Targeting de Novo Pyrimidine Biosynthesis by Leflunomide for the Treatment of COVID-19 Virus Disease

Summary

The global COVID-19 pandemic has caused unprecedented strain on health care services around the world.The absence of specific anti-viral medications to treat the underlying infection led to a proliferation of clinical studies and trials aimed at re-purposing existing medications. Human dihydroorotate dehydrogenase (DHODH) is vital enzyme utilised by viruses to replicate in the host cell. Leflunomide, a drug that is already licenced to treat rheumatoid arthritis, is a potent inhibitor of the enzyme DHODH. Importantly, this drug has dual anti-viral and anti-inflammatory properties so it targets viral replication and suppresses host inflammatory response which plays a role at more progressive stages of infection. DEFEAT-COVID is a multi-site, international, interventional, pragmatic, parallel group design, open label, randomised CTIMP with a pilot phase that will allow to adapt procedures and assessments if required. A phase III clinical trial of leflunomide for treating COVID-19 has been registered in China, Registration number: ChiCTR2000030058). The current proposal extends the original clinical study of leflunomide in China (People's Hospital of Wuhan University) to the UK through a structured collaboration.

Timeline

Start

2020-09-16

Primary completion

2022-07-01

Completion

2022-07-01

Publications

• Kralj-Hans I, Li K, Wesek A, Lamorgese A, Omar F, Ranasinghe K, McGee M, Brack K, Li S, Aggarwal R, Bulle A, Kodre A, Sharma S, Fluck D, John I, Sharma P, Belsey JD, Li L, Seshasai SRK, Li HL, Marczin N, Chen Z; DEFEAT-COVID Investigators. Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial. BMJ Open. 2023 Apr 13;13(4):e068179. doi: 10.1136/bmjopen-2022-068179.

Drugs

Indications