Roche's IL-6R Antibody Actemra Fails in Phase III COVACTA Trial for Severe COVID-19

Today, Roche announced that its IL-6 receptor antibody Actemra (generic name: tocilizumab) failed to meet the primary endpoint and key secondary endpoints in the Phase III COVACTA clinical trial. The trial enrolled COVID-19 patients with severe pneumonia requiring hospitalization, comparing the impact of Actemra versus placebo on patient outcomes when added to standard of care. The missed primary endpoint was the 7-point ordinal scale for clinical status. Actemra also failed to improve the key secondary endpoint of four-week mortality, although it appeared to shorten hospital stay. Given the failure to meet the primary endpoint, this improvement is considered not clinically significant. Previously, Actemra had already failed in a Phase III trial for mild COVID-19. Similarly, Kevzara (generic name: sarilumab), an IL-6 antibody developed by Regeneron and Sanofi, also failed in a Phase III trial involving patients with severe and critical COVID-19.

Drug Source Analysis

Given the precedent set by Kevzara, the recent failure of Actemra was hardly unexpected. Consequently, IL-6 can essentially be ruled out as a therapeutic target for COVID-19. The sudden and severe onset of the pandemic forced the academic and pharmaceutical communities to respond hastily. Much like a serial killer simultaneously attacking locations worldwide, law enforcement needed to identify the culprit quickly. IL-6, akin to a conspicuous ex-convict with a prior record at the crime scene, immediately drew suspicion. Moreover, two approved drugs targeting the IL-6 pathway—Actemra and Kevzara—were readily available, allowing for the immediate “arrest” of IL-6. As the saying goes, “if all you have is a hammer, everything looks like a nail”; the IL-6 hypothesis represented the most easily testable therapeutic approach at the time. Other potential suspects, such as IL-18—comparable to heavily tattooed, muscular individuals in the crowd—lacked readily available pharmacological interventions. Another factor that accelerated the adoption of IL-6 inhibitors was the experience from early CAR-T therapy development, where severe cytokine release syndrome (CRS), characterized by a dramatic surge in IL-6, was observed. Dr. Carl June, whose daughter had been successfully treated with off-label Actemra for macrophage activation syndrome (MAS), a rare cytokine storm disorder, decided to use Actemra off-label for CRS. The young patient, Emma, made a remarkable overnight recovery. This clearly appeared to be a success worth replicating.

As China experienced the outbreak earlier, Actemra was first tested there. Given the chaotic circumstances at the time, controlling patients’ conditions was far more critical than demonstrating drug efficacy; consequently, this trial was not a rigorously controlled study. Nevertheless, the seemingly positive results made the IL-6 hypothesis even more appealing. Later, France even reported that Actemra significantly reduced mortality. However, this trial, along with another French clinical trial that spurred intense demand for HCQ, both suffered from implementation flaws. In retrospect, IL-6 merely joined the crowd of onlookers, drawn to the scene by the gruesome nature of the “killer.” Indeed, industry insiders, such as the former head of Immunology and Oncology at Roche, had long pointed out that IL-6 levels in COVID-19 were not in the same order of magnitude as those observed in CAR-T therapy, and thus should not be conflated.

Although highly specific IL-6 inhibitors have shown no efficacy, dexamethasone, a broad-spectrum immunosuppressant whose use in the treatment of other coronavirus infections has been controversial, significantly reduces mortality in critically ill patients. However, the benefit appears to be primarily confined to patients under 70 years of age, and it may even be harmful in those with mild disease. Although not as widely used as its antiviral counterpart, alpha-interferon, beta-interferon for multiple sclerosis (MS) has demonstrated accelerated viral clearance and reduced risk of disease progression in two small controlled trials; its potential for market approval remains to be determined. The direct-acting antiviral remdesivir, while not reducing mortality, has shortened hospital stays and has received Emergency Use Authorization (EUA) for widespread use in early-stage patients.

Fighting a battle without preparation is inherently difficult. Although drug repurposing was extensively attempted during the COVID-19 pandemic, only dexamethasone has proven truly effective. Regardless of how complex an emerging disease may be, there is an instinctive hope that it will be simple and manageable. However, COVID-19 is far from being merely a pneumonia similar to influenza; many patients continue to experience varying degrees of symptoms months after recovery, and multiple organs, particularly the heart, sustain differing levels of damage. To date, we still do not fully understand why COVID-19 causes such severe outcomes in a small subset of patients. Even if the mechanisms were understood, effective countermeasures might not be available in the short term, as decades of effort to address bacterial sepsis and other forms of acute respiratory distress syndrome (ARDS) have yielded limited success. Broad-spectrum antiviral drugs targeting host factors have attracted the attention of top-tier venture capital firms such as ARCH Venture Partners, representing perhaps the most promising strategy for responding to sudden outbreaks of novel viral infections.