Kidney Compass: ASSIST Trial Shows Atrasentan Benefit on Top of SGLT2 Inhibitors

As the treatment landscape for IgA nephropathy grows increasingly complex, new data presented at the World Congress of Nephrology 2026 in Yokohama, Japan, are beginning to clarify how emerging therapies may work together.

In this episode of Kidney Compass, hosts Brendon Neuen, MBBS, PhD, and Shikha Wadhwani, MD, MS, sat down with Hiddo Heerspink, PhD, PharmD, to discuss the phase 2 ASSIST trial, which evaluated the efficacy and safety of atrasentan in combination with SGLT2 inhibitors.

Throughout the discussion, Heerspink emphasized that the trial was intentionally designed to address a rapidly evolving standard of care. As he explained, growing evidence supporting SGLT2 inhibitors in chronic kidney disease, specifically in IgA nephropathy, prompted the need to understand whether additional therapies like atrasentan could provide incremental benefit when layered on top. Neuen and Wadhwani both highlighted this rationale, framing the study as a forward-looking effort to anticipate real-world combination therapy.

To efficiently generate these data, Heerspink noted that the investigators used a randomized, placebo-controlled crossover design, allowing each patient to serve as their own control. As Neuen pointed out during the conversation, this approach improves statistical efficiency and reduces the required sample size. The study enrolled 51 patients, each receiving atrasentan and placebo sequentially on top of background SGLT2 inhibition, with both short-term (12-week) and longer-term (24-week) treatment periods incorporated into the design.

Wadhwani underscored another key distinction raised by Heerspink: the inclusion of patients with lower levels of proteinuria, starting at 0.5 g/day. According to Heerspink, this decision, made before the latest guideline updates, allowed the trial to explore efficacy in a broader, earlier-stage population than many prior phase 3 studies. Both hosts noted how this aligns with a growing emphasis on earlier diagnosis and intervention in IgA nephropathy.

In presenting the results, Heerspink stated that atrasentan reduced proteinuria by approximately 25% compared with placebo when added to SGLT2 inhibitors, with effects apparent by 12 weeks and sustained through 24 weeks. He further emphasized that the drug did not produce an acute decline in eGFR, challenging longstanding assumptions about endothelin receptor antagonists, and that its effects on blood pressure were modest.

Safety was a central focus of the discussion. Heerspink highlighted concerns around fluid retention with this class of agents but noted that, in ASSIST, these risks were minimal when atrasentan was combined with SGLT2 inhibitors. Both Neuen and Wadhwani pointed to the reassuring safety signals, including stable body weight and no clinically meaningful changes in biomarkers, reinforcing Heerspink’s conclusion that the combination appears both safe and well tolerated.

Looking beyond the trial, the conversation turned to broader implications for clinical practice and research design. Wadhwani raised the potential for crossover studies to help individualize therapy, prompting Heerspink to suggest that such designs could offer insight into patient-specific responses. However, he cautioned that variability in proteinuria measurements must be carefully considered when interpreting individual-level changes.

Heerspink additionally challenged the conventional sequencing of therapies. As he explained during the episode, the order in which drugs are developed should not dictate how they are used in practice. Instead, he advocated for a more pathophysiology-driven approach, tailoring treatment selection and sequencing to disease mechanisms and stage rather than defaulting to historical standards of care.

Editors’ Note: Relevant disclosures for Heerspink include AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Chinook Therapeutics Inc., Gilead Sciences, Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Travere Therapeutics, and others. Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer and Ingelheim, Janssen, and others. Relevant disclosures for Wadhwani include the National Institute of Diabetes and Digestive and Kidney Diseases, GSK, Calliditas and Travere Therapeutics.