PMX 205 (PMX205) is an orally active, selective C5aR antagonist. Animals treated with PMX 205 (1 mg/kg/day, oral) displays a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX 205-treated animals also display reduced levels of astroglial proliferation in the lumbar spinal cord. SOD1^G93A rats are orally dosed with PMX 205 (1 mg/kg/day) from two time points (days 28 and 70) before the onset of major clinical symptoms. Both treatment groups have a significant extension in survival time compared with untreated rats (p=0.022, day 28; p=0.015, day 70), with no clear differences in outcomes between the two treatment regimens^[2]. Tg2576 mice are treated with PMX 205 (PMX205) at 20 μg/mL in the drinking water (n=17) from 12 to 15 mo of age, the time frame at which there is a rapid accumulation of amyloid deposits in these animals. Untreated Tg2576 animals (n=11) are used as controls. After 3 mo, animals treated with PMX 205 show significantly less fibrillar plaque load (thioflavine reactivity) than do untreated animals. In 3×Tg mice, PMX 205 also significantly reduces hyperphosphorylated tau (69%)^[3].