Clinical Expert Panel on Monitoring Potential Lung Toxicity of Inhaled Oligonucleotides: Consensus Points and Recommendations

Abstract

Oligonucleotides (ONs) are an emerging class of drugs being developed for the treatment of a wide variety of diseases including the treatment of respiratory diseases by the inhalation route. As a class, their toxicity on human lungs has not been fully characterized, and predictive toxicity biomarkers have not been identified. To that end, identification of sensitive methods and biomarkers that can detect toxicity in humans before any long term and/or irreversible side effects occur would be helpful. In light of the public's greater interests, the Inhalation Subcommittee of the Oligonucleotide Safety Working Group (OSWG) held expert panel discussions focusing on the potential toxicity of inhaled ONs and assessing the strengths and weaknesses of different monitoring techniques for use during the clinical evaluation of inhaled ON candidates. This white paper summarizes the key discussions and captures the panelists' perspectives and recommendations which, we propose, could be used as a framework to guide both industry and regulatory scientists in future clinical research to characterize and monitor the short and long term lung response to inhaled ONs.

Clinical potential of oligonucleotide-based therapeutics in the respiratory system

“…In moving forward, it will also be important to take into consideration that both 2 nd and 3 rd generation ASO are principally loaded into alveolar macrophages, and administration of 2 nd generation ASO (at least) promotes macrophage accumulation in the airways. Indeed, concerns around lung macrophage effects have been upgraded to promote use of exploratory inflammatory / toxicology biomarkers (Alton et al, 2012), as encouraged by Cook et al in the context of high confidence drug discovery. To date, the activation status of resident and recruited macrophages in the lung and any chronic tissue effects remain unclear (Forbes et al, 2014).…”

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma

“…Asthmatic patients had generally greater systemic exposure than healthy subjects at a given dose, most probably because of compromised epithelium. 9 In conclusion, the phase I program for SB010, a novel inhaled DNAzyme targeting GATA3 mRNA, showed the agent to be safe and well tolerated in the limited number of subjects exposed. In view of the good safety profile and limited systemic exposure found in the phase I program, a phase IIa proof-of-concept study in asthmatic patients (clinicaltrials.gov identifier: NCT01743768) was initiated.…”

“…In addition to strict adherence to standard guidelines on study design, additional expert panel recommendations were implemented to monitor the potential lung toxicity of inhaled oligonucleotides. 9 The study in asthmatic patients was carried out to exclude drug-induced airway hyperresponsiveness. The 3 studies were conducted with a total of 108 subjects (75 receiving active treatment and 33 receiving placebo) and 720 single administrations (534 receiving active treatment and 186 receiving placebo).…”

Oligonucleotide Therapies for the Lung: Ready to Return to the Clinic?

“…these studies, despite high confidence in the treatment rationale and drug mechanism of action, it appeared that oligonucleotides delivered topically to the airways either rapidly entered circulation or were removed by alveolar macrophages, perhaps too efficiently, offering limited (<50%) benefit at the tissue level and inducing a foamy macrophage phenotype. [8][9][10] Notably, in 1998, Ionis published on the rapid systemic access of 30mer 2 nd generation ASOs delivered topically to the lung, 11 and evidence of systemic access and even urinary elimination at the lower limit of assay detection for this compound class was reported even in man. 12 More recently, 16-mer 3 rd generation LNA ASOs, chemically comparable to the 3 rd generation cEt chemistry 4 employed by Crosby et al, 3 were also shown to rapidly reach circulation and end up in the urine as early as 15 min after intratracheal dosing in mice.…”

“…9 More importantly, from a patient safety perspective, a separate clinical expert panel on the safety of inhaled drugs recommended studies of the foamy macrophage phenotype induced by oligonucleotides upon topical dosing to the lung to rule out long-term immune risks. 10 This matter is acutely relevant to airways disease when such phenotypes have been linked with deterioration of respiratory status, at least in asthma. 14 Despite these reports, Crosby et al 3 claim lack of systemic access or activity in the kidney following inhaled administration of their 3 rd generation ENaC ASOs.…”