Understanding the DUPLEX Trial and Sparsentan in FSGS, with Michelle Rheault, MD

Michelle Rheault, MD
Credit: University of Minnesota

Although most forms of glomerular disease are associated with a significant impact on long-term prognosis and quality of life, few place the same burden on patients as focal segmental glomerulosclerosis (FSGS).

With an estimated prevalence of 7 per 1 million, FSGS is classified as a rare disease, but for nephrologists represents a condition that is well known and, without any approved treatments, difficult to manage. Immunosuppressive therapies are often prescribed for these patients, but only 40 to 60% of patients experience a response to steroid therapy.

At the American Society of Nephrology Kidney Week 2023, the nephrology community was offered a glimmer of hope for patients with FSGS in the form of the phase 3 DUPLEX trial, which examined use of sparsentan against irbesartan for FSGS. A 371-person, 108-week trial, DUPLEX missed its primary efficacy endpoint of change in eGFR slope at the time of final analysis relative to irbesartan, but provided signal of benefit in many other outcomes of interest included in the trial, including an increased percentage of patients with partial remission of proteinuria at 36 weeks (P=.009), which was sustained through 108 weeks.

At 108 weeks, the following results were observed for eGFR:1

• No significant between-group differences in the eGFR slope
• A between-group difference in total slope of 0.3 mL/min/1.73m2 (95% confidence interval [CI], −1.7 to 2.4)
• A between-group difference in the slope from week 6 to week 108 of 0.9 mL/min/1.73m2 per year (95% CI, −1.3 to 3.0)

Additional results highlighted by Michelle Rheault, MD, a pediatric nephrologist and professor of pediatrics at the University of Minnesota, included an apparent trend towards benefit for a composite kidney failure, with 6.5% and 11.2% of the sparsentan and irbesartan groups, respectively, reaching this endpoint (RR, 0.58; 95% CI, 0.31 to 1.07).

For more on the results of this trial and how it might inform potential use of sparsentan in the management of FSGS, the editorial team of HCPLive Nephrology sat down with Rheault as part of the on-site coverage of Kidney Week 2023. Part of that conversation is the subject of the following Q&A.

Michelle Rheault, MD, on Sparsentan in FSGS

HCPLive Nephrology: Can you describe what the effects seen in this trial might translate to, from a patient-centered perspective, for those with FSGS?

Rheault: I think, for a patient with FSGS, they're at such high alert for that next stage they disease that anything that we can offer them that might slow that down is really going to be of benefit. So in this trial, we showed a 0.9 mL/min/1.73m2 difference in chronic slope between patients treated with sparsentan and irbesartan. Over a longer period of time, that can really make a big difference for a teenager, for example, who has been diagnosed with FSGS.

I have a number of patients who are 15 or 16 years who get diagnosed and, if we're thinking about needing to start dialysis or transplant when they're 20 or 22 years old, that's a big deal. It's right in the middle of college, potentially, and they are starting to have their adult life. If we can extend that even to if they're just 25 to 30 years old, that is a huge difference and kind of lets them establish themselves. So, I think sparsentan gives us an option to have something else to be able to give these patients.

HCPLive Nephrology: How would you coach a nephrologist through a conversation about sparsentan if a patient expressed interest in the agent following the DUPLEX trial?

Rheault: So, most of the drugs that are available to you for FSGS are drugs that suppress your immune system and they often have many, many side effects that are hard on patients, including infections. There can be a lot of side effects that the patients do not like. Sparsentan is really one of the first drugs we have available that is not an immunosuppressive medication.

I think there are two different populations for whom this could potentially work well. One would be patients with genetic types of FSGS. We still need to do the analysis and see how those patients in our study responded, but because there is really nothing else available to treat those patients, having something that can reduce proteinuria and slow progression in that population would be fantastic.

The other population would be patients who have already received all of the immune suppression and have not really responded to that. So, again, sparsentan gives us the opportunity to have something to offer patients that is not just another immunosuppressive medicine.

HCPLive Nephrology: Although it did not reach statistical significance, how do you interpret the differences in adverse kidney outcomes seen in this trial?

Rheault: So, because FSGS is such a rare disease, it's challenging to have enough patients in the clinical trials in order to show that kind of statistically significant reduction in event rates, like end-stage kidney disease. For some of the chronic kidney disease trials, you might have 5000 to 7000 patients enrolled. In our study, there was 370 patients and that was already the biggest trial ever done in FSGS.

So, we probably are never going to have a study that shows those event rates to be reduced, but we showed an effect on things intended to predict the development of end-stage kidney disease. We did show that there was a significant increase in patients who reached the partial remission of FSGS endpoint. So, we would predict, based on that, their long-term outcomes, if we followed them further, would be beneficial. I think the fact that all of those outcomes are showing a trend in favor of sparsentan is really encouraging that we're going to be able to really make a difference in patients' lives.

References:

1. Guruswamy Sangameswaran KD, Hashmi MF, Baradhi KM. Focal Segmental Glomerulosclerosis. [Updated 2023 Feb 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532272/
2. Rheault MN, Alpers CE, Barratt J, et al. Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis. New England Journal of Medicine. Published online November 3, 2023. doi: 10.1056/NEJMoa2308550