London hospitals partner with Chinese researchers to study use of rheumatoid arthritis drug in improving COVID-19 outcomes in trial of 178 patients
Ashford and St Peters Hospital NHS Trust, Guangdong Uni-Innovation Pharmaceuticals Co., Ltd.
Targeting de novo Pyrimidine Biosynthesis by leflunomide as a Novel Concept for the Treatment of Corona Virus Disease 2019 (COVID-19) (DEFEAT-COVID study)
A group of London hospital trusts in collaboration with researchers in China, and with funding from LifeArc, is set to commence clinical trial testing of leflunomide – a drug licensed to treat rheumatoid arthritis – in hospitalised COVID-19 patients.
Leflunomide has previously been investigated in a small pilot study conducted in Wuhan, China. Patients with moderate or severe clinical symptoms of COVID-19 who were treated with leflunomide demonstrated favourable clinical outcomes with a shorter clinical recovery time compared to the placebo arm, and no side effects were observed. This LifeArc funded study now aims to explore these initial findings in a larger patient cohort.
- Dr Zhong Chen, Ashford and St Peters Hospital NHS Trust, Brompton and Harefield Hospital Trust
- Dr Honglin Li, East China University of Science and Technology, Shanghai, China
- Dr Shengqing Li, Huashan Hospital, China
- Dr Wing-Chiu Candy Sze, Barts and Royal London Hospital NHS Trust
- Dr Nandor Marczin, Imperial College and Brompton and Harefield Hospital Trust
- Dr Anna Reed, Brompton and Harefield Hospital Trust
- Dr Sundeep Kaul, Brompton and Harefield Hospital Trust
- Dr (Caroline) Ling Li, University of Kent
- Dr Sreenivasa Rao Kondapally Seshasai, St Georges Hospital NHS Foundation Trust
- Dr Lei Shan, Guangdong Uni-Innovation Pharmaceuticals Co., Ltd., China.
Potential of repurposed therapeutic for COVID-19 pandemic
Research into optimal strategies for the treatment of virus infections has identified the protein Human dihydroororate dehydrogenase (DHODH) as a potential therapeutic target. The human enzyme DHODH is responsible for producing the building blocks that are required to make RNA molecules. After an RNA virus infects a human cell it is particularly dependent on the host human protein DHODH to complete efficient viral replication.
Initial proof-of-concept work has demonstrated that direct-targeting of DHODH acts as a broad anti-viral mechanism and importantly inhibition of DHODH was also able to prevent replication of the coronavirus responsible for COVID-19 disease, SARS-CoV-2 (manuscript under review). Furthermore, inhibition of DHODH also has anti-inflammatory properties as the proliferation of immune cells is suppressed. The dual actions of DHODH inhibition make it a promising therapeutic target for COVID-19.
Leflunomide is a DHODH inhibitor drug and is an approved drug for the treatment of rheumatoid arthritis. Based on the dual actions of DHODH inhibition (anti-viral and anti-inflammatory properties) a small pilot study of 10 patients was conducted in Wuhan, China. Hospitalised COVID-19 patients experiencing severe clinical symptoms were treated with leflunomide. The PILOT study demonstrated feasibility with favourable clinical outcomes, including a shorter recovery time for patients receiving leflunomide compared to patients who received a placebo. Additionally, a tolerable safety profile was observed in leflunomide-treated patients.
Researchers have secured funding from LifeArc to conduct a multicentre clinical trial in the UK and China to investigate the treatment of hospitalised COVID-19 patients with leflunomide. This trial aims to further explore the findings from the Wuhan pilot study and is formed of an initial 80 participant UK PILOT study (40 in each trial arm) that will be expanded to include a total of 178 trial participants (89 in each trial arm).
The DEFEAT-COVID trial aims to evaluate the efficacy and safety of leflunomide compared to the standard of care (SoC). The study will specifically consider outcomes for a loading dose of leflunomide 100 mg daily for three days, followed by leflunomide 10-20 mg daily, to maintain a total course of ten days, versus SoC. The primary outcomes that will be measured within the trial are time to clinical improvement, defined as the number of days from the initiation of study treatment until improvement of two categories is observed based on the World Health Organisation 7-category ordinal scale.