Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates

Article type: Research Article

Authors: Carver, Michael P.^{a; *} | Charleston, Jay S.^a | Shanks, Courtney^a | Zhang, Jianbo^a | Mense, Mark^b | Sharma, Alok K.^b | Kaur, Harjeet^b | Sazani, Peter^c

Affiliations: [a] R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., Cambridge, MA, USA | [b] Covance Laboratories, Inc., Madison, WI, USA | [c] Research and Innovation, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Correspondence: [*] Correspondence to: Michael P. Carver, Ph.D., Associate Director, R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., 215 First Street, Cambridge, MA 02142, USA. Tel.: +1 617 274 4022; E-mail: [email protected].

Abstract: 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.

Keywords: Duchenne muscular dystrophy, eteplirsen, AVI-4658, phosphorodiamidate morpholino oligomers, exon skipping, splice switching oligonucleotides, toxicity studies, non-human primates, kidney toxicity

DOI: 10.3233/JND-160157

Journal: Journal of Neuromuscular Diseases, vol. 3, no. 3, pp. 381-393, 2016