Transforming IgA Nephropathy Care: New Drugs Expand Treatment Options

This transcript has been edited for clarity.

Hello. I'm Pietro Canetta. I'm a nephrologist practicing at Columbia University in New York City, where I specialize in the care of patients with glomerular diseases. Today I'm going to talk to you about the treatment of immunoglobulin A (IgA) nephropathy. IgA nephropathy is a disease that has seen a lot of progress and a lot of research in the past few years, as well as movement in drug approvals. So, I think it's a good time to talk about it.

Why do we care about this disease? It is the most common form of primary idiopathic glomerulonephritis. It affects people early in their lives, usually in their twenties and thirties, and progresses to kidney failure in a large proportion of people within their midlife.

Traditionally it has been hard to study this disease because of the duration of time to kidney failure. In the past few years, we have seen approvals of drugs based on surrogate endpoints, especially proteinuria, and rate of change of glomerular filtration rate (GFR).

This has led to a world in which, 3 years ago, we had no drugs approved for IgA nephropathy. Since then we have had three drugs FDA-approved for the treatment of IgA nephropathy. This has been really wonderful for patients, and it has been challenging for academics like me who need to keep on top of treatment algorithms and redefine treatment paradigms.

How do we do this? The current way to think about the treatment of IgA nephropathy is really to think of it as two types of approaches that are done simultaneously. One approach is treating the generic aspects of proteinuric kidney disease. This is something that we should be good at as nephrologists and that is true for many of our patients with chronic proteinuric diseases. This is focusing on aspects of glomerular hyperfiltration and damage that are going to be true of all these diseases.

What are these types of interventions? Lifestyle changes like sodium restriction in the diet, smoking cessation for smokers, optimizing weight, blood pressure control, getting a systolic blood pressure less than 120 or 130, use of medications like angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) that we know are going to decrease proteinuria, decrease glomerular hyperfiltration, and improve glomerular health over the long term.

The second approach is disease specific — specific to those aspects of IgA nephropathy that are largely regulated by the immune system, such as interventions to decrease the production of IgA molecules and to decrease the inflammation that happens in the glomerulus.

Let's talk about the new drugs that have been approved. The first of these is targeted-release budesonide. This drug was originally developed under the brand name Nefecon. It is a type of steroid that is encapsulated in such a way that it is released especially in the distal small intestine and proximal large intestine, where it acts on the mucosal lymphatic tissue to decrease the production of IgA in that mucosal tissue.

The drug itself then undergoes 90% first-pass metabolism in the liver so that you don't get the substantial systemic effects of steroids. This drug has been shown to decrease proteinuria and to decrease the rate of change of GFR in patients with IgA nephropathy.

Its nearest comparator is what we had in the old days, systemic glucocorticoids — "the old days" meaning more than 3 years ago. Actually, we still do have systemic glucocorticoids. They have been shown to be effective in IgA nephropathy. They are not FDA-approved because they are old drugs used in so many different inflammatory diseases. But they have a lot of side effects, and that has been the problem with them historically.

While targeted budesonide has not been directly compared with systemic glucocorticoids, at least superficially, it seems to be much better tolerated and to have many fewer systemic side effects.

The next drug that was approved is sparsentan. Sparsentan fits more in the paradigm of supportive care. It is a dual endothelin antagonist and ARB. You can think of this drug as being a substitute for an ACE inhibitor or an ARB; that is how it was studied. Compared with an ARB in the large phase 3 study, it decreases proteinuria in patients with IgA nephropathy substantially more: 50% with sparsentan vs 15% with an ARB. Again, this is acting on the glomerulus to decrease glomerular hyperfiltration. It can be used daily. It doesn't just decrease proteinuria; it decreases the rate of change of GFR by about 1 mL per minute.

The third drug is iptacopan, a factor B inhibitor. It is a complement-acting drug; it acts on complement factor B to decrease activation of complement, which is a big part of the local glomerular inflammation in IgA nephropathy. This drug was just FDA-approved. It decreases proteinuria by about 30%-40%, and we are looking for more long-term data to see if it will change the GFR trajectory as well.

On top of these approved drugs, there are also several more drugs in development that are very exciting and that have been releasing really interesting data from phase 2 and phase 3 studies. These are drugs that act on B cells and on plasma cells. So, in the next couple of years, I think we are going to see more drugs approved for this disease.

It's a really exciting time for patients with IgA nephropathy and for the doctors who treat them.