Equillium, Inc. (EQ) Earnings Call Transcript & Summary

Welcome, and thank you for joining us this morning for Equillium's announcement regarding interim data from the Type B portion of the EQUALISE study found in patients with lupus nephritis. Presenting on behalf of the company this morning is Mr. Bruce Steel, Chief Executive Officer; Maple Fung, Senior Vice President of Clinical Development; and Dr. Stephen Connelly, Chief Scientific Officer. Before we begin, I would like to remind you that any statements made during this call are not historical, are considered to be forward-looking statements within the meaning of the Private Securities Litigation Reform of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors. This includes those discussed in the Risk Factors section in the company's most recent quarterly and annual reports form on 10-K and 10-Q, as well as other reports filed with the SEC. I'll remind you that this call is being recorded, and a replay will be available on the company's website following the conclusion of the call. And with that, I'm pleased to turn the call over to Mr. Bruce Steel, Chief Executive Officer for Equillium. Go ahead, Mr. Steel.

Thank you very much, and good morning, everybody, for joining us this morning for Equillium's update on the EQUALISE study of itolizumab, with interim data on the Type B portion of patients with lupus nephritis. Pleased to have Dr. Steven Connelly, our Chief Scientific Officer and Co-Founder; and Dr. Maple Fung, with me this morning. I would like to highlight that we will be making forward-looking statements as part of this discussion. I suggest you review our safe harbor statement. We also have additional information available regarding the recently announced Metacrine transaction for your reference. Today, we'll be covering a review of the goals of lupus nephritis in the treatment of this disease, Equillium's approach, a quick recap of data we provided in the Type A portion update, which was conducted in patients with lupus without a confirmed diagnosis of lupus nephritis, as well as some early data around activity that we observed in patients with elevated proteinuria in that portion of the study. And then, of course, we're very excited to provide a detailed update on the Type B portion in subjects of lupus nephritis. In short, the subjects we've evaluated to date have entered the study with very high levels of proteinuria with a mean of 5.8 grams. This is significantly higher in terms of UPCR, urine protein creatinine ratio, than patients that have been observed in recent studies, including approved therapies. And what we've observed are we believed to be early, rapid and deep reductions in proteinuria that will exceed what would otherwise be expected on background standard of care. So we're very pleased to report these results to you to date. And this continues to build on the body of evidence that itolizumab is safe and well tolerated and as a first-in-class, highly novel and differentiated therapeutic agent could potentially be used not only in lupus nephritis where there remains very high unmet medical need, but in a broad range of severe autoimmune and inflammatory disorders. So we're very pleased to provide this update to you today. And with that, I'll turn the call over to Steve.

Thanks, Bruce, and good morning to everyone. So first, let's take a revisit of lupus nephritis in numbers. As you're aware, 50% of lupus patients will progress to have lupus nephritis with severe manifestation of the disease, and that puts it at about 100,000 lupus nephritis patients in the U.S. About 10% to 30% of these patients will progress to end-stage renal failure requiring kidney replacement therapy. Now on standard of care or standard induction, which typically uses MMF and steroids, you see about 50% of patients achieving a 50% reduction in UPCR by 6 months on standard of care. The 2 recently approved therapies incrementally improved this number, but we're still seeing about 60% of patients at the year mark that haven't achieved this all-important complete response of the low between 0.5, 0.7 grams of UPCR. So let's just recap on proteinuria and albuminuria and why this is so important. So proteinuria and albuminuria cause renal damage and fibrosis and are markers of disease. You can see on the right-hand side, this table, highlighting the increased levels of proteinuria and albuminuria actually are markers of severe kidney damage. And the key takeaway here is the more proteinuria and the longer you have it, the graver the outcome is in terms of kidney survival. Now what we need here are therapies that just decrease the levels of proteinuria early, rapid and deep to minimize kidney damage. Now proteinuria is an approved surrogate endpoint for the treatment of glomeronephritis, including therapies such as lupus nephritis. I want to spend a minute on what the treatment goals are for lupus nephritis. Here, you can see the EULAR/ERA-EDTA lupus nephritis guidelines. And in the blue, there's a target decrease of proteinuria of at least 25% at 3 months, at least 50% by 6 months or a complete response as defined by a UPCR below 0.5 to 0.7 grams. Now in addition to this, you really want to be reducing steroids to at or below 7.5 mg per day between 3 to 6 months. Now one of the really interesting things about this guidance, if you read the document, is that those patients in the nephrotic range having over 3 to 3.5 grams of proteinuria may take an additional 6 to 12 months to achieve desired clinical outcomes due to slower proteinuria recovery, highlighting that higher UPCR can be more challenged to decrease. Okay. So this is a really interesting study that was published more recently by the Accelerated Medicines Partnership, or AMP. This is a public private parts between the NIH, FDA, pharma and nonprofit organizations, aimed at looking at everything from molecular interactions and pathways to clinical outcomes in patients with lupus nephritis amongst other diseases. Now what you're looking at is the AMP lupus nephritis cohort, a cross section of longitudinal analysis of 121 patients with lupus nephritis, with a mean UPCR of 3.2 on standard of care, looking at response rates at 12, 26 and 52 weeks. Now these patients had to have had a recent biopsy confirming lupus nephritis and a baseline UPCR of above 1. Now this stage is really interesting because it's representative of a U.S. multicenter, multiethnic real-world experience, but it's also consistent with the placebo groups seen in recent clinical trials. So focusing on the left-hand side, you can see at 12, 26 and 52 weeks the levels of nonresponders in gray, partial responders in blue and complete responders in green. Now at week 12, 70% of patients do not respond to standard of care therapy. By week 26, about 43% achieved at least a partial response or at least a 50% reduction. And that marginally improved by week 52, so we have a split of 50% of patients getting at least a 50% reduction and 50% of patients not responding to therapy at all. Now this highlights the need for additional therapy. So what are those additional therapies? Well, more recently, we've seen the approval of 2 agents into the lupus nephritis space. Now what's really interesting about these studies is if you look at the placebo group, they're actually very similar to what the AMP cohort had been able to describe, very low rates of ORR at 12 and 24 months. Now on the left-hand side, looking at Lupkynis. Lupkynis at 6 months had an ORR of about 50%. And about 50% of -- with the placebo group, and about 50% of those patients are not responding. That didn't really change much between 6 and 12 months. We're still at 12 months, 50% of patients not responding and 52% of patients achieving at least a 50% reduction. The addition of Lupkynis actually saw some improvements there, where at 6 months and 12 months, you see at least 70% of patients getting at least a 50% reduction. On the right-hand side, if we look at Benlysta, Benlysta actually reports data out at 24 months, usually using the PERR, but what's shown here is the complete response ratios. And what you see is a 24 months in the placebo arm, 63% of patients do not respond to therapy, meaning that they do not achieve at least a 50% reduction in their proteinuria. Now when you add Benlysta to this, you improve the ORR to just shy of 48%, 50%, and 52% of those patients at 24 months are not responding to therapy. Now this highlights that although we have improvements over standard of care, there's still a grave need for therapies that can rapidly and deeply reduce the levels of proteinuria in more patients safely without broad immunosuppression. Okay. I want to spend a little bit of time just recapping on itolizumab, the CD6 outcome pathway and our approach in lupus nephritis. As you know, CD6 is a co-stimulatory molecule expressed on T effector cells, becomes overexpressed during activation and is down regulated on the regulatory T cells. We know that CD6 high cells exhibit a greater pathogenic capacity shown on the right, higher proliferation, pathogenic phenotypes and increased secretion of pro-inflammatory cytokines. Now the CD6 outcome pathway is important for the formation of a competent immune synapse, the activation of T cells, as well as the trafficking of those T cells into tissues. Okay. So what I want to highlight here is our recent data published in the general clinical investigation that shows a sort of bench to bedside approach, indicative of how we think about indication selection at Equillium. Now starting with translational data from humans, what's noted is that these antigen-specific autoreactive T cells in SLE and LN pathogenesis are CD6 positive. A single cell RNA data set from lupus nephritis kidneys versus normal kidneys showed a 16-fold increase of infiltrating CD6 positive T cells and a ninefold increase of ALCAM expression on renal tissues. Now what's also important is that the [indiscernible] for CD6 ALCAM in its soluble form in the urine is a strong biomarker of active lupus nephritis. It has been published in multiple independent articles, highlighting that not only is this pathway up regulated from a tissue perspective, but we're seeing elements of this pathway as specific biomarkers of disease. Now following up on that translational data, we completed multiple animal models of SLE and LN in glomernephritis, showing the blockade of the CD6 ALCAM pathway was as effective as at least [indiscernible] LMF in these animal models. And lastly, as we'll cover today, a little bit of the exploratory analysis in our SLE patients who had elevated levels of UPCR and UACR upon treatment of itolizumab, saw an improvement in these numbers, and thus a decrease in their UPCR. But I think this slide really tells a story of why we're excited about this approach in lupus nephritis. It's this unique upstream disease-modifying mechanism selectively targets autoreactive T effector cells activity and trafficking to promote immune homeostasis and induced durable remission. Now starting on the left-hand side, blockade of the CD6 outcome pathway can inhibit multiple inflammatory cells and cytokines synergistically. While in the middle, we know that where an ALCAM is overexpressed on tissues, that leads to an enrichment specifically of these pathogenic CD6 type cells. So we can shut down that enrichment of cells at the site of inflammation. Now more importantly, on the right-hand side, but most often overlooked, is that because of autoimmune inflammatory disease, it's often the loss of tolerance or the imbalance between the good T regulatory cells and the bad T effector cells. With CD6 being overexpressed on effector cells while down-regulated on T regulatory cells, we have the way of selectively modulating effective cell activity and actually augmenting the T regulatory compartment with the potential, we hope, to induce durable remission in patients. Now I'll hand over to my colleague, Dr. Maple Fung, to discuss the Type A SLE study.

Hi. Good morning, everyone. As noted, I will first review the Type A study design and some top line results that were previously shared on Type A, and then we will get into the exciting new interim analysis of the Type B patients. So this first slide shows the study design of Type A. It was a Phase Ib open label dose escalation study. The patients had active or inactive lupus, but without known lupus nephritis. Patients were dosed 2 doses of itolizumab subcutaneously on days 1 and 15. We dosed 35 total subjects across 5 dose cohorts from 0.4 milligrams per kilogram up to 3.2 milligrams per kilogram. The primary objective of this portion of the study was to assess the safety and tolerability in these lupus patients, with or without active lupus, but without known lupus nephritis. And again, to look at PK and PD of itolizumab. So to start first with the data safety summary for Type A cohorts, this subject -- the safety was monitored by independent data review committee for dose escalation purposes. 49% of subjects have experienced at least 1 adverse event, but predominantly the adverse events were noted in the highest dose cohort where multiple injections were required per dose. Most common terms of the adverse events were headache and injection site reactions, again, predominantly in the highest dose cohort. There were 2 serious adverse events in 1 subject in that highest dose cohort that was unrelated to study treatment as they occurred greater than 30 days after his final dose. There was 1 dose-limiting toxicity based on protocol-specified criteria, and that was 1 lymphopenia event in the 2.4 milligram per kilogram dose. But based on the safety profile and in conjunction with the PK/PD data, which I'll show you on the following slide, the 1.6 milligram per kilogram was selected for Type B subjects to be dosed bi-weekly for 24 weeks in the Type B portion of the study. So this next slide shows that all important dose-dependent pharmacokinetics and rapid pharmacodynamics that we gained from this trial. On the left-hand side of the study, we see the dose-dependent itolizumab exposures that were observed. This is a log scale, showing the 0.4 up to 3.2 milligram per kilogram dosing exposures. Preliminary data suggests there's no impact on antidrug antibodies on pharmacokinetics. On the right-hand side, at the pharmacodynamic portion of the study, showing our primary PD markers with the reduction in cell service levels of CD6 on both CD4 and CD8 cells. This portion of the graph shows the CD4 cells. And what we're looking at here is that change in the percent of CD6 from baseline in the middle panel there for day 15. This is 2 weeks after the first dose, right, prior to the second dose, you could see that the magnitude of decrease is comparable at the 1.6 milligram per kilogram dose and higher. Similarly, that's seen as 14 days after the second dose on day 29. So this next slide shows an exploratory analysis of lupus subjects. From this Type A portion that had elevated proteinuria. This and the other type A data was presented at ASN and ACR of last year. So the left-hand side of the figure is a graph that details this exploratory subgroup analysis of patients that had elevated urine protein creatinine ratio or urine, albumin, creatinine ratio. And you could see that with just the 2 doses, there was a meaningful change of up to 50% across the patients after those initial 2 doses. This analysis was in part initiated based on a similar analysis conducted by the 52 belimumab trial, and that's what we see on the right-hand side. The median percent reduction of elevated -- in patients with elevated proteinuria in the initial lupus trials are shown. And then here, you can see the reduction across 52 weeks, which is a much longer duration, but approximately 38%. And so superimposed on that, we have, for illustrative purposes, included the bright blue line that although much smaller numbers, we do see a deep and early response even in these patients with a low degree of proteinuria. So what we find here is that low-grade proteinuria is both present and treatable in patients with lupus, and provides a positive signal of drug activity for the treatment of lupus nephritis. This trial -- this exploratory analysis gave us conviction to that there was clinical activity with itolizumab in lupus patients, and that we should continue into this important Type B portion of the study and looking at [indiscernible] patients with active lupus nephritis. So in summary, for the Type A portion of the study, we concluded that subcutaneous administration of itolizumab, particularly 0.4 to 2.4 milligrams per kilogram was well tolerated. The tolerability was reduced in that highest dose cohort of 3.2 milligrams per kilogram dose with over 50% of patients discontinuing treatment after the first dose in part because of the multiple injections that were required for the high dosing. Consistent with mechanism of action of itolizumab, CD6 on the surface of T cells decreased significantly in a dose-dependent fashion, with maximal effect achieved at doses of 1.6 milligrams per kilogram or higher. The exploratory subgroup that I just shared of Type A lupus patients with elevated baseline levels of proteinuria or albuminuria without a diagnosis of active lupus nephritis showed a decline in proteinuria up to 54% at 2 months following the 2 doses of itolizumab. The PK and PD analyses and the safety profile observed to date continue -- support continued evaluation of subcutaneous itolizumab in lupus and lupus nephritis and other chronic autoimmune diseases. So with that, I'm excited to move into the new portion of our presentation regarding the interim data results from the Type B portion of EQUALISE in patients with active proliferative lupus nephritis. So I'll start here first to review the study design of this Type B portion. We enrolled active proliferative lupus nephritis patients that required induction treatment due to new diagnosis or relapsing disease or patients that were incomplete responders to standard of care. Itolizumab is dosed 1.6 milligrams per kilogram subcutaneously every 2 weeks for a total of 13 doses. That's on weeks 1 through 24. Then the key clinical activity assessments are then done at week 28, with a follow-up period of through week 36. The goal is to study up to 20 patients. The key eligibility criteria are seen here in the middle of the slide. All patients are on Mycophenolate, 2 to 3 grams per day, induction patients may receive steroids, but they will need to be rapidly tapered to less than 10 milligrams per day by week 10. Patients must have a renal biopsy within 12 months, showing that ISN, RPS Class III or IV disease. They can have concomitant Class 5 disease as well. And all patients must have greater than 1 gram per gram of proteinuria. And again, we are focused on safety and tolerability is our primary objective. The secondary objectives include characterizing the pharmacokinetics and pharmacodynamics, and we are starting to look at that initial clinical activity. And here, today, we'll be focused on the change in urine protein creatinine ratio, as well as looking at the proportion of subjects that achieved response. So this first slide shows the key demographics of the patients that have been enrolled to date. We'll talk a little bit about the patients for all of our analyses. But the safety population includes all 13 patients that have been dosed. The mean age was 33.7. Predominantly, these patients were female, and predominantly, they were Asian, with 3 patients enrolled in the United States and 10 enrolled in India. The mean lupus duration of their disease have been -- is 7 years. The mean of their lupus nephritis duration is 6 years. And 9 or 69% of patients had a history of previous induction treatment. This next row shows the lupus nephritis class type, and you'll see that the majority of patients enrolled had concomitant classified disease along with their Class III or IV disease. The mean urine protein creatinine ratio was quite high with a mean of 5.8 gram per gram, and the median was 5. The mean eGFR at baseline was approximately 110 ml per minute per 1.73 meter square. So this next slide then demonstrates the subjects that we will be reporting on. As of our data cut, 13 subjects have been dosed again. That's our full safety population. However, 12 subjects have received greater than one dose and have a post-baseline assessment making our efficacy population. There was just the 1 subject that discontinued due to unrelated adverse events after just one dose, and they do not have post-baseline efficacy assessments. 6 subjects have completed through week 28 or the end of study with all of their follow-up visits, and 11 subjects have passed week 12. Again, these patients are highly proteinuric, with the baseline mean urine protein creatinine ratio of 5.8 grams per gram. So I'll first start by discussing the safety in these patients. Again, the safety population of 13 subjects and reviewing the left-hand side, which is our safety overview, 77% of subjects have reported at least one adverse event, and these have predominantly been mild to moderate in severity. There are 2 subjects that have had an adverse event of special interest, and that is lymphopenia. Lymphopenia events are tracked very carefully across all of our itolizumab studies and programs in part because based on the mechanism of action, this can also be tracked as a PD marker. These reversible events have not resulted in any clinical sequela and 2 subjects, again, have reported a Grade III or IV events. Two subjects also had at least one serious adverse event. All serious adverse events have been unrelated to study treatment. And these 2 subjects did early terminate due to these adverse events, but they were on terminate study treatment due to these adverse events. However, none of them were related to study treatment. There was 1 additional subject that discontinued study drug due to physician decisions. And you could see some details of these adverse events here on the -- in the table on the right. So this next slide shows the pharmacokinetic and pharmacodynamic portions of the study. And on the right-hand side, you'll see that the pharmacokinetics is similar between the Type A and B subjects, superimposed upon the figure that was previously shown regarding the pharmacokinetics in a dose-dependent manner. In the Type A subjects, you'll see a light blue dotted line of the Type B patients dosed here at 1.6 milligram per kilogram, and it was reassuring to see the comparability despite the different patient populations in Type A and Type B. Additionally, the reduction of cell surface CD6 as the PD marker is consistent with the mechanism of action. And to date, no subjects have exhibited high titers of antidrug antibodies. There have been no changes to pharmacokinetics in patients that have low levels of antidrug antibodies. So next, we're excited to share the next 4 slides, which show the interim data, efficacy data as we currently see it. So the first slide shows the clinical responses of all subjects. So there's 3 different panels here, and each panel is at a different time point, but this is the summary data. Starting on the left-hand side at week 12, there are 11 subjects. And you'll see in the top green bar, this is the percent of patients that have a complete response of greater than 50% urine protein creatinine ratio reduction and have reached the bar of having less than 0.5 grams per gram of urine protein. In the blue bar following that is the partial responders. So at week 12, an additional 27% patients have greater than 50% reduction in urine protein creatinine ratio, and that overall response rate of complete responders in addition to partial responders is 45% as early as week 12. In the middle column, we have the 6 patients that have completed through week 28 or the end of study. And here, we have added an additional component of the light green bar, which is complete responders of greater than 50% urine protein creatinine ratio that have reached a bar of between 0.5 and 0.7 grams per gram. You'll see in the dark green, it was 17% of patients that reached the stringent bar of 0.5 grams per gram, an additional 33% between 0.5 and 0.7. Here also 1/3 of patients, 33% had a partial response of greater than 50% reduction as well with an overall response rate then of complete responders and partial responders of 83% by week 28. And on the right side, we see all patients that have been dosed with that post-baseline assessment, so the total of subjects is 12. And here, we see 17% of patients with a complete response at the bar of 0.5 grams per gram, and below that at 25% -- additional 25% patients were at the urine protein creatinine ratio of 0.5 to 0.7. So therefore, the overall response rate here is 67% for all subjects, regardless of with how far they are in dosing, and we'll be looking at a little bit more subject-level dosing in the next couple of slides, but we find that this overall response rate achieved by 12 and 28 weeks is greater than what might be expected with standard of care alone. So this next slide shows subject level data over time with their longitudinal disposition. So on the left-hand side, you'll see the subject -- individual subjects and their baseline urine protein creatinine ratio, and crossing the slide is how far these subjects have progressed through the study. So the first 6 subjects are noted above the initial line here. And what we see here is both how long the patients have dosed, but then more compelling are the diamonds. So the diamonds indicate the first noted partial response in blue and then the first noted complete response in green. And so what we see is, very early on, on the study, on the left-hand side of the slide, a number of diamonds showing that early response. And then when they become green diamonds, it shows that deep response where they in green have achieved a complete response. And what's interesting about it is not just the early responders that we see, but then there are patients, for example, subject #2, where you see the more expected response from patients where the responses are seen a little bit later, for example, the blue triangle at week 16, but later than became a green triangle further on in the study at week 32. So this next slide shows, again, individual subject level data, and these are the patients, the 12 patients that have greater than 1 dose and at least 1 post-baseline assessment. So this slide has a lot of information on it, but to start, the change in UPCR, their best clinical response is noted with the decline showing maximum reductions in urine protein creatinine ratio, and the color bars show that best response. So on the left side, you see the gray bars, these are the nonresponders that had less than a 50% reduction, some getting close to 50%, but nonetheless, less than 50%. The middle bar show the blue partial responders, and although they are greater than 50% reduction, nearly close to 75% and 80%, they did not quite reach those bars of 0.5 or 0.5 to 0.7 grams per gram. On the far right side, you see the complete response patients, and these have all, again, had greater than 50% response and some close to 90% response with, again, the dark green being those that reach the bar of 0.5 grams per gram, and the lighter green being those between 0.5 and 0.7 grams per gram. Of note, the asterisks are the patients that are still actively dosing. So we are hopeful that they too can reach a complete response. So this is the last data slide showing all the subjects together and the change in urine protein creatinine ratio over time, again with the maximum patient number of 12 here. On the right-hand side, we've actually highlighted some of the change in urine protein creatinine ratios from baseline at key time points, such as week 12 and at week 28 or the end of study. And further on the far right is the daily steroid dose, showing prednisone equivalents here at baseline, a median of 50 milligrams was noted to week 12, where this had declined expectedly to 6.2 milligrams, and to week 24, the end of study, at 5 milligrams. What's notable on this slide is that at a median 51% urine protein creatinine was reduced by week 12. So my last slide here shows that itolizumab added to the standard of care treatment shows clinically meaningful benefit. And to contextualize it, we bring back those EULAR/ERA-EDTA treatment goal for patients with lupus nephritis. And these are seen on the left-hand side with the treatment goals at 3 months, 6 months and 12 months. And to contextualize it again, we have that AMP standard of care longitudinal data that Steve previously shared in the middle column. And then on the far right is the itolizumab interim analysis data. So what we see is that by week 12, with a targeted reduction in proteinuria at least 25%, we have 64% of patients at that target. And at 6 months with the goal being partial clinical response or a 50% reduction in proteinuria, where AMP saw a standard of care treatment of 43% of patients reaching that goal, we see 83% of patients. And we also note the complete clinical responses that we have seen at week -- at month 6 as well there. So with that, I will turn it back over to Steve to share some of the highlights of EQUALISE.

Thanks, Maple. And I think the key takeaways here, as we think about how this moves the needle in lupus nephritis is that although these are highly proteinuric patients at baseline with a mean UPCR of 5.8 grams, 83% of these subjects had at least a partial response by week 28, which is much greater than is expected with standard of care alone, and a median time to response of 12 weeks. Now broken out even further, at 28 weeks, 83% of these patients achieved a partial -- at least a partial response. And 4 of 6 or 67% of these patients had a mean reduction of over 80% reduction in their UPCR. Now if we consider all of the patients in the study regardless of where they are in their dosing, we see that 67% of patients achieved at least a 50% reduction in their UPCR, and we have a mean reduction in proteinuria by over 60%. But in ground level, that's a mean reduction of over 3 grams in UPCR across all of those patients regardless of where they are or continue to dose in that paradigm. So as we think about the goal for lupus nephritis in terms of reducing levels of proteinuria and the damaging effects of proteinuria, we remain very, very excited about these results in terms of their impact to clinical outcomes. And with that, I'll pass it over to Bruce to talk about next steps.

Thanks, Steve. Thanks, Maple. We're very pleased, obviously, with what we've observed so far in the study. We believe itolizumab continues to demonstrate a favorable safety and tolerability profile, the 1.6 mg per kg dose level really across our studies appears to be sort of an optimal dose level. We're also pleased that we've now been able to dose patients through 6 months and continue to demonstrate a good safety and tolerability profile. This emerging product profile in this indication does suggest differentiation in terms of early rapid and deep responses, and particularly, calling out again the fact that these patients had very high levels of protein, suggesting quite severe disease. Adding to our conviction that the clinical activity of itolizumab is highly differentiated and has the potential to be impactful as a therapy for patients with severe autoimmune and inflammatory diseases, particularly within lupus nephritis, obviously, now that we have this data, this is backed up with very strong conviction that the pathway we're targeting, the CD6 ALCAM pathway, is highly unregulated in this disease. And so we're -- we're pleased to see the consistency from that initial signal, the lupus study that's now showing follow-through in the lupus nephritis part of the study. Based on this data, as well as significant KOL feedback on this data, we do plan to continue enrolling the EQUALISE study. We do expect top line data now midyear 2023. We will continue to analyze serologies, as well as carefully paying attention to biomarkers with particular focus on the CD6 ALCAM urinary biomarkers that have shown to be upregulated in patients with lupus nephritis. And we are now preparing for later-stage development program that can potentially support product registration. And we'll be looking for ways to differentiate the program moving ahead clinically. So with that, we're happy to take any questions that the audience may have.

[Operator Instructions] Your first question comes from the line of Roger Song.

Congrats for the data. A couple from us. So start from the baseline UPCR, maybe can you just comment, is this surprising to get such high baseline compared to other LN study in the past? Particularly, any key difference kind of a different enrollment inclusion criteria versus other trial made you get this high baseline UPCR.

Yes, sure. So Roger, [indiscernible] last bit there, but perhaps I can just comment on the levels of UPCR. So they're in the range that you see in patients. Perhaps what you're seeing is that now with changes in approved drugs, et cetera, is that we're just left to enrolling maybe extensively sicker patients here or patients who have a greater level of UPCR. We did exhibit -- we did observe that this level of UPCR seemed to be consistent across jurisdictions. So it wasn't driven by any one ethnicity or any one sort of territory for which patients were recruited from. Now if you look at the ranges in some of these studies, you can see very high levels within those. It's just the averages from a mean perspective are skewed to some of the lower. So it could just be that we're now sort of at the end of the funnel where we're seeing patients who, as is our study, have had a mean duration of LM for 5 years and perhaps they're just not responding to therapy. So one could think about this as just a sensibly sicker patient population, but these levels are within the realms of what is often observed with these patients. We're just now seeing a SKU in our trial to enroll in patients who have a higher mean level across the board. Does that help answer the question? And perhaps you can reiterate the final portion of your question, if I missed that.

No, I think that answers. Just the final question is the enrollment inclusion criteria is any different. I believe you say kind of basically those patients end of tunnel and they are I think...

We. We weren't seeking out these patients with higher proteinuria, that's just the patients we recruited with pretty standard recruitment terms.

Yes. Got it. Okay. Great. And then in terms of the background therapy, since you allowed the induction and the other people -- patients not responding to the stable therapy. Just do you have a sense how many of those patients received the induction versus the backlog therapy not responding? And another kind of follow-up question after that is what is the expected complete response rate or the partial response from those induction therapy kind of can gain?

Yes. So I'll start first with the previous treatment. And so these patients were predominantly induction patients. But as I shared, there -- most of them have had previous induction treatments already. I think that's the answer to your first question. And the second question is the most recent approvals of both Benlysta as well as Lupkynis were in similar patient populations in newly induced patients.

Okay. Great. So maybe just last one from us. For the complete response and you separate by UPCR less than 0.5, and 0.5 to 0.7, maybe just comment how meaningful less than 0.7 for this population with such high UPCR? And what is the target for the complete response for that population?

Yes. Sure, Roger. So the target criteria, if you look at the ERA-EDTA guidelines is to -- for a complete response is to get below 0.5% to 0.7%. Now when you're in those ranges, it can be quite noisy. Benlysta was approved on a primary efficacy renal response, which used 0.7, and Lupkynis used 0.5. Now I think the key takeaway is when you're into this range, that's where if you look at long-term outcome studies, you're seeing better outcomes. So when you move from something like 11 grams of proteinuria and you just consider a 50% response, we wanted to separate out those who have 0.5, 0.7, and those who had 50%. Now you can actually see where our target decreases are per patient, we've provided that information. But I think between 0.5 and 0.7 is clearly where the meaningful range of reduction is, and I think it's going to be quite noisy. Now if you look at Slide 28, you'll note that many of our patients who we report as between 0.5 and 0.7 were either at, say, 0.55 or 0.6. So they're within 5%, 10% of that 0.5%. And we wanted to differentiate those responses from those in the blue bars where they may have started with above 12, 13 grams of proteinuria are still dosing, and those have only achieved a partial response, which is a 50% reduction to, say, 6 or 7 grams of proteinuria. So I think overall, you want to be driving those levels down as quickly and as rapidly and as low as possible. And there's probably very little difference in terms of outcome measures if you were at 0.5 or 0.7, but we wanted to remain consistent with the ERA-EDTA guidelines.

Yes. And then probably worth just revisiting that on a UPCR basis, sort of the range of normal is up to 150 milligrams, above 200 is considered well outside the range of normal. So we think what is most impactful, particularly in this patient population with severe disease and very high proteinuria, there's not so much whether you hit 450 milligrams or 550 milligrams but the magnitude of reduction. And I'd say the KOLs that we have been speaking with, I'd say, are most impressed by both the rapidity as well as the order of magnitude of reduction in these patients with very high proteinuria that they have considered to be well in excess of what you would typically expect to achieve on background standard of care regardless of sort of induction therapy or not a timing thereof. And as Steve highlighted, this is a pretty impactful chart in that if you look going left to right, we've got 6 patients still in the dosing window, including 3 patients who are still pretty early in the study, patients subject 7, 8 and 13, and then 2 of the 3 patients that are partial responders are still dosing as well. So we're extremely pleased with these rapid and deep responses in patients that came in with quite high levels of baseline proteinuria. I hope that answers the question.

No, that's very, very helpful. Congrats for the data again.

Your next question comes from the line of Dae Gon Ha.

Congrats from us as well. A couple of clarifying questions. One on the patients that were coming in, can you comment on whether any of them have actually been failures to either Lupkynis or Benlysta in addition to standard of care? Second is just looking back at the Type A and Type B lymphopenia, there seems to have gone from 3% in Type A to now about 15%. Can you comment on what happened to the Grade 3 lymphopenia in the Type B, whether they are continuing the study or not and whether there have been dose differences there? And what do you think happened between Type A and Type B since Type A was lymphopenia, you did 2.4 milligram per kg, but here, we have 1.6 milligram per kg giving rise to both? And then I've got one last question.

I'll start with the first question. There were no patients in this trial that have previously been on Lupkynis or Benlysta. These patients had previously failed cyclophosphamide definitely in previous MMF treatments as well. And I think that's your first question. The second question in regards to lymphopenia is that this is very early portions of our study, very few patients have been dosed in this portion of the trial. It may be a bit early to draw comparisons and percentages between this and previous portions of the study as well as other studies with itolizumab as well.

I think, Dae Gon, also want to reiterate that the transient reductions in lymphopenia have been observed with itolizumab from the very first studies, it's a known pharmacodynamic effect of the drug that has not been associated yet with any downstream negative clinical sequelae. And in fact, there are several drugs whose main mechanism of action is sequestering lymphocytes. So we don't view this as a limitation. Certainly, it's a measurement we're monitoring as we continue to advance the program. But I'd say this is consistent with what's been previously established in terms of the mechanism of itolizumab. We know we're not depleting T cells. We believe this is a migration. And we'll continue to monitor this. But so far, this is a clinical assessment. Steve, you wanted to have a comment.

Yes. We provided all this data to regulatory bodies, et cetera. We continue to monitor it. So far, we've not seen any correlation, covariance with any clinical sequelae, and nor have the regulators given us feedback that we need to limit target, seek any threshold levels here. We'll just, like many other drugs, just be monitoring. I think what gives us encouragement about this is that it's clearly a pharmacodynamic marker of the drug activity. Now interestingly, it's very specific on CD4 cells that have high levels of CD6 consistent with expression profile, and we don't see any other changes to other hematopoietic markers. So this isn't changing hematopoiesis. What we believe we're seeing is a margination of sequestration of those lymphocytes and the peripheral broad compartment. So what you're seeing is a change in a lab number that, again, I reiterate, does not have any correlation with any adverse or [ biliterious ] clinical sequelae. So we continue to characterize this moving forward, but we've not had any cause for concern internally or from the regulators on this matter.

And look, we'll -- as we get into larger placebo-controlled studies, we'll be mapping this for clinical outcomes versus background standard of care. And the initial first Phase III study in psoriasis patients, the safety and tolerability profile was quite clean compared to placebo. And the main thing we looked at in that study was infection rates did not go up. In fact, they were a little bit lower in the itolizumab arm than the placebo arm.

On that, the grade 3 lymphopenia patients, so can you walk me through what happened in terms of dose titration there? Are they seeing the same 1.6 or decreasing and to what level? And I guess, if it is decreasing, what do you suspect would be sort of the longer-term efficacy profile? Do you think there might be some kind of a rebound in proteinuria or maintenance of efficacy? And then final question from me is, can you remind us the protocol design in terms of when or how often the blood draw happens for ALCAM measurement.

Maybe I'll start on the last question before I forget it. We collect soluble outcome along with PK and any other serological markers. We're continuing to analyze that along with other potential biomarkers that are associated with lupus, lupus nephritis. We'll provide those updates when we've got a larger end because they're more sensitive to the end value there as well as a lag in being able to analyze those. What I can tell you is that consistent with what we've published and what has been published independently is that those patients with lupus nephritis have much higher levels of soluble outcome in their urine than those in the SLE. And that was replicated when we looked at our Type A versus Type B. So I can certainly divulge that. So that's consistent. What we do want to do is to do more deeper analysis with other immunological markers to see if soluble outcome can provide a little bit more fidelity on perhaps responder relationships. But until we get a greater number of patients perhaps at the 6-month mark, we were being a little bit cautious on what we say there. Does that help? And now I'll hand it over Maple to answer the question with regards the lymphopenia result.

Okay. So to jump in regarding your question on the Grade III lymphopenia event is, as per protocol, patients with lymphopenia are permitted to decrease their dose in half. And so one of these patients has done so, and she continues to dose successfully. As we've mentioned, it is tracking as a pharmacodynamic marker as well. So this patient is one of the complete responders. Her PI is quite pleased with her progress, and we just monitor the lymphocyte count as expected in the protocol.

Your next question comes from the line of Thomas Smith.

Let me add my congrats on the data. I guess, first, just on the safety tolerability. I know it was deemed unrelated to treatment, but can you provide any additional color on the patients who discontinued related to the liver enzyme elevations?

Sure. So this patient actually -- the discontinuation due to the elevated liver function occurred almost 30 days after her final dose. She had been hospitalized for, again, some unrelated adverse events. And although she also was a responder, she did not want to resume treatment, and therefore, discontinued after a hospitalization for dehydration. And this was thought perhaps to be in part due to her extremely good response, and so her hydration status quickly deteriorated after responding very well to our treatment. And so therefore, she discontinued, and it was unrelated even with her elevated LFT.

Okay. Got it. That's helpful. And then just on the efficacy. It looks like you're seeing a pretty good mix of rapid responses and maybe some responses that manifest with longer treatment duration. It sounds like you're still working through some of the data, but I'm curious how well the PD data are tracking with the clinical improvements in UPCR, I guess, even in this relatively early data set?

Yes. I'm going to pass it to Steve to answer your question about the pharmacodynamic marker. But just to mention, there have been no changes in AST or ALT noted across this program or any of our itolizumab programs to kind of close the loop on that question. But here, Steve, do you want to respond about the dynamic marker?

We'd be looking at the changes in levels of CD6. And similar to what we're doing with GVHD, which is sort of a PK/PD response exposure analysis, we'll continue to do that. What we have seen is that the levels are rapidly reduced in these patients. There does appear to be maybe an early signal of an exposure response relationship. Again, like many of the biomarkers, we want to sort of get as many of these patients past the 6-month mark just to increase our end there, as well as trying to be mindful about how we batch our data analysis in terms of sample and the samples for PD. But the mechanism appears consistent from the peripheral blood markers. We say very rapid loss of CD6, and those levels stay down through the course of treatment. Now of course, we're looking at peripheral blood. What could be happening in the kidney might be important. And I think that's where exposure response relationships may be able to tease that out. But of course, like I said, we'll wait until we have a larger end number here as some of these patients who are roughly around the 12-week mark, get closer to the 6-month mark. So expect a full update on that at top line.

Okay. Great. Extremely helpful. And maybe just last question. Can you just walk us through, I guess, the anticipated cadence of updates here? Is it your intention to perhaps present these interim data at a scientific venue? Or should we be looking forward to the top line full data set here in mid-'23 as kind of the next update?

Yes. Good question, Tom. I think we'll be looking obviously for opportunities to present our data at relevant conferences. We obviously feel quite good about what we've observed so far. We think this will have interest at the conference level. And then, yes, we expect our top line data from this portion of the study midyear next year. And then, of course, we do expect in terms of cadence of other data from the rest of our pipeline, we do expect data during 2023 from both the EQ 101 and 102 as well.

Your next question comes from the line of Raghuram Selvaraju.

This is Mitchell on for Ram. The first one is we just wanted to ask what happens after you've disclosed the top line full data set from the Type B part of the study? Do you go to the FDA and ask them in the study meeting? Or what are the next steps after that?

Yes. I think we're going to be starting now, or actually, we already have started thinking about what the next phase of development should look like. I think we want to be thoughtful and perhaps creative about how we advance the program, vis-a-vis other programs that are in the LN space. I think we're particularly intrigued by what we feel are pretty deep rapid reductions in patients with high levels of proteinuria, which may be a significant point of differentiation compared to other programs. We know some of the other programs that are still in development have shown data on patients with significantly lower levels of proteinuria with good results. I think we're going to focus where we think we can have a big impact for these patients. And we'll be approaching the agency at the appropriate time to open that discussion on how best to advance the program with the goal of getting this drug to patients as quickly as possible if we continue to see success as we've observed so far.

Great. And then could you comment on what a pivotal study might look like? Do you anticipate that it's an active with comparator or active with placebo-controlled design or any other thoughts on how that might look?

Yes, as I just said, I think we'll come back to our stakeholders when we're ready with what we think the next phase of development should be. There's an abundance of pivotal study designs from approved drugs that you can refer to, as well as some of our peers are starting to get into more advanced development. So it'll be interesting to see sort of how they're approaching it. But again, we'll be looking to differentiate what we think is a unique product profile here for the program as we carry forward. But a little bit premature to discuss what a pivotal study will be.

Next question comes from the line of Prakhar Agrawal.

Congratulations on the data. Firstly, any details on the EGFR curves for these patients? And how does that look? And I had a few follow-ups.

Yes. So it is mentioned on one of the slides that the EGFR has remained stable in these patients so far to date.

Okay. And does the induction therapy and the compliance for induction therapy in Asia, where most of these patients were enrolled, were you compared to some of the other geographies? And would you expect any differences in the response by ethnicity for LN?

So as you're aware, LN disproportionately is in minority populations. And I don't -- I'm not aware of any literature that supports that there would be a difference in response between ethnicity type. We haven't seen that across our other itolizumab programs either in terms of pharmacokinetics or pharmacodynamics.

Okay. And the UPCR reduction data obviously looks very good, but could you comment on the complete response data that you're seeing taking into account the definition used in some of the other trials in the space that includes components such as EGFR, rescue meds, like with the complete response on the [ 7.5 ] to meet that criteria. And just as looking ahead, what benchmarks are you looking for complete response at 6 months to make a decision on taking this forward given induction therapy has a roughly 20% complete response?

So in terms of the definitions, I mean, we put out just the thresholds of UPCR, but of course, there are a lot of other components into that such as stable EGFR, no rescue meds, et cetera. We're all very consistent with that. You can't just take additional therapy and still be consider a respondent. That's one example, same as worsening eGFR. As we think about the thresholds for UPCR. So we're using the ERA-EDTA guidelines, right, and it's exciting now to get below between 0.5 and 0.7, Benlysta used 0.7, Lupkynis used 0.5. And as we think about getting into those levels and maybe had a benchmark it, what is very clear from that guidelines, if you read it into the minutia, is that they suggest that the patients are responding on therapy that the continued dosing because those that have higher levels of UPCR can take longer for those patients to resolve. So how does that impact how we think about the data? Well, if we have higher staffing levels of UPCR and we continue to see those levels track down, it may just take a little bit longer in those patients if we have a greater number of them with higher UPCR to get into that sort of all important CR range. So I think we have to just temper the fact that if you have high CR rates with low levels of UPCR, that may be easier to achieve than the high rates of CR with much higher levels of UPCR at a 6-month interval. So I think we'll take all of that into consideration. Another interesting element of our data which stands out is that we appear to have more overall responders. So if you look at the number of patients who do not respond -- consistently do not respond to standard of care. That's a greater number across both the standard of care as well as the approved drug. So it does appear that perhaps our mechanism may grab more of those patients and start to move their UPCR down. So that's an important element that we should be focusing on here. And noting also that Benlysta takes 2 years to work. So I think at 6 months, we're not going to be overly focused on hitting a specific CR rate. I think we'll look at the data qualitatively and say, we have very high levels of UPCR, and in a great number of patients, we're seeing that UPCR decrease, not just past the 0.5, past the 50% range, but actually closer to the 0.5 and 0.7. Now you're hoping a placebo-controlled trial, if those levels hold for both of the arms, that you can still show a meaningful benefit in that population above placebo. So we are encouraged by what we see on a number of levels, the speed, the rapidity of that loss of -- reduction in UPCR, as well as the greater number of patients that appear to be responding. So all of those are in line with what we think differentiates itolizumab as a molecule in the lupus provider space. Does that help answer the question?

Yes. Of course.

Your final question comes from the line of [ Kathryn Novak ].

Congrats on the data. My first is I wanted to ask a little bit more about next study steps. Given the strong results that you've seen and that you've already identified, it does -- can you maybe give more color on what the next steps would be? Would it be a larger Phase II study? Or is this potentially registrational given what you've shown?

I think we do feel pretty good about the dose level, and this is informed not only in this study, but across the studies, itolizumab in different patient populations as well as what we think is a pretty reliable now pharmacodynamic marker and looking at the levels of CD6 on T cells. So yes, I think we feel good about the dose. I think whatever we do as a next step will be designed to support registration, whether it's a single study or 1 of 2 studies that may be required. I think we'll have to leave that open until we have a more firm kind of strategy going ahead. But we're actively working on that. And I think we'll be prepared to move into future studies pretty quickly with a target sometime during next year.

Got it. And then I want -- just one question about the kinetics of UPCR lowering. Did you tend to see deepening responses for patients after the end of therapy? And was this expected based on what you've seen earlier studies and the itolizumab mechanism of action?

Yes. Look, if we get to the patient disposition slide, you'll note that there's a patient, yes. So say, for instance, subject 2. So they had a partial response about week 16. They were counted as a partial response as we took that data at week 28, and only continue to get better as the -- shortly after the last dose. Now if you recall from our asthma data and even the SLE data, the half-life of this antibodies is about 20 days. And at this level, we expect to see quite a durable tail on the pharmacodynamic effect. So you can see that some of these patients had an early response which is very consistent with the mechanism of action. But inflammation in the tissues may take longer to resolve in certain patients over others, depending on the types of cells that are there, the ability for those patients to respond, regenerate, and that manifest on a lowering of UPCR. I think what we found most striking was that we tended to see a greater number of at least responses than you typically observed for standard of care. And in many of those instances, those responses continue to get deeper as you continue to dose out through itolizumab even in the presence of that steroid taper reducing steroids to below that recommended 7.5 mg or below via the ERA guideline. So hopefully, that answers your question. It's very hard a priority to say which patients may respond quickly. We just don't know enough about the underlying immunological landscape in the kidneys, and it's very hard to get kidney tissue from those patients. But it's very consistent, at least, the early responders to what we've seen in acute GVHD, where the first dose was seemed to be very important, and we saw rapid resolution of GI inflammation. So I think what you're seeing perhaps in some of these early responders is exactly that. And some of these later responders may just have a different phenotype in the kidney or a different immunological landscape and/or damage profile that just takes a little longer to resolve. I think it's just important to note that they continue to get better, and we see more responses in more patients than as expected with standard of care.

Got it. And just finally, you mentioned the lack of hemodynamic impact from itolizumab. Can you talk about how the safety profile looks versus standard of care approved therapy on the market?

I'll start with the lack of hemodynamic effects. There's a nice article, I think, that was published by Brad Rovin more recently as a review on the space. Now Lupkynis as the C&I is supported to have some hemodynamic effects. And I think one of the questions is do you see a change in UPCR because of the hemodynamic effects, but when you biopsy the kidney, you may still have an underlying inflammatory environment or T cells still causing an issue. I think we still wait to see some of that data. You'd expect that molecule to be both immunomodulatory as well as perhaps hemodynamic. Now our molecule shouldn't have any hemodynamic effects. It doesn't change any of the -- any of those parameters. It should be a pure immunomodulator, it should modulate not only activity of T cells in those tissues, but the cycling of T cells into the inflamed organ itself. And then also restoring the immune homeostasis, which we hope actually manifests as a differentiating element, which is a longer, more durable remission in these patients. Now this shouldn't be broadly immunosuppressive because you're really targeting those antigen-specific activated T cells and not shutting down other inflammatory cells that might lead to more broad immunosuppression. So as the therapy that you add on to standard of care, you ideally want something that's very targeted and not to continue to play on the top, more broad, deep, toxic immunosuppressants with limited therapeutic windows. So we think this molecule could be used to replace immunosuppressives in the long term. That's something that we've given a lot of thought to and is a great goal. But in this interim, we're very excited that we can improve what we think are outcomes in these patients on top of standard of care and do not appear to see anything that would suggest that we've changed the safety or risk benefit profile on top of standard of care.

And just to add to that, I'll just elaborate that we're fortunate to be able to combine the safety data across all of the patients that have previously been dosed across many different programs. And of course, already approved in India and has a lot of usage there as well. So the safety profile is pretty well delineated and we're not seeing anything particularly to this population, which is reassuring, especially these patients are all, again, like Steve mentioned, on steroids as well as mycophenolate.

There are no further questions at this time. Mr. Steel, I turn the call back over to you.

Thanks, everybody, again, for joining us this morning for this update. We're, again, quite excited about what we've observed and look forward to advancing the program. Please feel free to reach out at any time with any follow-up questions or comments. Thank you.

This concludes today's conference call. You may now disconnect.