A broader use for Regeneron’s Covid-19 antibody combo

Casirivimab plus imdevimab could at last add a hospitalised Covid-19 patient treatment string to their bow.

Trial Results

Having earlier failed with its antibody combo in the sickest hospitalised Covid-19 patients Regeneron yesterday claimed an important success. This came courtesy of the UK’s Recovery trial, which has backed the treatment thanks to being large enough and looking primarily at patients failing to mount an immune response of their own.

The result could see the US emergency use authorisation for Regeneron’s combo extended, as this currently covers only non-hospitalised patients. However, such a move would likely call for patients presenting in hospital with Covid-19 first to be tested for seropositivity, to weed out those who are already mounting their own immune response.

This is key to the findings in this cohort of the Recovery trial, which randomised 9,785 people hospitalised with Covid-19 to receive either Regeneron’s casirivimab plus imdevimab with standard of care, or standard of care alone.

Though these were all-comers in terms of serostatus, the primary analysis concerned only those seronegative at baseline, amounting to 3,153 of those enrolled. 5,272 were seropositive, meaning that they were producing their own antibodies against the coronavirus, and the remainder’s serostatus was unknown.

It was in the primary, seronegative, population that Regeneron’s combo scored on Recovery’s primary endpoint of all-cause mortality at 28 days: with median survival not reached for either arm, a landmark analysis showed 76% survival at 28 days with casirivimab plus imdevimab, versus 70% for standard care.

This amounted to a 20% reduction in risk of death at any point in the 28 days (p=0.001). The University of Oxford, Recovery’s sponsor, said this amounted to six fewer deaths for every 100 seronegative patients treated with the antibody combination – a result that seems strong enough to back authorisation in this setting.

Smart statistical decision

The decision to focus primarily on seronegatives was taken after a smaller phase 1/2 trial in hospitalised Covid-19 patients suggested a benefit in this subgroup, though only in terms of viral load, which was reduced significantly versus placebo at day five, while no effect was seen in seropositives.

A sequential analysis in Recovery also looked at all-comers, and found no statistically significant effect on 28-day mortality, which was 20% for the combo versus 21% for standard care (p=0.17). Moreover, specifically in seropositives there was a 9% greater risk of death across the 28 days for the combo versus control.

It seems rational that patients unable to mount their own immune response would benefit most from an antibody treatment, and those who do mount a response would logically skew any benefit by improving survival in the control as well as the active group.

Source: Recovery investogators & Medrxiv preprint server.

Yesterday’s positive result owes much to smart statistical decision-making, based on previous experience. That experience included an earlier setback in Regeneron’s hospitalised patients trial, in which cohorts with the sickest patients were halted owing to a negative risk/benefit profile.

Based on that result it came as a surprise that a week later an advisory committee recommended the continuation of Recovery cohorts in all hospitalised patients – a decision vindicated by yesterday’s readout.

Regeneron might thus be putting clear blue water between casirivimab/imdevimab and competitor MAbs from Lilly and Astrazeneca. While Astra’s AZD7442 yesterday failed in the post-exposure prophylaxis setting, Lilly and Regeneron have both shown encouraging clinical data in prevention of Covid-19 infection among at-risk individuals.

But Regeneron appeared to pull ahead in prevention, with positive pivotal data in April, and yesterday a preprint of the same study, but focusing on 314 asymptomatic patients, found that casirivimab/imdevimab prevented progression to symptomatic disease by 31.5% versus placebo (p=0.0380). Nevertheless, prophylaxis might remain a mere curiosity if antibodies have to be administered in a hospital.

This gives additional importance to the Recovery readout. Dr Martin Landray, one of Recovery’s authors, has suggested a scenario whereby a Covid-19 patient presenting in hospital is first tested for serostatus; if they have antibodies of their own there is no need to give them more, but if they do not then giving them the Regeneron combo cuts chances of death by a fifth.

All that needs to happen now is for casirivimab/imdevimab to be authorised additionally for this use, and for medical practice to include seropositivity testing.

Selected Regeneron MAb combo data in hospitalised Covid-19
Trial Design Result
Hospitalised patients  Four cohorts (low-flow oxygen/no oxygen/high-flow oxygen/mechanical ventilation) 30 Oct 2020 - high-flow oxygen & mechanical ventilation cohorts halted on IDMC advice
29 Dec 2020 - treated seronegative low-flow oxygen patients showed viral load reduction vs placebo
Recovery Seropositive, seronegative and serostatus unknown patients 15 Jun 2021 - primary analysis in seronegatives shows stat sig reduction in 28-day mortality
15 Jun 2021 - seropositives and all-comer analyses show no effect on 28-day mortality

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