Clinical pharmacology and tolerability of REC‐994, a redox‐cycling nitroxide compound, in randomized phase 1 dose‐finding studies

• Published in: Pharmacology research & perspectives Vol. 12; no. 3; pp. e1200 - n/a
• Main Authors: Alfa, Ron, Considine, Timothy, Virani, Shafique, Pfeiffer, Matt, Donato, Anthony, Dickerson, Daniel, Shuster, Diana, Ellis, Joel, Rushton, Kristen, Wei, Helen, Gibson, Christopher
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-06-2024; John Wiley and Sons Inc; Wiley
• Subjects: Administration, Oral; Adolescent; Adult; antioxidants; Body mass index; Cyclic N-Oxides - administration & dosage; Cyclic N-Oxides - adverse effects; Cyclic N-Oxides - pharmacokinetics; Dose-Response Relationship, Drug; Double-Blind Method; Drug dosages; Female; Genes; genetic diseases; Health sciences; Healthy Volunteers; Hemangioma, Cavernous, Central Nervous System - drug therapy; Humans; Life expectancy; Machine learning; Magnetic resonance imaging; Male; Middle Aged; Mutation; Original; Oxidation-Reduction; oxidative stress; Permeability; Pharmacokinetics; phase 1; Proteins; Spin Labels; Young Adult; genetic diseases; pharmacokinetics; phase 1; antioxidants; oxidative stress
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.1200

Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC‐994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC‐994 in healthy volunteers. Single‐ and multiple‐ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18–55). SAD study participants received an oral dose of REC‐994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC‐994 or matching placebo, once daily for 10 days. Thirty‐two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC‐994 dose after single doses of 50–800 mg and after 10 days of dosing over the 16‐fold dose range of 50–800 mg. Median Tmax and mean t1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC‐994 was well tolerated. Treatment‐emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC‐994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose‐limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM.
Cerebral cavernous malformation (CCM) pathogenesis involves elevated reactive oxygen species (ROS) levels. REC‐994 restores ROS balance, and in double‐blind, placebo‐controlled, trials in healthy volunteers, had low potential for off‐target adverse effects and pharmacokinetics suitable for phase 2 development.