DUBLIN – Genentech has succeeded where Sanofi SA and its partner, Regeneron Pharmaceuticals Inc., have failed, in obtaining some sort of a positive signal from a clinical trial of an interleukin-6 (IL-6) inhibitor in COVID-19. Genentech, a subsidiary of Basel, Switzerland-based Roche Holding AG, reported Sept. 18 that hospitalized patients who received Actemra/RoActemra (tocilizumab) plus standard of care were 44% less likely to require mechanical ventilation than those on standard of care only. The treatment did not improve survival, however.
In absolute terms, 12.2% of those in the active treatment arm progressed to mechanical ventilation over 28 days, as compared with 19.3% of those in the control arm. The mortality rate was actually higher in the Actemra arm (10.4%) than in the placebo arm (8.6%), but the difference was not statistically significant (p=0.5146). The formal primary endpoint of the study was actually a composite of progression to mechanical ventilation or death, and the study has attained it.
However, Actemra also failed to attain several other key secondary endpoints, including reducing time to hospital discharge and reducing time to clinical failure. Although it was numerically superior to placebo on both of those measures, the differences were not statistically significant. Actemra was not associated with any increase in infections or serious infections by day 28. The most common side effects associated with Actemra were constipation (5.6%), anxiety (5.2%) and headache (3.2%).
The phase III Empacta study recruited 389 hospitalized patients who were not in need of mechanical ventilation or non-invasive ventilation but who were hypoxic, with an oxygen saturation level below 94% while on ambient air. About 85% of the study participants were from ethnic groups who are usually under-represented in clinical trials but who are also particularly vulnerable to severe COVID-19 disease. The majority of participants were Hispanic; the study also recruited significant numbers of Native American and Black patients. The trial was conducted across the U.S., South Africa, Kenya, Brazil, Mexico and Peru.
Roche said it plans to share the data with the FDA and other drug regulators around the world, but the timing of a regulatory application is unclear. “It is premature to speculate on filing an EUA [emergency use authorization] at this time,” a Roche spokesman told BioWorld.
The data provide some evidence that Actemra may be useful. Given the trauma and long-term sequelae associated with mechanical ventilation, any reduction in its use would be welcome, but it is not clear who would be likely to derive most benefit from the therapy. A recent study from Mount Sinai Hospital in New York identified IL-6 as being strongly predictive of decreased survival. The study authors suggested that patients with moderate disease but high IL-6 levels could benefit from an IL-6 inhibitor but that hypothesis has yet to be tested prospectively.
Part of the problem is the variation in the cytokine profiles of COVID-19 patients experiencing cytokine storm is greater than that seen in cancer patients undergoing therapies that can also induce cytokine storm, such as chimeric antigen receptor T-cell (CAR T) therapy or certain bispecific antibodies. “In COVID-19, there may be more diverse presentations, where IL-6 may not always be the driving pathogenic inflammatory mechanism. It would therefore be important to stratify tocilizumab treatment by IL-6 baseline levels,” Sacha Gnjatic, associate professor at the Tisch Cancer Institute at the Icahn School of Medicine and corresponding author on the study, told BioWorld. He added the caveat that it is difficult to interpret the reported outcomes from the Genentech trial without seeing the full dataset.
His group also reported that TNF-alpha and “to some extent” IL-8 also had predictive value independent of IL-6. The reduced probability of patients progressing to mechanical ventilation may be too late to reverse the disease course. “It is an intriguing finding, as it suggests a reduction in severity (and possibly inflammation), but it may not be sufficient to revert organ damage caused by other cytokines and soluble analytes,” he said. For that reason, combined cytokine blockade, particularly of IL-6 and TNF-alpha, would also be worth exploring.*
The present study is the second phase III trial of Actemra in COVID-19 that Roche has completed. In July, it reported that the Convacta trial in adult hospitalized patients with severe pneumonia failed to meet the primary endpoint of improved clinical status. It also failed to demonstrate any improvement in survival. A third phase III study, the Remdacta trial, is still recruiting. It is comparing a combination of Actemra plus the antiviral nucleotide analogue Veklury (remdesivir, Gilead Sciences Inc.) with placebo plus remdesivir in hospitalized patients with severe disease.
Paris-based Sanofi and Tarrytown, NY-based Regeneron have already terminated COVID-19 development of Kevzara (sarilumab), following two unsuccessful phase III trials. Unlike Actemra, Kevzara was never approved for treatment of cytokine release syndrome (CRS) during chimeric antigen receptor T-cell (CAR T) therapy – so its developers had less evidence to build on when testing the drug in COVID-19. But it has become increasingly evident that CRS during CAR T therapy and during COVID-19 treatment are not the same thing. The Mount Sinai study, led by Sacha Gnjatic, demonstrated that the cytokine profiles in COVID-19 are more varied and unpredictable than those associated with CAR T therapy. London-based Tiziana Life Sciences plc 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.
*Story updated Sept. 21, 2020, to include Gnjatic's comments.