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Safety, Tolerability, Bioavailability, and Biological Activity of Inhaled Interferon-α2b in Healthy Adults: The IN2COVID Phase I Randomized Trial

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Abstract

Background and Objectives

Interferons have been identified as a potential treatment alternative for coronavirus disease 2019. This study assessed the safety, tolerability, bioavailability, and biological activity of inhaled interferon-α2b (IFN)-α2b in healthy adults.

Methods

A double-blind, randomized, phase I clinical trial was conducted with two cohorts of healthy subjects aged 18–50 years. The first cohort received 2.5 MIU of inhaled IFN-α2b twice daily for 10 days (n = 6) or placebo (n = 3); the second cohort received 5.0 MIU of inhaled IFN-α2b in a similar scheme (n = 6) or placebo (n = 3). The first two doses were administered in an emergency department, then participants completed their treatment at home. Safety was measured through vital signs, new symptoms, and laboratory tests. Tolerability was measured as participants’ treatment acceptability. Bioavailability and biological activity were measured from serum IFNα concentrations and real-time quantitative polymerase chain reaction of interferon-induced genes in blood before and after treatments.

Results

Exposure to inhaled IFN-α2b at 2.5-MIU or 5-MIU doses did not produce statistically significant changes in participant vital signs, or elicit new symptoms, and standard hematological and biochemical blood measurements were comparable to those recorded in individuals who received placebo. A total of 58 adverse events were observed. All were mild or moderate and did not require medical care. All participants reported very high tolerability towards a twice-daily nebulized treatment for 10 days (98.0, 97.0, and 97.0 in the placebo, 2.5-MIU, and 5-MIU groups, respectively, on a 0- to 100-mm visual analog scale). A dose-dependent mild increase in serum IFN-α concentrations and an increase in serum RNA expression of IFN-induced genes were observed 11 days after treatment (p < 0.05 for all between-group comparisons).

Conclusions

Inhaled IFN-α2b was preliminarily safe and well tolerated, and induced systemic biological activity in healthy subjects.

Clinical Trial Registration

The trial was registered in ClinicalTrials.gov (NCT04988217), 3 August, 2021.

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Acknowledgments

We recognize the Clínica San Carlos de Apoquindo Ambulatory and Emergency Department clinical team, especially Dr. Felipe Maluenda and Pamela Flores, for their support during the study. We also thank Activa8 contract research organization, Daniel Ernst M.D., Mirentxu Iruretagoyena, M.D., Ph.D., and Inia Perez, M.D., for their monitoring and supervision of the trial, and Mahmoud Saghaei, M.D., for his support using the clinical trial randomization software Qminim. Finally, we thank Juan Pablo Huidobro-Toro, Ph.D., for the review and comments of an early version of the manuscript.

Collaborators of the IN2COVID Research Team: Juan Pablo Olivo, Katherine Suisbert, Andrea Cruz, Katterine Perez, Romina Valdivieso, Diego Navarro, Francisco Pereira, Vanessa Monge, Marisol Dibarrart, Krisbeth Salazar, Morgan Bracho, Lidia Pontanilla.

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Authors and Affiliations

  1. Department of Family Medicine, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    Diego Garcia-Huidobro

  2. Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN, USA

    Diego Garcia-Huidobro

  3. Translational Allergy and Immunology Laboratory, Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    Carolina Iturriaga, Guillermo Perez-Mateluna, Paula Fajuri, Marcela Urzúa, Juan Pablo Fraga & Arturo Borzutzky

  4. Pharmacology and Toxicology ProgramSchool of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    Nicolás Severino

  5. Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile

    Javiera de la Cruz & Cecilia Poli

  6. Department of Pediatric Pulmonology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

    José A. Castro-Rodríguez

  7. Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada

    Eleanor Fish

  8. Department of Immunology, University of Toronto, Toronto, ON, Canada

    Eleanor Fish

Authors
  1. Diego Garcia-Huidobro
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Consortia

the IN²COVID Research Team

  • Juan Pablo Olivo
  • , Katherine Suisbert
  • , Andrea Cruz
  • , Katterine Perez
  • , Romina Valdivieso
  • , Diego Navarro
  • , Francisco Pereira
  • , Vanessa Monge
  • , Marisol Dibarrart
  • , Krisbeth Salazar
  • , Morgan Bracho
  •  & Lidia Pontanilla

Corresponding author

Correspondence to Arturo Borzutzky.

Ethics declarations

Funding

This study was funded by Altum Pharmaceuticals Inc., Vancouver, BC, Canada.

Conflicts of Interest

Diego Garcia-Huidobro, Carolina Iturriaga, Guillermo Perez-Mateluna, Paula Fajuri, Nicolás Severino, Marcela Urzúa, Juan Pablo Fraga, Javiera de la Cruz, Cecilia Poli, José A. Castro-Rodríguez, Eleanor Fish, and Arturo Borzutzky have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments) and were approved by the Pontificia Universidad Católica de Chile Scientific Ethics Committee (approval #210224003).

Consent to Participate

All participants were informed about the study and provided written consent to participate.

Consent for Publication

All participants provided consent to use their data in publications.

Availability of Data and Material

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy restrictions.

Code Availability

Not applicable.

Authors’ Contributions

All authors contributed to the study design and/or implementation. The study protocol was designed by AB, CI, DG-H, EF, and JAC-R. Material preparation was performed by CI, PF, MU, and AB. Participant recruitment and data collection procedures were supervised by PF and MU. Laboratory samples and analyses were processed by GP-M and JPF. JdlC and CP conducted the interferon gene signature analyses. NS oversaw the drug storage and administration. Data analyses were conducted by DG-H, JdlC, and AB. The first draft of the manuscript was written by DG-H and all authors commented and reviewed subsequent versions of the manuscript. All authors read and approved the final manuscript.

Additional information

The members of the IN²COVID Research Team are listed in the Acknowledgements section.

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Garcia-Huidobro, D., Iturriaga, C., Perez-Mateluna, G. et al. Safety, Tolerability, Bioavailability, and Biological Activity of Inhaled Interferon-α2b in Healthy Adults: The IN2COVID Phase I Randomized Trial. Clin Drug Investig 43, 447–461 (2023). https://doi.org/10.1007/s40261-023-01278-3

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