Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology
Background Local priming of the innate immune system with a Toll-like receptor (TLR)2/6 agonist may reduce morbidity and mortality associated with viral respiratory tract infections, particularly for the elderly and those with chronic diseases. The objectives of the present study were to understand...
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| Format: | Article |
| Language: | English |
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European Respiratory Society
2024-12-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/10/6/00199-2024.full |
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| author | Francesca A. Mercuri Scott White Hayley A. McQuilten Charlotte Lemech Stephan Mynhardt Rana Hari Ping Zhang Nicole Kruger Grant McLachlan Bruce E. Miller Nicholas P. West Ruth Tal-Singer Christophe Demaison |
| author_facet | Francesca A. Mercuri Scott White Hayley A. McQuilten Charlotte Lemech Stephan Mynhardt Rana Hari Ping Zhang Nicole Kruger Grant McLachlan Bruce E. Miller Nicholas P. West Ruth Tal-Singer Christophe Demaison |
| author_sort | Francesca A. Mercuri |
| collection | DOAJ |
| description | Background
Local priming of the innate immune system with a Toll-like receptor (TLR)2/6 agonist may reduce morbidity and mortality associated with viral respiratory tract infections, particularly for the elderly and those with chronic diseases. The objectives of the present study were to understand the potential of prophylactic treatment with a TLR2/6 agonist as an enhancer of innate immunity pathways leading to accelerated respiratory virus clearance from the upper airways.
Methods
Two randomised, double-blind, placebo-controlled clinical trials were conducted in healthy adult participants. The first dose-escalation study assessed safety, tolerability and mechanistic biomarkers following single and repeated intranasal administrations of INNA-051. The second was an influenza A viral challenge study assessing the impact of treatment on host defence biomarkers and viral load.
Results
INNA-051 was well tolerated in both studies, with no dose-limiting toxicities identified. Mechanistic biomarkers assessed in both studies demonstrated the expected engagement of pharmacology, including innate immune pathways. There were lower than anticipated rates of infection. Post hoc analysis conducted in laboratory-confirmed infected participants with low or no antibody titre against the challenge virus showed INNA-051 treatment led to a significantly shorter duration of infection and increased expression of genes and pathways associated with host defence responses against influenza.
Conclusions
The safety and pharmacology profile of INNA-051 confirms preclinical studies. INNA-051 increased expression of genes and pathways associated with host defence responses against influenza and was associated with a shorter duration of infection. These studies support further clinical assessment in the context of natural viral respiratory tract infections in individuals at increased risk of severe illness. |
| format | Article |
| id | doaj-art-5373e0f5d2574cceb64fe4d4a156e750 |
| institution | Kabale University |
| issn | 2312-0541 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj-art-5373e0f5d2574cceb64fe4d4a156e7502025-01-14T09:50:22ZengEuropean Respiratory SocietyERJ Open Research2312-05412024-12-0110610.1183/23120541.00199-202400199-2024Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacologyFrancesca A. Mercuri0Scott White1Hayley A. McQuilten2Charlotte Lemech3Stephan Mynhardt4Rana Hari5Ping Zhang6Nicole Kruger7Grant McLachlan8Bruce E. Miller9Nicholas P. West10Ruth Tal-Singer11Christophe Demaison12 ENA Respiratory, Melbourne, VIC, Australia ENA Respiratory, Melbourne, VIC, Australia ENA Respiratory, Melbourne, VIC, Australia Scientia Clinical Research Ltd, Randwick, NSW, Australia Resolutum Global Pty Ltd, VIC, Australia Scientia Clinical Research Ltd, Randwick, NSW, Australia Griffith Biostatistics Unit, Griffith Health, Griffith University Gold Coast Campus, QLD, Australia ENA Respiratory, Melbourne, VIC, Australia ENA Respiratory, Melbourne, VIC, Australia ENA Respiratory, Melbourne, VIC, Australia School of Pharmacy and Medical Science and the Institute for Biomedicine and Glycomics, Griffith University, Gold Coast Campus, QLD, Australia ENA Respiratory, Melbourne, VIC, Australia ENA Respiratory, Melbourne, VIC, Australia Background Local priming of the innate immune system with a Toll-like receptor (TLR)2/6 agonist may reduce morbidity and mortality associated with viral respiratory tract infections, particularly for the elderly and those with chronic diseases. The objectives of the present study were to understand the potential of prophylactic treatment with a TLR2/6 agonist as an enhancer of innate immunity pathways leading to accelerated respiratory virus clearance from the upper airways. Methods Two randomised, double-blind, placebo-controlled clinical trials were conducted in healthy adult participants. The first dose-escalation study assessed safety, tolerability and mechanistic biomarkers following single and repeated intranasal administrations of INNA-051. The second was an influenza A viral challenge study assessing the impact of treatment on host defence biomarkers and viral load. Results INNA-051 was well tolerated in both studies, with no dose-limiting toxicities identified. Mechanistic biomarkers assessed in both studies demonstrated the expected engagement of pharmacology, including innate immune pathways. There were lower than anticipated rates of infection. Post hoc analysis conducted in laboratory-confirmed infected participants with low or no antibody titre against the challenge virus showed INNA-051 treatment led to a significantly shorter duration of infection and increased expression of genes and pathways associated with host defence responses against influenza. Conclusions The safety and pharmacology profile of INNA-051 confirms preclinical studies. INNA-051 increased expression of genes and pathways associated with host defence responses against influenza and was associated with a shorter duration of infection. These studies support further clinical assessment in the context of natural viral respiratory tract infections in individuals at increased risk of severe illness.http://openres.ersjournals.com/content/10/6/00199-2024.full |
| spellingShingle | Francesca A. Mercuri Scott White Hayley A. McQuilten Charlotte Lemech Stephan Mynhardt Rana Hari Ping Zhang Nicole Kruger Grant McLachlan Bruce E. Miller Nicholas P. West Ruth Tal-Singer Christophe Demaison Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology ERJ Open Research |
| title | Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology |
| title_full | Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology |
| title_fullStr | Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology |
| title_full_unstemmed | Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology |
| title_short | Evaluation of intranasal TLR2/6 agonist INNA-051: safety, tolerability and proof of pharmacology |
| title_sort | evaluation of intranasal tlr2 6 agonist inna 051 safety tolerability and proof of pharmacology |
| url | http://openres.ersjournals.com/content/10/6/00199-2024.full |
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