It’s been a tough couple of weeks for immune-based therapies for COVID-19.

We know that immune modulation in this disease, especially in its most severe manifestations, can improve outcomes.

Favorable results from the RECOVERY study of dexamethasone have made it the standard of care for most hospitalized patients who require oxygen. And we also know that our own immune system plays a major role in clearing this nasty virus.

So can we succeed with more targeted approaches? Either inhibition of our overly exuberant immune response or “boosting” our own immune systems through monoclonal antibodies?

(Some might classify the latter as antivirals rather than immune-based therapies. How about considering them both?)

Let’s start with tocilizumab, an interleukin-6 (IL-6) inhibitor widely used off-label for treatment of COVID-19 since the start of the pandemic. Multiple observational and small prospective studies also strongly suggested clinical benefits.

Well, in a remarkable 48 hours late last month (October 21-23, to be exact), no fewer than four multicenter randomized clinical trials of tocilizumab appeared in print — three in peer-reviewed journals and one as a pre-print. All were done on hospitalized patients not receiving mechanical ventilation, and all compared tocilizumab with a “usual care” control.

• RCT-TCZ-COVID-19 (n=126): The primary endpoint was hypoxemia (protocol defined), ICU admission, or death. Investigators stopped the study early due to futility.
• CORIMUNO-19-TOCI-1 (n=131): Two endpoints were of primary interest — scores higher than 5 on the WHO 10-point Clinical Progression Scale (WHO-CPS) on day 4, and survival without need of ventilation (including noninvasive ventilation) at day 14. Tocilizumab did not demonstrate efficacy on the first measure and “might” (I quote the paper) have reduced the need for mechanical ventilation (results were borderline). No impact on mortality.
• BACC Bay Tocilizumab Trial (n=243):  Unlike the first two, this was a placebo-controlled trial, with a 2:1 randomization to tocilizumab or placebo. Tocilizumab did not significantly reduce the requirement for intubation or mortality, the primary endpoint. Since the confidence intervals around the point estimate for benefit or harm were wide, the study could not exclude either one.
• EMPACTA (n=389):  Also placebo-controlled, this study’s primary endpoint was death or mechanical ventilation by day 28. Here, tocilizumab did reduce the risk for mechanical ventilation, but mortality at day 28 was not improved — strangely, it was numerically higher with the treatment (10.4% vs 8.6%). (The study is not yet peer-reviewed.)

If that’s not enough, a September press release on the largest randomized study — COVACTA, with 450 participants — did not meet its primary endpoint of improved clinical status nor the secondary endpoint of reduced mortality.

What can we glean from this flurry of study results? I agree with this excellent review by Dr. Jonathan Parr, who wrote that the findings “do not support routine tocilizumab use in COVID-19.”

Oh well. Time will tell whether any secondary benefits from this targeted and powerful immunosuppressive accrue, but given its extremely high cost and potential adverse effects (including increasing risk of infection), we should not be using tocilizumab in routine clinical practice for COVID-19.

But at least we’ll soon have monoclonal antibodies, right? Well, monoclonal antibodies are promising — but if they work, and if so in what patients, both remain unclear.

What does appear clear is that the monoclonals in late-stage clinical trials — being developed by the companies Lilly and Regeneron — don’t improve outcomes in severely ill hospitalized patients. First, the NIH halted the study of LY-CoV555 in this population:

The Data Safety Monitoring Board reviewed data from the ACTIV-3 trial on Oct. 26, 2020 and recommended no further participants be randomized to receive LY-CoV555 and that the investigators be unblinded to the data. This recommendation was based on a low likelihood that the intervention would be of clinical value in this hospitalized patient population.

This followed an action-pausing enrollment in that study for a possible safety issue, but ultimately, the decision stemmed from a lack of benefit, also known as a futility analysis. Importantly, study of LY-CoV555 continues in outpatients with COVID-19, who may yet benefit as evidenced by a reduced need for hospitalization in the phase 2 study.

Next, Regeneron announced it had halted its own study of REGN-COV2 (an antibody “cocktail”) in patients requiring high-flow oxygen or mechanical ventilation, citing both a lack of efficacy and a potential safety concern. Could “immune enhancement” be playing a role? The trials of this treatment in other patient populations continue.

If REGN-COV2 rings a bell, that’s because it’s one of several therapies given to the president during his stay at Walter Reed Medical Center. It’s also part of the larger RECOVERY study conducted in Britain, and these negative results will prompt a data review by the study’s independent Data Monitoring Committee. 

So neither antibody treatments worked in the more severely ill COVID-19 patients. And if they end up as promising treatments for milder disease — and I hope they do — imagine the logistical hurdles required to administer these intravenous therapies to outpatients with COVID-19. The mind boggles.

Let’s finish with the latest discouraging newsflash on COVID-19 immune-based therapies, this time with anakinra, the interleukin-1 (IL-1) inhibitor.

The halted study — yes, called ANACONDA — compared anakinra versus optimized standard of care in hospitalized patients with COVID-19. It was open-label, with a planned enrollment of 240, and a primary endpoint of “being alive and not requiring any invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).”

And now it has been halted due to excess mortality in the intervention arm. Ouch — the worst possible outcome. More details to come.

How about the favorable observational studies?

As with tocilizumab, these data can be highly misleading, even when explanatory models show that the treatment should work. Our brains have a tendency to make up scientific rationales for treatments that we want to work, it’s just something we can’t help doing. Such instincts are stronger than our ability to identify and control for all potential confounders.

As for these disease models, let’s remember that the immune system is oh so complicated — at its best, fine-tuned to protect us from pathogens, but not so strong as to cause uncontrolled autoimmune disease.

Just like we can’t open up a broken computer and disconnect random wires or remove various circuit boards to fix it, we can’t selectively suppress the immune system and expect favorable outcomes when treating a new disease. Which is why, ultimately, all of these treatments need data from controlled clinical trials before they can be broadly adopted.

It’s hard work, and it takes time, but it needs to happen.