DUBLIN – Sanofi SA and Regeneron Pharmaceuticals Inc. are terminating all further development in COVID-19 of their interleukin-6 receptor (IL-6R) inhibitor, Kevzara (sarilumab), following the antibody’s failure to meet the primary endpoint, as well as a key survival endpoint, in an ex-U.S. clinical trial in 420 hospitalized patients with severe or critical disease.

The news comes as no great surprise, following the failure in July of a Regeneron-sponsored U.S. phase III trial of the same drug in COVID-19 patients in need of mechanical ventilation. At the same time, the two trials raise as many questions as they provide answers. IL-6 is, as a recent study from the Mount Sinai Health System established, an independent predictor of COVID-19 severity and death in patients. But various efforts to establish the clinical efficacy of IL-6 inhibition in COVID-19 have, so far, been unsuccessful.

The ex-U.S. study (NCT04327388) randomized patients to receive either 400 mg (n=173) or 200 mg (n=161) of sarilumab or placebo (n=86). The protocol allowed for one or two doses. The primary endpoint was a minimum two-point improvement on a seven-point ordinal scale of clinical severity, on which a score of 1 represents death and a score of 7 indicates the patient is no longer hospitalized. The key secondary endpoint was the 28-day survival rate.

The study investigators did observe a numerical trend in favor of the drug on the ordinal scale; they also observed that the drug was associated with a two-to-three-day reduction in the duration of hospital stay. However, neither was statistically significant. A non-significant reduction in mortality was also seen in the critically ill group, defined as requiring ICU care, ventilation, requiring oxygen by high-flow nasal cannula or non-rebreather mask. This was not seen in the severely ill group, defined as requiring oxygen by nasal cannula, simple face mask or similar delivery device.

In the U.S. study (NCT04315298), minor positive trends, which were not statistically significant, were seen in mechanically ventilated patients who received 400 mg of the antibody. Those were countered, however, by negative effects seen in patients in receipt of the drug who were not undergoing mechanical ventilation at baseline.

Neither study included patients’ baseline IL-6 levels as an inclusion criterion. The Mount Sinai study, led by Sacha Gnjatic, an associate professor in the Icahn School of Medicine, suggests that they should have.

The latter study, which followed 1,484 patients from admission to either discharge or death, employed a rapid multiplex cytokine assay to measure IL-6, IL-8, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) and found that high levels of each at the time of admission were “strong and independent predictors of patient survival.” The “vast majority” of patients in the study presented with cytokine storm, the study authors reported, but the patterns of cytokine elevation were far more varied than they had previously observed in patients undergoing chimeric antigen T-cell receptor (CAR T) therapy who experienced cytokine release syndrome, an indication for which Roche Holding AG’s IL-6R blocker, Actemra (tocilizumab), is approved.

For IL-6, the statistical association between elevated level and disease severity and survival was particularly robust (p<0.0001), even when adjusted for a range of other factors, including common laboratory inflammation markers, hypoxia and other vital signs, demographics, and a wide range of underlying conditions, including obesity, hypertension, diabetes, chronic kidney disease, atrial fibrillation, active cancer, congestive heart failure, asthma, chronic obstructive pulmonary disease, sleep apnea, as well as a current smoking habit or a history of smoking. Men had significantly higher levels of the cytokine than women did (p<0.0001). Elevated levels of TNF-alpha were also significantly predictive (p=0.014) of disease severity and survival. The findings were validated in a second cohort of 231 patients. The data were published online in Nature Medicine, on Aug. 24, in a paper, titled “An inflammatory cytokine signature predicts COVID-19 severity and survival.”

Gnjatic and his co-authors cautioned that the data “do not demonstrate a causative role for IL-6 or TNF-alpha in disease outcome,” but they suggested that levels of each cytokine should be considered when treating patients and stratifying clinical trials. Their insight comes too late for the sarilumab studies and, also, for the phase III Covacta study (NCT04320615) of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. Basel, Switzerland-based Roche reported in July that the study in 450 patients failed to reach its primary endpoint. Investigator-initiated studies of tocilizumab are still underway in Mexico, Denmark, Switzerland and Spain, but none of those is stratifying patients according to IL-6 levels either.

Roche and Foster City, Calif.-based Gilead Sciences Inc. are also collaborating on a phase III combination study (NCT04409262), Remdacta, which is comparing tocilizumab plus the FDA-approved antiviral drug Veklury (remdesivir) with remdesivir plus placebo in hospitalized patients with severe COVID-19 pneumonia. If that study fails, it could well signal the end of the road for IL-6-targeted therapies in COVID-19, even if their potential has not been fully explored. London-based Tiziana Life Sciences plc remains a wildcard, however. It plans to move an inhaled formulation of an anti-IL-6R antibody, TZLS-501, into a clinical study in the first quarter of next year.