Toxicity of a novel therapeutic agent targeting mitochondrial complex I

Area of Science:

• Biochemistry
• Pharmacology
• Clinical Trials

Background:

• Peripheral artery disease (PAD) causes exercise limitation.
• R118 was investigated as a potential therapy for PAD.
• R118 targets mitochondrial complex I and activates AMP kinase.

Purpose of the Study:

• To evaluate the safety and tolerability of R118 in a Phase I clinical trial.
• To assess the effects of R118 on exercise limitation in PAD.

Main Methods:

• A randomized, placebo-controlled Phase I trial involving 24 subjects.
• Escalating doses of R118 were administered.
• Plasma lactic acid levels and adverse events were monitored.

Main Results:

• R118 demonstrated partial and reversible mitochondrial complex I inhibition in preclinical studies.
• Transient plasma lactic acid elevations occurred, particularly at higher doses.
• All subjects at the highest dose required hospitalization, with two experiencing severe metabolic acidosis and requiring intubation.

Conclusions:

• Inhibition of mitochondrial complex I by R118 leads to severe lactic acidosis.
• The observed toxicity profile renders R118 unsuitable for further development for PAD.
• The mechanism of action involving mitochondrial complex I inhibition presents unacceptable risks.