Finding immunosuppression sweet spot could be next up for COVID-19 after second IL-6 failure

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A Phase III miss for a second IL-6 inhibitor in COVID-19 patients could be the death knell for the drug class in the disease. But the mortality benefit demonstrated by dexamethasone suggests a broader immunosuppressive approach -- rather than targeting that specific cytokine -- may offer a more effective treatment.

Actemra tocilizumab from Roche (SIX:ROG; OTCQX:RHHBY) missed the primary and key secondary endpoints in COVACTA, a randomized, double-blind placebo-controlled study in hospitalized adults patients with severe COVID-19-associated pneumonia.

The anti-IL-6 mAb plus standard of care (SOC) failed to improve the primary endpoint of clinical status, as measured by a seven-point scale, compared with placebo plus SOC (odds ratio=1.19; 95% CI: 0.81, 1.76; p=0.36). The drug also missed the secondary endpoint of improving patient mortality.

The trial isn’t the end for Actemra in COVID-19. Roche is sponsoring three more COVID-19 trials that include the drug, including two of monotherapy: the Phase III REMDACTA study, which is evaluating the IL-6 inhibitor in combination with remdesivir from Gilead Sciences Inc. (NASDAQ:GILD); the Phase III EMPACTA study, which is recruiting underserved and minority patients; and the Phase II MARIPOSA trial, which is enrolling patients with moderate to severe disease. The U.K.’s RECOVERY master protocol also has an Actemra arm (see “The U.K.’s Push for COVID-19 Master Protocols”).

In early July another rheumatoid arthritis drug failed in Phase III for COVID-19. Sanofi (Euronext:SAN; NASDAQ:SNY) and Regeneron Pharmaceuticals Inc. (NASDAQ:RGEN) reported that Kevzara sarilumab missed the primary and key secondary endpoints in a Phase III trial in critically ill COVID-19 patients on mechanical ventilation. The IL-6 inhibitor failed to increase the percentage of patients who achieved at least a one-point improvement on a seven-point ordinal scale, compared with best supportive care (see “Phase III Data for an IL-6 mAb in COVID-19 Disappoint”).

The rationale behind IL-6 inhibitors to treat COVID-19 stems from how the pro-inflammatory cytokines are central to cytokine release syndrome, the runaway inflammatory reaction thought to be a major driver of acute respiratory distress syndrome (ARDS) in COVID-19 patients (see “Four Compounds that Disrupt Interleukin Pathways”).

Although targeting the cytokines has yet to show a benefit in COVID-19, immune modulation has emerged as a leading approach. Mortality data for dexamethasone has underscored the case for broad immunosuppression to treat patients with late disease (see “Clinical Scorecard for COVID-19”).

Inhibition of GM-CSF, a growth factor and pro-inflammatory cytokine, is also being explored as a method of modulating the immune system in the indication. The target has broader effects than IL-6, but leads to more narrow immunosuppression than dexamethasone.

Six companies have mAbs against GM-CSF in the clinic, according to BioCentury’s COVID-19 Resource Center.

This week, NIH’s National Institute of Allergy and Infectious Diseases selected anti-GM-CSF mAb lenzilumab from Humanigen Inc. (Pink:HGEN) to include in its Big Effect Trial (BET) in hospitalized COVID-19 patients.

The placebo-controlled study, which is testing repurposed therapies backed by human data, will evaluate the antibody in combination with remdesivir. The trial will enroll 100 patients per arm, with an interim efficacy analysis expected after each cohort enrolls 50 patients.

Humanigen said published data demonstrating lenzilumab’s ability to prevent and treat cytokine storms support its use to treat COVID-19, and suggest its mechanism of action may be synergistic with remdesivir.

Lenzilumab is in Phase II/III testing to prevent and treat acute graft-versus-host disease, and Phase II testing for chronic myelomonocytic leukemia.

Kiniksa Pharmaceuticals Ltd. (NASDAQ:KNSA) reported the first data of an antibody inhibiting the GM-CSF pathway in June; mavrilimumab, an antibody against CSF2RA, was given to COVID-19 patients under an expanded access protocol. None of the 13 patients treated with the mAb died as of day 28, compared with a 27% mortality rate in the 26-patient standard of care arm (p=0.086) (see “InflaRx, Kiniksa mAbs Yield Trend Toward Lower Mortality”).

Kiniksa is enrolling patients hospitalized with severe COVID-19 in a Phase II/III trial of mavrilimumab.

Targets

CSF2RA (GMR; CD116; GMCSFR) - Granulocyte macrophage colony-stimulating factor receptor

GM-CSF (CSF2) - Granulocyte macrophage colony-stimulating factor

IL-6 - Interleukin-6

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