BACKGROUND: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon 
skipping drugs including eteplirsen, which has shown considerable promise for 
treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy 
(DMD).
OBJECTIVE: Toxicity studies in non-human primates (NHPs) of 12 weeks duration 
with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a 
chronic study in NHPs of 39 weeks duration for eteplirsen, are described here.
METHODS: PMOs were administered once-weekly by bolus intravenous (IV) injections 
to male NHPs. Endpoints evaluated included plasma exposures, clinical 
observations, body weight/food consumption, eye exams, electrocardiograms, male 
reproductive hormones/endpoints, complement alternative pathway, clinical 
pathology, urinalysis, and macroscopic/light microscopic pathology.
RESULTS: Findings in these studies were limited to the kidneys, with a common 
presentation of tubular basophilia, vacuolation, and/or minimal degeneration 
that was considered non-adverse. No necrosis, glomerular lesions, or effects on 
renal function tests such as serum creatinine or urea nitrogen were observed, 
suggesting that PMO-related kidney findings are not likely to develop into frank 
nephrotoxicity. There were no adverse effects on other potential target organs 
after repeated IV injections at the highest dose levels tested, 320 mg/kg.
CONCLUSIONS: Nonclinical results in NHPs for these three PMOs, together with the 
excellent clinical safety established for eteplirsen to date, suggest that 
once-weekly IV administration of PMOs for lifetime durations at therapeutic 
doses will be well tolerated by patients with DMD.