Mitoquinone mesylate as post-exposure prophylaxis against SARS-CoV-2 infection in humans: an exploratory single center pragmatic open label non-randomized pilot clinical trial with matched controls
Keren Chen, Nicholas J Jackson, Theodoros Kelesidis
eBioMedicine, doi:10.1016/j.ebiom.2024.105042
Background An ongoing important need exists to rapidly develop novel therapeutics for COVID-19 that will retain antiviral efficacy in the setting of rapidly evolving SARS-CoV-2 variants and potential future development of resistance of SARS-COV-2 to remdesivir and protease inhibitors. To date, there is no FDA-approved treatment for post-exposure prophylaxis against SAR-CoV-2. We have shown that the mitochondrial antioxidant mitoquinone/ mitoquinol mesylate (Mito-MES), a dietary supplement, has antiviral activity against SARS-CoV-2 in vitro and in SARS-CoV-2 infected K18-hACE2 mice.
Methods In this exploratory, pragmatic open label clinical trial (ClinicalTrials.gov identifier NCT05381454), we studied whether Mito-MES is an effective post-exposure prophylaxis treatment in people who had high-grade unmasked exposures to SARS-CoV-2 within 5 days prior to study entry. Participants were enrolled in real-world setting in Los Angeles, United States between May 1 and December 1, 2022 and were assigned to either mito-MES 20 mg daily for 14 days (n = 40) or no mito-MES (controls) (n = 40). The primary endpoint was development of SARS-CoV-2 infection based on 4 COVID-19 diagnostic tests [rapid antigen tests (RATs) or PCR] performed during the study period (14 days post exposure). Findings Out of 40 (23 females; 57.5%) study participants who took Mito-MES, 12 (30%) developed SARS-CoV-2 infection compared to 30 of the 40 controls (75%) (difference -45.0%, 95% confidence intervals (CI): -64.5%, -25.5%). Out of 40 (19 females; 47.5%) study participants in the control group, 30 (75.0%) had at least one positive COVID-19 diagnostic test and 23 (57.5%) were symptomatic. With regards to key secondary outcomes, among symptomatic SARS-CoV-2 infections, the median duration of viral symptoms was lower in the Mito-MES group (median 3.0, 95% CI 2.75, 3.25) compared to the control group (median 5.0, 95% CI 4.0, 7.0). None of the study participants was hospitalized or required oxygen therapy. Mito-MES was well tolerated and no serious side effect was reported in any study participant. Interpretation This work describes antiviral activity of mito-MES in humans. Mito-MES was well tolerated in our study population and attenuated transmission of SARS-CoV-2 infection. Given established safety of Mito-MES in humans, our results suggest that randomized control clinical trials of Mito-MES as post-exposure prophylaxis against SARS-CoV-2 infection are warranted.
References
Cao, Wang, Jian, Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies, Nature
Dashdorj, Jyothi, Lim, Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines, BMC Med
Fujimoto, Kurihara, Hirata, Takeda, Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases, Clin Investig
Gandhi, Klein, Robertson, De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report, Nat Commun
Gane, Weilert, Orr, The mitochondria-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients, Liver Int
Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for high-risk, nonhospitalized adults with covid-19, N Engl J Med
Higgins, Phillpotts, Scott, Wallace, Bernhardt et al., Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers, Antimicrob Agents Chemother
Hu, Bogoyevitch, Jans, Subversion of host cell mitochondria by RSV to favor virus production is dependent on inhibition of mitochondrial complex I and ROS generation, Cells
Hu, Schulze, Ghildyal, Respiratory syncytial virus coopts host mitochondrial function to favour infectious virus production, Elife
Lother, Abassi, Agostinis, Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial, Can J Anaesth
Marzolini, Kuritzkes, Marra, Recommendations for the management of drug-drug interactions between the COVID-19 antiviral nirmatrelvir/ritonavir (paxlovid) and comedications, Clin Pharmacol Ther
Mcburney, A dose ranging study of the pharmacokinetics and safety of mitoquinone administration in healthy adult volunteers, Huntingdon Life Science Ltd
Nalbandian, Sehgal, Gupta, Post-acute COVID-19 syndrome, Nat Med
Patsopoulos, A pragmatic view on pragmatic trials, Dialogues Clin Neurosci
Pham, Macrae, Broome, MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle-aged men, Eur J Appl Physiol
Ribero, Jouvenet, Dreux, Nisole, Interplay between SARS-CoV-2 and the type I interferon response, PLoS Pathog
Robinson, Mirza, Gallagher, Limitations of molecular and antigen test performance for SARS-CoV-2 in symptomatic and asymptomatic COVID-19 contacts, J Clin Microbiol
Rossman, Santos-Parker, Steward, Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults, Hypertension
Smith, Murphy, Animal and human studies with the mitochondria-targeted antioxidant MitoQ, Ann N Y Acad Sci
Smith, Porteous, Gane, Murphy, Delivery of bioactive molecules to mitochondria in vivo, Proc Natl Acad Sci U S A
Snow, Rolfe, Lockhart, A double-blind, placebocontrolled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease, Mov Disord
Sticher, Lu, Mitchell, Analysis of the potential for N (4)-hydroxycytidine to inhibit mitochondrial replication and function, Antimicrob Agents Chemother
Tan, Chan, Juni, Post-exposure prophylaxis against SARS-CoV-2 in close contacts of confirmed COVID-19 cases (CORIPREV): study protocol for a cluster-randomized trial, Trials
Vandyck, Deval, Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection, Curr Opin Virol
Williamson, Hughes, Cobley, Davison, The mitochondria-targeted antioxidant MitoQ, attenuates exerciseinduced mitochondrial DNA damage, Redox Biol
Zaki, Strategies for oral delivery and mitochondrial targeting of CoQ10, Drug Deliv
Zhou, Hill, Sarkar, beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells, J Infect Dis
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'first-page': '1547',
'DOI': '10.1038/s41467-022-29104-y',
'article-title': 'De novo emergence of a remdesivir resistance mutation during treatment '
'of persistent SARS-CoV-2 infection in an immunocompromised patient: a '
'case report',
'volume': '13',
'author': 'Gandhi',
'year': '2022',
'journal-title': 'Nat Commun'},
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'article-title': 'Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models',
'author': 'Petcherski',
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'first-page': '96',
'DOI': '10.1111/j.1749-6632.2010.05627.x',
'article-title': 'Animal and human studies with the mitochondria-targeted antioxidant '
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'DOI': '10.1111/j.1478-3231.2010.02250.x',
'article-title': 'The mitochondria-targeted anti-oxidant mitoquinone decreases liver '
'damage in a phase II study of hepatitis C patients',
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'author': 'Gane',
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'mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy '
"in Parkinson's disease",
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'author': 'Snow',
'year': '2010',
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'improves vascular function in healthy older adults',
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'exercise-induced mitochondrial DNA damage',
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'favour infectious virus production',
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'author': 'Hu',
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'is dependent on inhibition of mitochondrial complex I and ROS '
'generation',
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'author': 'Hu',
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'colitis by suppressing NLRP3 inflammasome-mediated inflammatory '
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'journal-title': 'Dialogues Clin Neurosci'},
{ 'issue': '8 Suppl',
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'first-page': 'S162',
'article-title': 'Effects of coenzyme Q10 administration on pulmonary function and '
'exercise performance in patients with chronic lung diseases',
'volume': '71',
'author': 'Fujimoto',
'year': '1993',
'journal-title': 'Clin Investig'},
{ 'issue': '6',
'key': '10.1016/j.ebiom.2024.105042_bib25',
'first-page': '1868',
'article-title': 'Strategies for oral delivery and mitochondrial targeting of CoQ10',
'volume': '23',
'author': 'Zaki',
'year': '2016',
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'article-title': 'Intranasal interferon as protection against experimental respiratory '
'coronavirus infection in volunteers',
'volume': '24',
'author': 'Higgins',
'year': '1983',
'journal-title': 'Antimicrob Agents Chemother'},
{ 'issue': '7',
'key': '10.1016/j.ebiom.2024.105042_bib27',
'doi-asserted-by': 'crossref',
'DOI': '10.1371/journal.ppat.1008737',
'article-title': 'Interplay between SARS-CoV-2 and the type I interferon response',
'volume': '16',
'author': 'Sa Ribero',
'year': '2020',
'journal-title': 'PLoS Pathog'},
{ 'key': '10.1016/j.ebiom.2024.105042_bib28',
'series-title': 'A\xa0dose ranging study of the pharmacokinetics and safety of '
'mitoquinone administration in healthy adult volunteers',
'first-page': '1',
'author': 'McBurney',
'year': '2006'},
{ 'issue': '4',
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'doi-asserted-by': 'crossref',
'first-page': '601',
'DOI': '10.1038/s41591-021-01283-z',
'article-title': 'Post-acute COVID-19 syndrome',
'volume': '27',
'author': 'Nalbandian',
'year': '2021',
'journal-title': 'Nat Med'}],
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