Kidney Week

Abstract: SA-PO276

Sparsentan Receptor Occupancy Modeling, Clinical Actions, and Safety

Session Information

• Pharmacology: Kinetics, Genomics, Medication-Related Problems
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

• 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

• Hendry, Bruce M., Travere Therapeutics Inc, San Diego, California, United States

Bruce M. Hendry,

• Kohan, Donald E., University of Utah Health, Salt Lake City, Utah, United States

Donald E. Kohan,

• Geletka, Rob, Travere Therapeutics Inc, San Diego, California, United States

Rob Geletka,

• Jenkinson, Celia P., Travere Therapeutics Inc, San Diego, California, United States

Celia P. Jenkinson,

• Chen, Charles, Travere Therapeutics Inc, San Diego, California, United States

Charles Chen,

• Bedard, Patricia W., Travere Therapeutics Inc, San Diego, California, United States

Patricia W. Bedard,

Background

In the PROTECT study, sparsentan, which targets both the endothelin type A (ET_AR) and angiotensin type 1 (AT₁R) receptors, reduced proteinuria vs active comparator in IgA nephropathy with minimal changes in fluid status. This contrasts with greater fluid retention, including heart failure hospitalization, in studies using agents targeting ET_AR alone (ERA). This may relate to differences in comorbidities; however, aspects of dual receptor binding by sparsentan may also be a factor. Since ET_AR blockers favor fluid retention while AT₁R blockers may promote fluid excretion, continual high blockade of AT₁R during ET_AR blockade may help maintain normal fluid balance. The pharmacokinetic (PK) properties of sparsentan were used to estimate diurnal changes in receptor occupancy (RO) at steady state in the PROTECT study.

Methods

Receptor affinities (Ki) were determined for sparsentan at ET_AR, ET_BR, and AT₁R using radioligand binding assays. PopPK modeling of sparsentan was used to derive 24-hour PK and RO profile of patients in PROTECT.

Results

Sparsentan receptor affinities and PK data of a typical IgAN patient in the PROTECT study are shown in Fig. 1A. The 24-hour plot of sparsentan RO for ET_AR, ET_BR, and AT₁R using PK data estimated for 400 mg daily shows RO is ~60%-90% for ET_AR, >95% for AT₁R, and <1% for ET_BR (Fig. 1B).

Conclusion

Sparsentan has a stable 24-hour relationship in relative RO of ET_AR to AT₁R in which AT₁R RO always exceeds ET_AR RO. In contrast, when a drug solely targets ET_AR, on top of AT₁R blockade, periods of relatively unaccompanied ET_AR antagonism may occur, representing a risk for fluid retention. This could partly explain the fluid retention seen with ERA and the minimal changes in fluid status seen with sparsentan.

Fig 1: (A) Sparsentan receptor binding parameters and steady-state mean PK estimates from the PROTECT study. (B) Sparsentan receptor occupancies (right axis) over 24 hours for a single daily 400 mg oral dose in the PROTECT study, steady-state mean exposure (left axis).

Funding

• Commercial Support – Travere Therapeutics, Inc.