Jonathan Barratt, PhD, FRCP: 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?

Gerald B. Appel, MD: 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.

Jonathan Barratt, PhD, FRCP: 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?

Transcript Edited for Clarity