Background: One of the many massive challenges of the COVID19 pandemic has been the lack of targeted therapeutics. Extensive efforts have been invested into research with only glimmers of benefit for most drugs. The exception to this has been dexamethasone which was shown in the RECOVERY trial to have remarkable impacts on death in patients requiring O2 (NNT = 29) and in those requiring invasive ventilation (NNT = 8.5). A number of other drugs showed promise in observation and retrospective studies (HCQ, convalescent plasma) only to prove ineffective in well-done RCTs. Others (i.e. remdesivir) have shown inconsistent results at best.
Monoclonal antibody infusions have gained national attention as a potential therapeutic. This drug class works by binding to domains on SARS-CoV2 spike protein blocking its ability to bind to ACE2 receptors on cells and thus stopping cellular invasion. Previously, we reviewed the interim analysis of BLAZE-1 which demonstrated a small reduction in viral load with one of the three studied doses. However, this difference fell below the author’s preset threshold, raised questions of biological plausibility and found no difference in any clinically meaningful outcome. Additionally, we recently reviewed the REGN-CoV2 antibody cocktail data which also failed to demonstrate any meaningful benefits. Today, we dive into the full BLAZE-1 data as the study has been completed.
Paper: Gottlieb RL et al. Effect of Bamlanivimab as Monotherapy of in Combination with Etesevimab on Viral Load in Patients with Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA 2021. PMID: 33475701
Clinical Question: What is the effect of bamlanivimab monotherapy and in combination with etesevimab on viral load in patients with mild to moderate COVID19?
Population: Adults > 18 years of age with a confirmed SARS-CoV2 infection, had 1 or more mild to moderate symptoms and presented within 3 days of their first positive test result.
Intervention: Four treatment arms
- Bamlanivimab 700 mg IV X 1
- Bamlanivimab 2800 mg IV X 1
- Bamlanivimab 7000 mg IV X 1
- Bamlanivimab 2800 mg + etesevimab 2800 mg IV X 1
Control: Placebo
Outcome (Primary):
- Change from baseline to day 11 in SARS-CoV-2 Viral Load (reported primary outcome in publication)
- Percentage of participants who experience COVID-related hospitalization or death
- Percentage of participants with SARS-CoV-2 viral load greater than. Prespecified threshold
Outcomes (Secondary): There were 84 prespecified secondary endpoints including a number of clinically important endpoints including hospitalization, death and symptom resolution.
Design: Final report of a phase 2/3, randomized, double-blind, placebo-controlled trial of outpatients recently diagnosed with mild or moderate COVID-19
Exclusion:
- SpO2 ≤93% on RA
- P/F ratio <300
- RR ≥30
- HR ≥125
- Require mechanical ventilation or anticipated need for mechanical ventilation
- Known allergies to any of the components use in the formulation of interventions
- Hemodynamic instability requiring use of pressors within 24hrs of randomization
- Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVDI-19)
- Comorbidity requiring surgery within <7d
- Pregnant or breast feeding
- History of convalescent COVID-19 plasma treatment
- Had received treatment with a SARS-CoV-2 specific monoclonal antibody
- Participated within the last 30d in a clinical study involving an investigational intervention or received investigational intervention
- History of positive SARS-CoV-2 test
Results:
Primary Results
- 592 patients were randomized to one of 5 arms
- 577 patients received an infusion
- 44 patients did not complete the study (lost to follow up)
- Patients were randomized and received study infusions within a median of 4 days of symptom onset
- Mean age: 44.7 years
- 67.1 % had > 1 risk factor for severe COVID (age > 55 years, BMI > 30 or > one comorbidity)
- 77.8% had mild symptoms at enrollment
Critical Results
|
Change in Viral Load vs Placebo at Day 11 (95% CI) |
Hospitalization/ED Visit |
||
|
Bamlanivimab 700 mg |
0.09 (-0.35 to 0.52) |
1.0% (1/101) |
|
|
Bamlanivimab 2800 mg |
-0.27 (-0.71 to 0.16) |
1.9% (2/107) |
|
|
Bamlanivimab 7000 mg |
0.31 (-0.13 to 0.76) |
0.9% (2/101) |
|
|
Bamlanivimab 2800 mg + Etesevimab 2800 mg |
-0.57 (-1.00 to -0.14)* |
0.9% (1/112) |
|
|
Placebo |
5.8% (9/156) |
*Statistically significant difference
- Change in log viral load at day 11 vs placebo
- Bamlanivimab 700 mg: 0.09 (95% CI -0.35 to 0.52) NOT STATISTICALLY SIGNIFICANT
- Bamlanivimab 2800 mg: -0.27 (95% CI -0.71 to 0.16) NOT STATISTICALLY SIGNIFICANT
- Bamlanivimab 7000 mg: 0.31 (95% CI -0.13 to 0.76) NOT STATISTICALLY SIGNIFICANT
- Bamlanivimab 2800 mg + etesevimab 2800 mg: – 0.57 (95% CI -1.00 to -0.14)
- Finding is statistically significant
- Log difference did not surpass prespecified threshold of 0.9 logs
- Proportion of patients with COVID19 related hospitalization or emergency department visits at day 29
- Bamlanivimab 700 mg: 1.0% (1/101)
- Bamlanivimab 2800 mg: 1.9% (2/107)
- Bamlanivimab 7000 mg: 0.9% (2/101)
- Bamlanivimab 2800 mg + etesevimab 2800 mg: 0.9% (1/112)
- Placebo 5.8% (9/156)
- Statistically significant difference only with the monoclonal antibody combination treatment
Strengths:
- Randomized, double-blind, placebo-controlled trial
- Multicenter study increasing external validity
- Enrolled patients with recent disease onset to evaluate the effect of early intervention
Limitations:
- The study does not ask a clinically relevant question. Decrease in viral load is clinically irrelevant. Nasopharyngeal viral load has not been validated as a predictor of clinical disease course
- Study protocol had three primary endpoints with four different interventions making a total of 12 primary endpoints
- Baseline characteristics were not equal particularly when comparing the monoclonal antibody combination therapy to placebo. BMI > 30 and risk factors for severe COVID19 were imbalanced and favored the combination therapy
- Convenience sample of patients
- Study not large enough to comment on safety
- Study lumps hospitalization, emergency department visits and death at day 29 as their primary clinical outcome. The factors combined in the composite outcome are not equivalent (ie it’s much worse to die than to have to go to the ED)
Discussion
-
Monotherapy with bamlanivimab has no disease oriented or patient centered benefit.
- In the interim BLAZE-1 report, bamlanivimab 2800 mg was found to significantly reduce viral load in comparison to placebo (though not the 700 or 7000 mg dose).
- In the final data, this finding has disappeared as all patients were followed out to 29 days.
- Bamlanivimab should not be administered to patients outside of an RCT
- The idea of treating symptomatic patients with a monoclonal antibody is flawed
- Even early in the disease process, the body mounts a significant, polyclonal antibody response (similar to what we see with vaccine)
- In the REGN-CoV2 study, 45% of patients had SARS-CoV2 spike protein antibodies at the time of enrollment. Why do we think adding a monoclonal antibody (or two) to the already circulating antibodies would benefit patients?
- It would make more sense to see if monoclonal antibodies work prophylactically (ongoing studies currently) but, vaccines would still be a better option as they create a polyclonal antibody response
- While it looks like there’s only one primary outcome, there are actually three that were prespecified and since they look at four doses, there are a total of 12 primary outcomes.
- The manuscript is misleading in that it is written as if there is only one primary outcome
- The more outcomes you look at, the more likely that one will reach statistical significance by chance alone.
- Although a secondary endpoint, there was a reduction in ED visits and hospitalizations with combination therapy
- Numbers of patients for this endpoint were small and confidence intervals were wide.
- We are not given granular detail on how many patients were admitted to the hospital versus how many simply presented to the ED
- Once again, we see ED visits and hospitalizations conflated. These are not the same outcome. I’m happy to have patients return to the ED if they need reassurance or are having new symptoms.
- Patients were randomized and received study infusions within a median of 4 days of symptom onset. It will be challenging in real world scenarios to do this on a broad scale. Additionally, this will require substantial resources since this is an infusion.
- 10 out of 84 secondary outcomes positive. None clinically meaningful and unclear if statistical noise. There was no consistent differences between monotherapy groups or combination therapy group vs placebo in viral load or clinical symptom scores which highlights this fact
- There is some limited exploratory data on variant resistance to bamlanivimab
- 7.1% in the 700mg
- 9.8% in the 2800mg
- 11.3% in the 7000mg
- 1% in the combo
- 4.8% in the placebo
- Monotherapy seems to induce more mutation with increasing dose
- There was no reduction in mortality as no patients in either arm died
- Monoconal antibody monotherapy and cocktail therapy were run in series. Patients enrolled in the bamlanivimab monotherapy were enrolled from June to Aug, 2020 but the patients enrolled in the bamlanivimab + etesevimab were enrolled from Aug to September 2020.
Author Conclusion: “Among nonhospitalized patients with mild to moderate
COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy. Further ongoing clinical trials will focus on assessing the clinical benefit of antispike neutralizing antibodies in patients with COVID-19 as a primary end point.”
Bottom Line: This study does not show any significant evidence of improved clinical outcomes resulting from treatment with bamlanivimab or the combination of bamlanivimab and etesevimab. While there was a reduction in viral load at day 11 in the combination treatment, the reduction did not reach the prespecified threshold and, reduction in viral load is not an important clinical outcome.
Clinical Take Home Point: Monoclonal antibodies and antibody cocktails should only be used in clinical trials as there is no evidence that they lead to improved clinical outcomes in patients with SARS-CoV2 infection.
For More on This Topic Checkout:
- Brief19: Regeneron’s Antibody Cocktail Shows Promise in the Lab but, Little Difference for Patients
- REBEL EM: BLAZE-1: COVID-19 Neutralizing Antibody (Bamlanivimab)
- EMCrit: I’m So Confused About Bamlanivimab
- REBEL EM: No Evidence that REGN-CoV2 Regeneron Antibody Cocktail Has Clinical Benefits
- PulmCrit: Follow-Up Bamlanivimab Study Unmasks Statistical Chicanery
Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)
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