A mechanistic view of four compounds that disrupt interleukin pathways to treat severe COVID-19

The biological rationale behind the popular approach of using rheumatoid arthritis drugs to treat COVID-19

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Master protocols for COVID-19 clinical trials are testing half a dozen molecules that aim to prevent respiratory distress in patients with severe disease by targeting the host immune system -- four of these compounds intervene in interleukin signaling pathways.

Kineret anakinra, Olumiant baricitinib, Actemra tocilizumab and Kevzara sarilumab are all anti-inflammatory agents approved to treat rheumatoid arthritis. The rationale behind using them to treat COVID-19 stems from another feature they have in common -- they all impinge on interleukin signaling in one way or another.

IL-6 and IL-1 are central to cytokine release syndrome, the runaway inflammatory reaction thought to be a major driver of ARDS (acute respiratory distress syndrome) in COVID-19 patients.

In particular, Actemra stands out for its approval to treat severe or life-threatening cytokine release syndrome induced by CAR T cell therapies.

These “cytokine storms” occur through a positive feedback mechanism wherein increased release of the pro-inflammatory cytokines IL-6 and IL-1 from immune cells in the lungs leads to recruitment of more pro-inflammatory cytokine-releasing immune cells.

The build-up of cells and cytokines increases vascular permeability and damages lung epithelial cells, allowing fluid, immune cells and cytokines to enter alveoli. The result is impaired alveolar gas exchange and a lack of oxygen in the blood.

Actemra and Kevzara target IL-6 receptors, whereas Kineret targets an IL-1 receptor. Olumiant inhibits JAK-STAT signaling downstream of IL-6 receptor activation.

Kineret and Kevzara are being tested in the REMAP-CAP master protocol led by UMC Utrecht, Monash University and Unity Health. Actemra is in both REMAP-CAP and the RECOVERY master protocol sponsored by University of Oxford.

REMAP-CAP hasn’t disclosed readout timelines; the RECOVERY website says it expects results by July 2021.

Olumiant is being tested in combination with Veklury remdesivir vs. Veklury alone in the ACTT-II master protocol led by the NIH’s National Institute of Allergy and Infectious Disease (NIAID). Data from the ACTT trial pitting Veklury vs. placebo contributed to Veklury’s Emergency Use Authorization for COVID-19. It has not been disclosed when data are expected from ACTT-II.

Some early results from outside of the master protocols have already come in for the IL-6 inhibitors, and the findings have been mixed.

At least 11 published studies, comprising a collection of small prospective and retrospective studies, have claimed a survival benefit for tocilizumab, whereas four have not. Kevzara failed to improve survival or the need for ventilation at day 14 in severe and critically ill COVID-19 patients in a Phase II controlled trial (see “Clinical Scorecard for COVID-19”).

Kineret and Olumiant are each being tested in five COVID-19 trials with primary completion dates this summer. Actemra is in 22 such trials and Kevzara is in four (see BioCentury’s COVID-19 Clinical Trial Dashboard).

Targets

CD121A - Interleukin-1 (IL-1) receptor 1

CD126 - Interleukin-6 (IL-6) receptor

IL-1 - Interleukin-1

IL-6 - Interleukin-6

IL-1α - Interleukin-1α

IL-1β - Interleukin-1β

IL1RAP - Interleukin-1 (IL-1) receptor accessory protein

IL-6ST (gp130) (CD130) - Interleukin-6 (IL-6) signal transducer

JAK - Janus kinase

MYD88 - Myeloid differentiation primary response gene 88

NF-kB (NFKB1) (p105) (p50) - Nuclear factor of kappa light polypeptide gene enhancer in B cells 1

STAT - Signal transducer and activator of transcription

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