Submit your picks! | NephMadness 2023 | #NephMadness | #IgAN

Shikha Wadhwani @SWadhwaniMD

Dr. Wadhwani is an Assistant Professor and Director of the Glomerular Disease Program at Northwestern University’s Feinberg School of Medicine. She also leads a joint Rheum-Renal Lupus Nephritis clinic and is program director for the GN fellowship program. She is passionate about bringing new therapies to GN patients through clinical trials and studying outcomes of glomerular diseases in the NIH-funded CureGN cohort.

Competitors for the IgA Nephropathy Region

Team 1: Non-immunosuppressive Therapy in IgA Nephropathy vs Team 2: Supportive Care with Immunosuppression

Copyright: Ethan Daniels/Shutterstock

Good teams become great ones when the members trust each other enough to surrender the ‘Me’ for the ‘We’ – Phil Jackson

“I-G……..A-N!”

You can already hear the chants and cheers from high up in the bleachers! Fans are rooting for Ig A Nephropathy (IgAN) in this match-up to skid right past TMA to the Final Four and reserve some energy in the tank (and buy some time for their rookies to gain their bearings) before taking it to the finals. Can you blame them? IgAN is (and has been) the talk of the town—not just in GN circles, but in Nephrology at large for the past year. Scouts were at every corner at ASN Kidney Week 2022, and the press is a buzz with a new story about an IgAN therapy every few weeks in 2023 (and it’s ONLY March!)

The once-forgotten glomerular disease has been more than resurrected. Sure, there are likely some fair-weather fans, but the diehards (who have been waiting for their moment to shine) do not care if you are more excited by AKI or CKD, or whether you care for pediatric or adult patients. All IgAN varieties are welcome! But before we look at the two teams and their line-ups, let’s all take a collective moment of silence to recognize the people who paved the way for IgAN (does this sound like a trophy acceptance speech already? Maybe—but confidence is sexy so just run with it!) There are countless patients who have put in grueling hours training the players in the off-season and ensuring injuries are promptly recognized and overcome. And we cannot forget the clinical trial investigators who have studied tapes (we see you TESTING 1.0) and designed intricate playbooks to ensure that therapies are not only efficacious but also safe(r). Finally, let’s not forget that the only reason we have all-star additions to both teams is due to the FDA’s important recognition of proteinuria as a surrogate endpoint for accelerated approval in IgAN clinical trials. So which IgAN team is going to win this bracket?

The non-immunosuppression team has an impressive line-up:

First up: the well-known RAAS blockers. They are the backbone of the Non-IS team and are not only reliable when it comes to scoring, but also consistently lead the league in (proteinuria) blocks. BP reduction often gets overshadowed by RAAS blockers despite their diverse skillset with multiple MOAs. Look for them to really make their mark with assists!

SGLT2i used to be part of the Endo league but have since moved over to Nephro and received widespread support from CKD fans (they even won NephMadness Rookie of the Year a few years back). While the data in IgAN patients from EMPA-KIDNEY are not yet published, we know that the findings from the pre-specified IgA subgroup in DAPA-CKD were very robust. It is important to keep in mind that patients in this trial did not receive optimized RAASi for 12 weeks prior as done in IgAN-specific studies (they were just required to be on a “stable” RAASi dose for 4 weeks). Whether the addition of an SGLT2i to maximally tolerated doses of RAASi would result in such profound proteinuria reduction and eGFR preservation is not known. Additionally, given entry eGFR was 25-75 ml/min/1.73m², IgAN patients with more preserved kidney function (but significant proteinuria) were not included. Finally, patients on steroids or other IS therapy were excluded from DAPA-CKD. As we have more drugs approved for an IgAN indication and move into an era of combination therapy, we will need to watch closely for potential side effects when combining SGLT2i with medications that suppress the immune system (and some may consider delaying SGLT2i initiation until after a course of IS).

The most recent addition to the 2023 Non-IS team is sparsentan. This new center may be young but has impressive stats when blocking both angiotensin receptors and endothelin receptors. Sparsentan’s uncle also played basketball and got a bad rep for liver issues, but this has not been the case in clinical trials studying sparsentan and does not seem to be a class effect.

Accordingly, sparsentan is trying to make its own name for itself and show how much it can offer to IgAN with anti-inflammatory and antifibrotic effects (as well as beneficial effects on mesangial cells and podocytes). Even with the AST/ALT testing for all and pregnancy testing for women (REMS), it is confident its near 50% proteinuria reduction stat cannot be beat and certain it will be in the running for player of the year. An accelerated FDA approval in its first year isn’t a bad start, sparsentan! However, we do await completion of the Phase III PROTECT trial and the associated publication.

The immunosuppression team, however, is equally striking—especially after reflecting on their prior losses and revamping their game. Corticosteroids have been involved in controversies for years, but the new low-dose makeover has seen increased jersey sales given substantial proteinuria reduction is still seen with lower doses, all while reducing infection risk. But this veteran player must now compete with the new kid on the block: Nefecon (Delayed-Release budesonide). While nefecon has never gone head-to-head against systemic corticosteroids, it has received significant interest in scrimmage games given its unique proposed mechanism of action and purported improved side effect profile. It not only showed substantial proteinuria reduction (after a 9-month course, but topline results from the completed trial note that “UPCR reductions observed were durable, reflecting a long-lasting treatment effect during the 15-month follow-up period off treatment”. Additionally, 2-year eGFR data (key primary endpoint) favored nefecon compared to placebo (on a background of optimized RASi), though the publication is awaited and subgroup analyses may be telling. Not only was nefecon the first-ever drug to obtain accelerated FDA approval for an IgAN indication, it seems to now have the confidence and momentum to make an MVP bid (and seek full approval by the FDA).

In other news, MMF is getting a new chance as a starter after impressive results and long-term follow-up led to a JAMA Network Open publication just a few weeks ago. Whether the results can be applied to a non-Chinese population is not yet known. Cyclophosphamide essentially is now reserved for those rare half-court shots when the team is trailing and there are only a few minutes left in the game. And rituximab has been benched indefinitely as other anti-B cell therapies seem to be showing more promise (though like complement inhibitors, are not yet ready for prime time).

So, who is going to win this matchup? With the rapidity of new data in the IgAN field in the last several weeks to months, this is a tough prediction to make, and I would not at all be surprised if we ended up in overtime. My “gut” feeling is that IS may make a game-winning shot (after all, they do incorporate some of the supportive therapies and as a team, have the potential to target multiple IgAN hits).

At the end of the game, regardless of the victor, there will be plenty of post-game (and post-tournament) analysis with several questions left unanswered:

• Does combination therapy (e.g., SGLT2i + nefecon, low-dose CS +SGLT2i, SGLT2i + sparsentan, sparsentan +low-dose CS, MMF + SGLT2i, nefecon + sparsentan, etc.) lead to better outcomes with an acceptable safety profile?
• Given the availability of new data and novel therapeutics, what criteria should be met in order to recommend additional therapies (uPCR, eGFR, MEST-C score)?
• Which IgAN subgroups should we target for combination or sequential therapy?
• Should we re-define “maximal supportive care” in IgAN, or should we create a separate new category for SGLT2i and dual endothelin/angiotensin blockers?
• Do we need accept that it is time for maintenance therapy in high-risk IgAN patients (as we do in lupus nephritis)? Should this be focused on steroid-sparing immunosuppressive drugs or newer non-immunosuppressive drugs?
• In the absence of validated biomarkers, should we be doing repeat biopsies (perhaps with tissue interrogation) to better guide our decisions?

Further discourse is encouraged as we eagerly await the Blue Ribbon Panel decision!

– Guest Post written by Shikha Wadhwani @SWadhwaniMD

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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