In an update on Monday (October 26), Eli Lilly stated that the pause of the ACTIV-3 trial was made permanent. The reason was not a safety issue with the antibody treatment – i.e. unanticipated side effect – but rather that it was ineffective on patients already hospitalized with advanced COVID-19. As noted by Dr. Eric Topol, a clinical trial expert at the Scripps Research Institute, who has been following the treatment’s development:
the news “tells us they stopped the trial due to futility, as suspected,” and that it “suggests that the timing of monoclonal antibody administration — early — will be important.”New York Times, October 26, 2020: By Katie Thomas
Why is this the case? Two key factors are critical.
- How antibodies – and antibody treatments – work.
- How late stage COVID-19 make you so sick or kills you
How Antibodies – and Antibody Treatments – Work
In our blog on October 6th:
we wrote about how:
- the Innate Immune Response – which is rapid but not specific to the virus – and;
- the Adaptive Immune Response – which takes time to recognize the virus and respond, but is much more effective at eliminating it.
are triggered and kick-in after infection to produce either mild or severe disease outcomes. There are two key points and attributes of how antibody-based drugs work, and can be applied to protect people that are vulnerable through prevention of infection in the first place, or stop a new infection rapidly and prevent severe symptoms and disease in the second. The mechanism is the same in both cases: antibody-based drugs simulate the body’s adaptive immune response – which is far more specific and effective at stopping viral replication than the innate immune response. Why? Because these antibodies have seen the virus before! They can immediately attack, bind and block the ability of the virus to enter the host’s cells and replicate.
Prior to Exposure
If given prior to exposure, antibodies If the antibodies are effective and properly dosed, in most cases this baseline will be sufficient to stop the viral replication in its tracks. Very much like stopping a fire, being able to respond immediately when the match is lit is a game changer.
Immediately or Very Rapidly After Exposure
It is easy to see that the sooner after exposure it is given, the lower the curve of uninterrupted viral replication and load, and the more effective it is likely to be. This is why doctor’s rushed to treat President Trump recently with Regeneron’s REGN-COV2 antibody cocktail – to prevent the progression of the disease. In his case, based on the symptoms that have been reported, he may well have been 5 days or more into his infection. Thus, other antivirals were also added to the treatment regime. If he could have received REGN-COV2 within a few days after exposure, he might well have avoided severe symptoms. Very much like putting out a fire, the speed of response makes all the difference to preventing a lot of damage, or death.
We cannot know the details of the severity of illness for the patients in the ACTIV-3 trial, of course, and in general healthcare providers have gotten much better at aggressively detecting and hospitalizing vulnerable patients more rapidly. However, we can say that by definition a patient that is hospitalized with COVID-19 is displaying symptoms that show rapid progression to severe disease and indicate high viral loads and replication rates. At that point, the viral load has already overwhelmed your immune system, and while not harmful, antibody treatment is not nearly as helpful. Very much like putting out a fire, if you wait until the whole building is in flames, the damage is already done. This is especially the case with COVID-19.
How Late Stage COVID-19 Makes You So Sick or Kills You
There is a great deal of literature, and many clinical studies on this topic, but it can be boiled down to simple concept: with COVID-19, it is not usually “the virus” that kills you, but rather a cascading set of reactions and complications caused by your body’s response and effort to destroy to the virus. There is no doubt that the virus attacks many different parts of your body, and is the direct cause of disease. But the proximal, direct cause of life threatening illness or death range across the now infamous “cytokine storms” that destroy victim’s lungs, and this and other systemic reactions that cause kidney failure, liver damage and even brain damage. Sometimes, this can be the side effects from the treatment itself – including in particular ventilators, which have multiple high risk factors.
Age and underlying health conditions are also now known to be important factors influencing disease severity.
- A study of more than 1.3 million COVID-19 cases in the United States, published June 15 in the journal Morbidity and Mortality Weekly Report, found that rates of hospitalizations were six times higher and rates of death were 12 times higher among COVID-19 patients with underlying conditions, compared with patients without underlying conditions. The most commonly reported underlying conditions were heart disease, diabetes and chronic lung disease.
- About 8 out of 10 deaths associated with COVID-19 in the U.S. have occurred in adults ages 65 and older, according to the U.S. Centers for Disease Control and Prevention (CDC). The risk of dying from the infection, and the likelihood of requiring hospitalization or intensive medical care, increases significantly with age. For instance, adults ages 65-84 make up an estimated 4-11% of COVID-19 deaths in the U.S, while adults ages 85 and above make up 10-27%.
- These trends tend to overlap because so many elderly people have the exact chronic medical conditions that can exacerbate the symptoms of COVID-19, according to the CDC. The ability of the immune system to fight off pathogens also declines with age, leaving elderly people vulnerable to severe viral infections
Science: How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes
So, Of Course Antibody Treatments Are Not Likely to Work in Late Stage COVID-19
When you consider all of these factors, then it is easy to understand why the results from Lilly’s ACTIV-3 trial were not only “suspected”, but expected. Given all of the other pathologies that have kicked in with patients at this stage, and the fact that hospitalization itself is a strong indicator of other factors that cause severe disease or mean the patient was already chronically ill, it would be very surprising if antibodies were a “silver bullet.” To return to our fire analogy, the fire is already raging and has caused so much damage that it will take a multi-front effort to put it out and undo the damage caused. In some cases, sadly, it is simply too late.
Does this mean that they are not worth giving? It depends. That is a clinical decision made by physicians considering all of the complex events happening in the body at that stage, and constantly learning from our experience. For LY-CoV555 and LY-CoV016, the clinical trial results say not for hospitalized patients with severe disease and complications.
It also does not mean that antibody treatments will help every person that receives it immediately after or prior to exposure. But both the well understood principles behind antibody treatments, which go back over 100 years, and an increasingly large body of data from clinical trials for both antibodies and vaccines, tell us that they are effective. The only question is how effective – which will vary according to specific drugs, and the specific factors of each patient When compared to the available options, and the benefit versus risk ratio, early and aggressive antibody-based therapeutics are clearly wise – and the earlier the better.
There was rarely a case where the old maxim was more true: an ounce of prevention is worth a pound of cure.