Aurinia Pharmaceuticals Inc. (AUPH) Earnings Call Transcript & Summary

[Audio Gap] And thank you to the National Kidney Foundation and all of the sponsors of this meeting that worked so hard to make sure that we could join you virtually today. I have the honor of representing the AURORA study group to present the results of our Phase III randomized trial, which assessed the superiority of voclosporin in combination with standard of care therapy over standard of care therapy alone in patients with active lupus nephritis. These are my disclosures. So as many of you on this call are quite familiar and aware, the pathogenesis of lupus is quite complex. It likely represents the interplay of multiple genetic and environmental interactions that ultimately lead to the loss of a tolerance of self-antigens, and in particular, loss of tolerance of nuclear debris from apoptotic cells. These antigens combine to viral particle receptors and get presented by antigen-presenting cells, which then leads to polyclonal expansion of autoreactive lymphocytes and the production of measurable antibodies that we're all familiar with like anti-nuclear antibody, anti-double-stranded DNA, anti-Smith, et cetera, et cetera. Now the result of this cascade is a chronic and often disabling autoimmune disorder that can affect over 0.5 million people in the United States. By and large, the overwhelming burden of this disease is seen in women. Lupus is highly heterogeneous and, in fact, can affect almost any organ and tissue system. In its more severe forms, the kidneys are involved, and we can see quite a bit of inflammation and chronic damage. And up to 50% of lupus patients, in fact, will develop lupus nephritis. Clinically, we may see leakage of large amounts of blood proteins in the urine or proteinuria, and this is often a very clinical -- clinically significant feature of lupus nephritis. When we are lucky and we see early treatment responses in our patients, we know that their long-term outcomes measured by proteinuria reduction is quite good. Unfortunately, in 10% to 30% of our patients, despite our standard of care therapies, we see progression to end-stage kidney disease within 15 years of diagnosis. So as you can imagine, this confers a huge cost to overall health, quality of life and excess burn to the health care system. Now we understand that T cell-mediated immune response is definitely an important feature of the pathogenesis in lupus nephritis. We also understand that the podocyte injury that occurs in conjunction with ongoing immune insult in the kidney, is another important factor in the clinical presentation of the disease, and in fact, often leads to proteinuria. Again, a very common hallmark of our clinical presentation. So what might the potential role of calcineurin inhibitors play in lupus nephritis? Well, in fact, the influence of calcineurin inhibitors in proteinuric kidney disease has been shown in multiple studies to involve [ 2 ] separate mechanisms. There are clear direct effects on the immune system resulting from the reduction in fat levels which leads to down regulation of cytokines that otherwise would lead to widespread tissue damage. Separately, we understand that there is an extra immunological effect involving podocyte stabilization. So if you look at this figure here on the right and focus on this molecule synaptopodin, synaptopodin is an important molecule in the stabilization of the podocyte cytoskeleton. So anything that damages a podocyte cytoskeleton can cause podocyte effacement and that, in turn, causes proteinuria. Calcineurin inhibitors have been shown to block the calcineurin-mediated dephosphorylation of synaptopodin, and by doing this, promotes the stabilization of the podocyte actin cytoskeleton, conferring a potential disease-modifying effect of reducing proteinuria. Enter voclosporin. So voclosporin is a novel calcineurin inhibitor, and it's distinguished from cyclosporine A by this single carbon extension with a double-bond. Now there are a few advantages that we found of voclosporin over our traditional or legacy calcineurin inhibitors. And one of these key advantages includes its more predictable pharmacokinetic and pharmacodynamic relationship, which essentially eliminates the need for therapeutic drug monitoring. So this is a huge advantage. Moreover, we found that voclosporin is almost 4x as potent as cyclosporine A. So again, another huge advantage of this novel calcineurin inhibitor. So our study group after the completion of a proof-of-concept trial, which included 7 patients, completed a Phase II double-blinded randomized controlled trial of 265 patients. In this Phase II study, we looked at voclosporin layered upon standard of care therapy defined as mycophenolate mofetil and corticosteroids to a control arm of standard of care alone. The primary endpoint of this Phase II trial was renal response at 24 weeks, mostly driven by proteinuria. And within the study, we found that there was a 14% higher renal response rate in that voclosporin arm over the control arm. There additionally was a secondary endpoint that was assessed in this Phase II trial at 48 weeks, again, looking at renal response. And there, we found a 25% higher renal response rate over that control arm. So based upon these Phase II studies, we went into the Phase III double-blind randomized controlled trial. And the remainder of my presentation will be dedicated to presenting the core analyses from this study. So both the AURORA Phase II study and the AURORA Phase III study have similar inclusion criteria and primary endpoints. In fact, the -- all main differences are really highlighted here in bold. So to be included in the AURORA trial, patients had to meet a diagnosis of lupus based upon standard ACR criteria. The majority of patients enrolled in this study had a kidney biopsy within 6 months of study entry to confirm histologic diagnosis of active lupus kidney disease. Now this is starred because there is a minority of patients, so less than 10% of trial participants that had a biopsy that was outside of the 6-month window up to 2 years. And they qualified on the basis of other markers of active kidney disease, including things like doubling of serum creatinine. All patients had biopsy-proven lupus nephritis Class III, Class IV or Class V, either alone or in combination with a proliferative lesion. And all patients had a sizable amount of proteinuria with a UPC greater than or equal to 1.5 or for our Class V lupus nephritis patients, a UPC greater than or equal to 2. The primary endpoint in the AURORA trial was a renal response at 52 weeks. And renal response here is defined as a UPCR of less than or equal to 0.5 and the inclusion of all of these safety parameters. So they also had to have maintained eGFR greater than or equal to 60 or no confirmed decrease from baseline of greater than 20% and be able to be maintained on a low dose corticosteroid throughout the study and needed to not require administration of rescue medications. This slide depicts the design of our study. Patients were randomized 1:1 to either the voclosporin arm, which included a standard dose of 23.7 milligrams twice a day, layered upon standard of care therapy here, mycophenolate mofetil at 2 grams and oral corticosteroids given as a rapid steroid taper, as you see outlined in this below table. Or they were randomized to our control arm, which include a standard of care therapy alone, again, which included mycophenolate mofetil at 2 grams and oral corticosteroids given us a rapid steroid taper using the same design. I would like to highlight that this trial includes a blinded optional 2-year extension study. So a lot of patients are rolling over into this extension trial, which we think will provide some valuable long-term data on benefits and risk of voclosporin. So again, I think this is an incredibly valuable component to this study. Overall, 758 patients were screened and 357 patients were successfully randomized. Most of the screen failures were explained by patients that failed to meet the eGFR criteria of greater than 45 ml per minute or had a UPCR that was too low to be enrolled. 178 patients were enrolled in the control arm, 179 in the voclosporin arm. 147 or 83% completed this control arm, and 162 or just over 90% completed the active voclosporin arm. So looking closer at these 357 patients that were enrolled, you'll see that there are really no differences between our control arm and our voclosporin arm in looking at age, sex, baseline weight, baseline proteinuria or even geographic region of origin. And so a pretty diverse population. If we focus on specific renal parameters, again, there were no significant differences between our control arm and voclosporin arm in looking at GFR at baseline, again, proteinuria or even looking at histological lupus nephritis class type. And one thing I would like to draw attention to here is that this study does provide us a fairly diverse group of individuals in regards to histologic type. And in thinking about the dual mechanism of voclosporin with both the immunologic effects and the nonimmunologic effects of podocyte stabilization, I think it's critically important that we have a sizable representation of a lupus nephritis phenotype that is earmarked by podocyte damage. So if I had drums, I would play it in the background. But thankfully, for everybody on this call, I don't. So I will simply say that this is probably one of the most important slides of this talk. The AURORA trial met its primary 52-week endpoint, showing a renal response rate of 40.8% for the voclosporin group compared to 22.5% for those receiving standard of care therapy alone. With this delta of about 18.3%, this was a statistically significant difference with patients in the voclosporin arm being 2.65x as likely to achieve remission over those in the control group. We're also pleased to report that all prespecified secondary endpoints were met, including our renal response at 24 weeks. So here, 32.4% versus 19.7%. Partial renal response defined as a UPCR reduction of greater than 50% from baseline, both at 24 and 52 weeks. And even the median time to achieve a UPCR of less than 0.5 was much faster in the voclosporin arm versus the control arm. So if you look at this top graph, you can see that there was a very early separation. So even within the first month, a separation in the number of patients achieving UPCR of less than or equal to 0.5. If we focus -- if we look at the median time for half of the patients enrolled to reach a UPCR of less than 0.5, you'll see that those in the voclosporin arm achieved that almost twice as fast as those in the control group. And the median time for 25% of these patients to achieve a UPCR less than or equal to 0.5, again, much faster in the voclosporin arm over the control arm. So again, to summarize. In all of the prespecified secondary endpoints across the board, voclosporin outperformed standard of care therapy alone as marked by renal response at 24 weeks, a partial renal response at 24 and 52 weeks, and even time to achieve a UPCR of less than 0.5. I didn't present this data already, but we also looked at time to 50% reduction in UPCR, so sort of a partial response, if you will. And again, the patients enrolled in the voclosporin arm outperformed those that were in the standard of care arm. Taking a closer look at the study population. The benefit of voclosporin was observed in all prespecified subgroups, including by age, by sex, by race, by biopsy class, geographic region of origin and MMF exposure at screening. As many of you on this call are aware, calcineurin inhibitors can cause some degree of vasoconstriction, which may lead one to wonder if the reduction in proteinuria is in any way attributable to hemodynamic changes in GFR. As you can see here, the eGFR for both groups remained relatively stable throughout the 52-week trial. Folks enrolled in the voclosporin arm saw about a 1.2 ml per minute reduction in GFR over 52 weeks. And those in the control arm saw a slight increase in their GFR of 1.9 ml per minute. Again, this was not statistically different. And the story is the same if you look at serum creatinine alone. Calcineurin inhibitors are also known to increase blood pressure in patients. But in this study, you can see that there was really no differences in either systolic or diastolic blood pressure between the voclosporin and control groups across the 52-week period. In fact, both groups truly achieved a slight reduction in blood pressure over time, and it was noted even before 24 weeks. You can make the argument that maybe this was due to some reduction in disease activity, and these are analyses that our study group are going to investigate a little further. So what about those patients that may have required dose adjustments across the study, dose adjustments, including interruption or reduction and reescalation? So these were all implemented according to a pretty stringent eGFR reduction protocol, of course, after excluding potential contributing factors. So to recap, overall, there was an 18.3% increased response rate in those that were enrolled in the voclosporin arm over the control arm. If we focus on those patients that required a dose adjustment but then were able to be reescalated to our target dose, you will see that there was still a considerable higher response rate in those 31 patients over those that were enrolled in the standard of care therapy arm. If we look at patients that required a dose adjustment because of GFR changes, and were unable to be reescalated to the target dose, again, 16 patients, but again, these patients still had a greater renal response rate over those that were enrolled in the standard of care arm. So to me as a clinician, these data are important because this states that personalized dosing may not lead to compromise and efficacy. So I think that's very important. In my mind, safety is just as important as efficacy. And while we are, of course, excited that this study met primary and secondary endpoints, we're just as pleased to see the comparable safety data between the control groups and voclosporin that was sort of add-on therapy. So if you look at adverse events, serious adverse events, including serious infections, treatment-related events, events leading to drug discontinuation, death rates, or disease-related adverse events, there are really no difference between these 2 arms. So again, despite this being add-on therapy, the safety profile is very comparable. So in summary, the positive benefit-risk profile observed in our Phase III study confirms the treatment effect that we saw in the Phase II study comparing voclosporin as add-on therapy to MMF and steroids versus standard of care treatment alone. The odds of achieving a renal response on voclosporin therapy were 2.65x greater than control, all while still maintaining a comparable safety profile. So in my mind, there's no question that we've seen advancements in the care of lupus patients over the last decade. But as a nephrologist, I think that we are seeing a therapy to potentially move the needle specifically in the subpopulation of lupus patients with active kidney disease. And with that, I will close.

Great. So thank you. Dr. Gibson, that was a very interesting presentation. We just heard the AURORA Phase III study, voclosporin in lupus nephritis with present proteinuria attenuation. I will ask you to enter your questions into the question box for the faculty Q&A. We will be answering all the questions at the conclusion of this session. I want to thank you for your attention, and we're going to transition from lupus nephritis to pruritus.