today. The phase II portion of the MISSION study met its target enrollment of 20 subjects earlier this month, and for the first time, I will share some interim data with you. Here we present the trial schema for both parts of the MISSION study. Part I-B, shown on the left, was a study of 6 dose cohorts of KZR-616 in patients with SLE. The doses explored were KZR-616 45, 60, and 75 milligrams via subcutaneous injection once weekly. One of the most important learnings at the time was that the safety and tolerability profile is quite consistent across the range of those three doses, which all lead to greater than 80% inhibition of the immunoproteasome without significant inhibition of the constitutive proteasome. The other important learning is that patients do better if they receive an initial dose of KZR-616 30 milligrams the first week and then follow it with a target dose of 45, 60, or 75 milligrams. We refer to the lower initial dose as step-up dosing. We also learned that KZR-616 has many attributes that position it well as a chronic therapy for autoimmune disease. KZR-616 modulates innate and acquired immune responses without signs of immunosuppression. Weekly administration results in consistent PK and pharmacodynamics. This occurs through selective inhibition of the immunoproteasome via targeting of the specific subunits LMP2 and LMP7. Weekly dosing leads to consistent exposure and clearance with a half-life measured at less than 5 hours. KZR-616 is not predicted to result in clinically significant drug-drug interactions. It demonstrates rapid and sustained immunomodulatory gene expression changes consistent with an anti-inflammatory effect, and it has a very favorable safety and tolerability profile. Very importantly, even in our earliest study, we saw improved signs and symptoms of lupus and lupus nephritis as measured with exploratory endpoints and symptoms, serologic markers, reduction in proteinuria, and reduction in markers of specific kidney inflammation. These are signs and symptoms that are meaningful to clinicians and to patients. The safety and tolerability found in the phase Ib study supported use in chronic disease, and as I will share with you, the MISSION phase II interim analysis shows a similar or even improved safety and tolerability profile with six months rather than 13 weeks of weekly administration. The commonest adverse event continues to be injection site reactions. A lot was made in the early days of KZR-616 regarding upper gastrointestinal symptoms like nausea and vomiting. As you see, as in the later MISSION phase Ib cohorts, the MISSION phase II data will demonstrate that step-up dosing makes an important difference. While the MISSION phase Ib study included stable patients with lupus, we did enroll two patients who had the renal manifestations of lupus nephritis. These patients were considered stable enough for a safety and tolerability dose escalation study. Nonetheless, these two patients had active proteinuria, which means protein is being lost through the urine. Any protein in the urine is abnormal, and the more protein in the urine, the worse the damage from inflammation, and the more likely permanent kidney damage is incurred. We previously reported the two patients shown here, patient one and patient two. It was quite unexpected that both patients experienced a greater than 50% reduction in UPCR, a normalized measurement of protein in the urine. The reduction in UPCR for the 13-week study and its 12-week observation period is shown in purple. We also confirmed that the reduction in UPCR was due to decrease in inflammation, which is shown by reduction in the sCD163, a measure of macrophage activity in the kidney, as shown in blue. Today, for the first time, we will learn a bit more about LN patient number 1 from Dr. Samir Parikh, so keep this graph in mind. Neither patient 1 nor patient 2 were included in the MISSION phase II study and thus are not included in the interim data. Now let's move on to the MISSION phase II study, a trial of KZR-616 in patients with active lupus nephritis. Just as a reminder, the results we are showing are interim preliminary data, and the top-line data will be available late Q2. Mission phase II had a target enrollment of 20 patients, and as we announced last week, we did reach our target enrollment. The patients in Mission phase II had LN class III or IV ± class V, and active proteinuria with a UPCR greater than 1. They received 24 doses of KZR-616 once weekly, with the first dose of 30 milligrams followed by the target dose of 60 milligrams. End of treatment is assessed at week 25, one week following the last dose. There is an additional 12-week safety assessment. The primary endpoint of the study is number of patients with greater or equal to 50% reduction in UPCR compared to baseline. One key difference between the Mission study and the recently published interventional trials in LN is that patients did not receive high doses of MMF or corticosteroids at the start of the study. KZR-616 was added to whatever medications the patient was on, and we documented this was the only change in therapy. In addition, we did not force a taper of glucocorticoids, but at their discretion, investigators were allowed to lower the doses of prednisone or equivalent, as well as any doses of usual care therapies. MISSION 2 is an open-label study with a primary endpoint of number of patients with greater than or equal to 50% reduction in UPCR compared to baseline at 24 weeks. In addition, we define clinically meaningful secondary endpoints as complete renal response and partial renal response. Our protocol-defined definitions are shown here. A complete renal response is defined as a UPCR less than or equal to 0.5, a preserved glomerular filtration rate of greater than or equal to 60 and no worsening from baseline, prednisone or equivalent of less than or equal to 10 mg, and no use of prohibited medications. The definition of partial renal response was 50% reduction in UPCR and/or a UPCR less than 1 if the baseline started at less than 3, and a UPCR less than 3 if the baseline started above 3. Preservation of the glomerular filtration rate and no use of prohibited medications is also part of this definition. Not all studies define CRR and PR exactly the same way, and for our interim data, we use the labels of CRR and PR on the basis of absolute values of UPCR. Just one more background slide before we get to the interim data. The interim data is from laboratory and safety sources, which means that there are still outstanding questions that can only be answered when we have the complete data set available. The interim analysis was conducted for any patient who had completed 13 weeks of treatment with KZR-616. 10 patients met the goal of at least 13 weeks treatment at the time of the interim analysis. Five of those 10 patients reached end of treatment. Just as a reminder, patients did not receive induction or high-dose therapies, and there was no mandated taper of glucocorticoids or other agents. However, reduction of prednisone or other baseline medications was permitted. Our interim analysis found that KZR-616 60 mg q-week is associated with clinically important renal responses. Of the five patients who reached end of treatment, four of the five demonstrated clinically meaningful reductions in proteinuria. Two complete renal responses and two partial renal responses were observed. One patient did not have a reduction in proteinuria. We are very encouraged that four of five patients had an overall response, and I will now break it down for you with more detail in the next few slides. This swim lane slide shows that at the time of the cut-off of the interim data analysis, there were 11 patients who could have had greater than or equal to 13 weeks of treatment. 5 patients reached end of treatment. 10 patients reached 13 weeks. 2 subjects discontinued, both for reasons unrelated to KZR-616. One before week 13, who is not included in the analysis, and one after week 13 but before end of treatment. This patient is included in the week 13 analysis. Here we show the demographics of the 10 subjects. The majority are women with a mean age of 39 years, very consistent with the general population of patients with LN. The patients were diagnosed with lupus or lupus nephritis approximately 7.5 years prior to participation in this study, which is longer than other trials that may include newly diagnosed patients. The mean UPCR was 2.2, which you may think is lower than what is seen in trials that will include more recently diagnosed patients or patients with severe flares of their LN. Nonetheless, a mean UPCR of 2.2 indicates significant disease and suggests that these patients need alternative therapy to treat their LN. The mean dose of prednisone or prednisone equivalent was just under 15 milligrams daily. On the right, you see that eight of 10 patients were on MMF or an equivalent. One was on azathioprine. All 10 were on prednisone, and five were on hydroxychloroquine. When we look at the results from the interim analysis, four of five patients had meaningful reductions in their absolute UPCR at end of treatment. Two had UPCR less than 0.5, and two had UPCR 0.5 to 0.8. This is a meaningful reduction in proteinuria for patients who started with a mean UPCR of 2.2. Two subjects met our definition of complete renal response. Not only was their UPCR less than 0.5, but they also had stable or reduced doses of prednisone or equivalent, a stable eGFR, and no prohibited medications. Two subjects met our definition of partial renal response with UPCR less than 1 and actually less than 0.8, with stable eGFR and no use of prohibited medications. Looking at the% reduction in UPCR, 3 of 5 patients achieved the primary endpoint of greater than or equal to 50% reduction in UPCR at end of treatment, and 1 patient reduced UPCR 25% to 50%. While this patient did not meet a full 50% reduction, the absolute UPCR is actually less than 1, consistent with our definition of a partial renal response. All patients at end of treatment were on either the same or reduced doses of glucocorticoids or other therapies compared to the start of study, and no one had an additional intervention. This suggests that the clinical improvement is related to the addition of KZR-616. Now let's look at the data from the 10 subjects who had completed at least 13 weeks at the time of the interim analysis. By week 13, 4 subjects had reduced UPCR by 50%, and another patient had reduced UPCR to 25%-50%. By our protocol-defined labels, 5 of 10 patients had at least a partial renal response within 13 weeks. Of the 4 with a greater or equal to 50% reduction in UPCR, you can see that 3 of the 4 had even reduced their absolute UPCR to below 0.8, a clinically meaningful number associated with overall better outcomes for patients. In addition to meaningful reductions in proteinuria, we also found serologic evidence of anti-inflammatory effects. Of 9 patients with abnormal anti-double-stranded DNA at baseline, 7 improved within 13 weeks. Complement, which can be low in patients with active LN and lupus, returns toward normal in patients who had low levels at study entry. Also importantly, we found no negative changes in serum markers, including cell counts. Symptom score data will be provided with the complete study results in 2022. With respect to safety and tolerability, KZR-616 continues to show a favorable profile. There were 2 serious adverse events reported. One patient suffered a migraine headache that was considered related to study drug administration. This patient temporarily held doses and then resumed KZR-616 and continues to receive 60 mg weekly. The second patient suffered from worsening pulmonary arterial hypertension, which predated entry into the study. This event was considered not related to study drug, but given the severity of the patient's condition, the patient was withdrawn. Injection site reactions continue to be the commonest adverse event and appear to be irritations directly related to study drug. There is no evidence of immunologic or vasculitic reactions. There have been no discontinuations from the study related to KZR-616. Previously, we reported that patients had gastrointestinal symptoms, primarily nausea and vomiting, related to initiating KZR-616. This was seen primarily in the earliest cohorts from MISSION phase Ib. In MISSION phase II, we instituted step-up dosing, and this seems to have mitigated initial tolerability issues. We found 10 reports of nausea and 6 reports of vomiting, which occurred in 4 patients. Many of the events occurred together. All nausea and vomiting lasted less than a day. No patients reported nausea or vomiting with the first dose, and most isolated incidents occurred many weeks into the study. With 204 doses of KZR-616 received in total at the time of the interim analysis, the current rate of nausea and vomiting at 3%-6% is well below what is seen with commonly used therapies, including MMF, for patients with lupus nephritis. Last but not least, no opportunistic infections have been reported in the MISSION phase II to date. Now, many of you will ask how to interpret these interim data. Comparing these results to recently published inter-interventional trials of other investigational agents is challenging given the significant differences in trial design. We looked at it from the perspective of the clinician who is trying to improve outcomes for their patients with LN. Essentially, the MISSION phase II study population is patients who have not fully responded to usual care. Here we match up the EULAR/ERA-EDTA goals of treatment for patients with LN to our findings with KZR-616. At 3 months, the EULAR/ERA-EDTA treatment goal is to reduce proteinuria by at least 25%. 5 of 10 patients achieved this goal with 616. At 6 months, the EULAR/ERA-EDTA treatment goal is to reduce proteinuria by at least 50%. 3 of 5 patients who had completed 24 weeks or 6 months of treatment achieved this goal. At 12 months, the treatment goal is to reduce proteinuria to less than or equal to 0.7. 2 of 5 patients had a UPCR of less than 0.7, and 2 of 5 patients had a UPCR of less than 0.8, essentially representing rounding errors at 6 months. The KZR-616 interim analysis suggests a clinically significant renal activity, and Kezar is planning for later phase studies. The MISSION phase II interim data learnings include that 60 mg weekly dosing, starting with a step-up dose, demonstrates a favorable safety and tolerability profile. Weekly dosing demonstrated meaningful reductions in proteinuria in patients with LN, including those who are refractory or hard to treat. KZR-616 continues to appear to be immunomodulatory rather than immunosuppressive. Top-line data is anticipated for late second quarter 2022, but given the strength of our interim analysis, Kezar is planning next studies of 616 for the treatment of LN. Now, in addition to the phase II interim data, we have one additional case report to share with you today. I am pleased to have introduced Dr. Samir Parikh, an international expert in lupus nephritis. His patient was the LN patient number one in the Mission phase I trial, and as you will hear, he took the initiative to restart KZR-616 in this patient as part of an investigator-led IND. This case report is distinct from the Mission Ib and II studies. Dr. Parikh. Hello, everyone. Thanks, Noreen, for that introduction, and thanks for having me today. Just give me one second. Okay. What I'm gonna share with you is our experience with KZR-616 in an investigator-led IND study of patient 1 from the MISSION phase Ib study. Okay. This patient was a 29-year-old Asian female who was diagnosed with lupus over a decade ago and developed her first flare of lupus nephritis in 2015. At that time, she was treated with mycophenolate and prednisone. She attained a response, but then during the course of the next 5 years, developed leukopenia due to the mycophenolate, which had to be stopped and was treated for her lupus with tacrolimus, leflunomide and prednisone. Flared through that regimen and in 2019 developed again class IV + V lupus nephritis. At that point, she was started on the phase Ib clinical trial. Her baseline therapy and regimen at that time was hydroxychloroquine, leflunomide and prednisone. At trial enrollment, she had 3.9 grams of proteinuria. Sorry about that. As Noreen showed you earlier, this is the graph to the right in red is her urine protein creatinine ratio at the time of trial enrollment and toward the end and in black is urine sCD163, which may be a marker of lupus nephritis, but is a marker of kidney inflammation in general and may reflect macrophage dendritic cell activity. What I wanna highlight. There's a couple points I wanna highlight here. She was the first patient enrolled in MISSION phase Ib. She received her first dose, but after her first dose, she developed a systemic inflammatory response, so SIRS. About eight hours after her first dose, she developed fever, tachycardia, hypotension. She actually needed to be sent to the emergency room. She was given IV fluids, steroids, and admitted for overnight in the hospital. After that initial reaction, we were a little bit reluctant to resume her in clinical trial. However, you can see these drug holidays here. However, after discussions with the patient, she actually wanted, she encouraged us and actually wanted to resume because she felt that, and this is subjective, but she felt that after that initial response, that she was actually starting to feel better. Subsequently, she resumed her the injections, the weekly injections, and you can see the proteinuria level from week 9 down to week 17 plummeted. Dropped dramatically from 4 grams to about 500 milligrams per day. Additionally, you can see even predating this, and this is what we think about urine sCD163 in the setting of lupus nephritis, is that it may be a predictive marker of response, but that needs to be validated. In general, though, you can see urine sCD163 also decreased at the same time, suggesting that we have control of inflammation and adequate suppression of proteinuria was suggesting control of her lupus nephritis. If we look at other markers of disease activity, so anti-dsDNA, C3, C4 complement levels, you can see at baseline the double-stranded DNA was elevated, C3 was low, C4 was low. These are common findings in the setting of active SLE or active lupus nephritis. Over the course of treatment and at the end of study, you can see the double-stranded DNA decreased by half. Complement levels of C3 normalized and the C4 stabilized, remained stable or trended up just slightly. Now, if we look at the indices of disease activity, the SLEDAI-2K is what we commonly use for global or for lupus activity, where we score all of the different manifestations of lupus that can occur. At baseline, her SLEDAI-2K was 17. At the end of treatment, it was 8, so cut in more than half. Her cutaneous lupus score was 7, and that went to 0 at the end of treatment study. Then her overall, so her global assessment improved from 67 to 35, all suggesting that not just the lupus nephritis, but lupus had improved. After stopping or completing the study, she was maintained on her leflunomide, low dose prednisone, I think it was down to 5 milligrams at that point. She was off hydroxychloroquine, excuse me. Her urine protein creatinine ratio at the end of trial was 0.56 milligrams per milligram on the ratio. This is three months following completion of MISSION phase I. Fast-forward to nine months following, her urine protein creatinine ratio increased up to 5.5 grams. At that clinic visit, she had not only increased levels of protein in her urine, she also complained of alopecia, more arthralgias, and she was noted to have a higher blood pressure. Her laboratory-wise, her C3, C4, her C3 decreased down to 69. At that point, the patient was started on high-dose prednisone, 40 milligrams per day for 30 days, which was then subsequently tapered. At that point, she expressed interest and wondered if she could go back on the KZR-616, and this led to our approach to Kezar to see if that would be a possibility, and graciously, they said yes. We submitted an investigator-led IND to the NIH, and that took a little bit longer than we'd like to get approval, at mostly due to just administrative delays. Ultimately, it was approved, and she was able to start on the KZR-616. At the time of enrollment into the investigator-initiated IND, her prednisone dose was down to 15 milligrams per day. With the prednisone alone, her proteinuria did improve from 5.5 to 2.4 grams, but it remained there until starting the KZR-616 therapy. Here you can see the proteinuria trend with this is at the end of the MISSION study here. You can see the trend over a 15-month period. Her proteinuria actually increased to 5.5 grams, and then at the time of enrollment into the investigator-initiated IND, she was at 2.4 grams. This was baseline. You can see a considerable decrease in proteinuria. By week 28, it was down to 0.2 grams. Importantly, as I'll highlight in the next slide, we were able to successfully taper her off prednisone, and she did not require any additional medicines to help control her lupus nephritis. Lastly, I wanna highlight the other measures of disease activities. It goes down to SLEDAI-2K and her global assessment, and you can see all of those improved. Her SLEDAI-2K was zero at week 27, and her PGA improved dramatically. Her double-stranded DNA was not significantly elevated at the time of this flare, but her C3, C4 did normalize and remain normal on multiple assessments. What do we summarize from this patient? First, we had rapid improvement in proteinuria and clinical disease activity seen in the MISSION phase I. The patient developed a relapse of her disease to nephrotic range proteinuria 9 months following completion. After reinitiating the KZR-616, there were several improvements. First, her proteinuria declined considerably. Her overall SLE activity got better. There's some important secondary factors that we need to highlight. One, and importantly, she came off steroids. This is a big deal. This was a big deal for this patient. High-dose prednisone was, as is common for our patients, she tolerated them poorly, led to a lot of side effects, so she was quite happy with being able to come off the prednisone. Also, it's important to highlight that when she was on the investigator-initiated IND, she did not experience any of the major side effects that she experienced with her first injection. Most of what she experienced was injection site reactions that were pretty localized and fairly mild, for the most part treated with Tylenol alone. She did not develop much in the way of fevers. I wanna highlight one important point. This patient comes from about two hours away every week for this injection. She drives from Kentucky to Columbus, and about two hours one way, and comes for this injection and does not miss. One clear dedication on part of the patient, and we absolutely appreciate that on her part, but also just kinda suggests, maybe subjectively, that she's, in addition to the markers and everything else, that she's expressed this to me, that she feels like she's benefited from the therapy. Overall, we saw greater than 50% reduction in proteinuria observed at 14, week 14. Discontinuation of corticosteroids, as I mentioned. Her urine PCR was 0.4 at week 34. The patient reports feeling well and has no extra-renal manifestations of her lupus. How might I consider KZR-616 in the LN treatment landscape? The preclinical and early clinical data suggests that KZR-616 has broad immunomodulatory potential, as was highlighted earlier in this presentation. No major safety signals to date. One other point I'll highlight, and this is just an aside. The patient asked us about whether she could get her COVID vaccines while she was getting the KZR-616, and she was able. She did get both. As we tested later, she did develop an antibody response. Of course, this is one patient, but just kind of suggests, you know, one of the biggest concerns we have with immunosuppressive drugs is that patients may not have a vaccine response. This patient was able to mount a vaccine response, without much limitation to continuing her KZR-616. The possible roles that I see, first and foremost, I consider it a broad anti-inflammatory agent that may allow us to move potentially away or at least limit the amount of corticosteroids patients receive for lupus. There's a movement for this anyway on patients. It's a double-edged sword. Steroids are anti-inflammatories, so we like the initial response, but they cause so many side effects, and certainly our young female patients do not enjoy being on steroids for long periods of time. More than just the anti-inflammatory effect, because of its broad activity, it may have anti-autoimmunity effect and may allow us to consolidate our therapy long term. You keep in mind that lupus and lupus nephritis are not curable conditions, and relapses are common, and oftentimes these patients are left with multiple therapies for years. If there are therapies available that allow us to consolidate and limit the amount of medicines that patients need to take but still be able to control the disease, that would be highly valued by our patients and providers. I will stop there. I think that's my last slide and turn it back over to Noreen. Thank you for your time. Thank you very much, Samir. Dr. Parikh will join us for the question and answer session at the end of the presentation. We are finishing the MISSION portion of the presentation, and now we're gonna turn to KZR's second program with KZR-616. The PRESIDIO trial is a phase II study to evaluate the safety and efficacy of KZR-616 in patients with dermatomyositis and polymyositis. You saw this slide earlier, just want to highlight that we are now talking about the PRESIDIO trial, which met its target enrollment in August 2021. In addition, we offer an open label extension trial for patients who complete the parent trial. Dermatomyositis and polymyositis are chronic, severe, and debilitating diseases where essentially an autoimmune process attacks the muscles and/or the skin. They are both orphan diseases. Current best available therapies for these patients include corticosteroids at usually very high doses, corticosteroid-sparing agents such as azathioprine or methotrexate, rituximab, IVIG exclusively for patients with DM, hydroxychloroquine, corticotropin, and sunscreen. Now, as you will quickly recognize, most of these therapies have been around and in use for DM and PM for decades. Even more disconcerting, glucocorticoids, which are necessary in high doses, are associated with muscle atrophy, weakness, and skin thinning, all counterproductive off-target effects for patients with DM or PM. At this year's ACR Convergence meeting, KZR presented two posters together with our collaborators, Doctors Venuturupalli and Aggarwal, both experts in the field of myositis. These posters summarized extensive systematic literature reviews and demonstrated that there's a large unmet need for patients with these two diseases. This data represents the best care currently available, which leaves a lot of headroom for better therapy. With 120,000 patients in the U.S. alone, we recognize that DM and PM are a sizable market opportunity. KZR-616 is the only agent currently granted U.S. orphan drug designation for both DM and PM. Previously, we've shown you results from a preclinical model of inflammatory myositis. This is a well-characterized mouse model, which is also validated with IVIG. Mice with established disease were treated with mouse equivalents of human doses of KZR-616 and showed preservation of muscle strength, lack of evidence of muscle injury, and relatively normal muscle histology compared to untreated mice. These endpoints are similar to what we are measuring in the PRESIDIO trial. It is also notable that human muscle, which in normal conditions does not express the immunoproteasome, is shown to express the immunoproteasome when inflammation is present, such as in the muscles of patients with DM and PM. This suggests that immunoproteasome plays a role in the underlying pathophysiology of myositis. Now here's a reminder of the PRESIDIO trial schema. The study is a randomized, placebo-controlled, blinded crossover design trial with 16 weeks of KZR-616 at 45 mg weekly or placebo given in either order AB or BA. There's an open label extension study available to patients who complete the PRESIDIO trial, and this open label extension study was recently lengthened in duration to up to 96 weeks at investigator request. The top-line results for PRESIDIO will be available Q2 2022. The primary endpoint of the study is Total Improvement Score or TIS, which is the same endpoint used in label expansion for Octagam 10% and the phase III trial of lenabasum in dermatomyositis. TIS is a composite score that measures muscle strength, serum enzymes of muscle injury, patient and physician-directed symptom scores, and some extra muscular symptoms. Of note, we included patients with both DM and PM in the Presidio trial. PM patients have not been included in recent intervention trials at all. One of our goals from this trial will be to learn if we should move forward with registration studies for DM, PM, or both. For next steps for the development of KZR-616 in DM and PM, as mentioned before, we achieved our target enrollment in August 2021, which means top-line results are anticipated in the second quarter of 2022. Kezar is currently planning registration studies of KZR-616 in inflammatory myositis based on the very high unmet need, the strong preclinical data, as I showed you, demonstration of immunoproteasome activity in inflamed muscle, and last but not least, given the recent interim analysis from MISSION that we just shared with you that really demonstrates that KZR-616 is an active agent. The PRESIDIO study is the first study of KZR-616 for patients with idiopathic inflammatory myositis. We are looking to include patients with pediatric forms of the disease in our next study. In addition, if a therapeutic benefit is seen in patients with DM or PM, we will consider additional studies in patients with other forms of myositis, including necrotizing myopathy and inclusion body myositis. I'd like to thank everyone very much for joining us today. I will now turn it over to Dr. Christopher Kirk, our Chief Scientific Officer, to provide a deep dive into our second clinical asset, KZR-261, and the pipeline that utilizes the same Sec61 translocon platform. Thank you very much, Noreen, and I'm very excited to be finishing up this, analyst and investor presentation and talking to you about broadly our protein secretion drug discovery platform, as well as the KZR-261 program. As John mentioned in the beginning, timing for this deep dive couldn't be better as we announced last month that we've initiated our very first clinical trial with KZR-261 in solid tumors. We're excited to dig into the details, not only around how we designed the study, but the science behind the clinical trial as well. First, it's probably worth going through a little bit of Kezar history as well as the biology of the protein secretion pathway. Let's start first with the Kezar history. This has been a program at the company since its inception in 2015, and even prior to that, when Kezar's academic co-founder, Jack Taunton at UCSF, and researchers at Onyx Pharmaceuticals collaborated on protein secretion targeting in combination with proteasome inhibitors in multiple myeloma preclinical models. It has since grown tremendously, and I'm very excited to share with you the results of not only that research collaboration which continues today, but the great work by Kezar scientists going after this very important pathway. All right, so let's dig into the biology here a little bit. The cartoon you're looking at at the bottom of this slide is a process that's going on in every one of your cells all the time, and it's the initiation of the protein secretion pathway. About a third of our genome encodes for proteins that must make their way into the endoplasmic reticulum before exit from the cell, either as a secreted protein like a cytokine or a receptor such as PD-1. This occurs through unique signal sequences or signal peptides on those proteins and their recognition by a highly conserved heterotrimeric complex in the ER called the Sec61 translocon. Sec61 recognizes each one of these proteins and enables ingress into the ER through a process called co-translational translocation. Tumor cells utilize Sec61 in a number of ways. First, they can make their own growth factors or receptor tyrosine kinases that drive tumor growth. They'll express either factors that enable angiogenesis, receptors for metastatic spread, and of course, expression of cell surface receptors that enable evasion of the immune response. Sec61 and the protein secretion pathway represents a very novel and unique way to go after tumors at multiple points of attack. Kezar has been working on Sec61, in essence, three large buckets of drug discovery. Utilizing those unique signal peptides and the ability to bind to Sec61 and modulate its activity, we focused on three areas. On the left-hand side are our multi-protein secretion inhibitors. These molecules have the ability to impact many of the pathways that tumor cells utilize for their growth and survival. KZR-261 represents the first clinical candidate from this portion of our drug discovery campaign, and I'll talk about it in more detail in the coming slides. I'll finish up with a discussion of selective protein secretion inhibitors, either ones that modulate multiple targets in a specific physiologic response or single targets which one can think of as small molecule replacements to monoclonal antibody therapy. KZR-261 was discovered right here at Kezar through the use of our novel screening reporter assays and a high throughput screen that we conducted. And I'll go over some detail about the assays used to discover this molecule. We've learned quite a bit as we continue to develop the molecule. We've learned that it's unlike many of the published natural product-based protein secretion inhibitors. KZR-261 is actually quite a selective inhibitor of Sec61. In tumor cells, it only hits about 9% of all secreted and transmembrane proteins. In non-transformed cells, it's about 3%. Already we see a differential, as I discussed, around the sensitivity of tumor cells to Sec61 modulation versus normal. This translates into both broad anticancer activity, but good therapeutic index values in our animal models. We've seen an incredibly broad activity across a wide range of both hematologic and solid tumors, and in animal models, activity in chemo-resistant tumor xenograft models, as well as therapeutic index values that exceed chemotherapeutic agents, multikinase inhibitors, and proteasome inhibitors. Finally, with the completion of our GLP tox studies to enable our phase I study, we've learned that the toxicity is driven by on-target activity in sensitive organs. These toxicities are largely reversible and monitorable in the clinic. Here's an example on the top part of this slide of our unique platform for understanding protein secretion inhibition. This is a heat map showing you individual target inhibition in our reporter assays, where red indicates potent nanomolar-based inhibition and green is essentially inert activity against the target. We have well over 100 separate assays along this platform. I'm showing you here just a sampling of them and how KZR-261 performs. What you can see is that KZR-261 can hit a wide range of immune checkpoints as well as oncogenic drivers and angiogenic factors. This translates into clinical activity in multiple mouse models of cancer. I'm showing you here an example from a neuroendocrine tumor, a small cell lung cancer model on the left, a prostate cancer model or epithelial-derived tumor that is resistant to chemotherapy, and on the right, a hematologic tumor, a mantle cell lymphoma model. You get a sense of the broad anticancer activity that we've seen thus far in the lab with KZR-261. We think about how this drug is working in two ways. First, what's happening in the tumor? The direct anticancer activity is driven by induction of cell death through proteotoxic stress and other factors, as well as the reduced expression of those key growth factors and receptors driving tumor survival and proliferation. There's also microenvironment modulation around the tumor that increases the antitumor potential of 261, and this can include things like reduced VEGF expression for angiogenesis and reduced immune checkpoint expression as well. Finding particular tumor types to go after with KZR-261 was a bit of a challenge. In essence, it was we had so many avenues that we could go, finding particular tumor types to focus on was something that we needed to develop novel ways of doing analysis. What we did was start with what we had in-house, which was a large dataset of tumor cell lines treated with Sec61 inhibitors, almost 500 separate cell lines, so that we could rank sensitivity to Sec61 inhibition in terms of tumor cell growth. We had the ability to do agnostic gene module expression analysis. We utilized fast gene set enrichment analysis for this work. Taking those data and comparing them to large tumor databases such as the CCLE, The Cancer Genome Atlas, as well as normal tissue expression databases, gave us the opportunity to find specific tumor types that might be sensitive in the clinical setting. We selected a number of tumors, both solid and hematologic, but decided to focus our phase I on solid tumors for a couple of reasons. One, the strong scientific rationale that was the underpinning here, and the second was, the high unmet need in a number of the identified tumor types that I'm gonna talk to you about now. Taking the output of this, bioinformatics approach to find sensitive tumor types, we were able to rank both normal tissues and tumors for their sensitivity. What you can see there, each line represents a different tissue or tumor type, at the top considered the most sensitive, the bottom considered to be predicted to be the least sensitive. What you see is a heavy weighting of normal tissues at the bottom of the ranking and a heavy weighting at the sensitive side for tumors. That's an important feature that we of course think helps us understand the toxicity profile we've seen thus far in our animal model. Take the top 25% of the scoring tumor and normal tissue types, we see a large number of tumor types, and many of these, including melanoma, colorectal carcinoma, prostate cancer, and mesothelioma, have made their way into the expansion cohorts of our phase I study. We will be encouraging for all of the solid tumor types that ranked highly here enrollment into a biomarker cohort that I'm going to describe as well. Here's the design of the just initiated phase I study with KZR-261. Again, solid tumor patients in the advanced setting. Dose escalation is occurring through an adaptive 3+3 design, which hopefully will enable not only optimal selection of a phase II dose or doses, but also will be a rapid speed to identifying those doses. We're building in a very extensive biomarker and pharmacodynamic suite of assays for this phase I trial and the dose escalation and the expansion, and we'll be treating in the escalation all comers. Upon selection of a dose, we will move into the expansion cohorts. As I mentioned, there'll be distinct cohorts of melanoma, colorectal, prostate cancers, as well as mesothelioma, and then an all-comers arm in which patients must agree to both pre and on-study tumor biopsies. This is being done in Simon two-stage design, so that once we've achieved response characteristics in any one cohort, we'll be able to expand that cohort to up to 35 total subjects. The goal here, as it is for most phase I studies in solid tumors, looking for recommended phase II doses, but also assessing both the PK/PD and anti-tumor efficacy here. We're really excited about this. The first time a protein secretion inhibitor has entered clinical trial, and we're looking forward not only to understanding the anticancer potential of two-six-one, but understanding more broadly, how does modulation of this important pathway in cells, teach us about future drug design in this space. Let me turn to that future drug design, which is going after more selective protein secretion inhibition. We've presented some of these data before, but what we've been able to do is to take a molecule that has cytotoxic potential, in large part because it hits a good chunk of the secreted proteome or Sec61 clientome. You can see this molecule here, eight-three-four, in its highlights, lots of red and orange. It also has some cytotoxic potential against the tumor cell line. From here, we've been able to design molecules that have selectivity for a subset of immune checkpoints, and importantly, no cytotoxic activity on their own. This means that as we dial in selectivity for given Sec61 clients, we're ever improving the cytotoxic potential and most likely the safety potential once distributed into the animals in the clinic. We've been able to translate what we've learned from our reporter assays into primary cell assays, including mixed lymphocyte reactions, phenotypic analysis of primary T cells, and looking at immunosuppressive activity of tumor cells. We've been able to generate even more selective inhibitors of immune checkpoints. From those initial molecules that I've shared with you, we've been able to make highly selective inhibitors of PD-1 that demonstrate this selectivity in our reporter assay. As you can see, only PD-1 lighting up red in our heat map. Also importantly in primary cells, where only PD-1 is downregulated in activated T cells. This gets us. It's exciting to be able to move into small molecule targeted agents against well-validated and highly therapeutically relevant immune checkpoint space. It's not just isolated to immune checkpoints. We've been able to generate selective inhibitors that drive effects on direct cancer growth. What you're seeing here now is a much larger heat map for two molecules, one that has very broad targeting abilities, lots of red. That's the left-hand target, KZR-8445. Then another molecule related to it that has, as its primary target, the HER3 receptor, which is the co-receptor with HER2, the target of Herceptin. KZR-8445 is a broad anticancer agent, much like KZR-261. What you can see here in this slide is each dot representing an individual tumor cell line and their sensitivity to this molecule across just solid tumors. Now, KZR-9445 does not have that same selectivity. In fact, only one tumor cell line was determined to be sensitive to this particular molecule. It just so happens that this tumor cell line expresses the NRG1 fusion molecule on its cell surface. NRG1 is a ligand for HER3. By designing a highly selective inhibitor of HER3 expression on the cell surface, we've been able to make a selective inhibitor of HER3-driven tumor growth. This has led us to continue our discovery campaigns in the protein secretion platform. As I mentioned, we have the ability now to make selective inhibitors of validated targets, as validated by clinical activity to therapeutic monoclonal antibodies. These become potential targets for new discovery campaigns at Kezar. In addition, our ability to generate precision oncology targets has led us to generate our own oncology target program that has led us to 50+ targets, each of which we believe has the potential for discrete drug discovery campaigns. From here, we will understand chemical tractability, where our advantage of targeting Sec61 to modulate target activity will have a benefit. For instance, overcoming resistance in the kinase domain of receptor tyrosine kinases. We'll also, of course, look into how we can synergize these discovery programs with our current clinical development efforts in autoimmunity as well as oncology. This will lead to ever more drug discovery campaigns and new targets for us to be talking to you all about in the future. With that, I'll summarize by saying we're really excited. Again, that 261 is entering the clinic. This is a unique molecule with the ability to target multiple pathways driving tumor growth and survival, in essence, combination therapy in a single drug. From this program, as well as our continued efforts in the lab, we are truly unlocking the platform potential of the Sec61 translocon, a space in which I believe we are the undisputed leaders in terms of research and drug discovery work. I've shown you but some samplings of our ability to go after the Sec61 translocon, both broadly and selectively. We're looking forward to sharing even more detailed information about that at future research and medical conferences. With that, I'm going to turn it over to John Fowler for some closing remarks. Thanks so much, Chris. Now, before opening up for questions from our covering analysts, I just wanted to say a really large thank you to everyone for dialing in today. It's hard to understate how excited the whole team here at Kezar was to have this time today with you all to share the very exciting results from the MISSION phase II, as well as that one patient from the phase Ib who is appearing to benefit from KZR-616. A really special shout out and thank you to Dr. Parikh for joining us today, taking time out of his very busy day, and for having the kind of tenacity to file that investigator-led IND to help that patient. We're just so thrilled that even though the n's are still small, that we really appear to be making a difference in patients' lives with lupus nephritis. It may feel like this is a big day, and it is. It's really, I see it at the very beginning of an exciting chapter and journey for Kezar. We're very at the beginning of this journey with 2020 being a very data-rich year for the company. Top line readouts from both the MISSION and PRESIDIO studies. A lot more data to react to, a lot more reasons to be excited. We can't wait to share that data with you and talk frankly about the pipeline and the drug potential of KZR-616. We don't see it stopping just with lupus nephritis and the idiopathic inflammatory myopathies. This type of unique mechanism of action that we spoke about earlier begs to be tested elsewhere, and we look forward to sharing more about that over the coming year. I'm so glad we got to also finish with Chris's discussion of the protein secretion opportunity. If that doesn't have platform potential written all over it, I don't know what does. It really gets me so excited every time to hear it. As you can see from those slides, we've made a tremendous amount of progress, not just in characterizing the unique mechanism of KZR-261 that's now in patients, but the many other ways that we can either broadly or very selectively target proteins of interest. I just can't wait to unlock more potential there and bring more clinical candidates to the market to help patients with oncology. In oncology, but also in autoimmunity and beyond. A really huge privilege of mine to be a part of this company and to see this science coming to fruition. At this point, I'd love to welcome some of our analysts to share questions with us. Thank you, John. 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, please, each. To ask a question, please use the raise hand button at the bottom of your screen. Our first question comes from Matthew. Matthew, if you would please unmute yourself and ask your question. Hi, can you hear me? Yeah. Okay, great. Thanks, guys. Congrats on some really impressive data here for this update. You know, exceeding our expectations for sure. Noreen, one question quickly. There obviously was a patient that achieved a partial response that I guess maybe didn't have that 50% UPCR, 50% reduction, so maybe they, you know, went from a little over one to 0.8. Just wondering if you had any comments there. If we look at the patients that are just at week 13, I think this is on slide 24. I was wondering if you could help maybe separate out some of those patients that are still at week 13 versus those that maybe made it all the way to 24 and any kind of specifics on any of those. Thanks. Yeah. Thanks for the question, Matt. I think the most important thing to take home from the data is that what we see in this interim data at week 13 is that there are patients who do have kind of early and brisk response. It's not just a 50% reduction in UPCR, but it's also, you know, very quickly achieving a low UPCR consistent with kind of clinically meaningful goals. Not all patients who made it had a good response at the end of the trial actually had necessarily shown a good response at week 13. While some patients do have a brisk early response, if you don't achieve response at week 13, does not necessarily mean that you will never achieve a response. As a matter of fact, we see that as one of the important learnings that we will have when we get the complete data set for you. You know, right now all of the patients are at different phases in the study, and we've just limited it to the week 13 and the week at the end of treatment, as you've said. But again, the good learnings is that there are many patients that have a brisk week 13 response. We had a very strong overall response rate at week 25, and we have a lot more to learn with the completion of the study. Great. Our next question comes from Yanan. Yanan, if you'd please unmute yourself and ask your question. Great. Hi, thank you for taking my questions, and congratulations on the very impressive data set. I have a couple of questions for Dr. Parikh. Basically, on the variability of UPCR measurement, that's one question, and the other is on the patient profiles from the trial. On the UPCR variability, because the trial is uncontrolled, a natural question is, you know, what would you have expected in terms of the PR rate, if you know, it's a placebo, there's a placebo arm. Could we see any response from those kind of a setting? On the patient profile, I'm curious how do you compare these patients with the patients that were enrolled in the trials of the recently approved drugs. If the patient profiles are different, then could you give us a sense of what proportion of the patient population would fit the MISSION trial profile? Let me tackle the last question first. I think the patient profiles for the patients enrolled in the KZR-616 were similar to patients that are in the real-world therapeutics for lupus nephritis. What we're looking for, if we break it down by class, the enrollment is largely proliferative lupus nephritis, so that'd be class 3, class 4. And then potentially mixed class 3, 4, plus 5. If there's any differences, a lot of that would be in trial design in terms of timing to entry. Of course, you know, I think ideally, as you mentioned, a placebo-controlled trial is, of course, probably, I'm assuming, the next step here. But like, if we look at urine protein creatinine ratio, you're right. There can be variability with spot urine protein creatinine ratio. I'll highlight in our, the investigator IND, the data that we showed, we showed consistent suppression of urine PCR over three measurements, at the week 27 to 34, in that time period, where the urine PCR was down below 0.3, 0.4 consecutively. Additionally, you get rid of that variability a little bit when you do not a little bit, a lot, when you do 24-hour urine protein creatinine ratio, which is the target that we've been using that has been used in the KZR-616 study. When you do that, when you do the 24-hour urine protein creatinine ratio, the creatinine is constant. What you're doing is you're correcting for the potential variability in urine protein for an inadequate collection or an overcollection, and then you trend that over time. I think from that standpoint, you reduce the variability when you're going by a 24-hour urine protein creatinine ratio, which was done in this study. Does that answer some of your question? I wanna make sure I answered. I know you asked about the 24-hour or the protein creatinine ratio and about the patient population. Was there another question in there I missed? Essentially, you know, would you expect the response rate from a placebo- Oh, yes. -setting? Yeah. Good question. If we look at all of the clinical trial data, and of course, measurements for complete and partial response are variable across clinical trials, right? That's what makes it hard to compare one trial to the next. More recently, it's been a little bit closer in terms of the outcomes. If you look at a six-month complete response rate, it's dismal. It's somewhere between the 10%-20% range. If you look at a six-month PR, that might be closer to a 40%-50% response rate, especially if you track back to the ALMS study, for example. If you look at the twelve-month data on that, it's still fairly dismal, even with the FDA-approved studies, where the twelve-month response is still 50%. Clearly, the bottom line is there's room for improvement. That's where I think we're looking for novel therapeutics still to improve our CR. We don't wanna get caught up with PRs because there's a huge difference in long-term kidney outcomes from a PR and a CR. Early response, and there's some initial data to suggest that 25% reduction to 12 weeks might be a nice predictor. There's more data coming out on that in the near future. A quicker response, meaning, you know, a response at 13 weeks and then at 6 months really is ideal, of course, but not something that we commonly see in the landscape of LN. Okay. Our next question comes from Maury Raycroft with Jefferies. Maury, please unmute yourself and ask your question. Hi, everyone. I'll add my congrats on the update today. Great to see the data. I'm wondering if you're seeing any trends on responses or even on safety that's related to the background meds or the patient type. Can you provide any more details or anecdotal perspective on the number of patients who tapered on steroids or on their background meds? Yes. So in general, you know, given the low numbers, I think it's premature to start trying to draw straight lines between patient characteristics and the results that we're finding. Nonetheless, I think that what we're seeing is these kinds of strong early results across the board with obviously the 4 out of 5 patients with an overall response rate at the end of treatment. In general, the patients, as you saw from the demographics, were pretty consistent. The only new intervention that was given to them was KZR-616. Going back maybe to Yanan's question a little bit, you know, because we didn't use induction therapy, it's very hard to predict what a placebo rate would have been, because what we think of as placebo rates from recently published studies actually reflect high-dose induction therapy plus the investigational agent. We just added our investigational agent on top of what these patients were currently being treated with and not with the clinicians unable to achieve their goals. For these patients, for whatever reason, they had incomplete responses, and KZR-616 made a big difference for them. That's, I think, kind of a relatively new finding, especially in the absence of high-dose steroids or higher doses of drugs like MMF. The other part of your question was related to, you know, kind of individual characteristics of the patients, and I do believe that we will learn more with time. With respect to the tapering of the medications, we did see patients with at end of treatment and even earlier on with lower doses of prednisone as well as lower doses of MMF. Because we're talking about 5 patients at end of treatment, we're still in the single digit land. I think we'll wait until the end, till we have the complete results, until we draw any strong conclusions. Great. Our next question comes from Prakhar Agrawal from JonesTrading. Prakhar, please unmute yourself and ask your question. Hi, can you hear me? Yes. Yep. Congrats on the data, and thanks for taking my questions. My first question is, based on my interpretation from the slides, it looks like 3 out of the 4 patients who achieved a partial or complete response achieved that by week 13. First of all, is that correct interpretation? If yes, as you think about the future trial design strategy, could you forgo induction therapy completely, or do you plan to explore on top of standard induction therapy, as has been seen with other lupus trials? I wouldn't draw the conclusion that the four patients that had the strong response at week 13 were the same four patients that showed an overall response rate at week 25. As a matter of fact, that's not true. There are different patients in those groups. With respect to the question on induction therapy, I think, yes. Ideally, we do believe that KZR-616 has a very novel mechanism of action and could really change treatment paradigms. The question is how to best design a study where you can show off KZR-616 to its best without disadvantaging patients in a placebo arm. We're working through that right now, and obviously, this data will help inform us greatly. Our next question comes from Philip Nadeau from Cowen. Philip, please unmute yourself and ask your question. Good afternoon. Thanks for taking our question. Maybe just a follow-up to your, the answer you just gave, Noreen. In terms of the renal responses, I guess, is the general pattern that they're deepening over time in that the response rate at 52 weeks or 104 weeks would even be greater than what we're seeing here? It does strike us that some of these responses are pretty quick. Maybe the converse to that question, in terms of the grade 1 and 2 adverse events, do those tend to dissipate with time? Do those go away as people get more accustomed to six-one-six? Thanks. Certainly, this is a six-month study, and so we're not gonna have data outside of the six months to understand if longer duration gets a deeper response. That is something that we do believe that we may learn a bit from the open-label extension study from PRESIDIO. Again, a different disease, but again, an opportunity to look at longer duration and exposure with KZR-616. We'll decide how long the next phase trials for lupus nephritis will be. Can you repeat your second question? I apologize. Grade 1 and 2 AEs Oh, Grade 1 and 2 AEs. They go away with time. Yes. The grade one and two AEs do go away with time or become less bothersome. I think actually Dr. Parikh kind of gave his patients you know kind of relationship to the drug. You know, his patient is actually even though still reports injection site reactions and may even need to take his Tylenol from time to time because it bothers him, it's still worth making a four-hour round trip to get the drug. I think it speaks volumes to kind of the cost benefit to the patients for a drug that actually might help them feel better, that has a meaningful response that encourages their physicians, and that doesn't have a lot of the other untoward effects that we take for granted with some of the usual care therapies in patients with lupus nephritis and lupus. Samir, do you wanna add anything to that? Yeah. The only thing I will add is, of course, it's an N of one, right? But in that particular patient, she had pretty severe reactions at the very beginning in the first phase Ib. Severe meaning the injection site reactions were noticeable. She hardly notices them right now. Like we ask, that's why she mentions them, not because they're bothersome. That's-- it's again, it's one patient, but that's ultimately. Noticeably when we examine the reactions are fairly minimal in this particular patient after several weeks of KZR-616. Great. Our final question comes from Mitchell Kapoor. Mitchell, please unmute yourself and ask your question. Hi, everyone. Congrats on the data. I just wanted to ask a couple questions. I wanted to know about the fifth patient who didn't respond, if they had, you know, kind of a promising deepening cadence of their UPCR and if that could have potentially been a response later down the line. Separately for Dr. Parikh, could you characterize the quality of life improvements, you know, that you see from a PRR versus a CRR? To quickly address the patient that did not have a change in proteinuria, again, you know, one of the questions that we'll have at the conclusion of the study when we have a complete data set is even if the patient didn't have a change in proteinuria, were there benefits in terms of symptom scores or some other key markers of disease activity? One of the things that happens with patients with lupus nephritis is that they can accrue permanent damage to the kidneys, and that can often be expressed as proteinuria. Again, we'll be looking to see if we can learn something about the state of this patient's renal disease prior to starting the trial and if that influenced the results that we were seeing. We can't show that now. Samir, do you wanna answer the second part? Yeah. I think the question was in general quality of life differences between PRR and CRR. I think that's one. It's a great question. It's something as a society we're becoming more in tune to is, you know, quality of life and patients, what patients value when it comes to their overall lupus and treatment of lupus. I think what I can share with you is that if you look at the data available, there's a substantial difference in CR and PR when it comes to not just kidney outcomes, but risk for flare and need for higher doses of immunosuppressive therapy over time. In patients who achieve a PR, they are six times more likely to have a lupus nephritis flare in the future and progress to end stage kidney failure. That in and of itself, I'm sure I don't have to share with this audience what end stage kidney failure can feel like. It is like when we take care of our patients, that's the number one issue and number one concern that they express regarding quality of life downstream. That's just speaking to the kidney. You can imagine lupus is a systemic disease, so if you have a PR, a partial response, oftentimes their non-renal lupus is also not as well controlled as it possibly can be, and that leads to higher scores on, you know, when it comes to quality of life surveys and things like that. I think when you have a CR, the difference there is the disease is as quiet as it can get, and if it's prolonged, that means less immunosuppressive immunotherapy, less pill burden, less doctor visits. You can imagine how that can impact their quality of life and overall future outlook. I hope that answers your question. Great. I think that brings us to the conclusion of our event. I really appreciate all of our covering analysts for the thoughtful questions. Once again, just thank everyone who dialed in today to listen to the presentation. It was really a delight and treat for us all to share this data from the MISSION study and talk about Kezar overall. Obviously, the biggest thank you of all goes not only to Dr. Parikh for joining us, but for all the investigators and the patients, especially immunocompromised patients during the global pandemic, who've stepped up to participate in our studies and advance our program forward in with KZR-616. We're really grateful. The best is yet to come, and we're really excited about 2022 and look forward to more of these in the coming year. Thanks everyone for dialing in. Thank you.