A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of ELX-02 in Healthy Subjects.

ELX-02 is an investigational compound being developed as a therapy for genetic diseases caused by nonsense mutations such as cystic fibrosis. Structurally, ELX-02 is an aminoglycoside analogue that induces read-through of nonsense mutations through interaction with the ribosome, resulting in the production of full-length functional proteins. This phase 1 multiple-ascending-dose trial evaluated the safety and pharmacokinetics of ELX-02 in 62 healthy volunteers. ELX-02 plasma exposure was dose proportional, with no apparent accumulation, and followed by renal elimination. The most reported adverse event was injection site reactions that were mild to moderate in severity. At the top dose of 5.0 mg/kg, 1 of 6 subjects experienced auditory threshold changes in which ototoxicity could not be clearly ruled out, and 2 of 6 had hearing threshold changes consistent with possible ototoxicity. Two of 3 subjects receiving placebo in the 5.0 mg/kg group also had significant hearing threshold changes. All observed hearing threshold changes resolved or were trending toward resolution after withdrawal of the study drug. No severe or serious adverse events were reported.The results of this study support the evaluation of ELX-02 in phase 2 clinical trials with patients that have genetic diseases caused by nonsense mutations.

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

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.

Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of ELX-02, a Potential Treatment for Genetic Disorders Caused by Nonsense Mutations, in Healthy Volunteers.

ELX-02 is an investigational synthetic eukaryotic ribosome-selective glycoside optimized as a translational read-through molecule that induces read through of nonsense mutations, resulting in normally localized full-length functional proteins. ELX-02 is being developed as a therapy for genetic diseases caused by nonsense mutations. Two phase 1a, randomized, double-blind placebo-controlled, single-ascending-dose studies were conducted in healthy human subjects to evaluate the safety and pharmacokinetics of ELX-02. Single subcutaneously injected doses of ELX-02 between 0.3 mg/kg and 7.5 mg/kg showed an acceptable safety profile without severe or serious drug-related adverse events, including a lack of renal and ototoxicity events. Injection of ELX-02 resulted in a rapid time to peak concentration and elimination phase, with complete elimination from the vascular compartment within 10 hours. ELX-02 area under the concentration-time curve to infinity showed dose-exposure linearity (24-fold increase for a 25-fold dose increase), and the maximum concentration showed dose proportionality (17-fold increase for a 25-fold increase). The mean apparent volume of distribution was dose dependent, suggesting an increased distribution and tissue uptake of ELX-02 at higher doses. The primary route of excretion was in the urine, with the majority of the compound excreted unchanged. These results support the evaluation of the safety, pharmacokinetics, and efficacy of repeat dosing in future studies.