The proof-of-concept CATALYST trial has identified namilumab as offering benefit over usual care for some patients hospitalised with COVID-19 pneumonia.
The trial tested UK-based bio-pharmaceutical company Izana Bioscience’s namilumab (IZN-101) as a potential therapeutic to treat hospital patients with COVID-19 pneumonia, receiving “usual care”, as well as having high levels in their blood of a marker of inflammation known as C reactive protein (CRP). CRP levels rise when there is inflammation in the body, and elevated levels of CRP have been found to be a potential early marker to predict risk for severity of COVID- 19.
An antibody already in late-stage trials to treat rheumatoid arthritis, namilumab targets a “cytokine”, which is naturally secreted by immune cells in the body but, in uncontrolled levels, is believed to be a key driver of the excessive and dangerous lung inflammation seen in COVID-19 patients.
The trial, led by the Universities of Birmingham and University Hospitals Birmingham NHS Foundation Trust, in collaboration with the University of Oxford and funded by the Medical Research Council and carried out between June 2020 and February 2021, involved patients 16 and over with COVID-19 pneumonia either being treated on a ward or Intensive Care Unit (ICU) at nine NHS hospitals across the UK.
The study, published in The Lancet Respiratory Medicine, involved 54 patients receiving “usual care” (steroids and oxygen or ventilation, depending on the severity of disease) and 57 patients given usual care as well as a single intravenous dose of 150mg of namilumab.
As well as COVID-19 pneumonia, all study participants had CRP levels greater than 40mg/l. The researchers compared the probability of the reduction of levels of CRP in patients. Compared with usual care alone, the researchers found a 97% probability of CRP being reduced over time in those given namilumab when compared with usual care alone.
The patients were monitored, and after 28 days the study also showed there were fewer deaths and more discharges from hospital or ICU in those who had been given namilumab, compared with those receiving usual care alone.
By day 28, 78% (43) of the patients receiving namilumab were discharged from hospital or ICU, compared with 61% (33) of the patients given usual care. In the namilumab group, 11% (6) were still in hospital by day 28, compared with 20% (11) in the usual care group. Of those in the namilumab group, 11% (6) patients died compared with 19% (10) who died in the usual care group by day 28.
The team calculated the differences between the two cohorts in overall probability of those being discharged from ICU or a ward at 28 days. Of those on a ward, the probability of discharge at day 28 was 64% in the usual care cohort, compared with 77% in the namilumab cohort. Of those in ICU, probability of discharge at day 28 was 47% in the usual care group, compared with 66% in the namilumab cohort.
Dr Ben Fisher, co-chief investigator of the CATALYST trial at the University of Birmingham’s Institute of Inflammation and Ageing, and Consultant Rheumatologist at University Hospitals Birmingham NHS Foundation Trust (UHB), said: “Our research has provided important proof-of-concept evidence that namilumab reduces inflammation in hospitalised patients with COVID-19 pneumonia. However, our sample size is too small for a definitive assessment of clinical outcomes and further studies are required for this, as well as to understand better the population that may benefit most. Our results may not generalise to hospitalised patients without evidence of pneumonia or raised CRP or patients not requiring hospitalisation. It is important, therefore, that namilumab is now prioritised for further COVID-19 research in a much larger national Phase III clinical trial.”
Dr Someit Sidhu, co-founder of Izana Bioscience, said: “We are proud to support the CATALYST trial led by the highly experienced team at the University of Birmingham and UHB, Europe’s largest integrated critical care centre. We believe namilumab can play a significant role in dampening the hyper-inflammation seen in patients with severe COVID-19 infection and we are committed to working with regulators and partners worldwide to ensure this potential therapy can be developed for patients with COVID-19 who urgently need treatments. This is a particularly significant moment for me, supporting the global response to this pandemic through the work of the team at University Hospital Birmingham, where I trained as a junior doctor before going on to found Izana.”
The CATALYST team also tested a second drug called infliximab (CT-P13), currently used as a treatment for inflammatory conditions. They compared the same patients with COVID-19 pneumonia and CRP levels greater than 40mg/l receiving usual care, to 35 patients receiving usual care and a single intravenous dose of 5mg/kg of infliximab. However, the study found infliximab was not more effective than usual care, with just a 15% probability of CRP being reduced.
Fisher added: “Our findings relating to infliximab, while disappointing, are also important as we continue to investigate and identify existing and new anti-inflammatory drugs that may play a critical role in targeting and reducing the most serious symptoms of COVID-19.”
Study details
Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial
Benjamin A Fisher, Tonny Veenith, Daniel Slade, Charlotte Gaskell, Matthew Rowland, Tony Whitehouse, James Scriven, Dhruv Parekh, Madhu S Balasubramaniam, Graham Cooke, Nick Morley, Zoe Gabriel, Matthew P Wise, Joanna Porter, Helen McShane, Ling-Pei Ho, Philip N Newsome, Anna Rowe, Rowena Sharpe, David R Thickett, Julian Bion, Simon Gates, Duncan Richards, Pamela Kearns, Bryan Williams, Rebecca Turner, Vincenzo Libri, Francis Mussai, Gary Middleton, Sarah Bowden, Mansoor Bangash, Fang Gao-Smith, Jaimin Patel, Elizabeth Sapey, Mark Thomas, Mark Coles, Peter Watkinson, Naj Rahman, Brian Angus, Alexander J. Mentzer, Alex Novak, Marc Feldman, Alex Richter, Sian Faustini, Camilla Bathurst, Joseph Van de Wiel, Susie Mee, Karen James, Bushra Rahman, Karen Turner, Adam Hill, Anthony Gordon, Christina Yap, Michael Matthay, Danny McAuley, Andrew Hall, Paul Dark, Andrew McMichael.
Published in The Lancet Respiratory Medicine on 16 December 2021
Summary
Background
Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials.
Methods
In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903.
Findings
Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment–time interactions were –0·09 (95% CI –0·19 to 0·00) for namilumab and 0·06 (–0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group.
Interpretation
Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation, as measured by CRP concentration, in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19.
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