Lupus Unlocked - Journal Club Save

Hello, everyone. Welcome to Tuesday Night Rheumatology. Now, this month we'll be talking about lupus. Our campaign on lupus at RheumNow is called KEYS TO MASTERY, and we're starting off the campaign with a journal club talking about lupus nephritis and two pivotal trials that have been instrumental in changing the landscape. Tonight, I'm joined by the authors of these papers, Doctor.

Rich Fury, who's from the Feinstein School of Medicine as Chief of Rheumatology at Northwell in Long Island, and Doctor. Brad Rovan, a well known nephrologist member of the Lupus Nephritis Guidelines Committee who's Chief of Nephrology at Ohio State. Gentlemen, welcome.

Thank you.

I'm going to do a screen share, a slide share, and hopefully we'll get a nice view of what we're doing here. Hopefully you're seeing a full screen, if not, you'll let me know. I want to remind the audience that every Tuesday night in the month of May, we'll be featuring a discussion of lupus. This week, it's on lupus nephritis and the two pivotal articles. Next week, cutaneous lupus erythematosus with Victoria Worth and Bevy, a dermatologist who will tell us their views.

Third week, anti phospholipid syndrome, and the final week, pregnancy in SLE. Tonight, we're going to be discussing in our journal club two articles. I'll present the articles and ask for discussion from both gentlemen who were involved in these studies. The first one we're going to talk about is the Regency study published in New England Journal just recently in February 2025. It's obentuzumab in active lupus nephritis where Doctor.

Furey was the lead author. The second article is the AURORA-one study that was published a few years ago. It's the efficacy and safety of voclosporin versus placebo in lupus nephritis, and that was published in Lancet. I'm going to ask my team to put the citations in the chat box if you'd like to download these papers and play along at home as we go over the data. Did a survey ahead of doing these Tuesday night rheumatologists, do surveys of rheumatologists and survey with a single invite, we had two forty seven responses.

Half of them from The United States and ninety seven percent of them, and that's like eighty six percent are adult rheumatologists in The US and eleven percent were nurse practitioners and physician assistants also in The US. Tonight, I'm only going to show you the data from the half in The US, but the results are largely the same when it comes to these survey questions. There was a few results and I'll talk about it. I'm going to begin with the survey. The first question, I had part of the Regency study, which which of the following drugs is not FDA approved for use in lupus nephritis?

The number one answer was correct and rituximab is not FDA approved. The second answer, obentuzumab is also not FDA approved. They were right. I think that that was the same in The US and also outside The US. A few people got it wrong about belimumab and voclosporin not being FDA approved.

I think they need to get out from underneath the rock. But nonetheless, we asked them the question also, the Regency trial, the obinobizumab, the recent New England Journal article included which patients as a main inclusion criteria. Here we have a bit of a problem. I'm going to ask our faculty to comment on half of you said steroid refractory lupus nephritis. The right answer was Class III and IV and they could have had membranous nephritis as well, but they had to have Class III or IV to get in.

The other answers were not chosen recent renal biopsy and membranous proliferative or membranous. Gentlemen, what do you think of that? Is that a problem in trial design or how people might interpret data, steroid refractory as an inclusion?

No. We'll probably talk about that in a little bit when you look at the subgroup analyses. I think there's a misconception about prior history of lupus nephritis suggesting that maybe they were refractory, but not necessarily. So none of our trials require patients to be steroid refractory at all.

Brad, do you have the opinion that nephrologists are different and rheumatologists and how much they're relying on steroids in treating lupus nephritis?

Well, I certainly don't use a lot of steroids and my rheumatology colleagues down the hallway tend to use a little bit more than us. But I model my practice now after the, voclosporin trial, which we'll we'll get into. But I agree with Rich, I think that this was an unusual situation with the obinutuzumab trial. We had a lot of questions as to what it meant to have lupus nephritis in the past. And all the trials have had patients with lupus nephritis in the past.

They just happened to get better and then flare and then qualify for the trial. That didn't mean they were refractory. The only trials looking at refractory lupus now are the cell therapy trials.

Right. Yeah, and that's a big problem, I agree. Here's the gist of New England Journal article from three months ago. On the left, you can see it's a Phase III double blind randomized placebo controlled trial. Both the trials we're going talk about today were multinational, multicenter worldwide studies.

This one includes two seventy one patients with adult SLE. To get in, they had to have a recent renal biopsy within the last six months, and you had to be class three or four plus or minus a five. You also had to have the ANA positive and have urine protein creatinine ratio greater than one. Patients were randomized to either drug and there was a difference in there and how long, whether there was a one year treatment, I believe. But I think for the primary endpoint, probably doesn't matter.

Everybody's on a background of mycophenolate and prednisone. The primary endpoint is a complete renal response defined as a UPCR of less than 0.5 at week seventy six, and the GFR had to be above 85% of baseline, meaning no substantial change in renal function and no new intercurrent event or rescue medications and that sort of thing. The results were at week seventy six, OB was better than placebo, forty six percent versus thirty three percent, and that was significant. If you did add on to that, meaning that that primary endpoint plus the prednisone being less than or equal to 7.5, the results were forty three percent versus thirty one percent, or those with a UPCR of less than 0.8 as opposed to 0.5, the results look better at 55 versus 42. But again, I think that those are the take homes.

Gentlemen, do you want to make any comments about what was unique or important about inclusion or the primary endpoints and outcome?

Sure. Well, we haven't really talked about the history of this. So the REGENCY study was modeled very much after the NOBILITY trial, which was a phase II trial with obinutuzumab. And I must say that the NOBILITY trial was modeled in some fashion after the LUNAR trial, which goes back a couple decades. So basically, the thinking was more is better, and I'm not a more better, more is better kind of person, but more B cell depletion would yield better results.

And there was evidence for that not only in lupus nephritis, but also in SLE and in rheumatoid arthritis. So along came obinutuzumab, a far more potent B cell depleter than its predecessors. And so we put it to the test in nobility, which was a very successful study, and then tweaked the design of the Regency study. So Regency, unlike Knowbility, had an endpoint at seventy six weeks. Knowbility was at one year, though it was carried out actually to two years.

And the patients who entered this particular study were typical patients who get into a lupus nephritis trial. They had a proliferative disease with or without membranous. They had to be serologically active with a recent biopsy, as you said. With a one to one randomization of obinutuzumab versus placebo. But it's always important to emphasize that the patients are not just getting placebo, they're getting background standard of care.

And in this case, it was mycophenolate up to two to two and a half grams, and then prednisone early on, which was tapered, and also pulse steroids anywhere from two fifty milligrams up to a much higher dose. As far as the endpoint, that was tweaked also from Knowbility. What we learned in Knowbility was the endpoint may have been a little too harsh, and Brad could talk about this. There's always a tug of war between having too easy an endpoint to achieve versus something that's a little more rigorous. But in nobility, if the baseline creatinine went up by more than 15%, the patient was considered a non responder.

And in nobility, about a little over a third of the cohort started with baseline creatines of 0.6 or less. So there's not a lot of wiggle room there. If you go up fifteen percent zero point six, you're up at 0.7, and we would just write that off to noise. Anyway, so in Regency, the endpoint was relaxed a little bit, still requiring a protein creatinine ratio of less than 0.5 at week seventy six. But as far as creatinine or eGFR, the eGFR allowance was about 15%.

So you had to have a eGFR of greater than 85% of baseline. And then obviously you couldn't fail by there was a whole series of definitions which are included in the article.

Can you comment on why you chose week seventy six as the primary endpoint? Think usually would be 52. Why did you go that long?

Yeah, that's a good question. So again, we go back to the nobility study. Nobility, the treatment was a little bit different. Patients received obinutuzumab two doses, a thousand milligrams twice within two weeks at baseline. And then six months later, another course with an endpoint at fifty two weeks.

But the top line results showed an effect size that was maximized at week seventy six. So it's about 20 percentage point effect size. As I mentioned before, the nobility trial, though the primary endpoint was at one year, the patients were followed up to two years. So the peak effect was at week seventy six in the nobility trial. And that's why we had the primary endpoint at week seventy six in Regency.

So the phase two trial was the nobility trial and it was a positive trial, which is why you did the phase three. Doctor. Rhoven, did you have any comments on this?

Yeah, I wanted to point out a couple of things that were pretty unique about this trial. Based on sort of what we learned from voclosporin trial, which we're going to discuss in the BLIS LN trial where all comers were included, especially pure class five lupus nephritis. In neither of those trials, when we did sub analysis was pure class five statistically better with the drug that eventually got approved. But some of this had to do with numbers, simply because there were not a lot of patients with pure class five. But the other thing that many of us had been pushing for was to separate out class five from these trials, because it's really hard generally to get a complete renal response for class five, which is proteinuria heavily proteinuria usually, within the time spans of the trials, the way they're done.

And so many of us believe class five obviously needs to be studied, but in a trial by itself, where we can extend, sort of the time to see the complete renal response. We get a lot of questions about why class five wasn't included, because many of us think that the B cell therapies will be good for class five as well. That's the reason and I think the audience should understand that I have no doubt that it would work in class five, we just have to show that. So that's, one important, sort of takeaway, from this. And then I don't know if we're going to get into a little bit of the sub analysis, but many of us were a little bit surprised at the effect size here.

And some of that can be explained by the response in the male patients. Maybe you're gonna show that shortly in the

first Yeah, I didn't pull that one. But we can show it and maybe discuss it in the next slide. I want to remind the audience a few things I didn't say. One, we're going to take questions at the end, so you can write in your questions and we'll get to them at the end on both of these studies. Two, the sponsor of the campaign on lupus for the whole month is Aurinia, and actually that had nothing to do with the selection of these two articles, which were selected by my advisory panel, which is Maria Delaure, Michele Petrie, and Megan Clouse, and they chose the articles that they wanted us to discuss.

I think it's important to note that. In the trial, we asked them when was the study assessed? Most people thought it was a fifty two week trial, only thirteen percent knew that it was going to be seventy six weeks. Then the complete renal response as far as getting the right answer, half of them got it right, and it's the same in US and Ex US. But most people were kind of a little uncertain as to what the treatment effect size was in going forward.

These were the results, again, now represented graphically for the complete renal response 46 versus 33. You can see that when I show you double stranded DNA and complement levels, obviously having much better responses with obentuzumab, Then the B cell depletion being really complete going out here beyond fifty weeks. These are the results I wanted to show in serious adverse events. Pneumonia was the number one, infections were the number one overall infection, pneumonia being the major one, not renal impairment as many of you selected in a survey result. Brad, do you want to talk about this in that sub analysis about males?

Yeah, so it was really curious because I'll speak for myself, of course, many of us on the steering committee for this trial were really expecting a duplication of the pretty profound effect size that we saw of twenty percent in the nobility trial. And we were pleased that the trial was, you know, statistically significant and in favor of OB, because we sort of assumed that would be the case. However, we wondered why this effect size was a little bit diminished. It turns out that sixty seven percent of the men in this trial achieved a complete renal response by these definitions in the quote placebo group. So, the background therapy alone group.

When you remove the men which of course is a much smaller proportion of the total patient volume. The women did have a twenty percent effect size as we had had hoped for. I have no cogent explanation of why the men responded so well to mycophenolate and glucocorticoid. And that's certainly not what we generally see in practice with male lupus patients.

Yeah, that sounds odd. Other than the males with lupus nephritis, they're probably worse than females with lupus nephritis. Rich, you have a good explanation for that?

I do not, but we need to look into this obviously to see what their characteristics or baseline characteristics, their class of lupus nephritis and what their histories are and so forth.

Yeah, there was nothing obvious. Rich and I have been through these data looking for the sort of low hanging fruit to explain this and we have not succeeded yet. This may be one of the mysteries of clinical trials.

Yeah, that clearly happens and that's why we do them and sometimes why you need to do more than one. Serious adverse events There were mainly infections. You could see that COVID-nineteen was the most common infection actually. These were serious, meaning that they hospitalized, received IV antibiotics, a significant change in morbidity mortality. The first and second number is OB versus placebo.

There was more with obinutuzumab COVID-nineteen than there was with placebo. I can't imagine why that would be other than we know that B cell depletion is not good as a risk factor for COVID. And that's probably a good enough reason alone. But URI, gastroenteritis, they weren't substantially different. There were four deaths in the trial, three that were on obinutuzumab and one on placebo.

I'm going to go forward if there's no other concerns or questions. Jack, let

me just point out, this study was done at the peak of the pandemic. Alright, so that's not the optimal time to do a study with an immunosuppressive drug. We saw the same kind of events with anifrolumab, at least the long term extension of anifrolumab. And actually, if you look in the supplementary material, we had the events by time. And during the second half of the study, there were far fewer COVID related events than in the first half study as we learned how to handle COVID and vaccinations came around and so forth.

Which is the question about immunoglobulin levels with this B cell depletion. The rituximab data is when you do a rituximab trial. Imgliven levels don't change until you're on rituximab for the nineteenth course or something like that. But here, do imgliven levels change?

They do. Let me actually go back to the NOBILITY trial because we had more data, at least in the public domain there. It's really a tug of war between the effect of the B cell depleting agent and the loss of proteins in the urine. So again, going back to Knowbility, I think it was around twenty some odd percent of the patients started out with a low IgM and a similar number with low IgG. As the study went on, those who received obinutuzumab, there were far fewer patients who had low IgG.

Meaning as their kidneys got better and their proteinuria was diminished, their IgG levels went up. But the converse happened with IGG, and that was probably mechanism of action of the drug. So there is we have some IGG data. We don't have IGG data out in the public domain just yet. So again, it's important to think about that tug of war between mechanism of action on the B cells and improvement in kidney function.

There was a question as well about you get greater than 90% B cell depletion, but only fifty percent complete renal response. Does that mean that B cell depletion isn't the answer here or what we define as complete renal response is really complex?

I think this is a big problem for the entire field. What is a complete renal response is an arbitrary level of proteinuria that we've decided is a good thing and stability of GFR. And I think, there's several ways to look at it. First, we are extending this trial and it will go on for at least two years and probably longer. And we'll see how this looks over time in terms of complete renal responses.

The other thing you have to think about is that many of these patients had lupus nephritis in the past and this is a flare. Every time you flare and have a sort of a course of lupus nephritis, if you will, you accrue damage to the kidney. So, kidneys that are damaged tend to leak protein and it is likely that many of these patients will never decrease their proteinuria level below 500 milligrams a day and yet, they may have resolution of their serologies. They may have no more activity on kidney biopsy and they have a little bit extra proteinuria. They can never be called a complete responder.

Yet all of us taking care of that patient would be absolutely pleased with the response. So I would make it clear to the folks listening that we did something really cool in this study. We biopsied people obviously to get into the study and then sixty patients, thirty control, thirty OB patients had repeat biopsies at week seventy six. And we're going to correlate that with tissue B cell depletion, of course, and also look at patients who might not have had a complete renal response clinically, but to see what their actual histology looks like, to see if they have achieved a histologic response. In other words, no more inflammatory activity in the kidney.

So, stay tuned for that. These data are undergoing analysis right now. I I Rich and I have seen some of these. They're very exciting data and so the story will be unfolding but in no way would I ever suggest that B cell depletion is not effective.

Just a comment about that histogram that we're talking about in the top right. So B cell depletion in that histogram was defined as fewer than 10 cells per microliter, which is not very stringent. I'm going to take you back to the NOBILITY trial, where there was an analysis using a very stringent threshold of 0.4 cells per microliter. And so there were some interesting data generated with that. First of all, a comparison to rituximab, and obinutuzumab depleted to that threshold far better than rituximab.

But more importantly, we looked at those patients who achieved that very stringent threshold of B cell depletion and those who did not and looked at clinical responses. So those who had the profound and sustained B cell depletion had an edge on complete renal response rates by as much as 15 to 20 percentage points. And you know, as Brad was saying, there is a ceiling on effect size here, or I should say on response rate because of people coming in with pre existing damage. The best medicine in the world is not going to undo their damage. Therefore, they will never be complete renal responders.

And what that number is, I don't know. When I lecture, I usually say it's probably around seventy percent is the maximum response rate that we'll ever see in a lupus nephritis trial. That's why I'll be very transparent. I wonder how we're seeing one hundred percent response rates with the cell therapy trials in refractory lupus nephritis.

Or some of the studies coming out of China with teletocicept and others that where they look like eighty percent responses. Agree. Do both of you think that there's an advantage in the future to using urinary biomarkers as an endpoint as they correlate well with histology and multiple parameters, not just with proteinuria and seem to be superior to proteinuria? What do you think?

Yeah, I think that this is really where we need to go. We're still not entirely, you know, we have serologies, we have complement levels and double stranded DNA, which we tend to believe correlate very nicely with response. And of course, you know, in some patients that's correct and in others it is not correct. But I think we need to have a multi pronged approach to understanding what a complete response is in patients with lupus nephritis. And certainly one of the things we'd like to see is a complete resolution of inflammatory activity in the kidney.

And I will say that research from many laboratories, including my own, but many beyond that are starting to find biomarkers that really do sort of reflect what we see on kidney biopsy and reflect the inflammatory milieu of the kidney. So, my hope is that we're not going to abandon proteinuria ever because it's an important parameter. But my hope is we're going to have a really sophisticated endpoint for clinical trials that will allow us to take into account damage to the kidney proceeding. So patients that would normally never qualify will qualify for a complete response. So that is to me going to be the future.

Rich, do you have a wish list for future better endpoints?

No, we definitely need urinary biomarkers, can't keep doing biopsies. And I should say that the Lupus Research Alliance has a committee that's looking at urinary biomarkers of which Brad is a member.

Okay. Good. We're going to move on to our second report, which is the AURORA study. In our surveys of, again, two forty seven people. We asked the AURORA-one trial included which lupus nephritis patients, and the AURORA-one did include all GN-three, four, and five.

So only thirty six percent got it right, but still eighteen percent thought refractory to steroids or membranous only, eighteen percent there. The second question, what was the primary endpoint? The primary endpoint was UPCR less than 0.5, and that was right by sixty one percent. But others were thinking, again, no end stage renal disease, it's certain GFR, or reductions in overt proteinuria just as measured as grams per twenty four hours. Design of this trial, was published in Lancet in 2021, is a phase three double blind randomized placebo controlled trial.

Actually, before I do that, and I should have done this and Rich really did the right thing by giving me a history of the Regency study. Doctor. Roman, do you want to talk about the history of why we're using voclosporin or how this trial came to be?

Yeah, so if the audience remembers, there were a lot of trials of calcineurin inhibitors, mainly out of Asia, that suggested really better responses to standard of care therapy with cyclophosphamide or mycophenolate. These were mostly done with legacy calcineurin inhibitors to chrolimus, and some were done with cyclosporine. And so the group from Aurinia had this asset voclosporin which had been tested in transplant and was quite successful but it really never caught on. And the idea with the voclosporin was that it was sort of a new type of calcineurin inhibitor, it looks very chemically much like cyclosporine. It has one methyl group different.

But anyway, that changes its toxicity profile considerably. And as far as this drug compares with lots with the other two legacy calcineurin inhibitors, less diabetes, less electrolyte imbalances, even potentially the idea of maybe less calcineurin nephrotoxicity, which is a interstitial fibrotic lesion. So, they brought the idea sort of to the lupus community and said, we should do a trial that is including but not restricted to people of Asian ethnicity. You know, so a whole world trial and use a safer calcineurin inhibitor. So that was the origin.

In the phase two trial, we showed again, this was a very successful phase two trial. Prior to the phase three, we showed a good effect size that was really seen within six months of using voclosporin and continued on for a year with statistical improvement in the voclosporin patients, which gave a lot of impetus to use do this in a phase three trial. And that was sort of the origin of AURORA-one. And I think it all made perfectly good sense.

Yeah, I like these trials. I remember David Wopsy presenting the phase two and other data at ACR meeting and thinking this is really smart to go after a new indication of lupus, but do it in lupus nephritis where I think outcomes are probably better to, easier to assess as opposed to a SLETE I2K you know, Bicla and other things that we have to do. That's my bias. In retrospect, do you think it was a good idea to go after specifically lupus nephritis as opposed to general lupus with this drug and these trials?

Well, you're asking a nephrologist.

Oh yeah, okay.

I'm gonna say yes. But again, I think that the mechanism of action is really kidney centric, if you will. I mean, yes, this drug does affect T cell activation. And so it theoretically would be something useful for a general lupus, but I think the bang for the buck is in the kidney because it's podocyte protective, it's anti proteinuria, etcetera, etcetera. So going for lupus nephritis made perfectly good sense to me.

You should ask Rich though.

Yeah, Rich, what do you think? You know,

I'm with you, Jack. There's an incredible amount of subjectivity in our metrics for SLE outcomes, sleep eye, by lag, and that's why sometimes we see 100% placebo response rates. To talk about a ceiling, I said the ceiling for lupus nephritis may be about a seventy percent response rate and SLE could be one hundred percent, but for the wrong reasons.

When I was on the FDA advisory panel when they were considering outcomes in lupus, I think you're at that meeting, Rich. It was a fight over what the best outcome measures were in lupus because it wasn't so clear then and we certainly didn't have all the trials we have now. But certainly I think that the objectivity goes up a notch with nephritis. This trial was a Phase III double blind, multicenter, multinational trial, three fifty three patients with adult SLE. Here, the biopsy requirements were a little lax in that you had to have a biopsy within the last two years and had to be a three, four, or five, or combination thereof, and patients were randomized to either voclosporin or placebo, having received a background of standard of care, SOC, which was mycophenolate and steroids.

Both these trials had a regimen to taper steroids once they're on therapy. One hundred and seventy nine received voclosporin, one hundred and seventy eight received placebo. The primary endpoint here was at week fifty two with a urine protein creatinine ratio of less than 0.5, but you also had to have a stable GFR, no new rescue meds like a DMARD or any other immunosuppressive, and steroids less than or equal to ten milligrams per day. Did I get that right, Doctor. Rhoven, as far as the-

Yes, that's all correct. I wanna make a couple of points. I argued vehemently against a two year kidney biopsy. Because lupus nephritis, especially proliferative lupus nephritis is a disease that evolves fairly and can evolve very quickly. Also, there's no way that you would allow a person with active lupus nephritis to go two years without intervening medication, and not understanding what you're treating when you got into trial is very bothersome.

So let me qualify that. The compromise when we were designing the trial was that no more than twenty percent of the patients could have a biopsy out to two years. So the majority of the patients had biopsies much closer to the start of the trial, which is what we absolutely need in these sort of trials, so that we have a good idea of what we're treating. The other thing is the complete renal response. The GFR part was a little bit lax to me.

We allowed a GFR that could be within twenty percent of baseline as opposed to, for example, the Regency which was 15%, or a GFR greater than 60. The nephrology community has labeled chronic kidney disease as having a GFR of below 60. And I'm not sure why we did this. And I will excuse myself from responsibility because I never want a GFR less than 60 or at 60 to be considered normal. Okay.

So, this was a little bit I think there are stricter endpoints out there, but nonetheless, this is what the trial showed or looked at.

You know, I think the pushback on the duration from biopsy to inclusion really comes from, I mean, you guys that do this, you want to do the biopsies, you want to get them, you're aggressive about getting, guys like me that do trials in other diseases, but I do lupus trials too. I'm a weenie when it comes to biopsy. I don't want to do biopsies. What I'm learning this month with all the experts is that everyone is unified and saying we should be doing across the board more renal biopsies, including at the end of study, but certainly at the start of therapy to know what in fact we're dealing with because most of us are guessing and thinking that we can get by without it. I think that leads to suboptimal decisions and suboptimal management.

We'll see throughout the rest of the month, have a lot of people who going to address this issue. On the right, I show some of the demographics. In both these trials, about fifteen percent were African American or so. The number you could see in both groups here was eleven to fifteen percent that had pure class three, fourteen percent had pure class five, and majority had class four, and again, about fifteen percent had a mixture. Then the number that were on mycophenolate at screening was around fifty five percent in this trial.

The primary endpoint at week fifty two was achieved by forty one percent on voclosporin versus twenty three percent on placebo, and that was significant was a pivotal trial into the drug being FDA approved. This is a primary endpoint The blue bars are looking at the voclosporin and the pink bars is placebo. On the left, you're looking at the primary endpoint complete renal response, on the right, you're looking at the partial renal response, which is defined as instead of being 0.5 as a complete renal response, here it's a 50% reduction in their UPCR at weeks fifty two and twenty four. The most strict primary endpoint on the left showing you 32% versus 20 at six months, they went up to forty one and twenty three and fifty two. The numbers being better, but also your placebo responses are better when you make for maybe a lesser threshold of a fifty percent reduction in UPCR.

That's the primary endpoint. The safety endpoints are shown here, serious adverse events, twenty one percent, Lupus trials with a lot of steroids on board and multiple drugs, there's a lot of serious adverse events. The ones that are infectious were about half that rate, about ten percent. Treatment related was four percent, leading to drug discontinuation was eleven-fifteen percent, and deaths, there were no deaths in this trial. The last graphic on here is the time to response between voclosporin and the placebo group going out to one year, and you can see that it really starts off at two weeks being already significant.

Doctor. RheumNow, do you want to address these graphics at all?

Well, I'll just say that part of the response or the rapidity of the response that again, folks need to understand when using a calcineurin inhibitor is that it's a three part response. The one that takes the longest is the actual treatment of the lupus with the immunosuppressive properties of the anti T cell properties of the calcineurin inhibitor. But the very rapid response is due to two things. One is we decrease glomerular blood flow hemodynamically with a calcineurin inhibitor. That's why creatinine can go up a little bit.

And that tends to decrease proteinuria on a hemodynamic basis. And the other thing that is really important is that the calcineurin inhibitors sort of stabilize the podocyte foot processes, cytoskeleton, and help the foot processes stay functional. And that's really important because we don't wanna lose podocytes. If you lose a fixed number of podocytes, it's controversial whether we can replace them in life. And if you lose a lot of podocytes, that nephron is destined to die even if your disease is stopped right away.

So a lot of beneficial effects on the kidney that are not necessarily immunologic. And that accounts for the very steep separation between the vocal group and the placebo group. And then later on the immunologic effects come into play.

Okay. Yeah, I was not aware of that early effect and what the difference there was. Graphics I'm not showing here were the responses of double stranded DNA and complements. Do you want to address that?

Yeah, I mean, I don't think they were as profound, excuse me, as we see with the B cell drugs. And, you know, this sort of makes a little bit of sense to me. And that's why when we start making guidelines, when we talk about patients having a lot of extra renal disease, do we choose voclosporin or for example, a bulimumab as the third drug if we want to do a three drug regimen and I I think there is a case to be made that one might want to choose a a B cell drug if there's a lot of extra renal symptoms because drugs like Baluma Mab were designed to, you know, sort of look at or address the extra renal disease.

Okay. Well, when we did a survey here, we asked our audience what was the most frequent adverse event in the AURORA-one trial? They said renal worsening, and that didn't occur. I mean, the number one adverse event was pneumonia and infections in general. You want to address that Doctor.

Robin? Yeah. Know, I think some people might have thought about the expected rise. So like I was saying on the issue of what the calcineurin inhibitor does, we expect the calcineurin inhibitor to increase creatinine. That's not an adverse event, okay?

That's an expected event based on its mechanism of action. It can be misinterpreted as an adverse event. And I think we have to be very cautious about that because when people are using these drugs, if the creatinine goes up a little bit or the GFR goes down a little bit, that's not a reason to stop the drug. Usually I tolerate about a 30% increase in creatinine before I start to cut the dosing of the drug back. And we had rules in this trial to do cutbacks if the creatinine went too high.

Like any other drug that's an immunosuppressive, you know, the majority of the side effects are going to be infectious. And, you know, the lung is clearly unfortunately exposed to the environment. So none of that is surprising.

That guideline of thirty percent tolerance to the GFR, which we use in cyclosporine dosing when we use it, especially in rheumatoid arthritis and whatnot, that works out fine. It's when you get beyond that that you need to be very worried. A little concerning when we ask people what kind of drug is voclosporin, half said it was a calcineurin, a quarter thought it was anti proliferative, a quarter thought it was cytotoxic. I think there's still, even though this drug has been on the market for four plus years, or four years I should say, there's still some concern with twenty seven percent not having used this drug based on the last question, who would you use voclosporin? Half got it right according at least to the label and the indications or the inclusions in the trial, which was Class III, IV, and V.

But twenty seven percent haven't used it, only a quarter would use it only with large proteinuria. Based on the trials that were done, where should voclosporin be used, Rich? What do you think?

Well, I tend to use it for my pure fives with a lot of proteinuria. Now, there's a big pill burden and we know our lupus patients, first of all, they're in denial. They're, you know, it's a young crowd. They don't go to the doctor as often as they should and they don't take their pills. We know that from the hydroxychloroquine studies.

So to add another six pills to their, you know, whatever twelve pills that they're taking, I think is risky. But nevertheless, I do use it, especially in patients with a lot of proteinuria.

Brian, what do you think?

Yeah, I, you know, I use it. So there's clearly some division in how folks who want to use a triple regimen do things and it really goes along party lines if you will. Nephrologists tend to be very comfortable with the calcineurin inhibitors. We tend to use the calcineurin inhibitors a lot and less less so the B cell Bulimumab. Whereas rheumatologists seem to favor the B cell drug because they have less experience.

I think this is going to change over time as we use both. I tend to use I tend to use a calcineurin regimen for most of my lupus patients, heavy proteinuria or not. We'll consider using Baluma Mab in patients that have a heavy burden of extra renal disease or in patients as as Rich said who have issues with adherence. The pill burden with the calcineurin inhibitor is is quite high. Six pills to get the correct dosing twice a day.

So that's a big deal on top of all the other medicines they're taking.

So I have a few of this. I did a Twitter poll two weeks ago ahead of this campaign. I asked, what drug would you use in patients of class five? Two thirds said they would use a calcineurin inhibitor, and that was encouraging. I also asked them what their steroid dosing regimen was with class three and four nephritis, most choosing a high dose.

But do you both want to a moment to talk about steroid dosing when starting treatment with lupus nephritis? Again, here are the ACR guidelines that say everybody should be on antihypertensive, hydroxychloroquine. Whether you're on first line therapy for class three and four on the left or class five on the right, everybody gets pulse followed by a taper. Again, give us your regimen. Let's start with Doctor.

Rhoven first. Steroids when you're starting lupus nephritis therapy.

So over the course of my career, I've completely evolved my use of steroids. I used to avoid pulse steroids and start with oral prednisone about one milligram per kilo per day. And as I've become more used to how patients respond, I really like the steroid regimen that we used in the Aurora trial, which was up to a gram of solubendril, like five hundred milligrams and five hundred milligrams. And then I start with a low dose of oral steroid, because why are we using the steroids? We're using the steroids to control inflammation as quickly as possible especially in the proliferative diseases and so, pulse, methylprednisolone is about as quick as you can do and it really lasts a long period of time and then and then the glucocorticoid gets oral.

I think we can start low as we did in the Aurora trial and get rid of very quickly. So, the first drug I get rid of in almost all of my patients is is the glucocorticoid. Unless they're having joints and that that sort of thing, extra renal stuff because I think after a month or two, the immunosuppressive should be kicking in. And I really think they're much less toxic than the glucocorticoid.

So after pulse, you say start low, do you mean twenty milligrams?

Yeah, I've been starting, I haven't necessarily been brave enough. The excuse me. The dosing in radio came out to about. Three milligram per kilo per day. I usually start at about.

Four to. Five milligram per kilo per day. Much less than I used to use a milligram per kilo. And then I'm really getting down to the five milligram range by about three or four months. Much.

What's your

approach to steroids?

Well, like Brad, I grew up in the era of pulse steroids. Go back, I don't know when that article was published by Cathcart. So everybody was getting three grams of methylprednisolone way back then. But I obviously have trimmed my use of pulse steroids. So I still believe in it because I think it's a way to quiet down the kidney inflammation quickly, but not to the tune of three grams.

So I will customize it according to what the biopsy looks like. And then follow it up with oral prednisone, but again, not a milligram per kilogram, probably closer to anywhere from zero point two five to zero point five milligrams per kilogram. I try to get rid of it as quickly as possible.

Okay, very helpful. We have time for some questions. I want to thank our audience for sticking in there and asking questions. Someone asked the questions, a patient with pure class five and a UPCR of less than three, would belimumab be a good choice? I mean, it's indicated for lupus nephritis.

Are you going to take this Rich or?

I can. And I think Brad, said before, it takes a while for class five to improve. And I think belimumab is incredibly safe. And despite the subgroup analysis showing that PURE-five didn't respond to belimumab, except for the fact that there were fewer flares with belimumab in the PURE-five group over time. I will use it for mild, you know, what I'll call mild class five, and I've certainly seen my share of good results.

It just takes a while.

Okay. We got a question from Tina Kochar about how do we see obinutuzumab entering the marketplace? Is it going to come in with a lupus indication or nephritis indication or both? Again, neither of you know because the FDA has not made its decision. Maybe at the end of this year, we'll see something, by the end of the year we'll see something, but where do you see this being indicated and used initially?

Just throw out that I think we're going to see the initial, I'm hopeful that we're going to see an initial approval maybe before the end of the year in lupus nephritis. I know that a trial of OB is being done in non renal lupus as well. But I think it's going to come in and then it's going to have to be fit into these guidelines. These are the ACR guidelines which I had the privilege of working on. Rich is working on the Ular guidelines right now.

I work on the kidney guidelines and we are all going to have to fit it into this idea of, you know, a triple therapy regimen and I think it can fit it nicely.

Yeah, so as Brad said, there is a study being performed right now in SLE called the Allegory Study. But if a successful study, it would be the approval in SLE would be a year behind lupus nephritis.

Okay. Question, is there any evidence of renal scarring or a renal detriment with voclosporin or calcineurin inhibitors?

I will tell you that because we were worried about this sort of thing, we did a repeat biopsy study and it just came out in arthritis and rheumatology today. It had been out electronically. So you can see all the data, but sort of the top line is that over eighteen month period of time from biopsy one to the second biopsy after voclosporin. We really didn't see an increase in interstitial fibrosis or the damage scores of the NIH chronicity index. Now, you can say, okay, well, maybe it needs more time, etcetera and all of that's true.

I'll I'll just point out that one of the features that and it doesn't prove in humans anything but in animal studies, voclosporin seem to be less nephrotoxic than cyclosporine, for example. So in restrained timeframe, I think we will probably be able to use the drug without too much worry that it's causing chronic damage to the kidney.

Okay. I want to end with asking each of you to tell us that what's the hidden gem in each of the papers that you are lead author on? Something that doesn't get talked about enough That happens commonly in clinical trials, you have a primary endpoint, but that there are things that you find out after the fact that were interesting worthy of consideration. Rich, was there a hidden gem to Regency study?

Well, we didn't talk about eGFR slope, and we probably don't have enough time. But I think people should pay attention to that, and maybe Brad wants to make some comments. But we looked at eGFR slope in the BLISS LN, the nobility, and the Regency trial. That probably tells the story. That's the goal of what we're trying to do to these patients is to attenuate the reduction in eGFR over time.

So is that really a representation of time to response?

Well, the interval that we looked at in Regency was a year and a half, in nobility it was two years. So is it a surrogate for what happens over the next, you know, four or five decades? It probably is and there are lessons learned from the other nephritic diseases and that's where I, you know, my teacher about this is Brad. So, maybe Brad wants to make a comment.

So, it it's interesting. Rich picked what I was going to say about the extension of the Aurora trial which was Aurora two where they kept patients on who were doing well for total of three years and we did look at GFR slope and and you had asked earlier, Jack, about this idea of what will be an endpoint in the future and we talked about urine biomarkers, etcetera. What we absolutely want to see is stability of GFR over time. We wanna minimize the decline of GFR in in these folks so they hopefully never get to needing a transplant or dialysis. And as Rich said, if we preserve GFR by as little as one mil per minute per 1.73 meters squared per year, we extend the life of that native kidney for several additional years.

So that will be our ultimate goal. You can see those data for voclosporin in the AURORA two trial.

All right. I want to thank Doctor. Brad Rovan and Doctor. Richard Fury for a great discussion and great insights into these important trials. I want to remind the audience that we'll be doing Tuesday night rheumatology every Tuesday night, 7PM Eastern for the next three weeks.

Next week, it's cutaneous lupus erythematosus where I'm going to ask Doctor. Worth and her colleagues, why do we not have classy and skin outcomes as primary outcomes and a primary indication for lupus new drugs? We'll discuss that next week. Gents, thank you very much.

Pleasure. Thank you.