As hospitals around the country reach critical capacity of patients with COVID-19, treatment focus shifts to ways we can treat people more aggressively before they even need hospitalization at all. At this point, just about every medication already on the market has you been proposed as a possible treatment option. Honestly, it’s a bit overwhelming to keep up. Over the next few days to weeks, you will be hearing about a few new monoclonal antibodies identified as a potential treatment option for those patients who are identified as being at risk of getting worse, but don’t meet criteria for needing hospitalization. From what we know, 10% of those patients who are initially asymptomatic or have a mild disease at the time of diagnosis will develop severe disease requiring hospitalization later in the disease course. It would be ideal to target this population with treatment, before they worsen and would require hospitalization. This article focuses on one particularly monoclonal antibody, Bamlanivimab, as it was approved on November 9th by the FDA for emergency use in the treatment for a specific group of patients with COVID-19. At present, this medication is being allocated to each state at no cost by the U.S. Department of Health and Human Services. Once this allocation runs out, it is uncertain how costly the medication will be.
What is Bamlanivimab?
Bamlinivimab (LY-CoV555) is a human IgG1 antibody developed by Eli Lilly and company, a pharmaceutical company headquartered in Indianapolis, Indiana. But you may hear it called other names….
How does it Work?
Bamlanivimab blocks the spike protein on the SARS-CoV-2 virus, which prevents it from binding to the ACE-2 receptor in human cells. These receptors are scattered throughout the body, including the lungs, heart, bladder, pancreas, testis, kidney, nose, eye and brain (Muus, 2020). Its literally everywhere. This receptor has been a prime target for treatment development since it was first identified as playing a pivotal role in viral entry into the cell.
What does the ACE-2 receptor have to do with it?
After the virus binds to the ACE2 receptor in human cells, it enters the cell. Once the virus enters a cell, it begins to replicate and eventually kill the host cell. This triggers an inflammatory response that produces pro-inflammatory cytokines, activates macrophages and Th1 cells that leads to cytokine storm, respiratory distress syndrome and secondary hemophagoytic lymphohistiocytosis (Gubernatorova, 2020).
Who is our target population for this drug?
The bad outcomes we see from COVID-19 are strongly associated with those who develop severe respiratory distress syndrome from an over-active inflammatory response. People identified as being at risk for this response are those aged > 65 OR those aged > 55 with a history of chronic cardiovascular or respiratory diseases (i.e. pulmonary fibrosis, COPD, Asthma), diabetes, hypertension, obesity (BMI >35) and chronic immunosuppression (i.e. cancers, on immune suppressing medications) are > 65 years old. Further identified risk factors are pediatric patients between 12-17 years of age with a BMI > 85th percentile for their age, sickle cell disease, congenital heart disease, neurodevelopment disorders (i.e. cerebral palsy), dependent on a chronic medical device (i.e. tracheostomy, gastrostomy) and those with history of chronic lung disease (i.e. asthma) requiring daily medication for control. Growth charts for pediatric patients can be found here on the CDC website.
The goal of this medication is not to “cure” COVID-19. It is to decrease the amount of virus that is replicating in hopes that it will prevent an inflammatory cascade and limit the number of people who will progress to requiring oxygen supplementation and hospitalization. Below, I will discuss the actual data from the BLAZE-1 trial. For now, just know that patients who received this medication after they were already sick enough needing to be admitted to the hospital did worse. The only benefit was its use in patients BEFORE they developed severe pulmonary disease, and this is the population that we need to be targeting. The benefits are therefore time dependent. Give it early, or don’t give it at all.
Bamlanivimab is ONLY authorized for specific criteria…
- Has a positive SARS-CoV-2 test, PLUS
- Age 12 years or older with a BMI of at lease 40kg, PLUS
- Not sick enough to require hospitalization, PLUS
- Not sick enough to require oxygen therapy (this includes an increase flow rate for those on chronic oxygen), PLUS
- Considered high risk for progressing to severe COVID-19, PLUS
- Less than 10 days since symptom onset
Criteria to be considered high risk for progression to Severe COVID-19
- Have a body mass index (BMI) ≥ 35
- Have chronic kidney disease
- Have diabetes
- Have immunosuppressive disease
- Are currently receiving immunosuppressive treatment
- Are ≥ 65 years of age
- Are ≥ 55 years of age AND have
- cardiovascular disease, OR
- hypertension, OR
- chronic obstructive pulmonary disease/other chronic respiratory disease.
- Are 12 – 17 years of age AND have
- BMI ≥85th percentile for their age and gender, OR
- sickle cell disease, OR
- congenital or acquired heart disease, OR
- neurodevelopmental disorders, for example, cerebral palsy, OR
- a medical-related technological dependence, for example, tracheostomy, gastrostomy, OR
- positive pressure ventilation (not related to COVID-19), OR
- asthma, reactive airway or other chronic respiratory disease that requires daily medication for control
A few considerations on administration…
- The window of opportunity is just 10 days from symptom onset
- The patient must have a documented positive COVID-19 test
- It will take roughly 3 hours to administer the medication
- It infuses over 1 hour
- Patient must be observed for 1 hour after the completion of the infusion
- The mixture is stable for 7 hours at room temperature and 24 hours under refrigeration.
What are the risks?
Bamlanivimab is a new drug, and unfortunately the adverse effects are limited to only those seen in the BLAZE-1 trail (NCT04427501).
309 patients were included in the treatment arms of this study and out of these, 2 patients had severe reactions, 1 requiring epinephrine for anaphylaxis. Neither patient died. From the overall data of all 309 patients in the 3 arms that received Bamlanivimab at varying doses in the BLAZE-1 study, we get a number needed to harm (NNH) of 156.
One important thing to note is that there were 4 arms in the Blaze-1 trial (Placebo, 700mg, 2800mg and 7000mg). There were 0 severe or serious adverse events at the 700mg dose, which is the current dose authorized for emergency use by the FDA.
Interestingly, there was 1 serious adverse event in the PLACEBO group (defined at anaphylaxis, life threatening laryngospasm or laryngeal edema) with ZERO serious events in any of the 3 arms that actually received the drug.
Another interesting point to make is that there were a higher number of patient reported adverse events in the PLACEBO group than there were in any other arm of the study. So, overall it appears the risk of this medication is fairly low at the dose of 700mg being given.
All reported adverse events at the 700mg dose include (from 101 patients)...
- Nausea – 3%
- Diarrhea – 1%
- Dizziness – 4%
- Headache – 3%
- Pruritis – 2%
- Vomiting – 1%
- Pyrexia – 1%
- Rash – 1%
- Chest pain – 3%
- Dyspepsia – 1%
- Hypertension – 3%
- Lipase increased – 1%
- Thrombocytosis – 1%
- Hypersensitivity – 1%
- Nasal congestion – 1%
So, lets take a closer look at the study...
- Title: SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19
- Trial Type: Ongoing phase 2, randomized, double-blind, placebo-controlled, single-dose trial
- Population: 453 patients at 41 hospitals across the United States, who tested positive for COVID-19 with one or more mild to moderate symptoms confirmed COVID-19 positive
- Intervention: Single dose Bamlanivimab infusion over approximately 1 hour
- Treatment Arms:
- Placebo (N=143)
- 700mg dose (N=101)
- 2800mg dose (N=107)
- 7000mg dose (N=101)
Design: Follow-up on day 1 was on-site. Follow-up on days 2,4,5 and 6 were done by telephone. Follow-up on days and 7-29 were done at an outpatient clinic or with home visits. Lab markers followed include hsCRP, Ferritin, D-dimer, Procalcitonin and Troponin measured before infusion, and on day 1, 3, 15 and 29. Patients were also allowed to receive local standard of care (including lopinavir/ritonavir, chloroquine, hydroxychloroquine or other investigational agents. However, convalescent plasma was not allowed.
Serious Adverse Events: Defined at anaphylaxis, life threatening laryngospasm or laryngeal edema
Inclusion Criteria:
- Age > 18
- Men and non-pregnant women
- Not hospitalized at randomization
- Have one or more of the following symptoms:
- Fever, cough, sore throat, malaise, headache, muscle pain, GI symptoms, shortness of breathh with exertion
- First positive swab < 3 days from infusion
Exclusion Criteria:
- SpO2 < 93% on room air
- Respiratory rate > 30
- Heart Rate > 125
- Requiring mechanical ventilation or anticipated need
- Known allergies to drug
- Hemodynamic instability
- Suspected infection other than COVID-19
- Co-morbidity requiring surgery < 7 days
- Co-morbidity considered life threatening < 29 days
- Serious concomitant systemic disease
- Prior positive SARS-CoV-2 serology test
- Prior positive SARS-CoV-2 swab
- Received other treatment of prophylaxis (monoclonal antibody, convalescent plasma, vaccine, etc.)
- Pregnant or breast feeding
- Primary Objective:
- Change from baseline viral load to that seen on day 11 (+ 4 days)
- Secondary Objectives:
- Safety assessments such as adverse events and serious adverse events
- Change from baseline viral load to Day 11 (+ 4 days) viral load enrolled with < 8 days of symptoms
- Time to resolution of symptoms
- Time to symptom improvement
- Time to SARS-CoV-2 clearance
- Mean SARS-CoV-2 concentration on day 29
Results:
- The groups were balanced in regards to co-morbidities, age and risk factors
- By day 11, all groups (including placebo) had more than 99.97% elimination of viral RNA
- However, the biggest benefit to clearance was seen in the first 3 days, and this decrease was similar regardless of the medication dose given (see chart below)
- Hospitalizations were significantly lower in all treatment arms. This also didn’t seem to be dose dependent
- Symptom scores were better (although barely) in the pooled Bamlanivimab group compared to placebo
Conclusions: The current dose approved for emergency use by the FDA is 700mg infusion over 1 hour. Based on this study, we can currently discuss the following with our patients:
- There is a 1 in 4 chance of having mild side effects (nausea, headache, etc.). However, this was similar to people who do not receive the medication questioning if these are adverse effects of the medication, or just symptoms of COVID-19.
- There were NO serious adverse effects were not seen in the 101 patients who have received the dose we are giving you. 1 in 156 patients who have received higher doses of this medication had a serious reaction including anaphylaxis, but responded well to epinephrine without issue. No patients have died.
- This medication decreases the overall risk of hospitalization in patients in your similar situation from 6.3% to 1-2%.
- This medication will decrease the amount of virus you have over the next 3 days by nearly 35%, compared to if you do not get this medication. Our hope is this will prevent you from experiencing a more severe inflammatory response and keep you out of the hospital.
- You may have a slight improvement in the severity of your symptoms, but that is not the overall purpose of this medication.
Study Limitations:
- This trial has yet to conclude. It is an ongoing study, with plans to enroll 1,200 patients.
- It is an industry sponsored study, sponsored by Eli Lilly and Company, who manufactures the drug.
- Patient were excluded who have a serious concomitant systemic disease, condition or disorder. This decision was made based on the opinion of the investigator and not apparent in the protocol.
- The secondary outcome of decreased hospitalization wasn’t in the protocol. It is a nice bonus, but seems to be a shift in the entire focus of the study that occurred after the fact.
- Patients were also allowed to receive local standard of care (including lopinavir/ritonavir, chloroquine, hydroxychloroquine or other investigational agents. The exact impact number of people who received these medications are not immediately apparent in the published data.
A quick note about another Monoclonal Antibody (Regeneron):
It seems important to quickly discuss Regeneron, which is currently in phase 3 of their trial with monoclonal antibodies in the treatment of COVID-19. While limited raw data is accessible, this is what I have found so far…
They are using a combination of 2 different monoclonal antibodies as a single infusion. Phases 1 and 2 occurred in mice and hamsters and also suggest a significant decrease in viral load at 3 days after infusion. Phase 3 is currently up to 550 patients enrolled. So far, reported outcomes seem similar to the BLAZE-1 trial, in that there does not seem to be any large difference in viral load between difference doses given, but there is benefit over placebo. Apparent downsides to this study is that it appears to be a prospective trial, and not randomly controlled. This is unfortunate, as it is also industry funded.
The company claims a 57% reduction in repeat medical visits (repeat ER visits or hospitalizations) for all patients and a 71% reduction in those patients with > 1 co-morbidity.
More important to our current knowledge is that they also had an arm looking for benefit in hospitalized patients requiring oxygen. This arm was abruptly stopped last week as they found an INCREASE in harm when used in these patients.
Regardless, early data does support the data we have seen in the BLAZE-1 study. Patients with mild to moderate symptoms who do not meet criteria for hospitalization, are not hypoxic and have 1+ co-morbidities are likely to benefit.
- 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