Sparsentan Receptor Occupancy Modeling, Clinical Actions, and Safety

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Background: In the PROTECT study, sparsentan, which targets both the endothelin type A (ETAR) 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 ETAR alone (ERA). This may relate to differences in comorbidities; however, aspects of dual receptor binding by sparsentan may also be a factor. Since ETAR blockers favor fluid retention while AT1R blockers may promote fluid excretion, continual high blockade of AT1R during ETAR 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 ETAR, ETBR, 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 ETAR, ETBR, and AT1R using PK data estimated for 400 mg daily shows RO is ˜60%-90% for ETAR, >95% for AT1R, and <1% for ETBR (Fig. 1B).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).Conclusions: Sparsentan has a stable 24-hour relationship in relative RO of ETAR to AT1R in which AT1R RO always exceeds ETAR RO. In contrast, when a drug solely targets ETAR, on top of AT1R blockade, periods of relatively unaccompanied ETAR 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. Funding: Commercial Support - Travere Therapeutics, Inc.

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