Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

Abstract

Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.

Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy

“…The goal of developing REP 2165 was to have an NAP with the same modifications blocking pro-inflammatory activity as in REP 2139, but having lower organ accumulation and trough plasma levels with chronic exposure. The clearly reduced organ accumulation and trough plasma concentrations of REP 2165 with chronic exposure relative to REP 2139 demonstrated in this study are important performance improvements that could allow REP 2165 to be safely used in patients with heavy metal exposure because the reduced organ accumulation and plasma concentration observed with this NAP in cynomolgus monkeys is expected to translate well to humans 30 . Additionally, REP 2139 and REP 2165 were comparably well tolerated in cynomolgus monkeys with chronic exposure, consistent with the interim results of the REP 401 protocol recently presented 4 .…”

AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer

“…59.8 μg/g of tumor tissue, respectively (table S1) and were consistent with the respective doses evaluated, indicating that the distribution of ASOs in tumor is similar for both ASO chemistries and that the intrinsically higher cellular potency of cEt ASOs rather than pharmacokinetic differences drives the efficacy gain observed in vivo. Tissue concentrations of ASO in preclinical models have been used to predict efficacious dose levels in man (29). The tumor concentrations of AZD9150 achieved at doses associated with strong STAT3 depletion in tumors (25 mg/kg and 50 mg/kg) suggest that the corresponding doses in man would be expected to be in the range of 5-10 mg/kg per week, doses that are well within the range of what has been achieved previously with ASOs in man (10).…”

Metabolism and Disposition of Volanesorsen, a 2′-O-(2 methoxyethyl) Antisense Oligonucleotide, Across Species

“…Volanesorsen, like other 29-MOE partially modified ASOs, has similar tissue distribution characteristics between mice, rats, and monkeys, with the highest concentrations in the liver and kidneys ((Geary et al, 2003;Levin et al, 2007;Yu et al, 2015)). It is generally believed that ASOs distribute into tissues via receptor-mediated endocytosis (Crooke et al, 2017) rather than passive diffusion.…”