Is Sparsentan the New Kid on the Block for Treating Glomerular Disease?

From the Chair

About a year ago, there was huge excitement around the news that the US Food and Drug Administration (FDA) had granted accelerated approval to Travere for sparsentan, a dual endothelin and angiotensin receptor antagonist, in treating patients with IgA nephropathy (IgAN).¹ The interim analysis of the PROTECT study demonstrated that sparsentan reduced proteinuria by an additional 40% compared with the renin-angiotensin inhibitor irbesartan in patients with IgAN at high risk of progression (defined as a urine protein-to-creatinine ratio ≥1.5 g/g).² On this basis, the FDA granted accelerated approval for sparsentan in February 2023.³

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On a parallel front that same year, Travere’s DUPLEX study was reaching its conclusion. In the phase 3, randomized, controlled DUPLEX trial, sparsentan was evaluated in children and adults with focal segmental glomerulosclerosis (FSGS). Like the IgAN study, sparsentan was compared after maximizing renin-angiotensin-aldosterone system (RAAS) blockade with irbesartan for kidney end points, including proteinuria and kidney protection. Preliminary data from DUPLEX had demonstrated that sparsentan had a favorable benefit in proteinuria reduction relative to irbesartan.⁴

At the American Society of Nephrology Kidney Week 2023 in Philadelphia, Pennsylvania, the stage was set to hear the long-term kidney outcome data for sparsentan for both IgAN and FSGS. The excitement that two important glomerular diseases could benefit from a new nonimmunosuppressive agent was palpable. Sadly, so was the disappointment when the results were presented.

As the Dalai Lama has been quoted as saying, “Disappointment is the bridge between expectations and reality.” And so it was for sparsentan. Both studies have now been published—PROTECT in the Lancet⁵ and DUPLEX in the New England Journal of Medicine.⁶ The proteinuria benefit with sparsentan was sustained over the duration of follow-up in each of the trials; however, for both IgAN and FSGS, sparsentan missed the kidney protection end point of significantly slower kidney progression using estimated glomerular filtration rate slopes.

The investigators and Travere put a brave face on regarding the results. They suggested that sparsentan could be a foundational therapy for IgAN,⁷ and that while there wasn’t a statistically beneficial effect on kidney protection with sparsentan in IgAN, the benefit was clinically meaningful.⁷ Likewise, for FSGS, as others have editorialized,⁸ the reduction in proteinuria seen with sparsentan shouldn’t be scoffed at. FSGS is a disease that has the potential to be devastating, especially among children. Of course, it is possible that subgroups of patients, including those with genetically versus nongenetically caused FSGS, might benefit from sparsentan.

What’s the bottom line? First, the investigators, the investors, and the company, Travere, should be collectively proud of their support for sparsentan. After all, sparsentan was a castoff at Bristol Myers Squibb. Even more impressively, it was brought back from the ashes after the Martin Shkreli scandal. Doing trials for relatively rare diseases such as FSGS are hard. These studies were scientifically rigorous. They were well presented and published in high-impact journals. No mean feat!

With respect to reduction in proteinuria, the results could be important, especially since sparsentan was used in patients with severe high-risk disease who had already been treated with high-dose RAAS blockade prior to enrollment in the trial programs. Looking at patients in subgroups will also be important.

And, while the FDA didn’t advance the accelerated approval to full approval, there is the potential that, with additional data, the FDA might change its position. Missing a P value for efficacy doesn’t mean that the drug and the therapeutic strategy are a failure. Sagan’s quote, “absence of evidence is not evidence of absence,” is relevant here.

The benefit-risk ratio and considerations about unmet need are worth considering. For FSGS, where the disease can be devastating and the options for patients very limited, especially for children, sparsentan could satisfy an unmet need. One shouldn’t minimize the ease of taking sparsentan (an oral once-a-day therapy), nor its favorable safety profile. While it’s important to be watchful for adverse consequences of the drug in real-world settings (for example, the potential for liver injury and drug-drug interactions), the potential liver issue was recognized as manageable when the FDA granted accelerated approval with a Risk Evaluation and Mitigation Strategy.

More broadly, sparsentan has the potential to be an important therapy in the toolbox for treating all high-risk glomerular diseases because the mechanism of action is more hemodynamic than immunological, and the beneficial effect could be applied to many glomerular diseases. Of course, more data are needed, and the FDA is correct in being deliberate in its process of approving the drug. To paraphrase Winston Churchill, success comes from stumbling from failure to failure with no loss of enthusiasm.

References

1. Chiu AW, Bredenkamp N. Sparsentan: a first-in-class dual endothelin and angiotensin II receptor antagonist. Ann Pharmacother. 2023. doi:10.1177/10600280231198925
2. Heerspink HJL, Radhakrishnan J, Alpers CE, et al; PROTECT Investigators. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023;401(10388):1584-1594. doi:10.1016/S0140-6736(23)00569-X
3. Travere therapeutics announces FDA accelerated approval of FILSPARIᵀᴹ (sparsentan), the first and only non-immunosuppressive therapy for the reduction of proteinuria in IgA nephropathy. Travere Therapeutics. February 17, 2023. Accessed January 3, 2024. https://ir.travere.com/news-releases/news-release-details/travere-therapeutics-announces-fda-accelerated-approval
4. Trachtman H, Nelson P, Adler S, et al; DUET Study Group. DUET: a phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol. 2018;29(11):2745-2754. doi:10.1681/ASN.2018010091
5. Rovin BH, Barratt J, Heerspink HJL, et al; DUPRO Steering Committee and PROTECT Investigators. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet. 2023;402(10417):2077-2090. doi:10.1016/S0140-6736(23)02302-4
6. Rheault MN, Alpers CE, Barratt J, et al; DUPRO Steering Committee and DUPLEX Investigators. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N Engl J Med. 2023. doi:10.1056/NEJMoa2308550
7. Kuehn BM. High-impact clinical trials: sparsentan for IgA nephropathy and FSGS, SGLT2 inhibitor add-on therapies, transplant immunotherapy alternative show promise. Kidney News Online. December 1, 2023. Accessed January 3, 2024. https://www.kidneynews.org/view/journals/kidney-news/15/12/article-p7_3.xml
8. Ingelfinger JR. Sparsentan—another arrow in the quiver for treatment of FSGS? N Engl J Med. 2023. doi:10.1056/NEJMe2312324