November 1st, 2020

A Series of Disappointing Results of Immune-Based Therapies for COVID-19

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.

20 Responses to “A Series of Disappointing Results of Immune-Based Therapies for COVID-19”

  1. David Shulan says:

    The data for giving antibody treatment especially the monoclonals early in infection are promising. It looks like antibody treatment late in infection is futile. It will be challenging to get treatments to the appropriate population.

  2. Gordon Huth, MD says:

    Another useful summary. Thanks!

  3. Sébastien Poulin says:

    ant-GMCSF study should complete recruitment soon
    (gmCSF= more pleiotropic effects )

    I’m more optimistic about GMCSF inhibition than the single target inhibitors given the potential role of monocytes/macrophages in severe COVID-19

    If this doesn’t work… time to move on ?

  4. Arturo Azpiroz says:

    Being pathologically skeptical, we could say that after almost a year of SARS-CoV2
    “colds only have symptomatic treatment”

  5. Daniel says:

    Thought on msc and its potential to be apart of the story to returning to some normality.

  6. Mark Graber says:

    Consistent with the data that cytokine storm may not be the mechanism we should be targeting. Levels seem to be at least as high if not higher in other critical are conditions (given the limitations of the below study).

    Kox M, Waalders NJB, Kooistra EJ, Gerretsen J, Pickkers P. Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions. JAMA. Published online September 03, 2020. doi:10.1001/jama.2020.17052

  7. Victor M. Comparini, MD says:

    I want to present an idea for prevention of Covid.
    1- It has not been used a drug for public prevention of Covid 19.
    2- Most infections are in and from asimptomatic persons.
    3- Vaccines are a few months away.
    4- The portal of entry for the most serious infection is through the respiratory tract.
    My proposal is based on the following experiences:
    a- Iodine kills the virus,
    b- Ingested iodine has been used to prevent goiter, for chronic bronchitis and to prevent thyroxin crisis of operated patients with toxic goiter, in the salt or solutions of NaI or KI.
    c- Ingested iodine is secreted by glands of the respiratory tract and salivary glands.
    My proposal is to test for the population: To provide palatable salt with the highest tolerable amount of NaI and for exposed groups daily ingestion of X drops of aquos saturated solution of KI or the tablets that were produced in case of nuclear war, for the time of exposure.

  8. Ashraf Ali Khan says:

    If someone can write about consuming iodine, I’m encouraged to write this too:

    A cousin of mine who is a very smart scientist suggests layering the throat and middle chest(where the main bronchus is) with a warm muffler (reasonably tightly) when sick with a viral respiratory illness. The heat produced kills ALL viruses, he claims.

  9. Charles Morin says:

    Wouldn’t respiratory transmission be reduced if we kept our mouths shut even when wearing a mask? Stop talking, yelling, laughing as much as possible.? When I’m walking on the East Bay bike path, people pass by and say “hello” or “nice day” whereas I acknowledge them with eye contact and a half-wave.

    • S.J.Hasanain M.D. says:

      Respiratory transmission is reduced simply by wearing a mask. If proper surgical masks are not available, using two cloth masks would likely be as effective.

  10. Stephen A. Raphael, MD says:

    The questions generated by these outcomes are similar to the questions that arise when talking about the random use of batches of convalescent plasma given without quantification of the amounts/ratios of neutralizing and non-neytalizing antibodies, the levels of which could be responsible for ADE in selected patients.

  11. D.BOUROS says:

    How about chiken soup…could be safer than HCQ..

  12. thomas c borut m.d. says:

    If cytokine storm is not the answer to disastrous outcomes, what about the bradykinin hypothesis previously discussed in a number of preprints?

  13. Roger Jackson MD says:

    Please see the late stage 3 studies with leronlimab and aviptadil. These two immune modulators are both safe and effective.

  14. Barbara Emerson says:

    @Dr Comparing,

    Given that sodium may be contraindicated for hypertensive patients, look into kelp or dulse as an iodine source. You can find small containers of dulse at of all places, Whole Foods.

    Barbara

  15. camilo colaco says:

    Maybe its time we recognized that the pathophysiology of CoVID19 is more consistent with a DICS-like coagulopathy and not a cytokine storm induced ARDS. The clue was in the elevated levels of d-dimer that are seen early in infection and clearly correlated with mortality. This suggests early treatment with anti-coagulants and is supported by the reports of treatment with LMW heparin and even a Phase II clinical trial.
    1. Comment and refs in https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772184
    2. Phase II clinical trial: https://linkinghub.elsevier.com/retrieve/pii/S0049384820305302

    • Marco Cattaneo says:

      D-dimer is a great marker of inflmmation: this is why it is correlated with mortality in COVID-19. To consider it as marker of hypercoagulability and thrombotic risk in COVID19 is wrong, in my opinion. Please, remember that, for diagnosing thromvboembolic disease, it is useful only to rule out the diagnosis when it is negative. It is absolutely not useful to rule in the disease when it is positive, as it is too unspecific

  16. Warren Ward says:

    In all of the discussions about Covid, there is always the elephant in the room that nobody notices – sixty years of not researching the cause of high blood pressure, the usual co-morbidity of Covid.

  17. Howard Mitz says:

    Why has no one tried infliximab yet.
    There is anecdotal evidence through the Secure IBD registry that infliximab lowers mortality as well as those ending up in ICU or on a vent. Over 3,000 patients are in the registry
    the tocilizumab study would suggest that viral loads are not the problem the the reaction to the virus
    In CRS TNF plays a role.
    Why not try a TNF blocker as soon as the person enters the hospital?

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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NEJM Journal Watch
Infectious Diseases

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