Abstract: TH-OR93
MTX652, a Novel Selective USP30 Inhibitor for the Treatment of AKI: Phase 1 Results in Healthy Subjects and Model-Driven Human Efficacious Dose Projections
Session Information
- Onconephrology and Precision Pharmacology
November 02, 2023 | Location: Room 107, Pennsylvania Convention Center
Abstract Time: 04:48 PM - 04:57 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Aceves, Pau, Mission Therapeutics Ltd, Cambridge, Cambridgeshire, United Kingdom
- Thompson, Paul W., Mission Therapeutics Ltd, Cambridge, Cambridgeshire, United Kingdom
- Jones, Natalie, Mission Therapeutics Ltd, Cambridge, Cambridgeshire, United Kingdom
- Nurbhai, Suhail, Mission Therapeutics Ltd, Cambridge, Cambridgeshire, United Kingdom
Background
New treatments are needed for AKI. Dysfunctional mitochondria in kidney tubule epithelia are key drivers of kidney injury, therefore approaches to improving mitochondrial quality may be beneficial in kidney disease. Here we describe the clinical stage molecule MTX652 (also known as MTX115652), a novel, potent and specific inhibitor of USP30, a mitochondrial deubiquitylating enzyme which naturally antagonizes ubiquitin-dependent mitochondrial quality control mechanisms. In preclinical studies MTX652 protected against tubular atrophy and fibrosis in models of ischemia-reperfusion injury and unilateral ureter obstruction at doses from 0.5 to 5 mg/kg.
Methods
We report data from a randomized, double-blind, placebo-controlled first-in human study of MTX652 with cohorts evaluating SAD/MAD, elderly subjects, relative bioavailability (capsule vs. suspension), food effect and the DDI potential with a CYP3A4 inhibitor. MTX652 was administered as a solution/suspension in seven single dose cohorts between 0.25 to 200mg and four multiple dose cohorts between 3.5 to 100mg QD for 14 days. Safety was evaluated through the review of adverse events, physical examinations, clinical laboratory tests, vital signs and electrocardiograms. A PK/PD model was constructed to predict human target engagement (TE) at exposures which were effective in preclinical models.
Results
There were no Serious Adverse Events or safety or tolerability concerns in healthy subjects. MTX652 was rapidly absorbed with a plasma half-life of 8 hours. Cmax and AUC were dose proportional and there were no meaningful time-dependent effects on PK. Formulation (capsule) or food had no clinically relevant impact. Plasma exposures in elderly and younger adults were comparable. Simulations identified a once daily dosing regimen within the range tested in the clinic able to attain TE levels similar to those associated with maximal renal protective effects in preclinical models.
Conclusion
This is the first report of clinical data with a USP30 inhibitor. MTX652 presented an acceptable safety/PK profile in healthy subjects. PK/PD modelling enabled the selection of a safe and well tolerated dose predicted to have renal protective effects in humans. These results support further development of MTX652 as a potential therapy for AKI.
Funding
- Commercial Support – Mission Therapeutics Ltd