Phase 1 Renal Impairment Trial Results Supports Targeted Individualized Dosing of ELX‐02 in Patients With Nephropathic Cystinosis

Abstract

The aim of this study was to assess the pharmacokinetics (PK) and safety of ELX‐02 in a renally impaired population and apply these findings to the individualized dosing of patients with nephropathic cystinosis. This phase 1 renal impairment (RI; mild, moderate, or severe), single‐dose, PK, and safety evaluation included 6 participants assigned to each RI group. Six healthy controls with normal renal function were matched to participants with renal impairment. All received a single subcutaneous dose of 1‐mg/kg ELX‐02 on day 1 and were monitored for 72 hours after dosing with serial blood and urine samples. An estimated glomerular filtration rate (eGFR)‐PK model of ELX‐02 was developed from the RI study data and used to implement individualized dosing in a phase 2a study in patients with nephropathic cystinosis to achieve a weekly targeted exposure (area under the plasma concentration–time curve [AUC]). In participants with RI, ELX‐02 clearance decreased, and exposure increased with severity of RI. ELX‐02 plasma exposure was similar to healthy controls in participants with mild RI, but increasing severity of RI resulted in significantly decreased clearance, increased maximum plasma concentration, AUC from time zero to infinity, and half‐life compared to controls. ELX‐02 urinary clearance showed a similar pattern. Relationships between eGFR and exposure were defined supporting individualized dose determination for prediction of dose and AUC in patients with nephropathic cystinosis, achieving overall mean 110.7% of AUC targets. ELX‐02 was well tolerated by RI and nephropathic cystinosis populations. ELX‐02 exhibits a consistent PK profile across increasing degrees of RI with reduced clearance, increased exposure, and prolonged renal elimination proportional to reductions in eGFR. The defined relationship between eGFR and plasma exposure enabled individualized dose adjustment in patients with nephropathic cystinosis.

Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development

“…However, ELX-02 does not promote the readthrough of normal stop codons at concentrations that lead to PTC readthrough [ 67 ]. To date, three Phase I clinical trials (NCT03292302, NCT03776539, NCT03309605) have been completed to evaluate the safety, tolerability, and pharmacokinetics of ELX-02 in healthy adult volunteers and renal impaired population, with results indicating that ELX-02 was generally well tolerated in the subject population, no reported drug-related serious adverse events or nephrotoxicity and limited, reversible, auditory findings [ 68 , 69 , 70 ]. ELX-02 is poorly absorbed orally and nearly 100% bioavailable when administered subcutaneously [ 68 ].…”

“…It is excreted into the urine primarily as a parent compound via the kidneys, and its pharmacokinetic properties are similar to those of aminoglycoside antibiotics such as gentamicin [ 68 , 70 ]. Interestingly, the defined relationship between eGFR (estimated glomerular filtration rate) and plasma exposure based on the Phase I renal impairment trial (NCT03776539) made possible targeted individualized dosing of ELX-02 in patients with nephropathic cystinosis [ 69 ]. Four Phase II clinical trials with ELX-02 have recently commenced, including two in CF (NCT04126473, NCT04135495), one in nephropathic cystinosis (NCT04069260), and, one in Alport syndrome (NCT05448755).…”