Adjunctive ruxolitinib attenuates inflammation and enhances antiparasitic immunity in human volunteers experimentally infected with Plasmodium falciparum

Publications

Science Translational Medicine

Adjunctive ruxolitinib attenuates inflammation and enhances antiparasitic immunity in human volunteers experimentally infected with Plasmodium falciparum

Product:

Inflammation Panel 250

Topic:

Inflammation

Disease Area:

Malaria

Sample Type:

Plasma

Topic/Product:

Inflammation Panel 250

Disease Area:

Malaria

Sample Type:

Plasma

Abstract

Inhibiting the host inflammatory response to malaria represents a potential strategy to improve clinical outcomes and inhibit immunoregulatory pathways that underlie suboptimal development of antiparasitic immunity. Ruxolitinib is a JAK 1/2 inhibitor that reduces inflammatory biomarkers when used in myeloproliferative disorders, and inhibits type-1 interferons and enhances CD4+ T cell immunity when combined with anti-parasitic drugs in animal models. Here we report the results of a double-blind randomised placebo-controlled trial evaluating the ability of ruxolitinib to reduce inflammatory responses and boost anti-parasitic immunity in malaria-naïve volunteers inoculated with blood-stage Plasmodium falciparum. Twenty participants were inoculated, and randomized on day 8 to receive artemether-lumefantrine with either ruxolitinib or placebo. Ninety days later, participants who remained eligible were re-inoculated with a second infection. Ruxolitinib was safe and well-tolerated, and attenuated the host inflammatory response to the initial infection, with reduced post-treatment increases in the inflammatory biomarker CRP, as well as markers of disease severity including angiopoietin-2 and ICAM-1. Further, ruxolitinib enhanced the immune memory response following a second inoculation, with increased plasma levels of HLA-DR and CXCL13, indicating enhanced immune activation and germinal centre responses, respectively. These data support the further evaluation of ruxolitinib as an adjunctive treatment to improve clinical outcomes and boost anti-parasitic immunity in clinical malaria.

Authors & Affiliations

Rebecca Webster1*, Damian A. Oyong2*, Azrin N. Abd-Rahman1, Adam J. Potter1, Reena Mukhiya1,2,3, Nischal Sahai4, Indika Leelasena4, Eniko Ujvary4, Sue Mathison4, Dean W. Andrew1, Luzia Bukali1, Fabian de Labastida Rivera1, Jessica Engel1, Megan S.F. Soon1,2, Teija Frame1, Julianne Hamelink1,2,5, Mayimuna Nalubega1,2,5, Nicholas L. Dooley2, Jessica R. Loughland2, Tran Nguyen6, Yael Rosenberg-Hasson6, Sofia Maysel-Auslender6, Natalia Sigal6, Kira Foygel6, Jeremy Gower1, Jenny Peters1, Ria Woo1, Fiona Amante1, Timothy N.C. Wells7, Stephan Chalon7, Joerg J. Moehrle7,12,13, James S. McCarthy8, Geoffrey W. Birrell9, Michael D. Edstein9, Michael Leipold6, Gerlinde Obermoser6, Holden Maecker6, Christian R. Engwerda1#, Bridget E Barber1,10,11#, Michelle J. Boyle1,2,3,5# A

1. QIMR Berghofer, Brisbane, QLD, Australia
2. Burnet Institute, Melbourne, VIC, Australia
3. Griffith University, Brisbane, Australia
4. University of Sunshine Coast Clinical Trials, Brisbane, QLD, Australia
5. University of Queensland, Brisbane, QLD, Australia
6. Stanford University, Stanford, CA, USA
7. Medicines for Malaria Venture, Geneva, Switzerland
8. Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
9. Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, QLD, Australia
10. Royal Brisbane & Women’s Hospital, Brisbane, QLD, Australia
11. Menzies School of Health Research, Darwin, NT, Australia
12. University of Basel, Basel, Switzerland
13. Swiss Tropical and Public Health Institute, Allschwil, Switzerland

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.