Another hope dashed - Tocilizumab not as promising as hoped in a new trial

Earlier this week we covered three JAMA Internal Medicine papers assessing drug called tocilizumab, a monoclonal antibody that targets interleukin-6 receptors, thought to contribute to the human body's counterproductive immune response to SARS-CoV-2, the virus that causes covid-19. The studies from earlier this week were disappointing overall but left us with a glimmer of hope that the medication might still benefit a subset of patients.

The idea is that this medication reduces the inflammatory response seen in critically ill patients with covid-19. Released today in New England Journal of Medicine is an industry funded study looking at this drug's efficacy. Sadly these results are also not promising. Researchers at Massachusetts General Hospital studied whether drug administration affected the need for mechanical ventilation or death, prior to intubation. This well performed double-blind placebo-controlled study required patients to have confirmed SARS-CoV-2 and at least two of the following clinical features: fever, abnormal lung findings on radiological imaging (such as chest x-rays of CT scan), or the need for supplemental oxygen.

A total of 243 patients (58 percent of whom were men) were enrolled who had a median age of 59.8 years. Tocilizumab was found to have a hazard ratio of 0.83 for intubation or death, but the ratio crossed the 1.0 threshold (less than 1.0 would indicate fewer deaths, more than 1.0 would indicated more deaths), meaning that it cannot be said to be a statistically meaningful result (the authors are 95 percent certain that the "true" ratio is somewhere between 0.38 and 1.81). At two weeks, 18 percent of the patients who received the monoclonal antibody drug had disease worsening compared to 15 percent among those who received placebo. The discontinuation of supplemental oxygen was very similar in both groups as well (5.0 days vs 4.9 days).

Of note, a reasonable portion of the patient group studied was Hispanic or Latino (45 percent) which does tend to reflect previous studies looking at patient demographics hospitalized with severe or critical cases of covid-19.

Unfortunately the use of the monoclonal antibody, tocilizumab was not found to prevent death or intubation in patients with covid-19. Given the very large confidence intervals it was hard for the authors to draw a conclusion as to whether this medication is harmful or helpful to patients with respect to a number of different clinical outcomes.

Monoclonal Antibody Trial Halted for Safety Concern

Brief19 has learned that the ACTIV-3 monoclonal antibody trial for the treatment of covid-19 has been paused due to a potential safety concern. An email obtained by Brief19 (below) made the announcement today. 

The ACTIV-3 trial is a randomized blinded clinical trial testing the safety and effectiveness of a monoclonal antibody (Ly-CoV555) produced by the pharmaceutical giant Eli Lilly in combination with remdesivir, an anti-viral with emergency use authorization for covid-19. This trial is designed to test this combination against a combination of remdesivir and placebo alone.

No details regarding the nature of the safety concern have been obtained. However, this is the same kind of compound that President Trump received at the beginning of this month (made by Regeneron). President Trump also received remdesivir at that time.

Very few patients have received monoclonal antibodies designed to target SARS-CoV-2. Even fewer have received them in combination with remdesivir. Therefore, other than investor slide decks and press releases from the companies that make these compounds, little to nothing is known about how well they combat SARS-CoV-2 and how safe they are alone and in combination with other treatments. 

This news casts doubt as to the wisdom and safety of the approach used by President Trump's medical team. Trump, who became infected with SARS-CoV-2 sometime in late September, received a combination of medications, including a cocktail of monoclonal antibody for which there is scant clinical and safety data. 

Whether this current setback will turn out to be a small safety problem or a large one remains to be seen. Either way, this episode highlights the perils of proceeding with giving patients unvetted treatments on the basis of the fool-hardy premise that says, "what's the harm?"


Final remdesivir results published after 139 days of waiting

Joshua Niforatos, MD, MTS
Research Section Editor

The preliminary results of the Adaptive Covid-19 Treatment Trial (ACTT-1) randomized trial were published May 22 in The New England Journal of Medicine and covered by Brief19. ACTT-1 was a double-blind, randomized, placebo-controlled trial of the antiviral drug remdesivir, given to patients intravenously within 72 hours of laboratory-confirmed diagnosis of SARS-CoV-2, among hospitalized patients.

The primary outcome of the preliminary report was time to recovery from covid-19, which was broadly defined as either being released from the hospital or remaining in the hospital for infection-control purposes only. In the preliminary report, the average time to recovery in the remdesivir group was 11 days versus 15 days in the placebo group. No other results were statistically significant, including mortality or the percent of patients receiving oxygen therapy. Missing from the preliminary report was approximately one-third of patients who were enrolled in the study but had not reached day 29 of follow-up.

139 days later, the final report of the ACTT-1 trial has been published in The New England Journal of Medicine with the remainder of the participants included. Patients receiving remdesivir had a median recovery time of 10 days compared to 15 days in the placebo group. The authors also report that patients receiving remdesivir had non-statistically significant differences in mortality at both day 15 and day 29; by day 15, mortality rates were 6.7 percent (remdesivir) and 11.9 percent (placebo); by day 29, mortality rates were 11.4 percent (remdesivir) vs 15.2 percent (placebo). While these results were not statistically significant, the overall confidence intervals of the hazard ratio suggests there may be a mortality benefit though the trial itself did not include enough test subjects to detect either a net survival benefit or harm. Any mortality difference would be important, but not "game changing," in contrast to initial hype. The survival curves suggest that the patients most likely to benefit are those on nasal supplemental oxygen only. Furthermore, it seems that those ages 18 to 40 years and those with an onset of symptoms fewer than 10 days before treatment began are the most likely to benefit from remdesivir.

Similar to the preliminary report, the rate of serious adverse events was actually less in the remdesivir group (24.6 percent) compared to those in the placebo group (31.6 percent). One worrying finding emerged when assessing the time it took until recovery, divided into certain subgroups. While is important to remember that unless subgroups analyses are pre-planned and adequately planned for (statistically), any resulting data should be considered "hypothesis-generating" only. That said, Black, Asian, and Hipsanic/Latinx people did not benefit from remdesivir while white patients did. It is uncertain why this is the case and whether this represents ethnic / racial disparities, such as when the medication was given, how severe the cases were, or other potential factors. We hope the authors or other experts will address this issue soon.

Overall, the final report does not change the preliminary conclusions. Based on the research to-date, for critically ill covid-19 patients, remdesivir is unlikely to change survival or the need for mechanical ventilation. The only drug to-date that has shown to improve mortality remains dexamethasone, a generic and inexpensive drug.

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