Sanjeev Sethi, MD

I've said this many times, we're in the golden age of studies in glomerular disease. And we are making great strides in an ultra-rare disease like C3G. I know our center's certainly recruiting and there's a global network of GN centers now recruiting to these studies, which we'll hopefully deliver, but we are spoiled for choice Jerry, and we have lots of studies. I will you just first run us through your approach to managing patients in 2023 and the kind of opportunities that might be available with all the clinical trials that are happening at the moment?

I was hoping you'd come back to IgA nephropathy, because we've lacked a good biomarker. People have said, level of galactose deficient IgA or antibodies to galactose deficient IgA. But so far, we have not had a good biomarker. And the best correlation we've had is with proteinuria. Now, the good news is that the FDA realizes that some of these patients will only slowly progress. They're using the surrogate marker, which has been mentioned, a proteinuria reduction. The bad news is they're using a surrogate marker. We don't necessarily know what's going to happen to the GFR in all these cases. We've recently had 2 drugs approved in terms of treating patients with IgA nephropathy, first of all, without the final publication of the manuscript initially, and then without the final data in terms of what's happening to the GFR. And certainly, in terms of we've got the shorter terms data, not the longer term data that we might need. I'm not against the fact that the FDA is approving these, it's just making it more challenging in terms of following these patients without a good biomarker in terms of this. My view in terms of treating the patient is that given anybody with risk factors, I would put them on maximal supportive care. Now, if you look at KDIGO guidelines, they say that high risk is over 0.75 to one grams of proteinuria that persists for more than X amount of time. That which is 3 months is what they're talking about there. But in some of the studies, the stop trial that was done in Germany, they said you had to be on it 6 months. Before you had standard of care. The other thing is, none of the studies yet have included SGLT2 inhibitors, which are rapidly becoming standard of care. We already have data in IgA nephropathy that it makes a significant difference in terms of time and proteinuria and course of the patient too, in terms of GFR. Given that the standard of care has changed, we've upped the level blockade of the renal angiotensin system, strong consideration to SGLT2 inhibition, then the role of steroids, which we've certainly confused a lot of nephrologists by starting out by saying they worked because we had 3 or 4 trials, small, but they seem to work, then we all of a sudden have a big trial that looks like it's done very well, but it had unique features that made it a little different from some of the others. But the stop trial that said they didn't work long term, then we get to the testing trial that doesn't work at first, but then does work after they do it at a lower dose. Everybody has been changing what they're doing, and we're going back and forth. I feel sorry for a patient if they heard this, that the steroids you tried 3 years ago that we stopped, well now we're going to try them again. And whether those steroids or a non-absorbable steroid that works predominantly on the gut should be used, is just not clear. What we're left at least in IgA now in terms of standard of care. For anybody who's high risk, and I think high risk is probably going to be more than 0.5 grams not 0.75. It's very clear that there is data from Vega and other studies that show that, so at lower levels of proteinase should get standard of care. And then if they're not at the point that keeps them at high risk, and that's going to be different for different people, we should be doing something. And whether it's steroids, straightforward, old-fashioned steroids at a lower dose for still about a 6 month course, or whether you want to say, look a non-absorbable one because this person has high risk factors for steroids, they're they also have diabetes and where they don't want cosmetic changes that person might benefit from a non-absorbable steroid, which we don't have good proof that they're entirely non-absorbable but again, there's going to be individualization of therapy at the current time until we get more clear data or until we get a good biomarker. They are looking at new CD markers, CD8 I think it is, but they're looking at new markers trying to say that this is going to make a difference. And in some diseases it looks better than others in terms of lupus. Some people feel using urinary biomarkers is making a difference already now. But still for IgA we're left with getting what we wished for, we wished for the FDA to finally approve something, and now they're approving it faster than we know the data. And we can't make decisions based on it.

: It is a real challenge. You're right. I go to my therapeutic cupboard for my IgA patients and it's empty, and we're going to move from zero. We've had nothing for 50 years. Two new drugs in the last 18 months. Three phase 3 studies are likely to be reporting over the next 12 to 18 months. We are going to need to educate our nephrologists, our colleagues, how to use these with the right patients. What are the safety concerns? How might we potentially combine them?

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Anuja, you touched on something interesting in your context of post-transplant recurrent disease. Is transplant patients have a lot of immunosuppression on board. And it doesn't seem to impact greatly on recurrence of IgA, but also C3G in your, is that your experience?

And that shows a limitation really of conventional approaches.

Would you, in terms of your transplant practice, where would you see complement, therapies fitting in, in the context of patients already on often triple immunosuppression?

Following up on what Dr Nester mentioned, we are always worried about infections in these patients because as you said, as we know, these patients are on baseline immunosuppression to begin with. A few different things to keep in mind when we are using complement inhibition in transplant population or even in native kidneys, is that, as we've talked about, complement is part of innate immunity we are born with it, but as a person grows, your maturing adaptive immunity also starts playing a role in preventing infection. That's an important protective factor. The other thing depends on what inhibition you're using and which level that is. If you're using a C3 inhibitor, which is more central to the complement activation versus if you're using a more terminal inhibitor, you would worry that if you have a patient on a more C3 inhibitor, will that person be at a risk of broader infections. I would say that even though these drugs inhibit the complement system, they don't completely abolish the ac- abolish. There is even that little residual complement that you have is protective. And in our transplant population, my experience is that we've had a pretty good success with using these drugs, particularly patients that I take care of with atypical hemolytic UIC syndrome, where we use anti C5. And a very important factor is the vaccination. These patients are vaccinated, and the vaccination does bring down the risk of these infections, at least stand forward from what the literature shows. In addition, we keep our patients with prophylactic antibiotics. If you don't have enough time to vaccinate them and you must start the therapy, you could start them on antibiotics. And we keep our patients on antibiotics lifelong. There is a lot we can work with in using the inhibitors even in a more immunosuppressed population like the kidney transplant.

Anuja Java, MD, discusses the role of complement inhibitors in transplant patients with C3G.

Complement therapy in transplant patients in C3G

: If you take a step back and think about your pathophysiology if it's an autoimmune-driven process, you might want to target the B cells that are producing the autoantibody. If it's a complement-driven process, targeting the complement system is the direct route to take, isn't there?

That's correct. In fact, there have been, again, not any randomized controlled trials, but there have been attempts to block B-cells that have been almost flipping a coin, whether it's been successful or not. It works in some case reports. It doesn't work in other case reports. Routinely we can't depend on blocking B-cells to help us with this autoimmune disease. It sounds like a great idea, but it hasn't been clearly proven to be successful. But yes, you're right. If you believe that the disease is driven by alternative complement pathway dysregulation, then you need to block the complement system at the level that it needs to be blocked.

What clinic current clinical trials are you aware of attempting to do that?

You can go to clinicaltrials.gov and you can figure out, for instance, what trials are out there. But I would say that in thinking about where the disease is originating so if you think it's in the middle of the pathway at the level of the convertase, then there are at least three agents that are out there, or three ages that could target where we think. The first one would be that was trialed, was the factor D inhibitors. That trial is now closed. It wasn't as successful as we thought it would be, but it was probably because they didn't reach the appropriate PK studies. We can't say D is out, based on that. But then now there are also factor B inhibitors and factor - and C3 inhibitors. Both of those would be predicted to be a much better match to this disease or target the disease much more closely than we've been able to do, for instance, with terminal complement blockade.

: I believe some of that data has been presented at conferences.

Yes. The D inhibitor has been published, so that people can find that in the published literature. The factor B inhibitor and the C3 inhibitor both have been taken to multiple congresses. Any of the nephrologists or even hematologists can go to their congresses and actually see the fact that both of them have reported preliminary successes, actually.

That success has been reduction in proteinuria.

Reduction in proteinuria, improvement in GFR or at the very least stabilization in GFR and in some cases, even though it's a surrogate, improvement, or normalization of C3 as a surrogate of quieting the complement pathway. Those have shown up in our congresses and, I’m sure that both of those studies are in phase 3 right now. It's very important to be watching for the results because obviously as nephrologists, we want to know that they're effective, absolutely, but also that they're safe.

And that's important. And I think we do need to highlight the fact this is going to happen soon if these trials are positive, we are going to be faced with drugs hopefully that will be approved and will be coming into clinical practice for these patients with this devastating disease. But I'm just going to come back to safety, because that clearly is the critical other side of the coin, isn't it? We need to know these drugs are efficacious, but only in the context of them being safe. And what are your concerns if you were to use a complement inhibitor, what would be going through your mind in terms of things?

Again, if you think about it, again this is part of your innate immunity. This is part of your immune system that was meant to fight infections that you were not vaccinated against, for instance. You must think about those sorts of things. But the classic concerns are encapsulated organisms. Those are the organisms that you require your complement system to be functionally active to be able to defend against. Antibiotics work but you need your complement system to keep you safe while you're waiting for the antibiotics or wait to even be started or to even work. We think about encapsulated organisms, and that's meningococcus, streptococcus and hemophilus influenza are the 3. Fortunately, we have some data from the Eculizumab or the terminal complement blockade trials that we know that you can vaccinate for those three organisms and get some protection. So that's very important. And in fact, I believe that that's been carried forward in pretty much all the upcoming trials. You'll have to be vaccinated and be watching for those organisms.

: That's an important point to note. For those nephrologists who potentially may want to use these drugs in the future is that's really going to be critical in terms of managing the safety aspects of this drug.

I suspect that the regulatory agencies will require those vaccinations prior to the use just because they were part of the clinical trials.

Carla M. Nester, MD, MSA, FASN discusses recent clinical trials on complement inhibitors for C3G.

Clinical trial data on complement inhibition in C3G

If we think about what's happening in the therapeutic arena, Carla, I want you to talk us through where we are now with C3G or perhaps where we are not, and what are the opportunities you see on the horizon in terms of the clinical trials and therapeutic approaches that are being evaluated.

For C3 glomerulopathy, there are no clinical trials, randomized controlled trials that we can rely on to currently treat these patients. According to the most recent clinical guidelines, which are the KDIGO guidelines, we are supposed to attempt supportive cares, which in fact makes perfect sense. We should be controlling the blood pressure, we should be controlling the lipids, we should be controlling salt intake, et cetera, whatever the appropriate dietary things are. Let's face it, for an aggressive glomerular disease, they're not going to be the answer for most patients, but we should still start there. Then after the supportive care comes into play, if patients continue to have very significant glomerular diseases, and that's classically a suggestion of greater than a gram of protein persists, we should be thinking about immune suppression. Right now, again, based on retrospective studies, there's about 9, 10 reports out there that would suggest that mycophenolate mofetil and corticosteroids in combination will bring remission for some patients. I will tell you; it absolutely does work in some patients. Back to your idea of biomarkers, we don't know which patients it's going to work in, but it does work for some. It is important to supportive care and then consider the mycophenolate mofetil and the corticosteroids. After that and again, depending on which cohort you like to accept the data on, the response is anywhere from 30% to 75% with that sort of series of attempts to put these patients in remission. Then we will be thinking about terminal complement blockade. Even the data for terminal complement blockade, again, I mentioned earlier in my pathophysiology discussion, we believe that in the case of C3 glomerulopathy, the disease is driven upstream, not at the terminal pathway level. Now, patients can get a benefit because if you have a very active upstream, you have a lot of anaphylatoxins floating in the circulation, particularly C5A, for instance. It does make sense to potentially block C5A or block C5 so that you have been blocked C5A, but the published data is not terribly much better for terminal complement block A than it is for mycophenolate mofetil and corticosteroids. Even though everything we've got to try has been tried and has been reported reasonably well, I would still say we're stuck with a disease that doesn't have a really targeted therapeutic approach.

I guess the MMF prednisolone is directed at auto-antibody production or an inflammation within the kidneys.

I believe it's probably both. We have not been able to document that the nephritic factors, the autoantibodies have declined as a result of that approach. But to be fair, no one's looking that tightly at that to really understand whether that's happening but that's what we suspect might be happening. It's also probably an anti-proliferative approach so if you have a lot of circulating anaphylatoxins, perhaps blocking your own immune system response to those anaphylatoxins can be beneficial to the kidney. That's the theory behind how they may work for some patients.

Carla M. Nester, MD, MSA, FASN discusses the current therapeutic area for C3G and what is on the horizon.

Sanjeev Sethi, MD

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