• 1.

    Food U.S. and Drug Administration. Accelerated approval letter sent to Travere Therapeutics, Inc. February 17, 2023. Accessed November 7, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216403Orig1s000ltr.pdf

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Heerspink HJL, 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; 401:15841594. doi: 10.1016/S0140-6736(23)00569-X

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Rovin BH, 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 (published online November 3, 2023). doi: 10.1016/S0140-6736(23)02302-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Rheault MN, et al.; DUPRO Steering Committee and DUPLEX Investigators. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N Eng J Med (published online November 3, 2023). doi: 10.1056/NEJMoa2308550

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Tuttle KR, et al. Study design and baseline characteristics for aldosterone synthase inhibition in CKD. Am J Nephrol (published online October 30, 2023). doi: 10.1159/000534808

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Heerspink HJ, et al. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): A multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet (published online November 3, 2023). doi: 10.1016/S0140-6736(23)02230-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Kaufman D, et al. MDR-101-MLK update: Operational immune tolerance achieved in living related HLA-matched kidney transplant recipients [Abstract]. J Am Soc Nephrol 2023; 34:B3

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Garg AX, et al. Effect of a novel multicomponent intervention to improve patient access to kidney transplant and living kidney donation: The EnAKT LKD cluster randomized clinical trial. JAMA Intern Med (published online November 3, 2023). doi: 10.1001/jamainternmed.2023.5802

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Akizawa T, et al. AYAME study: Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in diabetic kidney disease (DKD) patients [Abstract]. J Am Soc Nephrol 2023; 34:B1

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Nangaku M, et al. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: Design and baseline characteristics of the AYAME study. Nephrol Dial Transplant 2023; 38:12041216. doi: 10.1093/ndt/gfac242

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Rossingnol P, et al. Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial (ALCHEMIST): Primary results [Abstract]. J Am Soc Nephrol 2023; 34:B2

High-Impact Clinical Trials: Sparsentan for IgA Nephropathy and FSGS, SGLT2 Inhibitor Add-On Therapies, Transplant Immunotherapy Alternative Show Promise

Bridget M. Kuehn
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Sparsentan showed promise for treating immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis (FSGS), two kidney diseases with limited treatment options, according to results presented during the High-Impact Clinical Trials session at Kidney Week 2023. Additionally, two phase 2 trials demonstrated the potential benefits of adding a selective aldosterone synthase inhibitor or a selective endothelin receptor agonist to sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD). Other studies presented during the session highlighted a potential alternative to long-term immunotherapy for patients with kidney transplants and showed that multipronged intervention did not increase transplant uptake.

Sparsentan

A dual endothelin angiotensin receptor antagonist, called sparsentan, received accelerated U.S. Food and Drug Administration (FDA) approval (1) in February for use in adults with primary IgA nephropathy at risk of rapid disease progression, based on a 36-week interim analysis of results from A Study of the Effect and Safety of Sparsentan in the Treatment of Patients with IgA Nephropathy (PROTECT) trial demonstrating a reduction in proteinuria compared with irbesartan (2). During the Kidney Week High-Impact Clinical Trials session, Brad Rovin, MD, FASN, director of the Division of Nephrology and vice chair of research at The Ohio State University Wexner Medical Center in Columbus, presented pivotal results of the trial, which followed patients for approximately 2 years.

The PROTECT trial randomized 404 adult patients with IgA nephropathy at risk of progression, who were already receiving maximized angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB) therapy, to receive sparsentan or irbesartan and followed them for 110 weeks (3). By 36 weeks, patients in the sparsentan group had achieved a 41% reduction in proteinuria that was maintained throughout 110 weeks, Rovin said during the press briefing. Additionally, 31% of patients receiving sparsentan achieved a complete renal response, compared with 11% in the irbesartan group. The sparsentan group also had superior estimated glomerular filtration rates (eGFRs) to the irbesartan group, with a 1.1-mm/minute per 1.73 m2 advantage in the chronic eGFR slope. There were no unexpected safety signals.

“We can consider sparsentan as a foundational therapy for [IgA] nephropathy upon which we can add immunosuppressive therapy guided by patient characteristics or kidney biopsy,” Rovin said. He suggested that upcoming guideline updates may want to recommend achieving even lower rates of proteinuria using newer IgA nephropathy drugs.

“The PROTECT trial provides further proof that there are now a lot of possible therapies for patients with IgA nephropathy,” said session co-moderator Tamara Isakova, MD, MMSc, the Margaret Gray Morton Professor of Medicine at Northwestern University's Feinberg School of Medicine, Chicago, IL. “Excitingly, this trial shows that for some patients with IgA nephropathy treatments that we consider to be hemodynamic, and not immunosuppressive, [the treatments] appear to have benefit. The key questions for patients and doctors are how best to know which of the many treatments to choose for which patient and which patients will still need immunosuppressive medications.”

Sparsentan also showed promise as a treatment for FSGS, for which there are currently no FDA-approved therapies. “FSGS is a disease that has a very high risk of progression to end stage kidney disease,” explained Michelle Rheault, MD, director of the Division of Pediatric Nephrology at the University of Minnesota Medical School in Minneapolis, during the press briefing. “Over 50% of patients will progress to end stage kidney disease within 5 to 10 years of diagnosis. There is a high unmet need for therapies that reduce proteinuria and help to slow the progression of kidney disease[s].”

Rheault presented the results of the phase 3 Study of Sparsentan in Patients with Primary Focal Segmental Glomerulosclerosis (FSGS) (DUPLEX) trial, the largest trial investigating FSGS to date, during the High-Impact Clinical Trials session (4). The trial randomized 371 patients between the ages of 8 and 75 years, with primary and genetic forms of FSGS, to receive sparsentan or irbesartan. At 36 weeks, patients receiving sparsentan were 55% more likely to achieve partial remission, with those results persisting at 108 weeks. At 108 weeks, patients in the sparsentan group showed a 50% reduction in the urine protein-to-creatinine ratio compared with a 32% reduction in the irbesartan group, Rheault also indicated during the press briefing. By the end of the study, 18.5% of the sparsentan group achieved total remission compared with 7.5% of the irbesartan group. There was no difference in the drugs’ safety profiles. “This is the first time that we are seeing an immunosuppressive or non-immunosuppressive drug for patients with FSGS that can make a difference long term,” she stated.

The trial, however, did not show a statistically significant difference in the eGFR slope between the two groups. “The study is promising with regard to a proteinuria endpoint, but it is disappointing [that] the necessary eGFR endpoint was not met,” Isakova said. “It is still a big step forward to have a trial for FSGS completed, and it is especially important to note that children were included in this trial.”

Rheault noted that the non-statistically significant improvement of approximately 1 mm/minute per year may still be clinically meaningful, particularly for pediatric patients with FSGS, by helping to delay kidney failure by 1 or 2 years. “Just getting them through high school or the first 2 years of college can make a big difference,” she said.

SGLT2 inhibitor add-ons

Several blockbuster trials have demonstrated the heart, kidney, and metabolic benefits of SGLT2 inhibitors in patients with kidney diseases, and the latest results show benefits for potential add-on therapies. “People with CKD remain at high risk of progression despite treatment with ACE inhibitors, ARBs, and SGLT2 inhibitors,” said Katherine Tuttle, MD, FASN, executive director at Providence Health Care and clinical professor of medicine at the University of Washington in Seattle, during the High-Impact Clinical Trials session at Kidney Week.

Excess aldosterone may accelerate progression. ACE inhibitors and ARBs do not fully block this effect and may contribute to hyperkalemia, Tuttle noted. However, adding SGLT2 inhibitors may add benefits while potentially helping to mitigate hyperkalemia. Aldosterone synthase inhibitors may add further benefit by reducing aldosterone production.

A phase 2 trial (5), conducted by Tuttle and her colleagues, showed that a selective aldosterone synthase inhibitor, called BI 690517, reduced albuminuria by up to 40% compared with placebo. The trial randomized 714 patients with CKD, taking a renin-angiotensin system inhibitor, to empagliflozin or placebo and then randomized 586 of the patients a second time to receive BI 690517 or placebo and measured the drugs’ effects at 14 weeks. Approximately 50% of patients taking the BI 690517 with placebo and 70% of patients taking the drug with the SGLT2 inhibitor empagliflozin achieved an albuminuria reduction greater than 30%, suggesting an additive benefit. Hyperkalemia occurred more in patients taking BI 690517 with or without empagliflozin. However, most cases did not require treatment, and there were no fatal hyperkalemia events, Tuttle said during a press briefing about the trial. “Aldosterone synthase inhibition is a promising new therapy that may add benefit to SGLT2 inhibitors in patients with CKD with and without diabetes,” she stated during the briefing. During the session, Tuttle announced the launch of a phase 3 trial, the EASi-Kidney trial, that will recruit 11,000 patients with CKD.

Similarly, the phase 2b Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) trial (6) showed that a low, 0.25 dose of the selective endothelial receptor antagonist zibotentan given with the SGLT2 inhibitor dapagliflozin reduced albuminuria more than did dapagliflozin alone. Hiddo Jan L. Heerspink, PhD, PharmD, professor and clinical pharmacologist at the University Medical Center Groningen, the Netherlands, noted in the press briefing that previous studies showed that endothelial receptor antagonists alone can reduce albuminuria and poor kidney disease outcomes but increase the risk of fluid retention and heart failure. However, combining an SGLT2 inhibitor, which has diuretic effects, may prevent fluid retention and related adverse events.

The ZENITH-CKD trial initially enrolled patients into six groups. The Data Safety Monitoring Committee stopped the 5-mg zibotentan monotherapy group—a 5-mg zibotentan plus 10-mg dapagliflozin group—and a placebo group due to excess fluid retention, Heerspink said. With a total of 447 patients, 0.25 zibotentan/10 mg dapagliflozin, 1.5 mg zibotentan/10 mg dapagliflozin, and placebo/10 mg dapagliflozin groups continued. Both zibotentan/dapagliflozin groups reduced the urinary albumin-to-creatinine ratio more than the dapagliflozin-alone group. However, there were modest increases in body weight and fluid retention in the 1.5-mg-dose group and two cases of heart failure. There were no changes in body weight or fluid retention in the 0.25-zibotentan group, but there was one case of heart failure. “The fluid retention profile for a low-dose combination zibotentan, 0.25 mg, with dapagliflozin supports further clinical trials,” Heerspink noted. He announced the launch of a phase 3 trial with 1500 patients during the session.

Isakova said the trials are part of the next phase in understanding how to best use SGLT2 inhibitors and said that she expects many more trials will investigate combining SGLT2 inhibitors with new medications. For example, upcoming company trials will also examine combining SGLT2 inhibitors and sparsentan to prevent CKD, she added. Isakova said it will be important for the phase 3 trials evaluating zibotentan and BI 690517 to use well-accepted, hard endpoints for kidney and cardiovascular disease. “Safety will also need to be evaluated further,” she noted.

Transplant trials

Updated results from the phase 3 Cellular Immunotherapy in Recipients of HLA-Matched, Living Donor Kidney Transplants (MDR-101-MLK) trial (7) showed ongoing immunotolerance among kidney transplant recipients treated with an immunomodulating cellular therapy created from their donors’ cells. “Kidney transplantation requires lifelong immunosuppression,” explained Daniel Brennan, MD, consulting chief medical officer of Medeor Therapeutics, which produces the therapy, and medical director of the Comprehensive Transplant Center and professor of medicine at Johns Hopkins Medicine, Baltimore, MD, during the press briefing. “[Immunosuppression] is associated with side effects, toxicities, infection, malignancy, and is expensive.”

To reduce the need for immunosuppression, Brennan and colleagues developed a cellular therapy that uses transplanted immune stem cells from the donor to induce immune tolerance in the recipient. Healthy donors received stem cell production-stimulating therapies, and immune stem cells were then collected from the donors and stored for transplantation. After transplant, recipients underwent total lymphoid irradiation; they began receiving their donors’ cells from 11 to 39 days after transplant. On day 40, patients started on tacrolimus therapy. Investigators monitored patients for “mixed chimerism,” or a mix of their own and donor immune cells at 6 months. If the donor cells remained, the patients tapered off tacrolimus over 6 months and were monitored for another 2 years.

Of the 22 patient-donor pairs screened for participation, Brennan said 20 completed the transplant, and 19 achieved mixed chimerism. Fourteen patients have completed the 2-year study, and 12 have remained free of immunosuppressive drugs. Four more patients have not yet completed the study. There were two rejections in the treatment group compared with one in a control group, and no deaths, graft loss, or graft-host disease were reported. Recipients who had eliminated immunosuppressive drugs also reported improved quality of life and a reduced burden on their families. “This study shows that some kidney transplant recipients can achieve ‘functional tolerance’ and be free of immunosuppressive drugs normally required to prevent rejection and failure of the kidney transplant,” said Brennan in a statement.

Isakova noted that many additional steps will be necessary to ensure that this approach is safe and efficacious, including longer and larger studies. But she called the results a step forward. “Innovation in how we manage transplant recipients is long overdue,” Isakova said. “Many immunosuppressive medications have adverse effects that affect the quality of life of patients and over time for some patients, result in death with functioning allograft. The approaches presented in this study are a step forward in figuring a new way to avoid immunosuppression.”

The Enhance Access to Kidney Transplant and Living Kidney Donation (EnAKT LKD) trial compared the effects of a multipronged intervention to increase the number of patients completing four steps toward receiving a kidney transplant with the effects of usual care practices across Ontario, Canada (8). “We know that patients with advanced chronic kidney disease have their best chance of a longer and healthier life if they receive a kidney transplant,” said Amit Garg, MD, PhD, associate dean of clinical research at the Schulich School of Medicine and Dentistry, Western University; medical director for the Living Kidney Donor Program, London Health Sciences Centre; and site director for the Institute for Clinical Evaluative Sciences (ICES) in Ontario. “From a health care system perspective, every hundred kidney transplants save the health care system $20 million over 5 years predominantly from averted dialysis costs because dialysis is a very expensive therapy. But the reality is, in many developed countries, many eligible patients today will never receive a transplant.”

The EnAKT LKD trial included 26 CKD programs serving more than 20,000 patients who were potentially transplant-eligible over approximately 4 years. Investigators randomized half of the programs to the intervention, which included administrative support for quality-improvement programs, transplant education resources, transplant donors and recipients sharing lived experiences, and program-level performance reviews, and half to usual care. The results were presented at Kidney Week and published simultaneously in JAMA Internal Medicine (8).

The four steps to transplant included 1) referring to a center for evaluation, 2) having a potential living donor contact a center for evaluation, 3) being added to the deceased donor waitlist, and 4) receiving a transplant. There was no increase in the number of patients who completed these steps in the intervention group compared with the usual care group. Garg said the COVID-19 pandemic, which occurred in the middle of the trial, dramatically impacted it, with patient and donor educators having to switch from in-person to virtual education and many clinicians choosing to retire.

“Although the results are disappointing, it is important to acknowledge that the investigators were attempting to do something really hard in a very pragmatic approach during a very challenging time,” Isakova said. She noted that additional studies are underway, including through many recently funded initiatives supported by the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases, that emphasize community-level interventions to eliminate racial and ethnic disparities in kidney health in the United States.

Garg and his team are currently revamping the intervention to improve implementation and results. “We are not giving up because this is a critically important problem,” Garg said. “We are deeply committed to fixing it because we know patients would benefit.”

Other trials presented during the High-Impact Clinical Trials session featured:

  • Bardoxolone methyl (BARD), a Keap1-Nrf2 pathway activator, slowed kidney function decline without reducing kidney failure rates in patients with diabetic kidney disease without heart failure risk factors (9). The phase 3 trial enrolled 1013 patients and found no differences in heart events compared with placebo. A previous phase 3 trial of the drug found elevated rates of heart failure in the BARD group (10).

  • The Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial (ALCHEMIST) enrolled 644 patients on hemodialysis with a cardiovascular co-morbidity or risk factor and found treatment with spironolactone did not reduce a composite endpoint of cardiovascular events compared with placebo. It did, however, lower heart failure hospitalization compared with placebo (11).

References

  • 1.

    Food U.S. and Drug Administration. Accelerated approval letter sent to Travere Therapeutics, Inc. February 17, 2023. Accessed November 7, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216403Orig1s000ltr.pdf

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Heerspink HJL, 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; 401:15841594. doi: 10.1016/S0140-6736(23)00569-X

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Rovin BH, 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 (published online November 3, 2023). doi: 10.1016/S0140-6736(23)02302-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Rheault MN, et al.; DUPRO Steering Committee and DUPLEX Investigators. Sparsentan versus irbesartan in focal segmental glomerulosclerosis. N Eng J Med (published online November 3, 2023). doi: 10.1056/NEJMoa2308550

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Tuttle KR, et al. Study design and baseline characteristics for aldosterone synthase inhibition in CKD. Am J Nephrol (published online October 30, 2023). doi: 10.1159/000534808

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Heerspink HJ, et al. Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): A multicentre, randomised, active-controlled, phase 2b, clinical trial. Lancet (published online November 3, 2023). doi: 10.1016/S0140-6736(23)02230-4

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Kaufman D, et al. MDR-101-MLK update: Operational immune tolerance achieved in living related HLA-matched kidney transplant recipients [Abstract]. J Am Soc Nephrol 2023; 34:B3

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Garg AX, et al. Effect of a novel multicomponent intervention to improve patient access to kidney transplant and living kidney donation: The EnAKT LKD cluster randomized clinical trial. JAMA Intern Med (published online November 3, 2023). doi: 10.1001/jamainternmed.2023.5802

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Akizawa T, et al. AYAME study: Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in diabetic kidney disease (DKD) patients [Abstract]. J Am Soc Nephrol 2023; 34:B1

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Nangaku M, et al. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: Design and baseline characteristics of the AYAME study. Nephrol Dial Transplant 2023; 38:12041216. doi: 10.1093/ndt/gfac242

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Rossingnol P, et al. Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial (ALCHEMIST): Primary results [Abstract]. J Am Soc Nephrol 2023; 34:B2

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