Infectious Diseases

FDA Approved Phase 3 Study of ​Bucillamine for the Treatment of COVID-19

Revive is developing a product and clinical development plan intending to unlock the full potential of Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine) for infectious diseases, including COVID-19.

Scientific Rationale for the Investigation of Bucillamine to Treat Infectious Diseases, including COVID-19

Current antiviral interventions for influenza have exhibited modest efficacy, especially in improving mortality in at-risk populations, such as the elderly.1,2  Novel antivirals have been plagued by poor oral bioavailability and lack of efficacy when not delivered early.1 This is because these drugs mostly act to prevent the early processes of virus binding to cells or viral replication.2  Thiols, particularly N-acetylcysteine (NAC), with antioxidant and reducing activity have been investigated as effective therapies that abrogate the potential for influenza to cause severe disease.3,4,5  Restoration of glutathione, the major intracellular thiol antioxidant, is a critical functional activity of NAC.6  Reactive oxygen species (ROS) generation during influenza virus infection aggravate destructive inflammation and programmed death of epithelial cells.7  Studies in human cells and animal models have shown that NAC works to prevent acute lung injury caused by influenza virus infection through inhibition of these ROS-mediated mechanisms.4,7  NAC has been investigated clinically and found to significantly attenuate clinical symptoms associated with influenza infection, especially in elderly at-risk patients.5  While NAC is easily taken up by cells and has low toxicity, clinical efficacy has required long-term and high-dose administration because of modest relative potency, limiting its clinical applicability.

Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine), which has a well-known safety profile and is prescribed in the treatment of rheumatoid arthritis in Japan and South Korea for over 30 years, is a cysteine derivative with 2 thiol groups that is 16-fold more potent than NAC as a thiol donor in vivo, giving it vastly superior function in restoring glutathione and therefore greater potential to prevent acute lung injury during influenza infection.8  Bucillamine has also been shown to prevent oxidative and reperfusion injury in heart and liver tissues8 and is highly cell permeable for efficient delivery into cells.8,9  Bucillamine has unrealized potential for the treatment of influenza with both proven safety and proven mechanism of action similar to that of NAC, but with much higher potency, mitigating the previous obstacles to using thiols therapeutically. It is also reasonable to hypothesize that similar processes related to ROS are involved in acute lung injury during nCov-19 infection, possibly justifying the investigation of bucillamine as an intervention for COVID-19.

References
1. Muthuri SG, Venkatesan S, Myles PR et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data Lancet Respir Med. 2014 May;2(5):395-404. doi: 10.1016/S2213-2600(14)70041-4.

2. Duwe S. Influenza viruses – antiviral therapy and resistance. GMS Infect Dis. 2017; 5: Doc04.

3. Zhang RH, Li CH, Wang CL et al. N-acetyl-l-cystine (NAC) protects against H9N2 swine influenza virus-induced acute lung injury. Int Immunopharmacol. 2014 Sep;22(1):1-8. doi: 10.1016/j.intimp.2014.06.013.

4. Ungheri D, Pisani C, Sanson G et al. Protective effect of n-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol. 2000 Sep-Dec;13(3):123-128.

5. De Flora S, Grassi C, and Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997; 10: 1535–1541 DOI: 10.1183/09031936.97.10071535

6. Poole LB. The Basics of Thiols and Cysteines in Redox Biology and Chemistry. Free Radic Biol Med. 2015 Mar; 0: 148–157. doi: 10.1016/j.freeradbiomed.2014.11.013.

7. Mata M, Morcillo E, Gimeno C, Cortijo J. N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem Pharmacol. 2011 Sep 1;82(5):548-55. doi: 10.1016/j.bcp.2011.05.014.

8. Horowitz LD. Bucillamine: a potent thiol donor with multiple clinical applications. Cardiovasc Drug Rev. 2003 Summer;21(2):77-90.

9. Sagawa A, Fujisaku A, Ohnishi K et al. A multicentre trial of bucillamine in the treatment of early rheumatoid arthritis (SNOW study). Mod Rheumatol. 2011 Jun;21(3):251-7. doi: 10.1007/s10165-010-0385-4