Glomerular Disease Clinical Case Review

In this video, Craig Gordon, MD, nephrologist at Tufts Medical Center and associate professor of medicine at Tufts University School of Medicine, discusses the chosen therapy and results in this case of IgA nephropathy:

Editor’s note: The following is an automatically generated transcript of the above video.

"Let's take a moment just to look at the international IGA nephropathy prediction tool. So very easy to do in any of the online calculators that exist. We need to enter information at the time of the biopsy, so estimated GFR, blood pressure, proteinuria. Some information about treatments such as ACE or ARB use at the time of the biopsy, immunosuppression at the time of the biopsy, and then the components of the MEST score. And then we can ask for an output at different time periods after the biopsy As far as the risk of a 50% decline in GFR or progression to kidney failure. I sometimes like to use five years largely because other risk scores that we use for other indications, often we're looking at the five-year risk. So at least for me this feels like I'm sort of comparing apples to apples a little bit, although obviously very different conditions.

And so for our patient, the five-year risk of this dual outcome occurring was nearly 47%. So this was a pretty high risk patient. Now I will point out that this prediction school doesn't tell you whether to treat the patient or with which drug to treat the patient. It just tells you what's their risk of progression and then you have to take the next step to decide how to proceed at least at this point in time. So let me return to the slide of the treatments and I'll highlight our discussion with the patient. So first we emphasized maximizing RAAS inhibition and discussed SGLT2 inhibitors. We took the discussion of endothelium antagonist for a little bit later in the conversation, as you'll see in a few slides. We encouraged clinical trials and tried to get a very educated patient in this case to consider the value of this and perhaps delaying treatment to allow himself to participate in those trials. And then we carried a discussion about the relative value of systemic corticosteroids versus the time release, budesonide, not highlighted here because these conversations occurred before the accelerated approval is we did not talk in much detail at that point about iptacopan (Fabhalta, Novartis).

So let's talk about steroids. So there's a lot of older data and some relatively newer data. The two large trials of steroids in IgA are the stop IgA trial and the testing trial. The testing trial was one that's more talked about recently because the effect of treatment was positive with the other side of it being that there was a high rate of adverse events, which I'll discuss in a moment. So you can see here the cumulative incidents of 40% percent decline in GFR kidney failure or death was lower with methylprednisolone in yellow here compared to placebo. And if you look on the right-hand side of kidney failure requiring dialysis or transplant, again lower with methylprednisolone versus placebo.

For those who know this trial well, this is data combining both the higher and the eventual lower doses of steroids. And the issue that occurred that led to the concern about this trial was if you look here at the overall cohort getting methylprednisolone or prednisone and then to the right at those receiving the high dose or the low dose, you can see lots of SAEs and individuals treated with steroids, especially the high dose, including high rates of hospitalizations, including deaths and very serious medical conditions. There was a 7% rate of hospitalization for severe infection overall, mostly driven by the high dose group and this was partially driven by a variety of infections, the most notable of which was PJP pneumonia. And so a subsequent tweak to the protocol given was to use a reduced dose of corticosteroids with the addition of prophylaxis for PJP. And you could see when that was done, the number of SAEs were still relatively high lower than those with placebo and there were fewer of these hospitalizations as a result of severe infection. So if we're going to use steroids in a patient, we want to use a protocol similar to this reduced regimen.

And obviously, for anyone receiving high dose systemic steroids, we want obviously to employ PJP prophylaxis, osteoporosis treatment, et cetera. So let me shift to Nefecon (Tarpeyo, Calliditas Therapeutics) or time released budesonide. This is data from the NEGAR phase three trial. You could see here Nefecon in blue and in red placebo. And in this figure we're looking at the change in UPCR from baseline. And you could see during the nine month treatment with Nefecon, proteinuria declined and actually continued to decline even for the first few months off of treatment. And then you could see subsequently the proteinuria levels started to return towards baseline. There was minimal to no change in proteinuria, unsurprisingly in the placebo treated patients. When we look at GFR, this is a zoomed in version of one of the figures, but you can see here in Nefecon there's initial slight increase in GFR followed by a slowing of the slope initially that probably eventually starts to parallel that of the placebo where there's just an ongoing loss in GFR. And so this data suggested an efficacy of Nefecon in treating IGA nephropathy.

Before I get to a discussion of adverse events, I do want to show the heart outcomes of a decline in 30% of EGFR kidney failure. And you could see here with the Nefecon, the budesonide, it was lower at 12% than placebo treated patients and this was statistically significant and also true whether the initial proteinuria was less than a gram and a half or greater than a gram and a half. But let's look at the adverse events. And this is really where things get interesting when you compare with traditional corticosteroids. And you can see that the adverse events were relatively on the low side when you know the treatment emergent SAEs were on the order of 8% in similar in the Nefecon group and the placebo group, but hardly any led to any serious outcome. And if you look at the types of side effects, they sound like systemic absorption to slight degree of steroids. So peripheral edema, hypertension rates were higher, acne minor increases in A1C, especially in those who were pre-diabetic at baseline there were comparable rates of infection with Nefecon and placebo, but very few serious infections. And I think when you take a look at these together, it's clear that if you look at this side effect profile of budesonide and compared even with the low doses of steroids, there are steroid side effects but much fewer and less severe. And this is I think where some of the enthusiasm about Nefecon comes from just because of our concern in a nine month or so course of steroids, what type sorts of side effects will be causing. We did not have a chance with this patient to discuss iptacopan (Fabhalta, Novartis), which is also a very exciting treatment for those at risk or high risk of progression based on its inhibition of complement factor B. It's recently received accelerated approval by the FDA based on data showing an improvement in proteinuria, waiting for the final data on EGFR.

But basically, regarding the discussion with our patient, he agreed to start SGLT2 inhibition and actually turn down our offer to explore the various clinical trials that were available. And his rationale this was a highly educated patient with a sort of a medical background, was he felt his disease was progressing too quickly to take on the 50% risk of being in a placebo arm. And it was a little bit hard to argue with that even though, you know, obviously our preference is to gain more information about novel treatments, et cetera. This was a valid concern in my opinion. When we turned to the discussion of systemic steroids versus budesonide, he was really concerned about the side effect risk of corticosteroids and even with reassurance that at his BMI of 27 and without even pre-diabetes and his risk profile, he was relatively low risk, but he really made a strong case for why would I take on that risk when maybe I could be treated with budesonide.

And so where we are as of right now is paperwork has been submitted for approval of budesonide per the patient's request. We did have a discussion with him about the theoretical higher risk of genital urinary infections that have been a concern when SGLT2 inhibitors are combined with immunosuppressive therapies. But our conclusion and his as well was the risk was relatively low and a person of male gender and the fact that we are hopefully going to be using budesonide and not systemic corticosteroids, although we didn't discuss iptacoban and we didn't get into April or inhibition because those are currently at the clinical trial level. We did discuss the possibility of changing his ARB to sparsentan the dual endothelium angiotensin receptor antagonist, but came to the conclusion that we'll potentially do that after a nine-month trial of budesonide. So with that, thank you for your attention and I appreciate you listening to this presentation."