Background:  SPD754 is a cytidine analogue with activity against HIV-1, including isolates resistant to other available NRTI. SPD754 was well tolerated and highly effective as short-term monotherapy in HIV⁺ patients. In vitro cytotoxicity and mitochondrial tolerability studies indicate that the (-) enantiomer, SPD754, has a more favorable safety profile than the racemic mixture BCH-10652. The objective of this study was to investigate the nonclinical safety profile of SPD754 over prolonged administration to monkeys.

Methods:  SPD754 was administered orally twice daily for up to 52 consecutive weeks to cynomolgus monkeys at doses of 50, 200, 500, and 1000 mg/kg/day. The racemate (BCH-10652) was also investigated as a positive control at a dose of 1000mg/kg/day.

Results:  During the 52 weeks of treatment with SPD754 at 1000 mg/kg/day, produced higher systemic exposure when compared to the race-mate, but only minimal mucocutaneous hyperpigmentation, mild gastrointestinal effects and minimal changes in the red blood cell counts and RBC parameters, all of which were generally reversible despite continuous treatment. Microscopically, increased pigmentation of the pinna skin was observed for 1 male treated at 1000 mg/kg/day, while minimal focal hyperkeratosis was observed infrequently in monkeys administered 200 and 500 mg/kg/day of SPD754. There was no mitochondrial abnormality in the liver, heart and skeletal muscle samples and no bone marrow toxicity. The NOAEL for SPD754 was found to be 500 mg/kg/day. In contrast, all monkeys given 1000 mg/kg/day of the racemate (BCH-10652) were sacrificed during the first 13 to 15 weeks because of clinical signs of toxicity. These were characterized by the development of a degenerative dermatopathy. Clinical pathology revealed decreases in red blood cell counts, hemoglobin and hematocrit, increased activated partial thromboplastin time and a change in the serum protein profile. The macroscopic and microscopic evaluation of the tissues revealed BCH-10652-related findings in the skin, oral cavity, lymph nodes, bone marrow, thymus and stomach

Conclusions:  Results of this study confirm that the (-) enantiomer SPD754 has a more favorable safety profile and is lacking the serious toxicity seen with the racemate BCH-10652. SPD754 is well tolerated and warrants further investigation in longer-term treatment studies in human patients.

Keywords: SPD754; Toxicology; Cynomolgus