TThe hypothesis that inhibiting the inflammatory cytokine granulocyte macrophage colony-stimulating factor can mitigate the effects of Covid-19 took a knock today with the failure of Glaxo’s mid-stage Oscar trial. The company's anti-GM-CSF MAb otilimab made little difference to the health of hospitalised Covid-19 patients when added to standard of care.
Glaxo is undeterred, pointing to positive findings in a prespecified subgroup of old patients. It has opted to expand this cohort in the hope of confirming a signal, but as vaccination programmes continue recruiting patients will become progressively harder.
The phase II Oscar study aimed to show that a single infusion of otilimab could cut rates of death and respiratory failure 28 days after it was given on top of standard therapies such as antivirals and corticosteroids, including dexamethasone. It did in fact make a slight difference, reducing these events by 5.3% versus patients given a placebo infusion, but this was not statistically significant.
That was in the entire population – 806 patients aged 18-79. In old patients the results were better, Glaxo says.
A pre-planned cut of the data by age revealed that, among the 180 patients aged 70 and over, 65.1% of those given the MAb were alive and free of respiratory failure at the 28-day point, versus 45.9% of those who received placebo. The nominal p value was 0.009.
Looking at mortality alone, death rates by day 60 were 40.4% among placebo-treated patients aged 70 and up, compared with 26.0% in those given otilimab, with a nominal p value of 0.040.
The study having missed its primary endpoint, these are just exploratory data. And explore them Glaxo will: it is amending Oscar’s protocol to add a further 350 over-70s in an attempt to confirm a benefit for otilimab.
Perhaps the anti-GM-CSF mechanism can echo the recent success of Roche’s anti-IL-6 MAb Actemra, which acts on a different inflammatory pathway (The big Covid-19 trials still to report, February 17, 2021). But locating a signal with Roche’s drug took a 4,000-patient trial – Glaxo clearly believes that in otilimab’s case 350 is enough.
Oscar is a worldwide trial, with sites in North and South America, Europe, Asia and Africa. In at least some of these places, and particularly the six sites in the UK, vaccination drives will soon start having a noticeable effect in terms of reducing the number of hospitalised over-70s available to join the trial.
Still, enrolling a few hundred patients from other sites ought to be achievable, and if the endpoints are measured within three months of treatment the data could come in the summer.
When they do, they will be relevant for a handful of other, smaller groups, such as Kiniksa and Humanigen, which are also looking at anti-GM-CSF antibodies in Covid-19. But Glaxo is by far the most significant player here, and will want a success given how comprehensively it has been trounced in the race for a vaccine.