Mitochondria as targets of drug toxicity: Lessons from the R118 phase I experience

Area of Science:

• Pharmacology
• Biochemistry
• Drug Development

Background:

• Claudication is a condition caused by peripheral artery disease, leading to leg pain during exercise.
• Adenosine monophosphate activated protein kinase (AMPK) is a cellular energy sensor, and its activation is a potential therapeutic strategy for metabolic disorders.
• R118 was developed as a novel activator of AMPK.

Purpose of the Study:

• To evaluate the safety and tolerability of R118 in a phase I clinical trial.
• To determine the maximum tolerated dose of R118.
• To explore the pharmacokinetic and pharmacodynamic properties of R118.

Main Methods:

• A single ascending dose study was conducted in healthy adult subjects.
• Participants received escalating doses of R118 or placebo.
• Safety assessments included monitoring for adverse events, vital signs, and laboratory tests.

Main Results:

• The phase I study of R118 was terminated prematurely due to a high incidence of serious adverse events.
• Participants experienced dose-limiting toxicities, indicating a substantial risk.
• A probable mitochondrial mechanism was implicated in the observed adverse events.

Conclusions:

• R118 demonstrated an unacceptable safety profile in healthy subjects.
• The development of R118 as a treatment for claudication was discontinued.
• The findings highlight the importance of considering mitochondrial toxicity in AMPK activator drug development.