GSK fails COVID-19 phase 2, subgroup finding fuels further work

GSK CSO Hal Barron
GSK CSO Hal Barron, M.D. (GSK)

A phase 2 clinical trial of GlaxoSmithKline’s otilimab in hospitalized COVID-19 patients has missed its primary endpoint. However, a preplanned analysis of older patients found signs of efficacy, leading GSK to expand the cohort in a bid to validate the finding. 

Otilimab is an experimental anti-granulocyte macrophage colony-stimulating factor (anti-GM-CSF) monoclonal antibody that GSK took into a suite of phase 3 rheumatoid arthritis studies in 2019. As evidence of the role the GM-CSF cytokine may play in negative COVID-19 outcomes emerged early in the pandemic, GSK initiated an 800-patient phase 2 study to evaluate otilimab in the indication.

Today, GSK shared data from the clinical trial, which enrolled people with severe COVID-19-related pulmonary disease requiring significant oxygen support or early invasive mechanical ventilation. GSK linked a single infusion of otilimab to a 5.3 percentage point improvement over standard of care in the proportion of patients who were alive and free of respiratory failure 28 days after treatment.

The numerical difference fell short of statistical significance, causing the study to miss its primary endpoint. A preplanned analysis of patients aged 70 years and older was more encouraging, though.

In the 180-subject senior subgroup, 65.1% of patients who received otilimab were alive and free of respiratory failure 28 days after treatment, compared to 45.9% of their peers in the control group. The difference has a nominal p-value of 0.009. GSK also saw a difference in mortality. Over the 60 days after treatment, 26% of patients on otilimab died, versus a 40.4% mortality rate in the control arm. 

The results come from a relatively small subgroup, leaving scope to question whether they accurately reflect the effect of otilimab in seniors, but GSK sees enough promise in the results to continue the study. GSK is now enrolling an additional 350 patients aged 70 years and older to validate the effect of its antibody on seniors. Results are expected in the second half of the year.

GSK’s interest in the effect of otilimab in patients aged 70 years and older is partly built on evidence that GM-CSF may play a bigger role in the immune responses of seniors. A preprint paper published last year identified elevated levels of D-dimer, CXCL10 and GM-CSF as ways in which people aged 70 years and older with COVID-19 differ from younger patients. 

GM-CSF is associated with disease severity, and COVID-19 outcomes are worse in older patients. As otilimab is designed to inhibit GM-CSF, there are reasons to think it may help a group of COVID-19 patients who still have limited good treatment options. GSK’s phase 2 failed to conclusively confirm or refute that hypothesis, driving the Big Pharma to keep testing the drug.