Diagnosis and Treatment of Immune-Mediated Kidney Diseases - Episode 20

Clinical trial data on complement inhibition in C3G

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

Jonathan Barratt, PhD, FRCP: 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?

Carla M. Nester, MD, MSA, FASN: 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.

Jonathan Barratt, PhD, FRCP: What clinic current clinical trials are you aware of attempting to do that?

Carla M. Nester, MD, MSA, FASN: You can go to 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.

Jonathan Barratt, PhD, FRCP: I believe some of that data has been presented at conferences.

Carla M. Nester, MD, MSA, FASN: 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.

Jonathan Barratt, PhD, FRCP: That success has been reduction in proteinuria.

Carla M. Nester, MD, MSA, FASN: 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.

Jonathan Barratt, PhD, FRCP: 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?

Carla M. Nester, MD, MSA, FASN: 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.

Jonathan Barratt, PhD, FRCP: 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.

Carla M. Nester, MD, MSA, FASN: I suspect that the regulatory agencies will require those vaccinations prior to the use just because they were part of the clinical trials.

Transcript Edited for Clarity