In November of 2020, we discussed the first clinical data for the Monoclonal Antibodies Bamlanivimab and Regenergon (mAb). For a refresher, you can check out the article here. Since that time, researchers have developed several different versions with varying results. There are three mAb products with Emergency Use Authorization (EUA) from the FDA. The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel (from here on out, we will just call them “the panel”) recommend the following dosing regimens for non-hospitalized patients with mild to moderate COVID-19 who are at high risk of serious illness.
- Bamlanivimab 700 mg plu etesevimab 1,400 mg
- Casirivimab 600 mg plus imdevimab 600 mg (a.k.a. Regeneron)
- Sotrovimab 500 mg
There have been three pivotal trials that have guided these dosing recommendations. A summary of these three Randomized Controlled Trials driving recommendations can be found in the table below. When looking at this data, you will see different numbers for absolute risk reduction (ARR) versus relative risk reduction (RRR) and warrants a little discussion. If you are not interested, skip to the table (not recommended).
Begin nerdy sidebar...
A relative risk reduction (RRR) tells us how much the mAb treatment decreased the risk of needing hospitalization when the treatment group was compared to the control group (patients who did not receive mAb treatment). While this measurement helps researchers see the benefit of a drug in a trial, patients want to know how much a drug decreases their own risk, and the RRR does not really tell us that.
For example, the RRR for Regeneron was found to be about 71%. That does not mean that you personally have a 71% lower chance of needing to be hospitalized by getting the treatment. It means that when two groups are compared, 71% fewer patients needed hospitalization in the group that got mAb treatment.
Looking closely at the raw data from Regeneron outcomes, there were only five patients in the mAb group vs. 18 patients in the placebo group that even needed to be hospitalized. However, there were about 740 people in each group. So, it is highly probable that you will not need to be hospitalized regardless of getting the treatment (1.5% overall risk of needing to be hospitalized). By dividing five by 18, we can see that ~ 71% fewer people ended up getting admitted if they got Regeneron (that’s our RRR).
When we want to know the individual’s percentage point reduction of overall risk, we need to calculate the absolute risk reduction (ARR). For mAb studies so far, the ARR is the percentage point decrease in risk of hospitalization to the patient if they get the treatment. The ARR considers the entire population at risk of an outcome (i.e., hospitalization). To keep it simple, up to this point, mAb treatment has decreased the absolute risk that high-risk patients will need to be hospitalized by about 3-6%.
While this may sound like a super small number, it really is not. The ARR is almost always low as the risk of a bad outcome is typically low when everyone is taken into account. For comparison, the ARR of Aspirin in decreasing the risk of death after a stroke is 1.3%, and it is considered standard of care by the American Stroke Association. As another example, the RECOVERY trial found corticosteroids to have an ARR of 3% at preventing death from COVID-19. Similarly, a Cochrane review found Tocilizumab to have an ARR of 3% at reducing mortality.
The ARR is also helpful to clinicians, as we can use it to calculate the Number Needed to Treat (NNT). That is the number of patients we will need to treat to prevent ONE bad outcome. In the case of mAb therapy, the outcome measured has been hospitalizations or all-cause mortality.
The NNT is an easy calculation that can really step up your study appraisal game. All you need to know is the ARR. Not all studies will give you the ARR. You can use this online calculator to calculate it yourself if you really want to nerd out.
NNT = 1/ARR
For reference, here are some NNT data for common drug interventions:
- Aspirin given immediately for heart attack (STEMI) = 1 in 42 to prevent death
- Aspirin after acute stroke = 1 in 79 to prevent death or dependence
- Aspirin after acute stroke = 1 in 140 to prevent recurrent stroke
- Blood Pressure Medication = 1 in 67 to prevent stroke
- Anticoagulation for atrial fibrillation = 1 in 60 to prevent stroke
- Steroids for croup = 1 in 11 to avoid repeat visit
- Steroids for COPD = 1 in 11 to prevent death
End nerdy sidebar...
Here is a table summarizing the three major RCT’s that drove “the panels” recommendations for mAb therapy.
Sources: Dougan, et al.; Weinreich, et al.; Gupta, et al.
Some things to consider when looking at the data in the table above. The phase 3 Blaze-1 trial (Bamlanivimab plus Etesevimab stopped enrolling patients into the placebo arm after an independent review of the preliminary data. This certainly adds bias to the predetermined outcome data. Further, in the grand scheme of randomized controlled trials, these are relatively small in size. All were underpowered to determine any benefit at decreasing mortality.
I am only discussing the details of these 3 studies, as they include the best data. However, there have been a total of six RCTs looking at outcome data for mAb therapy in non-hospitalized patients with COVID-19. A recent Cochrane review of all of these studies concluded that the certainty of evidence in favor of mAb therapy is low and the evidence is insufficient to draw hard conclusions. There are currently 36 ongoing studies for mAb in this patient group and may provide stronger evidence.
One major factor to highlight is that the dominant strains during the study period for all of the RCTs were pre-delta. Delta wasn’t even first identified in the US until March of 2021 and didn’t become the dominant variant until May of 2021.
Last month, the Mayo Clinic published a study examining the rate of developing a severe infection from the delta variant after monoclonal antibody infusion with Bamlanivimab plus Etesevimab or Casirivimab plus Imdevimab compared to the pre-delta era. Essentially, 3% of people who received mAb treatment pre-delta ended up hospitalized vs. 4.9% of patients who received mAb with Delta with an adjusted odds ratio of 2.04). I only say this as there is a high probability that if the original studies were re-done in the Delta era, the risk of hospitalization would likely be higher. The number needed to treat to prevent one hospitalization would likely be much higher, potentially by a factor of 2.
The lack of data on clinical outcomes with Delta is only one piece of the problem. Newer studies show that variants of concern, particularly the Omicron variant, may not be affected by some current mAb treatments.
In Vitro (not on humans) studies assessing viral susceptibility to these meds suggest that Sotrovimab is likely the only monoclonal Antibody that may still have activity against Omicron. However, to what degree is yet to be fully determined.
To do these in vitro studies, researchers literally take the drug and mix it with different concentrations of either live SARS-CoV-2 or an artificial version of the virus (called a pseudovirus). They then determine what concentration of the virus is needed to decrease viral replication by half. Regeneron and Bam-Etes couldn’t reach this threshold with the Omicron variant, even at super-high concentrations.
Sotrovimab was the only mAB that is currently available that was able to neutralize the virus. Still, it took THREE TIMES the concentration of the drug to neutralize Omicron than it took to neutralize all other variants.
Source figure: Touret et al.
The CDC has a nice summary table outlining which mAb therapies are likely to maintain neutralizing against the different variants.
There isn’t any real-world outcome data on Sotrovimab with Delta or Omicron. Still, the true absolute risk reduction for hospitalization will likely be less than what was seen in the original studies. It certainly still seems plausible that Sotrovimab is better than nothing, but it certainly is not a silver bullet. The cost of these therapies isn’t cheap either. Thee therapies each cost around $2,100 per dose. Currently, patients do not pay this cost directly. The available doses were purchased by the U.S. government and distributed to the states based on need.
As Omicron now makes up over 95% of all new COVID-19 cases in the United States, with daily positive cases the highest of the entire pandemic, hospitals are in short supply of Sotrovimab. Due to this limited supply, many patients who are candidates for mAb therapy cannot get it as supply is shunted to only those at the highest risk.
So, who is at the highest risk?
While some retrospective studies have shown a possible mortality benefit of mAb, these studies were done in the pre-delta era. Similar studies have produced mixed results (Cooper et al.; Ganesh et al.; Pannier et al.). Keep in mind, a definite mortality benefit was not seen in the more extensive randomized controlled trials as well as the Cochrane review.
The RECOVERY Trial (a large ongoing RCT that has driven most of “the panels” recommendations) found that Regeneron did not decrease mortality when all patients were included for analysis.
However, they also found that nearly one-third of all patients who were hospitalized with COVID-19 did not have measurable antibodies at the time of admission. Meaning, the immune system of 1/3rd of patients did not yet produce antibodies by the time they got sick enough to need admission to the hospital (we call this seroconversion). Those who were seronegative (no antibodies present in their blood) were TWO TIMES more likely to die than those who were seropositive (had antibodies in their blood) and also had a significantly higher viral load.
In patients who were seronegative on admission, getting Regeneron at admission decreased the duration of hospitalization by 4 days and reduced the relative risk (RRR) of death by ~18%. Based on the raw data, I am calculating an absolute risk reduction (ARR) of about 5% with a number needed to treat (NNT) of about 20. There was no mortality benefit seen to patients who were seropositive at the time of mAb treatment.
Again, the collection of this data ended in May of 2021, just as Delta was entering the scene. So, we can’t really generalize the data to Delta and Omicron. Still, I would be interested in seeing more studies specifically targeting patients presenting to the hospital and/or being admitted to the hospital and are seronegative as a target for possible mAb therapy, particularly in the setting of limited supply.
Other options on the horizon...
The FDA has recently issued EUA’s that allow two oral antiviral agents to be used in non-hospitalized patients with mild to moderate COVID-19 and at high risk of disease progression. These include ritonavir-boosted Nirmatrelvir (Paxlovid) and Molnupiravir.
Considering the high prevalence of the Omicron variant as well as supply and demand issues, on December 30th, “the panel” updated their recommended outpatient treatment options for COVID-19 (in order of preference):
- Paxlovid (nirmatrelvir 300 mg plus ritonavir 100 mg) orally twice daily for 5 days
- Sotrovimab 500 mg administered as a single intravenous (IV) infusion
- Remdesivir 200 mg IV on Day 1 followed by remdesivir 100 mg IV on Days 2 and 3
- Molnupiravir 800 mg orally twice daily for 5 days
Obviously, supply will be an issue for a while. The U.S. government began shipping 65,000 courses of Paxlovid in late December, with a goal of 20 million treatment courses to be delivered by the end of 2022. Discussion of these oral antiviral agents warrants a separate discussion. So, stay tuned…
- Monoclonal Antibodies for COVID-19 – An evidence based update - January 18, 2022
- COVID-19 Vaccines in Pregnancy - January 6, 2022
- COVID-19 Boosters….are they necessary? - October 8, 2021