Advantageous toxicity profile of inhaled antisense oligonucleotides following chronic dosing in non-human primates

• Published in: Pulmonary pharmacology & therapeutics Vol. 21; no. 6; pp. 845 - 854
• Main Authors: Guimond, Alain, Viau, Elisabeth, Aubé, Paméla, Renzi, Paolo M, Paquet, Luc, Ferrari, Nicolay
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2008
• Subjects: Administration, Inhalation; Animals; Antisense; Asthma; COPD; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; FANA; Female; Inhalation; Lung; Lung - drug effects; Lymph Nodes - drug effects; Macaca fascicularis; Male; Medical Education; Monkey; Oligonucleotides; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - chemistry; Oligonucleotides, Antisense - pharmacokinetics; Oligonucleotides, Antisense - toxicity; Pharmacokinetics; Phosphorothioate Oligonucleotides - administration & dosage; Phosphorothioate Oligonucleotides - chemistry; Phosphorothioate Oligonucleotides - pharmacokinetics; Phosphorothioate Oligonucleotides - toxicity; Pulmonary/Respiratory; Respiratory System - metabolism; Tissue Distribution; Lung; Oligonucleotides; Monkey; Antisense; Pharmacokinetics; FANA; Inhalation; Asthma; COPD
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2008.08.001

Abstract TPI ASM8 and TPI 1100 are two products containing modified phosphorothioate antisense oligonucleotides (AONs), which are undergoing development for the treatment of asthma and chronic obstructive pulmonary disease (COPD), respectively. TPI ASM8 is comprised of two AONs, one targeting the human chemokine receptor 3 (CCR3) and the other targeting the common beta-chain of the IL-3/IL-5/GM-CSF receptors. TPI 1100 is also a dual-AON compound targeting the phosphodiesterase (PDE) 4 and 7 isotypes. For both products, the AONs are present in a 1:1 ratio by weight. Both products will be administered by inhalation to patients, and TPI ASM8 is currently undergoing Phase 2 clinical trials. As part of the safety assessment of both products, the toxicity and disposition (i.e., pharmacokinetics of the AON components in plasma and tissues) were investigated in 14-day inhalation studies in monkeys at doses ranging from 0.05 to 2.5 mg/kg/day. Results indicated that both products were safe and well tolerated at all dose levels. Reversible treatment-related alterations were only observed at the high dose levels tested and were limited to changes in the respiratory tract which were characterized primarily by the presence of alveolar macrophages in the absence of a generalized inflammatory response. Plasma pharmacokinetic profiles showed very low plasma concentrations, and no plasma accumulation was observed after repeated doses. While significant amounts of the AONs of both TPI ASM8 and TPI 1100 were measured in trachea and lung, only limited amounts of the AONs could be measured in kidney and liver, which, in combination with the low plasma level data, is indicative of very low systemic exposure. Taken together, these results demonstrate that these two new AON-based products are safe and that delivery via the inhaled route achieves localized deposition in the pulmonary tract with very limited systemic exposure and reduced toxicity compared to other routes of AON administration.